PATHOLOGY X LABORATORY MEDICINE X LABORATORY MANAGEMENT JANUARY 2023

Evaluating post-treatment breast specimens

Karen Titus with a laugh. When they returned, they reviewed matter,” says Dr. Esserman, who is also professor
Laura Esserman, MD, MBA, can still recall her their cases. The results were startling. Using the of surgery and radiology, UCSF School of Medi-
Eureka moment. She had just seen a talk on residual new approach, she says, the complete response rate cine, and PI for the I-SPY trial network and the
cancer burden by pathologist W. Fraser Symmans, went down to 24 to 25 percent. WISDOM study. The line between patients’ treat-
MB.ChB, a pioneer in the field. The impact on patient care was sobering. “That ments and a standardized approach to evaluating
“When I saw Fraser present this,” says Dr. really taught me a lesson—these standards really and reporting post-neoadjuvant —continued on 23
Esserman, director, University of
Karissa Van Tassel

California San Francisco Breast Care

Center, “I knew immediately that
For blood cultures,
MRI would work and that residual a lab’s new system
cancer burden would complement it.
MRI was basically a snapshot of RCB and incubation time
over time. I realized that we had to Amy Carpenter Aquino
institute RCB—we had to standardize For the central microbiology labora-
our approach.” Until then, she and tory serving Barnes-Jewish and
her colleagues across the I-SPY trial four other hospitals in the St. Louis
sites relied on individual pathologist area, validating and implementing
assessment for each case. The patho- a new blood culture system and
logic complete response rate, or pCR, moving to a shorter incubation time
hovered at about 34 percent. came at a perfect time: right before
That insight was soon followed by the pandemic.
another. Intrigued by what she heard, “We implemented this just a
Dr. Esserman and her pathologist few months before we saw record-
colleagues from all the I-SPY sites breaking hospitalizations at our in-
traveled to MD Anderson, where Dr. stitution,” Eric M. Ransom, PhD,
Symmans helped develop the resid- D(ABMM), said of the work done
ual cancer burden system, for train- on the BacT/Alert Virtuo blood
ing. “We brought them all to Houston culture detection system (BioMéri-
on a hot summer day,” she recalls eux) at Washington University in
St. Louis in 2019. Dr. Ransom, now
Dr. Uma Krishnamurti of Yale School of Medicine. She assistant medical director of clinical
and others highlight the challenges in the pathologic microbiology at University Hos-
evaluation and reporting of post-neoadjuvant therapy pitals Cleveland Medical Center,
breast resection specimens. reported at the AACC meeting last
July on the Virtuo implementation,
including a study finding that a four-
Ins and outs of von Willebrand factor activity assays day incubation time was sufficient.
“We wouldn’t have had the space
Charna Albert said Marian Rollins-Raval, MD, MPH, session about the five major types of on our blood culture instruments
Guidelines for the diagnosis of von associate professor of pathology at the von Willebrand factor (VWF) activity if we didn’t have all that free space
Willebrand disease, published in University of New Mexico and medi- assays. Then, too, more clinical stud- we had generated by increasing our
2021, have raised questions about cal director, TriCore Special Coagula- ies evaluating the newer assays and capacity 20 percent,” he said (Ran-
which von Willebrand factor activity tion Laboratory, speaking in a CAP22 comparing them —continued on 20 som EM, et al. J Clin —continued on 17
assay laboratories should use. Each
has its strengths and weaknesses, and
the FDA has cleared or approved
some, but not all, of the newer auto- Flow cytometry
mated assays. In addition, not all the Inside new atlas: wide range
assays or guidelines use the same of hematolymphoid diseases
activity-to-antigen ratio cutoff to dis-
criminate type 1 from type 2 von Sample case and
Willebrand disease, making it diffi- Q&A with co-editor
cult to compare accuracy. David Dorfman, MD, PhD.
“That just begins the challenge,” Page 10

Vol. 37, No. 1 Moving? Fax a copy of above address with corrections to 847-832-8153.
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Abbott (Informatics) FILE— 1222-41 JANUARY 2023 page 2

 JANUARY 2023 | CAP TODAY 3

New starts: rapid-molecular pullback, fentanyl screen

Respiratory viruses were up in most states when Compass Group members met online pus sites. And we had to make a sub- screen we perform, we have to in-
Dec. 6 with CAP TODAY publisher Bob McGonnagle, and some were looking to centralize stantial commitment to one of the clude fentanyl screening in all general
their now decentralized rapid molecular testing. At least one system had already done so. vendors in our central lab and wanted acute-care hospital laboratory set-
In California, a new law requires fentanyl screening be included in drug screens in all to be able to continue to fulfill that tings. Currently our rapid drug screen
general acute-care hospital lab settings. What lab leaders had to say about that and about
contract. With test volumes decreasing, does not include fentanyl, so we’re
digital pathology, remote sign-out, and the No Surprises Act.
we needed that centralized volume. running fentanyl on our chemistry
Clark Day, with respiratory virus rates so high, analyzer. We added the screening test
CAP TODAY JANUARY 2023 Vol. 37, No. 1 what’s going on at IU Health? Dwayne Breining, has recentralizing molecular using a Sekisui reagent. It’s an FDA-
Copyright 2023 by the College of American Pathol- Clark Day, VP of system laboratory infectious testing been brought up within the approved third-party reagent and we
ogists. All rights reserved. None of the contents of this services, Indiana University Health: Northwell system? ran it on our chemistry platform, the
publication may be reproduced, stored in a retrieval
system, or transmitted without prior written permission If you look at a three-month moving Dwayne Breining, MD, executive Vitros 5600, but you can use it on
of the publisher. Views and opinions expressed in CAP
TODAY are not necessarily endorsed by the CAP.
average, our total RSV, flu, and director, Northwell Health Laborato- other platforms as well. Whenever the
President: Emily E. Volk, MD COVID is down versus the past two- ries, New York: We’re looking at it screening is positive, we reflex a con-
President-Elect: Donald S. Karcher, MD
Secretary-Treasurer: Alfred Wray Campbell, MD, MBA
year periods over constantly but haven’t pulled the firmatory test by liquid chromatogra-
Governors: Monica E. de Baca, MD; Earle “Smitty” September, Octo- trigger because we’re fearing another phy-tandem mass spectrometry sent
Collum, MD; Kalisha Ashara Hill, MD, MBA; Rebecca L.
Johnson, MD; Bradley S. Karon, MD, PhD; Guillermo G.
ber, and November. wave. It’s crowded here and we’ve to a reference lab. Since we’re just a
Martinez-Torres, MD; Jonathan Louis Myles, MD; Bobbi But flu is two-and- seen an uptick from around Thanks- few miles from the southern border,
S. Pritt, MD; Assad Joe Saad, MD; Richard M. Scanlan,
MD; C. Leilani Valdes, MD, MBA; Qihui “Jim” Zhai, MD a-half times what it giving of around 30 percent with our rate of positivity is high and there
President,CAPFoundationBoard:Eva M. Wojcik, MD was this time last COVID. In New York State the flu are a lot of overdoses in the area. I
Speaker, House of Delegates: Sang Wu, MD
Vice Speaker: Marilyn M. Bui, MD, PhD year, RSV is almost curve is vertical now, and we antici- went as far as reaching out to the
Residents Forum Chair: Amanda C. Herrmann, MD, PhD two times what it pate being in this for probably two vendor of our MedTox screen test kit;
Chief Executive Officer: Stephen Myers
Medical Editorial Board to CAP TODAY: Dorothy M. was this time last Day months. We’re looking to continue they have the panel that includes
Adcock, MD, chair; Sarah M. Bean, MD; Alain Borczuk, year, and COVID is doing a lot of testing and focusing on fentanyl but it’s not FDA approved in
MD; Marilyn M. Bui, MD, PhD; Dong Chen, MD, PhD;
Donna E. Hansel, MD, PhD; Frederick L. Kiechle, MD, down about 60 percent. So it is a shift figuring out a way to decant our the United States. The product is
PhD; Daniel Mais, MD; Deborah Ann Sesok-Pizzini,
MD, MBA; Beverly Rogers, MD; Serenall Serinelli, MD, from COVID to flu in particular. emergency rooms when they get available in Canada but not here. I
PhD; Huamin Wang, MD, PhD; Mary K. Washington, To ensure we continue to offer the overcrowded from people who need tried to follow up and escalate the
MD, PhD; Carla S. Wilson, MD, PhD
Contributing Editors: Raymond Aller, MD; Marcela best care for our patients while balanc- just testing. We have plans to do a urgency of getting the product ap-
Riveros Angel, MD; S. Emily Bachert, MD; Amarpreet
Bhalla, MD; Nancy Cornish, MD; Robert DeCresce,
ing good financial stewardship, we pseudo-drive-through or a walk- proved in the United States but
MD; Alicia Dillard, MD; Donna E. Hansel, MD, PhD; are moving to test only symptomatic through—go around the corner if you haven’t had any luck. Hard to believe
Shaomin Hu, MD, PhD; Rouzan Karabakhtsian, MD,
PhD; Frederick Kiechle, MD, PhD; Mark Lifshitz, MD; patients with local rapid PCR assays need just a test and then wait for your with the fentanyl crisis in the United
Andrés G. Madrigal, MD, PhD; Maedeh Mohebnasab,
MD; Liron Pantanowitz, MD, PhD, MHA; Erica Reinig,
in our region facilities. We’ll make results at home. States nationwide that no one has
MD; Deborah Ann Sesok-Pizzini, MD, MBA; James some exceptions for hospital settings come up with a rapid screen yet that
Solomon, MD, PhD; Dennis Winsten
in which double-occupancy rooms are Winnie Carino at Scripps, what do you have to includes fentanyl.
Editorial Office: College of American Pathologists
325 Waukegan Road, Northfield, IL 60093 the only boarding option or where share from Southern California?
847-832-7000; CAP TODAY fax 847-832-8153
patients are high risk or require time- Winnie Carino, MA, CLS, MLS Dhobie Wong, do you have insight on this
Publisher: Bob McGonnagle, 847-832-7476
Editor: Sherrie L. Rice, 847-832-7504, srice@cap.org sensitive treatment. All other routine (ASCP), director of laboratory ser- fentanyl requirement?
Managing Editors: Kimberly Carey PCR-based testing will be routed to vices, Scripps Health, San Diego: Dhobie Wong, MBA, MLS(ASCP),
847-832-7249, kcarey@cap.org; Karen Titus
Senior Editor: Amy Carpenter Aquino our central pathology laboratory to be We’re seeing an increasing number of CLS, VP of laboratory services, Sutter
847-832-7245, aaquino@cap.org
Associate Editor: Kristen Eberhard performed on our fully automated flu and COVID cases, also some RSV. Health, Sacramento, Calif.: Our ap-
847-832-7649, keberha@cap.org high-throughput platforms. We previously had proach is to add the fentanyl to our
Associate Contributing Editor: Charna Albert
847-832-7274, calbert@cap.org RSV centralized in urine drug screen, which is run on our
Circulation Director: Kimberly Gilfillan
847-832-7456, fax 847-832-8153, subscription@cap.org Is anyone else contemplating a similar move? our core lab, but chemistry analyzers. We’re in the
Digital Production Editor: Jennifer Laudadio, MD, professor we’re decentraliz- process of implementing that.
Mary Lindsay, 847-832-7377, mlindsa@cap.org
Managing Periodicals Editor: and chair, Department of Pathology, ing it again.
Keith Eilers, 847-832-7528, keilers@cap.org
Production Editor: Jane Ure University of Arkansas for Medical The state of Cali- Do you have to do a lot of validation to put it
847-832-7980, jure@cap.org Sciences College of Medicine: We’ve fornia passed a law on the urine drug screen?
Periodicals Production Assistant:
Tracy Erski, 847-832-7514, terski@cap.org already centralized at UAMS. It was [Senate Bill 864] ef- Dhobie Wong (Sutter Health): Yes.
Publisher/Sales Office: Bob McGonnagle
847-832-7476, fax 847-832-8153, bmcgonn@cap.org
partly due to continued inability to get fective January 1 It’s a work in progress, and there’s the
Sales Office: Keith Eilers, 847-832-7528, keilers@cap.org supplies for some of our regional cam- that for every drug Carino information systems —continued on 4
Advertising Directors:
Midwest and East—Alex Pacheco, 402-290-8203,
alex@captoday.org
West and East—Lori Prochaska, 402-290-7670,
lori@captoday.org
Classified advertising: Send copy to KERH Group at
In this issue
sales@kerhgroup.com or call 888-489-1555. Deadline: 15th
of month preceding desired issue date.
Indexed by: Hospital Literature Index. Select articles
found in National Library of Medicine’s Health Services/
10 Flow cytometry
Inside the new Color Atlas of Flow Cytometry, due out this spring.
One of its 71 cases and Q&A with co-editor David Dorfman, MD, PhD.
Technology Assessment Research online database.
Change of address: Notify publisher at least six
weeks in advance. Include both old and new addresses
and a mailing label from the most recent issue. Mail to:
CAP TODAY Circulation, 325 Waukegan Road, North-
13 Cytopathology in focus
Serous fluid cytopathology—progress and Yale’s experience. Plus, adequacy in
cytopathology: overview with a focus on FNA of lymph nodes and mass lesions.
P G
R U

28
field, IL 60093-2750. www.cdsreportnow.com/renew/now?ctd Roundtable on automation, reflex testing, assay wins,
O I

Coagulation testing
D D
U E

Advertising: The appearance of display or classified

C

and the Wild West, and our guide to coagulation analyzers.

T

advertising in this publication is not a CAP guarantee

or endorsement of the product or service or the claims
made by the advertiser.
40 Abstracts 49 Index to Advertisers 43 People
Printed in U.S.A. ISSN 0891-1525
The College of American Pathologists, the leading 47 Classifieds 9 Letters 50 Put It on the Board
organization of board-certified pathologists, serves
patients, pathologists, and the public by fostering and 6 Election 48 Marketplace 44 Q&A
advocating excellence in the practice of pathology and 9 From the President’s Desk 45 Newsbytes 42 Shorts on Standards
laboratory medicine worldwide.
4 CAP TODAY | JANUARY 2023

Compass Group sults with testing. There is a legal case

in which a false-positive result led to
Dwayne, what are your strategies around
fentanyl testing?
fentanyl. It has become a major prob-
lem in the street drug world because
continued from 3
a patient becoming upset regarding Dr. Breining (Northwell): It’s simi- the ready availability of cheap fen-
component, as with any new test how she perceived the medical staff lar to what other people have re- tanyl has flooded the illicit market. It’s
implementation. treated her. So we’re treading carefully ported. We looked for a point-of-care being used to enhance and cut every
with the fentanyl testing question. test option a few substance sold on the underground.
Milt Datta, what do you have to share on the months ago and
issue of fentanyl? Stan Schofield, would you like to comment on didn’t find any- Frank Beylo, where is your laboratory on this?
Milton Datta, MD, chair of pathol- fentanyl? thing. The potency And to be clear, this requirement is in California
ogy, Abbott Northwestern Hospital, Stan Schofield, president, NorDx, of fentanyl is so but it may become national?
Allina Health, Minneapolis: Lauren and senior VP, MaineHealth: We test high that the levels Frank Beylo, BS, MT(ASCP), di-
Anthony [MD, system laboratory for fentanyl, but we do it with mass you have to detect rector, operations and technology,
medical director], spectrometry. There’s nothing else; are tiny. The refer- Inova Health Systems, Falls Church,
who is in our group, there’s not a good immunoassay that ence toxicology labs Dr.Breining Va.: We’re working on validation of
looked at fentanyl we know of, though I haven’t we use seem to be fentanyl with our Abbott Alinity se-
testing with Henne- shopped this in the past year. We do doing a prescreen immunoassay. I ries. Yes, I would assume it may be-
pin County Medical not screen for fentanyl on presurgical don’t know what platform it is, and come national.
Center, which does or emergency cases unless medically they’re probably doing 100 percent
our rapid toxicology suspected or there’s a history, and it backup on liquid chromatography- Pete Dysert, what is top of mind for you at
screens. Because has to be a physician request. It’s not mass spectrometry to get the detec- Baylor Scott & White?
Dr.Datta
fentanyl is so po- in our normal screening panel for tion levels. We’d love to implement Peter Dysert, MD, chief, Depart-
tent, the testing can- toxicology primary drugs of abuse fentanyl testing systemwide in all our ment of Pathology, Baylor Scott &
not get a reliable and accurate read on because it’s hard to do and it’s expen- rapid-response labs but we haven’t White Health, Dallas: We’ve vali-
it. There were no rapid tests available sive using mass spec. Mass spec tech- found an option yet. It’s clearly the dated our digital imaging platform
as of June, when we did our study. nology is easy—getting the sample, right thing to do medically. at Baylor University Medical Center.
We’re cautious from a legal side, in setting it up, doing a run. Having In New York, virtually weekly So we’re looking forward to seeing,
particular for maternal screening with people at a dedicated machine is there’s a fatal overdose from someone largely in the beginning, efficien-
fentanyl because of false-positive re- what’s expensive. who didn’t think they were taking cies around —continued on 6

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Compass Group
continued from 4
our conference obligations. My de-
partment does more than 400 multi-
disciplinary conferences a year, at
which pathology either presents
slides or reviews reports and com-
ments on findings. Currently we’re
taking pictures and using PowerPoint
to present those things, and we’re
hopeful, with a digital imaging plat-
form, we’ll have a workflow that’ll be
more efficient for residents and staff.
We’re also looking at moving to Epic
Beaker and hopeful that integration
will not further erode surgical pa-
thologists’ productivity and efficiency
and will improve our current-state
workflows.
Are you planning to use the new CPT category
three digital pathology codes?
Dr. Dysert (Baylor Scott & White):
My administrative colleagues are
looking at the ability to apply those
billing codes to our practice.
Greg Sossaman, where does the ability to do
remote pathology sign-outs stand?
Gregory Sossaman, MD, system
chairman and service line leader, pa-
thology and laboratory medicine, Och-
sner Health, New
Orleans: It is still
permissible accord-
ing to the Centers
for Medicare and
Medicaid Services. I
was involved in the
Clinical Laboratory
Improvement Advi- Dr.Sossaman
sory Committee
and it has been in favor of extending
that and making it permanent
through CLIA. CLIAC is able to make
recommendations to the federal agen-
cies, and it came up at the last CLIAC
meeting. So the recommendation will
be for it to become a changed part of
CLIA going forward. Those things
can take a while to wind through the
system.
James Crawford, MD, PhD, pro-
fessor and chair, Department of Pa-
thology and Laboratory Medicine,
and senior VP, laboratory services,
Northwell Health, New York: This
was a formal CLIAC recommenda-
tion at the most recent meeting [No-
vember 2022], which, in essence,
sketched out recommendations for
the framework of the parent labora-
tory being the regulatory and compli-
ance host for remote sign-out. My
hope is that, with the relaxation in
effect, perhaps we’ll have a bit of a
honeymoon as this navigates along,
as opposed to trying to change some-
thing that hasn’t yet occurred.
Lee Bridges, what’s top of mind for you at Bon
Secours?
Autumn Farmer, MHA, chief labo-
ratory officer, Bon Secours Mercy
well spelled out. We haven’t had
blowback or pushback on billing
C. Lee Bridges, MD, regional med- Health, Cincinnati: It gives them a transparency.
ical director, Bon Secours Mercy huge leverage chip
Health, Richmond, Va.: I’ve heard because the pathol- Dwayne, what is the position on masking in
from several pathology groups ogy group never your laboratory now?
around the country that the No Sur- has the opportunity Dr. Breining (Northwell): At
prises Act has had devastating effects to present to the pa- Northwell it’s no longer required as
on their practices. I wanted to find tient, and say, This long as you’re in a nonpatient-care
out if others are experiencing some- is what your out of area. However, walking through the
thing similar. pocket will be. And lab today, I see around 75 percent of
the health system Farmer our people are still wearing masks.
Greg, do you have experience with the No doesn’t know. We
Surprises Act? don’t necessarily have that informa- Pete, what is the current policy at Baylor?
Dr. Sossaman (Ochsner): No, tion to share with the patient. So Dr. Dysert (Baylor Scott & White):
there is not an out-of-network issue you’re essentially in violation if you It’s in line with regulatory—relaxing
for us at Ochsner. I would suspect go out of network. and encouraging it to be worn.
this would be problematic for some
of our pathology colleagues who are It’s also my understanding that it’s difficult for John Waugh, I’ll ask you for the last word. What
in smaller group practices and who a pathology group to make a good-faith esti- is your holiday forecast for what’s ahead?
still may have some of those con- mate of what the cost would be to the patient John Waugh, MS, MLS(ASCP),
tracts with insurers, not through the of the work they’re being asked to do. system VP, pathology and laboratory
larger health system or institution. I Dr. Bridges (Bon Secours): Yes, medicine, Henry Ford Health Sys-
haven’t talked to anybody who’s had and the challenge is tem, Detroit: Health care systems, as
this issue. with arbitration. For we all know, are still facing strong
Dr. Bridges (Bon Secours): I know my colleague who financial headwinds, and there’s a lot
of one group out of state that hap- is going through of budget remediation going on. That
pened to go out of network prior to this now, the arbi- has occupied a lot of my and others’
the No Surprises Act being enacted, trators are so over- time during this month.
and they ended up in an untenable whelmed there’s no I like that our staff get an oppor-
situation. I anticipate payers will good, efficient way tunity to get away and spend time
start to renegotiate or cancel con- Dr.Bridges
to go through that with their families. Some are visiting
tracts because it’s to their advantage process. families far away, on the other side
to have practices not be in network of the world. It’s gratifying to see
with them now. That’s a concern I Stan, do you have contracted pathologists those things, and a lot of moms are
have. It has not directly affected our within MaineHealth? going to smile.
pathology group—we have 11 pa- Stan Schofield (NorDx): Yes, but I’m telling our staff: We recruit the
thologists in our practice—but I can we’re not having a problem with the best people every day, and we titrate
see some of the payers potentially No Surprises Act. We have a lot of the limited amount of capital we
initiating this, which could pose sig- pathologists but it’s a contained net- have because it will have to last us
nificant problems. work within the state. They do work until we get to the other shore. There
for other organizations but it doesn’t will be another side to the valley and
I think it’s largely true that most insurers are impact us. They’re a separate corpo- things will be better there, but it’s
seeking to make their networks ever more ration and it’s a supergroup—anes- going be a long walk up and down.
narrow and then have greater control over how thesia, radiology, and pathology to- There are no small jobs left in health
they deal with the few that are left in the nar- gether—and they provide additional care, only big ones, so focus on the
row networks. Is that a reasonable statement services in surrounding hospitals mission-critical things—length of
of fact? and states. We don’t have a problem stay and the legal and regulatory is-
Dr. Bridges (Bon Secours): It seems because we don’t do the professional sues that help our organizations and
that way to me. billing, and the technical billing is add value. n
Governors and president-elect positions to open, candidates welcome
The CAP election to fill four positions on the Board of Nominating Committee or by submitted petition signed
Governors will take place this summer. The CAP encour- by at least 100 CAP fellows who are eligible to vote. Elec-
ages members active in CAP volunteer activities who have tronic petition forms are now available. For more informa-
been CAP fellows for at least five years to take the next tion on becoming a Board member, visit www.cap.org (About
leadership step. the CAP > Board of Governors). To request petition forms,
Three incumbent governors—Kalisha Ashara Hill, MD, contact Leah Noparstak (847-832-7438 or lnopars@cap.org).
MBA; Bradley S. Karon, MD, PhD; and Assad Joe Saad, July 9 is the deadline for nomination by petition.
MD—are eligible for reelection to another three-year term The CAP Nominating Committee is expected to meet
on the Board of Governors. Jonathan Louis Myles, MD, in mid- to late May to interview candidates for office.
will complete his second term as governor and is ineligible Members of the 2023 Nominating Committee are Rebecca
for another governor term. Obeng, MD, PhD, MPH, chair; Jared Abbott, MD, PhD;
In addition, the CAP will elect a president-elect for a Samer Al-Quran, MD; Sue Chang, MD; Patrick E. Godbey,
two-year term. Eligible candidates must have been a CAP MD; Susan Marie Strate, MD; and Paul N. Valenstein, MD.
fellow for at least 10 years and have served on the Board Members of the Election Oversight Committee are Gail
of Governors. Habegger Vance, MD, chair; M. Elizabeth Hammond,
Fellows can be nominated for these positions by the MD; and William F. Hickey, MD.
JANUARY 2023 page 6
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1. DEA Warns of Increase in Mass-Overdose Events Involving Deadly Fentanyl, Drug Enforcement Administration, April 6, 2022. Accessed on October 31, 2022.
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3. Fentanyl, Drug Enforcement Administration. Accessed on October 31, 2022. https://www.dea.gov/factsheets/fentanyl#:~:text=Fentanyl%20is%20added%20to%20
heroin,is%20primarily%20manufactured%20in%20Mexico
4. Jones, D., Illinois Department of Human Services, IDHS/SUPR Practice Recommendations for Drug and Fentanyl Testing, Volume XV, Issue II – July 2021. Accessed on
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5. Synthetic Opioid Overdose Data, Centers for Disease Control and Prevention, National Center for Injury and Prevention Control, Updated June 6, 2022. Accessed on
October 31, 2022. https://www.cdc.gov/drugoverdose/deaths/synthetic/index.html
order of a physician, or to a clinical laboratory;
6. Langman, L. Jannetto, P., Using Clinical Laboratory Tests to Monitor Drug Therapy in Pain Management Patients. AACC Academy Laboratory Medicine Practice
and use is restricted to, by, or on the order of a
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8. Guideline for Prescribing Opioids for Chronic Pain, U.S. Department of Health and Human Services Centers for Disease Control and Prevention. Accessed on
October 26, 2022. https://www.cdc.gov/drugoverdose/pdf/prescribing/Guidelines_Factsheet-a.pdf SEFRIA is a trademark of Immunalysis Corporation.
9. SEFRIA™ Fentanyl Fact Sheet. Accessed on November 2, 2022. https://immunalysis.com/products/sefria/
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Abbott Diagnostics FILE— 1122-9 JANUARY 2023 page 8

 JANUARY 2023 | CAP TODAY 9

from the
President’s Desk
Emily E. Volk, MD
for health care systems with growing laboratory
facilities. Achieving an international standard en-
sures continuous quality and reliability even as labs
expand operations.
The CAP offers an excellent program and re-

Beyond excellence sources to help CAP-accredited laboratories achieve

When I was newly elected into my officer role at
the CAP in 2019, I had the opportunity to join a
meeting of a committee under the umbrella of the
Council on Accreditation. This was a committee
whose work I knew little about but which I quickly
grew to appreciate. In this committee
I saw an extreme focus on opera-
tional processes and quality manage-
ment structures. They wanted to
prevent errors, not just fix them. This
focus on process was different from
the focus on blame that we often see
in medicine. As I listened to Gaurav
Sharma, MD, lead the CAP 15189
Committee, I knew I was among
folks dedicated to pushing for ever-
better care and quality for our pa-
tients and our laboratories. If CAP
accreditation helps your laboratory
achieve excellence, CAP’s ISO 15189
accreditation makes it possible to go
beyond excellence.
What makes the ISO 15189 pro-
gram distinct is the focus on pro-
cesses and culture in the laboratory.
Risk management aspects of the
program encourage staff members to flag oppor-
tunities without fearing they will get blamed, and
quality and other controls help the entire team
improve operational efficiency. I have not yet over-
seen an ISO 15189 program myself, but I have been
impressed with the laboratories in which I have
seen it implemented.
ISO 15189 is an international quality standard,
and any lab with ISO 15189 accreditation is per-
forming as well as any other ISO 15189 lab else-
where in the world. The benchmark
offers laboratories key privileges,
such as the ability to participate in
pharmaceutical trials and other
highly regulated activities. Because
it is a voluntary standard, achieving
ISO 15189 compliance shows that the
organization’s leaders have real con-
fidence in their people. They would
never make the investment to go for
ISO accreditation without the strong
belief they could achieve it.
ISO 15189 is relevant to laborato-
ries of any size in any type of practice
and anywhere in the world. In a
survey of pathologists at ISO
15189-accredited labs performed by
the CAP, 95 percent said the program
has improved quality and patient
safety, while 87 percent said it im-
proved operational efficiency and 74
percent said it made their labs more valuable to the
overall organization. Anecdotally, the accreditation
improves employee retention by making team
members feel more respected and more empow-
ered to make better decisions. It’s also important
ISO 15189 certification. Developing this program
was a major investment for the CAP and it reflects
its commitment to quality and excellence in patient
care. More than 80 clinical laboratories have already
completed it and been accredited, and I expect
more will follow. Remarkably, despite the pan-
demic, we have seen growing interest in the ISO
15189 accreditation program.
The CAP’s ISO 15189 program recognizes that
each laboratory’s situation is unique and provides
customized support for achieving quality manage-
ment standards. Laboratory medical directors or
operational leaders should understand that ISO
15189 is a process that may take several years to
achieve and it may not be the right fit for all labo-
ratories right now. But should you choose to pur-
sue this lofty goal, professional assessors will help
you translate ISO 15189 criteria into practical, useful
steps for your lab and staff. The CAP also provides
the education and tools needed to implement pro-
gram requirements, measure progress in quality
management, and ensure that your culture and
operation can grow into and sustain ISO 15189
accreditation.
I’d like to thank Dr. Sharma, pathologist and
laboratory medical director at Henry Ford Health
System and past chair of the CAP 15189 Committee,
and Caroline Maurer, CAP 15189 program director,
for sharing their insights about CAP’s ISO 15189
efforts for this column. n
Dr. Volk welcomes communication from CAP members.
Write to her at president@cap.org.

Letters student laboratory. Unfortunately, the

The visible pathologist
The CAP president’s column, “The
visible pathologist” (CAP TODAY, No-
vember 2022), struck a chord that has
been reverberating through our spe-
cialty for many years when a medical
student who expressed an interest in
pathology was asked, “Why don’t you
want to be a real doctor?” You put it
in terms of “disappearing” as judged
by our role in the case of patients.
The angst that pathology is experi-
encing at this moment is one of ulti-
mate disappearance as in extinction.
Extinction can be the result of an im-
mediate catastrophic event or a slower
process with the loss of the ability to
adapt to an evolving environment.
However, the ability to reproduce
through natural selection is the key
element in the maintenance of the
species, which in this case is the pa-
thologist. The process for many of us
began as medical students and our
direct contact with pathologists and
their residents in the lecture hall and
contemporary integrated curriculum
has largely eliminated or severely
curtailed that interaction between
pathologist and medical student. The
pathologist in the curriculum today is
now a vignette in a secondary role if
that. How are the future physicians,
today’s medical students, to concep-
tualize the role of the pathologist in
their practice with such limited con-
tact? Yes, I know that we can create
opportunities through outreach ef-
forts in high school, a medical student
“shadow,” or interest group.
As a “hospital” specialty, many of
us are no longer a physical presence
in the hospital where we once inter-
acted on a personal daily basis with
our clinical colleagues. The latter cir-
cumstance was highlighted in CAP
TODAY in the article, “Pathology hos-
pitalists in place at UMich” (April
2022). In the story, Jeffrey Myers, MD,
related some of the self-inflicted
wounds to our specialty. Are such
efforts a gesture in an attempt to re-
cover what has already been lost? I do
not believe that the COVID-19 pan-
demic is sufficient to restore pathol-
ogy on any sustained basis.
These are reflections of a patholo-
gist who has practiced for more than
50 years and who made the right
choice of specialty for himself and
never looked back from that decision,
one that was fostered by a succession
of pathologist-mentors.
Louis P. Dehner, MD
Professor
Department of Pathology and Immunology
Washington University School of
Medicine in St. Louis
Transgender care
I, too, agree with the premises in the
transgender care article (CAP TODAY,
July 2022) and with the critique of Saul
Harari, MD (October 2022), of the
implementation proposed by the ar-
ticle’s sources. The best care we as
laboratory directors can provide to
patients and their doctors is to main-
tain the highest quality assurance
controls of laboratory procedures,
beginning with obtaining the speci-
men, and to report the results of the
procedures in a timely and appropri-
ate manner to those responsible for
the patient’s care. As for normal
ranges, it is the ordering physician’s
responsibility to know the patient’s
current medications and the influence
they might have on the results; the
reported normal range differences can
be listed for male and female, age
variations, fasting status, etc., as ap-
propriate, and those responsible for
the patient’s care can interpret the
results or contact the laboratory for
elaboration as indicated. Our reports
should be lean, accurate, and timely.
This approach in no way shows
disrespect for the patient or the trans-
gender community. Rather, it pro-
vides the best medical care on behalf
of the patient and his or her caregiv-
ers. The gathering, analysis, and re-
porting of normal ranges for the trans-
gender community is laudable and
not to be ignored.
William M. Davis, MD
Former Laboratory Director
Mary Black Memorial Hospital
Spartanburg, SC
Send letters to editor at srice@cap.org.

JANUARY 2023 page 9

10 CAP TODAY | JANUARY 2023
Array of flow cytometry cases in new color atlas
Due out this spring is the CAP’s Color
Atlas of Flow Cytometry. It consists of 71
cases and provides examples of the full
range of hematolymphoid diseases that
can be productively analyzed by flow
cytometric immunophenotyping. Its edi-
tors are David Dorfman, MD, PhD, of
Harvard Medical School and Brigham
and Women’s Hospital; William Karlon,
MD, PhD, of the University of California
San Francisco Medical Center; and Mi-
chael Linden, MD, PhD, of M Health
Fairview-University of Minnesota Medi-
cal Center. CAP TODAY recently asked
Dr. Dorfman a few questions about the
atlas. His answers to our questions and a
sample case follow.
Who is this atlas written for?
The CAP Color Atlas of Flow Cy-
tometry was created for students and
trainees in clinical flow cytometry
and hematopathology, medical tech-
nologists working in clinical flow
cytometry laboratories, practicing
hematopathologists, and clinical
immunologists.
Tell us about the origins of this atlas.
This atlas was designed and writ-
ten by members of the CAP Diagnos-
tic Immunology and Flow Cytometry
Committee, which produces numer-
ous proficiency testing Surveys for
clinical immunology and flow cy-
tometry laboratories. Two of those
Surveys, the current FL5 Survey and
the previously produced FL3CD Sur-
vey, consist of a series of flow cytom-
etry cases from the clinical flow cy-
tometry laboratories of current and
past committee members. Each year
the committee sends out de-identi-
fied clinical and laboratory data for
Here is case No. 29 from the CAP’s
Color Atlas of Flow Cytometry, due
out this spring. To order (PUB230),
call 800-323-4040 option 1 or go to
www.cap.org (Shop tab) ($148 for mem-
bers, $185 for others). If you are inter-
ested in writing a book, contact Katy
Meyer at kmeyer@cap.org.
COLOR ATLAS OF
FLOW CYTOMETRY
David M. Dorfman, MD,
William J. Karlon, MD, PhD
Michael A. Linden, MD,
k.indd
w Cytomery Boo
COVER O ptionA_ Flo
several cases, including dot plots of
the actual flow cytometry studies
that were performed by the submit-
ting laboratory, to Survey partici-
pants, who analyze each case, arrive
at a diagnosis, and report positive
and negative antigens, which they
submit to the com-
mittee for compari-
son with other Sur-
vey participants.
Committee mem-
bers prepare re-
ports on the Survey
results, including a
discussion of the
Dr.Dorfman
correct diagnosis,
other participant diagnoses, and im-
portant teaching points, that all Sur-
vey participants receive.
The idea for the CAP Color Atlas
of Flow Cytometry arose from a con-
versation several years ago with my
colleagues and co-editors, Drs. Wil-
liam Karlon and Michael Linden. We
thought a collection of past FL5 and
FL3CD cases could be a useful re-
source for clinical flow cytometry
laboratories, students and trainees,
and others interested in the flow cy-
tometric immunophenotypic analysis
of hematolymphoid neoplasms. We
include examples in the atlas of the
entire range of hematolymphoid dis-
eases that can be productively ana-
lyzed by flow cytometric immuno-
phenotyping. Because the atlas also
includes the results from Survey par-
ticipants, readers have the unique
opportunity to see how other flow
cytometry practitioners interpreted
the findings in each case. For many
disease entities, particularly the most
History
The patient is an 80-year-old man
with a history of hypothyroidism. He
is referred to hematology for leuko-
cytosis due to absolute lymphocyto-
sis, but he does not have anemia or
thrombocytopenia. A peripheral blood
sample is submitted for flow cytometric
immunophenotyping.
Laboratory results
WBC
11.9 × 109/L
[normal range 4.0–11.0 × 109/L]
Absolute lymphocyte count
PhD 6.8 × 109/L
PhD
[normal range 0.8–5.3 × 109/L]
M P
PM
12/20/22 3:173:17
12/20/22
3
common diseases encountered in
clinical practice, there is agreement of
interpretations by 90 percent or more
of Survey participants. In some cases,
however, significantly fewer Survey
participants arrive at the correct diag-
nosis. These cases provide readers of
the atlas with an opportunity to iden-
tify and appreciate those disease cat-
egories and specific disease entities
that are particularly difficult to diag-
nose correctly in clinical practice,
because of either the low frequency
of these diseases or the complicated
immunophenotypic patterns that
must be appreciated to arrive at the
correct diagnosis.
How is the book organized?
The cases in the CAP Color Atlas
of Flow Cytometry are organized into
sections by disease categories. Each
section has an overview chapter that
provides background and introduc-
tory information. Within each section
there are separate chapters for each
disease entity. Chapters begin with a
clinical history, laboratory results,
one or more photomicrographs, and
representative flow cytograms, so
that the favored interpretation is not
evident to readers at the outset. As a
result, the chapters may be used to
test readers’ ability to arrive at a di-
agnosis using the available informa-
tion. Readers can then compare their
interpretation of the data with the
interpretations of CAP Survey par-
ticipants and with the final, favored
interpretation of the chapter author
or authors. The interpretations of
CAP Survey participants also serve
to illustrate the relative difficulty of
Photomicrographs (peripheral blood smear; Wright-Giemsa stain)
arriving at the correct diagnosis. Al-
ternatively, the atlas may be used as
a reference text on the characteristic
findings of a wide range of clinical
entities encountered in clinical flow
cytometry practice. For this purpose,
the table of contents lists all the dis-
ease entities in the atlas and is orga-
nized by disease categories.
Would you like to say a few words about your
co-editors and the many contributors?
The clinical cases presented in the
atlas come from a variety of laborato-
ries around the country and were
contributed from 2009 to the present
by past and current members of the
CAP Diagnostic Immunology and
Flow Cytometry Committee (DIFCC).
Members of the DIFCC atlas subcom-
mittee developed and wrote the atlas,
along with several additional volun-
teers. We all wrote case discussions
and many of us contributed addi-
tional cases and case discussions, of-
ten for less commonly encountered
entities in clinical flow cytometry
practice. Two members of the DIFCC
with an expertise in the flow cytomet-
ric analysis of inborn errors of im-
munity, Drs. Roshini Abraham and
Vijaya Knight, contributed cases and
case discussions to illustrate the most
common disease entities encountered
in clinical practice and the flow cyto-
metric approach to evaluating these
disorders. My co-editors and I are
grateful for the hard work of the
members of the DIFCC atlas subcom-
mittee and other volunteers who
worked on the project, which we
hope readers will find useful and
informative. ■
—continued on 12
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12 CAP TODAY | JANUARY 2023
Flow cytometry atlas
continued from 10
Representative flow cytograms
The population color-gated in black comprises 34% of leukocytes.
Summary of flow cytometry findings (participant consensus)
Positive: CD5, CD19, CD20, CD23, CD45, kappa light chain
Negative: CD10, CD14, CD79b, lambda light chain
Favored interpretation
High-count monoclonal B-cell lymphocytosis (MBL)
Chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL)
Low-count monoclonal B-cell lymphocytosis
Reactive lymphocytosis
Other
Discussion
This case was intended to represent
high-count monoclonal B-cell lym-
phocytosis (MBL). The blood smears
showed a very mild leukocytosis due
to increased monotonous lympho-
cytes with high nuclear-to-cytoplas-
mic ratios, a small rim of basophilic
cytoplasm, and clumped or “cracked”
chromatin. The delineation between
these atypical cells and normal circu-
lating lymphocytes is difficult. On the
flow cytometry dot plots, the black
population is the population of inter-
est. These cells express CD45, B-cell
markers CD19 and CD20 (heteroge-
neous/dim), with coexpression of
CD5 and CD23, and dim monotypic
kappa light chain expression. They
account for 34% of leukocytes. Taking
the leukocyte count into consider-
ation, we get an absolute neoplastic
B-cell count of 4.0 × 109/L (WBC ×
neoplastic B-cell population % = ab-
solute neoplastic B-cell count; 11.9 ×
109/L × 34% = 4.0 × 109/L).
MBL with the phenotype of CLL
Participants (233)
Number % bered. If there are at least 5 × 109/L
146 62.7
75 32.2
10 4.3
1 0.4
1 0.4
cells—as seen in the current case—is
considered a precursor lesion. Natu-
ral history studies show that virtually
all cases of CLL evolve from MBL
(although not all MBL cases will
progress to CLL). MBL has a preva-
lence of less than 1% to 18% depend-
ing on the assay sensitivity and pa-
tient population investigated. Inci-
dence increases with age, from less
than 1% in patients younger than 40
years to 75% in patients older than 90
years. Patients are asymptomatic at
diagnosis and may be incidentally
detected. Without flow cytometry, it
is possible that many cases of MBL
are overlooked. The neoplastic cells
are only slightly atypical (mature
lymphocytes with small rim of baso-
philic cytoplasm and clumped/
cracked cytoplasm) and may be rare.
Flow cytometry increases sensitivity
and allows for more objective identi-
fication of cells with an aberrant
immunophenotype.
CLL-type MBL is the most com-
mon type of MBL and has the char-
acteristic CLL/SLL immunopheno-
type of positivity for B-cell markers
CD19 and CD20 (dim) with coex-
pression of CD5 and CD23, and dim
monotypic surface light chain ex-
pression. There are, however, two
other subtypes of MBL. MBL with an
atypical CLL immunophenotype
expresses B-cell markers CD19 and
CD20 (bright), with coexpression of
CD5, variable CD23 expression, and
moderate-to-bright monotypic sur-
face light chain expression. In this
scenario, it is important to rule out
peripheral blood involvement by
mantle cell lymphoma. Imaging to
look for a mass lesion and cytogenet-
ics/fluorescence in situ hybridiza-
tion to assess for t(11;14) may be
useful to identify mantle cell lym-
phoma. Another subtype of MBL has
a non-CLL immunophenotype. This
entity expresses B-cell markers CD19
and CD20 (bright), with moderate-
to-bright monotypic surface light
chain expression and negative or
dim CD5 expression. Some of these
cases have 7q aberrations and de-
velop splenomegaly, suggesting a
relationship with splenic marginal
zone lymphoma.
To make the correct diagnosis of
high-count CLL-type MBL, several
important criteria must be remem-
leukemic cells with the immunophe-
notype described above, the diagnosis
is CLL. If there are less than 5 × 109/L
leukemic cells, but there is significant
lymphadenopathy, splenomegaly, or
other extramedullary deposition of
cells with the same immunopheno-
type, the diagnosis is SLL. If neither
of these criteria are met, but there is a
population of atypical cells in the
peripheral blood, MBL can be diag-
nosed. It is interesting to note that the
percentage of bone marrow involve-
ment (in the absence of other diagnos-
tic criteria) does not change the diag-
nosis from MBL to CLL.
There are two subcategories of
CLL-type MBL based on the degree
of peripheral blood involvement.
Low-count MBL has less than 0.5 ×
109/L in the blood and high-count
MBL has at least 0.5 × 109/L. These
subcategories are of prognostic im-
portance because low-count MBL
rarely progresses to CLL, whereas
high-count MBL progresses to CLL at
a rate of approximately 1% to 2% per
year. In addition, high-count CLL-like
MBL is genetically and biologically
similar to CLL. Of note, some patients
vacillate for years between meeting
criteria for MBL and CLL.
The interpretation of the immuno-
phenotype in this case had high par-
JANUARY 2023 page 12
ticipant consensus: 99.1% or higher
for each antigen. However, the final
diagnosis did not reach consensus,
although the majority of participants
(62.7%) chose the intended answer:
high-count MBL. A significant per-
centage of participants (32.2%)
thought the case best represented
CLL/SLL, whereas a smaller fraction
chose low-count MBL (4.3%). Calcu-
lating the total monoclonal periph-
eral blood lymphocyte count is criti-
cal to arriving at the correct diagno-
sis. Although the total lymphocyte
count is 6.8 × 109/L, this cannot be
used as the estimate of the leukemic
cell population. Flow cytometric
analysis to identify the percentage of
neoplastic B-cells allows for calcula-
tion of the correct absolute neoplastic
B-cell count.
Major teaching points
■ MBL is defined as the presence
of less than 5 × 109/L clonal B-cells in
the peripheral blood.
■ There are three subtypes of
MBL: CLL-type, atypical CLL-type,
and non–CLL-type. CLL-type is by
far the most common subtype and is
a precursor to CLL.
■ CLL-type MBL has an immuno-
phenotype similar to CLL/SLL, and
is separated into high-count MBL
(≥0.5 × 109/L) and low-count MBL
(<0.5 × 109/L).
Bibliography
Campo E, Muller-Hermelink HK, Ghia P, et al.
Chronic lymphocytic leukaemia/small lym-
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E, Harris NL, et al, eds. WHO Classification of
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sues. Rev 4th ed. Geneva, Switzerland: WHO
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Fazi C, Scarfò L, Pecciarini L, et al. General popula-
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Kern W, Bacher U, Haferlach C, et al. Monoclo-
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ter classified as early-stage CLL. Br J Haematol.
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Nieto WG, Almeida J, Romero A, et al. Increased
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Shim YK, Rachel JM, Ghia P, et al. Monoclonal
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Strati P, Shanafelt TD. Monoclonal B-cell lym-
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 JANUARY 2023 | CAP TODAY 13

Cytopathology focus
FROM THE CAP CYTOPATHOLOGY COMMITTEE; TERESA M. ALASIO, MD, EDITOR

Serous fluid cytopathology—recent through V carries with it an increasing risk of ma-

progress and Yale’s experience
Muhammad Ahmed, MD
He Wang, MD, PhD
In recent years, a standardized classification system
for the cytology of serous body cavities has been
proposed. The system, known as the International
System for Reporting Serous Fluid Cytopathology
(ISRSFC), published by Ashish Chandra, et al.,1 in
Fig. 1. Non-diagnostic specimen (LBP, ThinPrep). Fig. 2. Negative for malignant cells (LBP, ThinPrep). Fig. 3. Atypia of undetermined significance
Pleural fluid with obscuring blood only. Pericardial fluid with reactive mesothelial cells
(center) and mixed inflammation.
lignancy (Table 1, page 15). This brief review article
aims to highlight the salient points of each diagnos-
tic category and includes discussion of recent pub-
2020, aims to enhance the reproducibility of cyto- lications and our own institutional experience.
logic diagnoses, thereby facilitating clearer com- I. Non-Diagnostic (ND). This category is used
munication with clinicians. The diagnostic catego- for those specimens that are either too paucicellular
ries are as follows: I. Non-Diagnostic; II. Negative to interpret or have other issues precluding accu-
for Malignancy; III. Atypia of Undetermined Sig- rate assessment, such as poor preservation, obscur-
nificance; IV. Suspicious for Malignancy; V. Malig- ing blood (Fig. 1), and poor processing.
nant. Each progressive diagnostic category from I II. Negative for Malignancy (NFM). This is the
most commonly used category (ap-
proximately 70 to 80 percent of cas-
es). The specimen does not reveal
any morphologic evidence of meso-
thelial or non-mesothelial malig-
nancy. The specimen essentially con-
sists of the normal constituents of
serous fluid: mesothelial cells, lym-
phocytes, and macrophages and/or
serositis (Fig. 2).
III. Atypia of Undetermined Sig-
(LBP, ThinPrep). Pelvic wash specimen showing nificance (AUS). This is an indeter-
rare papillary group of cells associated with minate category where the specimen
psammomatous calcifications that may possibly lacks either quantitative or qualita-
represent reactive mesothelial cells. However, an
tive features of malignancy. Malig-
ovarian epithelial process could not be excluded.
nancies with bland cytomorphology
in addition to degenerated cells and
cells more closely resembling reac-
tive atypia may fall under this cate-
gory (Fig. 3). —continued on 14

<<< Fig. 6. Suspicious for malignancy (claudin-4,

Fig. 4. Suspicious for malignancy (LBP, ThinPrep).
Pleural fluid showing rare group of highly atypical
cells showing nuclear enlargement, prominent
nucleoli, and high N:C ratios. Note the small
reactive mesothelial cells in the background.
immunohistochemistry). The atypical cells show faint
positivity for claudin-4. Only faint staining for cytokeratin
Fig. 5. Suspicious for malignancy (cell block, AE1/AE3 was observed while MOC31, multiple other
H&E). Similar rare, scattered cells are observed cytokeratins, and lineage specific markers were negative,
in the cell block. precluding further classification.

Adequacy in cytopathology: an overview with a some specimen types/sites, such as

focus on FNA of lymph nodes and mass lesions
Varsha Manucha, MD
Efrain Ribeiro, MD, PhD
Martin J. Magers, MD
Derek B. Allison, MD
The definition of “adequate” per the
Merriam-Webster dictionary is “suf-
ficient for a specific need.” In cytopa-
thology, it is defined by the quantity
and quality of the cellular material
sampled. The final interpretation of a
cytopathology report is almost uni-
versally preceded by an adequacy
statement. While the essence of “ad-
equacy” stays the same, its application
varies depending on the specimen
type and the site sampled. Further-
more, in the current era of personal-
ized medicine, the definition of ade-
quacy has expanded from “enough
cells to make a morphologic diagno-
sis” to “enough cells to make a diag-
nosis and perform ancillary studies.”
To achieve consistency in the usage
of the criteria for adequacy, standard-
ized terminology systems supported
by national and international profes-
sional organizations have been imple-
mented successfully in cervical, thy-
roid, salivary gland, urine, and serous
fluid cavity cytopathology. Others
have been conceived recently, and
more are in the pipeline. The adequa-
cy criteria described in the published
classification systems stem from the
review of the published literature,
surveys of practicing pathologists, the
practical experience of the contribut-
ing authors, and targeted research
studies performed during the devel-
opment of classification systems to fill
in gaps in the literature.1 Ultimately,
the goal of a published classification
system is to establish a common lan-
guage for pathologists and clinicians.
With this aim in mind, these systems
often provide an associated risk of
malignancy for each diagnostic cate-
gory, including “non-diagnostic/in-
adequate,” which in turn provides the
basis for patient management.
Table 1 (page 16) summarizes some
of the published criteria for defining
specimens as adequate. The common
theme in each system is quantitative
(number of cells) and qualitative (dis-
tinct and clear visualization of cells);
acellular/sparsely cellular or degen-
erated samples are typically inter-
preted as non-diagnostic/inadequate
for evaluation. There are, however,
bronchial brushing, bronchoalveolar
lavage, cerebrospinal fluid, lymph
nodes, bone lesions, and synovial flu-
ids, for which the adequacy criterion
is not clearly defined and others (i.e.
serous effusions, salivary gland, and
voided urine) for which the adequacy
criterion is not fully accepted.
One such site with poorly defined
adequacy criteria is lymph node cyto-
pathology. For example, a common
specimen in many pathology labora-
tories is an endobronchial ultrasound-
guided fine-needle aspiration (EBUS-
FNA) of an enlarged or PET-avid
lymph node. For EBUS-FNA, adequa-
cy depends on the result. If metastatic
carcinoma is present, sufficient mate-
rial to prepare a cell block is likely
necessary for immunohistochemistry
or molecular testing. When atypical
lymphoid cells (regardless of quantity)
are seen at the time —continued on 16

Q Dr. Alasio is president and medical director, TelepathologyDx, PLLC. Q Image atop page: Cell block, H&E. Pleural fluid: atypical mesothelial cells.
14 CAP TODAY | JANUARY 2023

Table 1.
Serous fluid cytopathology
continued from 13

Pericardial and peritoneal fluids have a higher mesothelial markers on I. Non-

incidence of this category as compared with pleu- immunocytochemistry. Diagnos
ral fluids. At our institution, we
IV. Suspicious for Malignancy (SFM). Speci- use calretinin and cyto-
mens that have cytomorphologic features compat- keratin 5/6 as our me-
ible with malignancy but are either quantitatively sothelial markers and II. Nega
or qualitatively insufficient for a definitive diag- MOC31 and Ber-Ep4 as Maligna
Fig. 7. Positive for malignancy (LBP, ThinPrep). Pleural Fig. 8. Positive for malignancy (cell block, H&E).
(NFM)
nosis of malignancy fall into this category (Figs. fluid with two populations of cells present: a population Sheets of enlarged atypical cells with vesicular our epithelial markers.
4–6). Cases with concurrent surgical follow-up of enlarged atypical cells (center left) and a smaller chromatin, prominent nucleoli, and a moderate Depending on the type
with malignant findings may be placed into the background population of reactive mesothelial cells. amount of vacuolated cytoplasm. of malignancy suspect-
malignant category (see below). Most cases in the ed, we may opt to use
AUS or SFM category are classified as such due to other mesothelial
low cellularity of malignant cells and/or low vol- markers such as WT-1
ume of fluid analyzed. Most patients have a prior or D2-40 since certain III. Atypi
history of malignancy or have malignant findings malignancies such as Undeter
on surgical follow-up. squamous cell carcino- Signific
(AUS)
V. Malignant (MAL). Specimens with findings ma may be positive for
that are unequivocal for malignancy either alone cytokeratin 5/6. The
or with concomitant ancillary testing are placed in new antibody, clau-
this category (Figs. 7–10). The cell of origin must din-4, is also used de-
be identified to the furthest extent possible. New Fig. 9. Positive for malignancy (claudin-4, Fig. 10. Positive for malignancy (TTF-1/napsin A, pending on cytopathol-
diagnostic criteria for the diagnosis of malignant immunohistochemistry). The atypical cells are immunohistochemistry). The atypical cells show ogist preference and
diffusely and strongly positive for claudin-4. IV. Susp
mesothelial proliferations are discussed next. strong diffuse positivity for TTF-1/napsin A dual the degree of suspicion
stain, consistent with adenocarcinoma of lung origin. for Mali
Diagnostic criteria for mesothelioma. The di- for malignancy. If the (SFM)
agnosis of mesothelioma is one of the most chal- cytomorphology (i.e. extremely hypercellular epithelial markers are positive, additional immu-
lenging on cytology alone. The clinical history and specimen containing cells with overt nuclear ab- nocytochemistry is added to further delineate the
radiologic findings must always be taken into normalities, cellular spheres, papillary tissue frag- cell of origin. If atypical lymphoid cells are present,
consideration. New diagnostic criteria have ments, morulae, or single cells). If BAP-1 is retained correlation with concurrent flow cytometry results
(nuclear staining), fluo- is warranted. If there is no concurrent flow cytom-
rescent in situ hybrid- etry and depending on how much specimen is left V. Malig
ization for p16 may be over, we may opt to add on CD3 and CD20 im- (MAL)
used. If the findings munocytochemistry stains. B-cell or T-cell receptor
show loss of p16, the clonality studies by molecular testing may also be
findings are also com- ordered on the leftover specimen if immunocyto-
patible with a mesothe- chemistry is not a viable option (i.e. too few or
lioma in the appropriate scattered cells present to make a distinction be-
clinical setting. If there tween B and T cells). Mesenchymal tumors with
is no deletion of p16, a recurrent molecular alterations are sent for molecu-
malignant mesothelial lar testing, if possible. Atypical mesothelial prolif- tively).
Fig. 11. Atypical mesothelial proliferation (LBP, Fig. 12. Atypical mesothelial proliferation (BAP-1,
ThinPrep). Atypical clusters of mesothelial cells immunohistochemistry). BAP-1 shows loss of
proliferation cannot be erations with clinical and radiologic findings con- portant
are present. Note the atypical mitotic figure nuclear staining in a subset of clusters. Calretinin excluded. Interestingly, cerning for mesothelioma are worked up according institut
(center). The patient radiologically had a large and CK5/6 were also positive. Surgical follow-up sarcomatoid mesothe- to the aforementioned new diagnostic criteria. commo
peritoneal mass, concerning for malignancy. revealed mesothelioma. lioma shows loss of p16 A word on pericardial and pleural effusions. pericar
in 90 to 100 percent of Pericardial effusions are more likely to be malig- most c
emerged for discerning malignant mesothelial cases while the epithelioid and biphasic variants nant than other serous effusions, and they tend to pericar
proliferations from reactive ones. In patients with show loss in only about 70 percent of cases. BAP-1 show mesothelial cells with a greater degree of angiosa
a compatible clinical and radiologic history, im- has low sensitivity (approximately 56 percent) but atypia and clustering than at other sites. Addition- malign
munocytochemistry for BRCA-associated protein very high specificity (approximately 100 percent). ally, recent studies in our institute have shown lioma
1 (BAP-1) has been shown to be lost in the majority General diagnosis. In our experience, when that pericardial cytology has a higher sensitivity commo
of malignant mesothelial proliferations (Figs. 11 compelling atypical cells are present in serous flu- than pericardial biopsy in detecting malignancy tolymp
and 12) when taken in conjunction with atypical ids, we opt to use two epithelial markers and two in this cavity (77 percent and 53 percent, respec- cardium
are nee
involve
Peri
ences b
ascites
Rece
experie
and ac
porting
positiv
showed
Fig. 13. Positive for malignancy (LBP, ThinPrep). Fig. 14. Positive for malignancy (cell block, H&E). Fig. 15. Atypical mesothelial proliferation (LBP, Fig. 16. Atypical mesothelial proliferation (cell
Pericardial fluid with atypical, elongated cells. Atypical, hyperchromatic, and angulated cluster of
malign
ThinPrep). Pleural fluid showing a round, knob-like block, H&E). Numerous groups of clustered atypical
cells. The cells were negative for a large panel of cluster with enlarged nuclei and prominent nucleoli. mesothelial cells. The cells were positive for ISRSFC
immunohistochemical markers. Surgical follow-up calretinin and CK5/6. BAP-1 showed loss of nuclear results
revealed angiosarcoma. staining. Surgical follow-up revealed mesothelioma. study o

JANUARY 2023 page 14

 JANUARY 2023 | CAP TODAY 15

Table 1. Summary of diagnostic categories in ISRSFC

Essential features Overall Risk of malignancy Examples
incidence (ROM)
kers on I. Non- g  Specimen is inadequate for interpretation 0.9% 17.4% +/- 8.9% g   Paucicellular specimen or specimen with communication of diagnostic catego-
mistry. Diagnostic (ND) g  Mesothelial cells required for adequacy though obscuring artifacts (i.e. blood, stain pre- ries to clinicians, thereby streamlin-
no specific quantity has been delineated cipitate), or poor processing
on, we ing patient management decisions in
g  Ideally 50–75 mL of fluid should be examined
d cyto- a more reproducible way. It will be
g  Any atypia precludes this category
ur me- interesting to see to what extent cy-
ers and II. Negative for g  No morphologic evidence of malignancy 70–80% 21% +/- 0.3% g   Endometriosis, inflammatory and infectious topathologists embrace this system
-Ep4 as Malignancy g  Specimen consists of a combination of meso- etiologies, renal failure, and heart failure in the future and what modifications
(NFM) thelial cells and inflammatory cells
arkers. it will undergo as more data on its
g  Mesothelial cells are identified by their smooth
he type usage become available. For now, we
nuclear contours with single or multiple small
uspect- nucleoli, a dense endoplasm, a lighter ectoplasm
embrace this new system with cau-
to use containing a wavy “skirt” composed of microvilli, tious optimism.  n
helial and the presence of gaps known as “windows” 1. Chandra A, Crothers B, Kurtycz D, Schmitt F,
eds. The International System for Serous Fluid
s WT-1 when the cells cluster into groups
Cytopathology. Springer; 2020.
certain III. Atypia of g   Indeterminate category where specimen 0.6–1.6% 66% +/- 10.6% g  Atypical cells with reactive or degenerative
2. Bearse M, Tang H, Chandler J, Wang H. Diag-
uch as Undetermined lacks quantitative or qualitative features of changes nostic yield for pericardial effusion is superior
arcino- Significance malignancy g  Well-differentiated malignancies to that of pericardial biopsy. Submitted and
(AUS) g   Ancillary testing is paramount to ruling out accepted for the United States and Canadian
tive for g   Benign tumors such as serous cystad-

malignancy Academy of Pathology Annual Conference 2023.

6. The enomas, fibromas, borderline tumors, and
teratomas 3. Tang H, Chen C, Wang H. Landscape of prima-
, clau- ry and secondary tumors of the pericardium and
g  Atypical lymphoid proliferations
sed de- pleura, a single institutional review. Submitted
g   Specimens with inconclusive ancillary and accepted for the United States and Canadian
pathol-
testing results Academy of Pathology Annual Conference 2023.
ce and 4. Ahuja S, Malviya A. Categorisation of serous
IV. Suspicious   Cytomorphologic features concerning for ma- 3.6–6.3% 82% +/- 4.8%   Monomorphous or atypical lymphoid pro-
spicion
g g
effusions using the International System for
for Malignancy lignancy, but specimen is quantitatively or liferations, mucinous material with or
. If the (SFM) qualitatively insufficient without bland epithelial cells, or highly
Reporting Serous Fluid Cytopathology and as-
sessment of risk of malignancy with diagnostic
immu- g Type of malignancy that is suspected should atypical epithelial cells on liquid-based accuracy. Cytopathology. 2022;33(2):176–184.
eate the be specified (i.e. epithelial, mesenchymal, cytology which are absent on cell block
5. Sun T, Wang M, Wang H. Risk of malignancy
present, hematolymphoid) material precluding further workup assessment of the International System for Re-
results g  Report should mention what type of follow-up porting Serous Fluid Cytopathology: experience
in a community hospital setting and comparison
cytom- may be needed (i.e. repeat thoracentesis)
with other studies. Cancer Cytopathol. Published
n is left V. Malignant g  Unequivocal cytomorphologic features of ma- 30% 99% +/- 0.1% g  Adenocarcinoma (of lung, breast, gastroin-
online Aug. 22, 2022. doi:10.1002/cncy.22638
D20 im- (MAL) lignancy are present (pleural) testinal primary, etc.), poorly differentiated 6. Layfield LJ, Yang Z, Vazmitsel M, Zhang T,
eceptor g  Cell of origin must be identified to the furthest
50% carcinoma, diffuse large B-cell lymphoma, Esebua M, Schmidt R. The international system
extent possible synovial sarcoma for serous fluid cytopathology: interobserver
also be (pericardial)
g  Ancillary studies including immunocytochemistry agreement. Diagn Cytopathol. 2022;50(1):3–7.
nocyto- Additional related sources:
and molecular testing for prognostic and/or
few or 7. Cibas ES, Ducatman BS. Cytology: Diagnostic
predictive markers is warranted, depending on
ion be- type of malignancy Principles and Clinical Correlates. 4th ed. Else-
rs with vier; 2014. http://www.clinicalkey.com/dura/
browse/bookChapter/3-s2.0-C20110071892.
molecu- Accessed Oct. 31, 2022.
prolif- tively).2 Thus, pericardial cytology plays an im- munity-based hospital setting, that each hospital 8. Gokozan HN, Harbhajanka A, Lyden S, Michael CW. Root cause
gs con- portant role in the diagnosis of malignancy. At our must determine its own institutional risk of malig- analysis of indeterminate diagnoses in serous fluids cytopathology.
cording institution, adenocarcinoma of the lung is the most nancy based off its own use of ISRSFC categories. Diagn Cytopathol. 2021;49(5):633–639.
ria. common metastatic malignancy detected in both This is namely because the parameter may vary 9. Dipper A, Maskell N, Bibby A. Ancillary diagnostic inves-
usions. pericardial and pleural effusions. Curiously, the between the patient populations seen at large aca- tigations in malignant pleural mesothelioma. Cancers (Basel).
2021;13(13):3291.
malig- most common primary malignant tumor of the demic centers and smaller community hospitals.
10. Pergaris A, Stefanou D, Keramari P, et al. Application of the
tend to pericardium we’ve encountered in our cohort is Additionally, studies have shown decent in- International System for Reporting Serous Fluid Cytopathology
gree of angiosarcoma while the most common primary terobserver agreement between the diagnostic with cytohistological correlation and risk of malignancy assess-
ddition- malignant tumor of the pleural cavity is mesothe- categories, with the greatest concordance seen in ment. Diagnostics (Basel). 2021;11(12):2223.
shown lioma (Figs. 13–16). Furthermore, although un- NFM and MAL cases (76 percent and 81 percent, 11. Pinto D, Chandra A, Crothers BA, Kurtycz DFI, Schmitt F.
The International System for Reporting Serous Fluid Cytopathol-
sitivity common in serous effusions to begin with, hema- respectively).6 The categories of AUS and SFM ogy—diagnostic categories and clinical management. J Am Soc
gnancy tolymphoid tumors more often involve the peri- showed poor interobserver agreement. The reason Cytopathol. 2020;9(6):469–477.
respec- cardium than the pleura.3 Larger cohort studies for this may lie in the subjectivity and experience
are needed to evaluate the variety of tumors that of the cytopathologist in using one diagnostic Dr. Wang is associate professor of pathology at Yale
involve both of these cavities. category over another. University School of Medicine and a member of the
Peritoneal washing and ascites. A few differ- Conclusion. Overall, the ISRSFC appears to be CAP Cytopathology Committee. Dr. Ahmed is a cy-
ences between peritoneal/pelvic washings and a feasible classification system that standardizes topathology fellow at Yale University.
ascites fluid must be taken into account (Table 2).
Recent studies of ISRSFC and our institutional Table 2. Few differences between ascites and peritoneal pelvic washings
experience. Publications assessing the feasibility Key differences
and accuracy of the International System for Re-
Ascites g   Mesothelial cells are more likely to present as single cells or small clusters with bland cytomorphology.
porting Serous Fluid Cytology have shown overall g   Bland epithelial inclusions (i.e. endometriosis/endosalpingiosis) are less likely to be seen.
positive results. A recent study by Ahuja, et al.,4
showed an incidence of each category and risk of Peritoneal/pelvic g  Mesothelial cells are more likely to present as flat sheets containing several cells or as clusters surrounding
tion (cell washings stromal material (collagen balls) with a reactive cytomorphology consisting of open chromatin with small nucleoli
malignancy comparable to that presented in the
d atypical and visible windows between the cells.
sitive for ISRSFC. Several other studies have shown similar
g  Benign epithelial inclusions (i.e. endometriosis/endosalpingiosis) are more visible; thus care must be taken not to
of nuclear results. Yale’s Sun, et al.,5 concluded from their mistake them for malignant cells.
othelioma. study on pleural and peritoneal fluids, in a com-

e 14 JANUARY 2023 page 15

16 CAP TODAY | JANUARY 2023

Adequacy critical that such a specimen be inter-

preted as non-diagnostic and not
nation, performance of FNA by palpa-
tion or ultrasound guidance, and
that reveals abundant clean mucin is
providing a diagnostic clue that there
continued from 13
“negative for malignancy” to avoid a availability of ROSE/adequate triag- is a mucin-producing abnormality,
false-negative diagnosis.4 The ques- ing at the time of the procedure. which although not diagnostic of a
of rapid onsite evaluation (ROSE), tion, however, remains as to how The concept that adequacy is intrin- specific entity is an abnormal finding
aspirate material is needed for flow many lymphoid cells are sufficient to sically tied to correlation with the clini- that helps narrow the differential diag-
cytometry, slides for cytomorphologic call the sample an adequate represen- cal context has become core to report- nosis. When interpreting an FNA per-
evaluation, and material for a cell tation of a lymph node and to ensure ing FNA cytopathology. Returning to formed for a mass lesion, solid or cys-
block to potentially perform immuno- a true negative interpretation. Sug- the definition of adequate, the “clinical tic, this concept can be applied across
histochemistry and molecular testing. gested criteria vary, including “many need” for the procedure must be many primary sites and doesn’t re-
At a minimum, approximately 50,000 small lymphocytes,” “lymphocytes known to determine whether the mate- quire a standardized reporting system
cells per tube is considered amenable comprising 30 percent or more of the rial is sufficient. If an FNA is targeting with complex or confusing criteria.
for flow cytometry analysis, and sam- cells,” “more than 40 lymphocytes per a mass lesion, the aspirate should con- In each case that is not adequate,
pling errors (poor viability, peripheral high-power field,” and “more than 100 tain material that corresponds to or communication is key to ensure the
blood contamination, and hypocellu- lymphocytes per low-power field.”4 helps explain the presence of a mass. patient workup continues and they
lar specimens, for example) are the In May 2019 in Sydney, Australia, For example, a sample from an EBUS- aren’t lost to follow-up. Consequently,
major reasons for sensitivity failures in a steering committee of international FNA of a lung nodule should contain it is recommended that an explanatory
flow cytometry.2 Thus, adequacy cri- cytologists proposed a system for re- abnormal material that helps answer comment be included stating the rea-
teria for lymph nodes historically have porting lymph node FNA, which in- the question “what is this nodule?”— son for the non-diagnostic/inadequate
been largely subjective. Most studies cluded efforts to reduce the variability whether it be necrotizing granuloma- specimen, such as: “The findings in
focused on EBUS-FNA of mediastinal of the adequacy criteria used. Accord- tous inflammation, a benign hamar- this case do not appear to explain or
lymph nodes have defined an inade- ing to the proposed Sydney System, toma, or adenocarcinoma. If the FNA be representative of the reported mass
quate specimen as a sample lacking inadequate or insufficient FNA of a is cellular but composed of pulmonary lesion. As a result, the case is best cat-
the following: tumor cells, granuloma- lymph node includes cases that can- alveolar macrophages and/or benign egorized as non-diagnostic and repeat
tous inflammation, or a significant not be diagnosed due to scant cellular- respiratory epithelium, the sample sampling should be considered.”
amount of lymphoid tissue with or ity, extensive necrosis, or technical does not provide an answer to the In summary, the criteria for ade-
without anthracotic pigment-laden limitations that cannot be overcome.5 clinical need for the procedure and is quacy in many cytopathology speci-
macrophages.3 It is not unusual for The group emphasized that lymph non-diagnostic/inadequate. In con- men types is still evolving. However,
these specimens to be highly cellular node FNA should be interpreted by trast, an FNA can be hypocellular or the underlying theme continues to be
but composed almost exclusively of cytopathologists in a proper clinical acellular but still be adequate in certain focused on the question: Is the mate-
reactive bronchial cells. In the absence context and in correlation with the clinical contexts. For example, a cystic rial sufficient to help answer the clini-
of lymphoid cells or tumor cells, it is clinical indication, ultrasound exami- mass in the parotid gland or pancreas cal question? In cytopathology, this
question will continue to be related
Table 1. Adequacy criteria to specimen quantity and quality, as
Standardized system Specimen type Adequacy criteria well as correlation with the clinical
The Bethesda System for Cervical cytology Must be well-visualized/preserved squamous/metaplastic cells scenario. n
Reporting Cervical Cytology Conventional smear: minimum of 8,000–12,000 1. Sundling KE, Kurtycz DFI. Standardized
Liquid-based: ≥ 5,000 terminology systems in cytopathology. Diagn
Cytopathol. 2019;47(1):53–63.
Lab discretion if >2,000 cells in setting of chemotherapy, radiation, postmenopausal, hysterectomy
2. Brahimi M, Arabi A, Soltan BE, et al. How
>25% of cells must not be obscured by inflammation, bacteria, or interfering substances we assess adequacy of fine-needle aspiration
Any atypical or diagnostic cells materials intended for flow cytometric analysis.
Hematol Oncol Stem Cell Ther. 2011;4(1):37–40.
Anal cytology Must be well-visualized/preserved squamous/metaplastic cells without significant
3. Bansal RK, Choudhary NS, Patle SK, et al.
degenerative changes or obscuring bacteria or fecal matter
Diagnostic adequacy and safety of endoscopic
Conventional smears: ≈2,000–3,000 nucleated squamous cells (NSC) ultrasound-guided fine-needle aspiration in pa-
ThinPrep: ≈1–2 NSC/ hpf tients with lymphadenopathy in a large cohort.
SurePath: ≈3–6 NSC/hpf Endosc Int Open. 2018;6(4):E421–E424.
4. Monaco SE. Practical approach to cytological
Any atypical or diagnostic cells
evaluation and adequacy assessment in EBUS-
The Bethesda System for FNA of thyroid nodules ≥6 groups of well-visualized follicular cells with ≥10 per cluster TBNA. In: Monaco SE, Khalbuss WE, Pantanow-
Reporting Thyroid Cytopathology Abundant colloid itz L, eds. Endobronchial Ultrasound-Guided
Transbronchial Needle Aspiration (EBUS-TB-
Features of lymphocytic thyroiditis NA): A Practical Approach. Karger; 2014:39–52.
Any atypical or diagnostic cells 5. Al-Abbadi MA, Barroca H, Bode-Lesniewska
The Paris System for Reporting Voided urine >30 mL without non-urothelial features obscuring urothelial morphology B, et al. A proposal for the performance, classifi-
Urinary Cytology cation, and reporting of lymph node fine-needle
Any atypical or diagnostic cells
aspiration cytopathology: the Sydney System.
Instrumented urine Non-obscured, “cellular specimen”; however, there is insufficient data for specific criteria Acta Cytol. 2020;64(4):306–322.
Any atypical or diagnostic cells
The Milan System for Reporting FNA of a mass lesion in Well-prepared slides not limited by artifacts or obscuring of diagnostic material Dr. Manucha is clinical professor, Depart-
Salivary Gland Cytopathology a major salivary gland Must contain more than just normal salivary gland elements in the setting of a clinically ment of Pathology, University of Missis-
or radiologically defined mass sippi Medical Center. Dr. Ribeiro is resi-
Any atypical or diagnostic features (including mucin in a cystic lesion) dent physician, Department of Pathology,
The Papanicolaou System for FNA of pancreatic Unobscured by artifacts, hemorrhage, or necrosis and well preserved Johns Hopkins University School of Medi-
Reporting Pancreaticobiliary mass lesions Provides diagnostic or useful information about the solid or cystic lesion sampled (not just cine. Dr. Magers is staff pathologist, Trin-
Cytology GI contamination or benign pancreas), such as clean mucin in a cyst or any atypical or ity Health IHA Pathology and Laboratory
diagnostic features Management, Ypsilante, Mich. Dr. Allison
is assistant professor, Department of Pa-
The International System Peritoneal cavity fluid, Unobscured and not limited by artifact
for Reporting Serous Fluid pleural effusion thology and Laboratory Medicine, Uni-
>50–75 mL of fluid
Cytopathology versity of Kentucky College of Medicine.
Any atypical or diagnostic cells
Drs. Manucha, Magers, and Allison are
The International Academy of FNA of breast mass Unobscured and not limited by artifact members of the CAP Cytopathology Com-
Cytology Yokohama Standardized Seven tissue fragments each with 20 or more epithelial cells mittee. Dr. Ribeiro was a member through
Reporting System for Breast Cytology Any atypical or diagnostic features or necrosis 2022 and at the time of this writing.

JANUARY 2023 page 16

 JANUARY 2023 | CAP TODAY 17

Blood culture Whether it’s ethical to divert pa-

tient blood to validate the new sys-
alternative or can be done in parallel.
“Here you have a lot more control—
to 10 CFUs per bottle. (For detail on
dilutions and more, he suggests
continued from 1
tem is a question, he said. “We sure which organisms you’re going to Clinical Microbiology Procedures
Microbiol. 2021;59[3]:e02459-20). hope our new system is going to test, making sure they represent the Handbook, fifth edition.)
Dr. Ransom, who is also assistant work equally well or better, but in a common pathogens at an individual
professor of pathology at Case West-
ern Reserve University School of
Medicine, said the pandemic forced
situation where it may not, you’re
taking all that blood from the patient
and putting it in a new blood culture
facility and are pertinent to those
patient populations.” And “here you
can control that starting inoculum,
W hether performing the clinical
  side-by-side comparison or
the seeded study, Dr. Ransom ad-
some institutions to go to a four-day system” when it could have been which would be important when vises a close look at organism recov-
incubation, “so this ended up being used for the existing system. looking at times to positivity.” He ery to ensure the same organisms are
important information to get out A seeded blood culture study is an recommends a common range of five recovered at the —continued on 18
there in the literature.”
Workflow improvements were
immediately apparent in the labora-
tory’s switch from the VersaTrek
(Thermo Scientific)
to the Virtuo sys-
tem, which Dr. Ran-
som described as
composed of an A
unit and three look­
alike B units. The
BacT/Alert resin
Dr.Ransom
culture bottles used
with Virtuo are
more durable in transit, he said, than
the glass bottles used previously. The
blood culture set—one FA Plus (aero-
bic) bottle and one FN Plus (anaero-
bic) bottle—is loaded onto the con-
veyer belt on the A unit, after which
staff can walk away.
“You’re not opening the door, re-
leasing all of that nice, incubated
warm air at the perfect 35, 37 de-
grees,” Dr. Ransom said. Virtuo is “a
mostly closed system in which a very
small door opens, maintaining that
temperature.” Positive bottles drop
out with no need to open the door for
retrieval, he said, noting that an alarm
sounds to alert the staff because it’s a
stat test. Negative bottles drop from
the machine into a discard bin at the
bottom, again eliminating the need to
open the door.
Dr. Ransom recommends the Clin-
ical and Laboratory Standards Insti-
tute’s guideline “M47: Principles and
Procedures for Blood Cultures,” sec-
ond edition, published in 2022. Its
authors advise, when implementing
a new blood culture system, testing
the new and existing systems in par-
allel (by collecting two culture sets
with equal blood volumes) and com-
paring them head to head. They rec-
ommend obtaining at least 20 posi-
tives, “ideally real-world pathogens”
and not contaminants, Dr. Ransom
said. “And 95 percent of these results
should agree with the current system
to be considered equivalent.” The low
positivity rate of blood cultures—five
to 12 percent at most institutions—
makes this good approach difficult,
he said. “So you’re going to have to
test a lot more blood cultures to get
those 20.” A high contamination rate
adds to the difficulty.

JANUARY 2023 page 17

 18 CAP TODAY | JANUARY 2023

Blood culture mean it fails, but it may warrant ad-

ditional investigation or review,” he
continued from 17
said.
same rate on both systems. “Com- n Account for all parts of the blood
pare your time to positivity,” he said. culture workflow, including bottle
“Hopefully it’s equal to if not bet- processing, which may require work-
ter than your current system.” And force retraining. “A lot of these bottles
evaluate all media. have unique adapters to get that
He advises the following also: blood out for subsequent testing, like
n Establish the acceptance criteria Gram stains,” he said. Since some
early on to avoid the temptation of Gram stain differences may be slight,
later adjustments to ensure passing “you may need to adjust your times
results. “Just because something for different steps in new Gram stains
doesn’t reach that threshold doesn’t to make sure you’re getting equiva-
lent results if you’re using a new
blood culture media.”
n Account for different thresholds
of detecting organisms on blood cul-
ture systems as rapid diagnostic
methods or direct aspartate amino-
transferase testing on positive blood
culture broth become more popular,
to avoid “a negative result down-
stream,” Dr. Ransom said. And keep
in mind that sterile body fluids or
platelets or other non-blood speci-
mens may be in blood culture bottles
and need to be evaluated also.
At Barnes-Jewish Hospital, a com-
bination of clinical and seeded study
methods was used to validate the
Virtuo. The seeded study used aero-
bic, anaerobic, and fastidious organ-
isms and yeast, and each was tested
in triplicate for each bottle type. “We
really kicked the tires on this valida-
tion, largely because at the time Vir-
tuo was very new to the market,
there wasn’t a lot of published litera-
ture on it. We wanted to make sure it
was robust and held to our stan-
dard,” Dr. Ransom said. They looked
at delayed entry onto the machine,
compared instrument bank one to
instrument bank two, assessed sterile
body fluids and platelet products,
and used the Verigene Gram-positive

Learn. Explore. Repeat. assay for the new blood culture me-
dia assessment.
“Overall, it was very comparable,
very equivalent,” Dr. Ransom said.
“As far as organism recovery, we
were able to recover the organisms,
regardless of the system.” The study
authors saw a difference in time to
positivity among organisms. “Thank-
fully, that was in our favor. The new
system ended up having a shorter
time to positivity, allowing us to get
those results out quicker to our pro-
viders.” In the subset of organisms
tested, the most significant time dif-
ference was found in Staphylococcus
aureus, which had a mean time to
positivity of 10.6 hours on Virtuo
versus 12.4 hours on VersaTrek.
“Unfortunately, not all organisms
saw improved growth rates,” he
said. Clostridium septicum, for ex-
ample, had an average time to posi-
tivity of 22.1 hours on Virtuo versus
an average TTP of 12.8 hours on
VersaTrek. For Candida albicans, it
was 26.8 hours on Virtuo and 23.6 on
VersaTrek. And for Cryptococcus
neoformans, 67.8 (Virtuo) and 64.2
(VersaTrek).
The validation went well, and roll-
out was expected. “But then we
started doing more assessments,” Dr.
Ransom said, one of which was of the
delay in transport times from hospi-
tals at a distance from the centralized
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directly on the machine, most bacte-
ria did not show a significant differ-
ence, he said. Streptococcus pneu-
moniae showed an average difference
Get the details at cap.org and of -0.9 hours in TTP in the FA Plus
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0016700_PathIslands_CT_Std-A_Ad_Final_R1.indd 1 7/25/22 9:26 AM

JANUARY 2023 page 18

 JANUARY 2023 | CAP TODAY 19

of eight hours. E. coli was actually
“faster” with delayed entry. “But
that’s merely showing the microbe
itself being able to replicate fairly
quickly at room temperature, so it
had a head start.”
Neisseria gonorrhoeae had a “bit of
a delay” in TTP (average difference
of 7.1 hours in aerobic bottles). Bacte-
roides fragilis “only grew anaerobi-
cally and it was very comparable
across,” Dr. Ransom said. “This was
great, reassuring us that we could
maintain being a centralized labora-
from technologists during rounds. At
least once a week, he would hear that
a culture went positive on day four.
“It’s going to be mixed. Why are we
working up these cultures?” they
would ask. He would reassure them
the cultures were worth doing, and
they would say that once they relayed
the result to the provider, the provider
would say, “The patient’s already
been discharged. This person’s fine.”
Hearing that time and time again, Dr.
Ransom thought “Maybe they’re onto
something.”
As incubation time increases, he
noted, so does the chance of detecting
all true bloodstream infections. “Un-
fortunately, this is not perfect,” he
said, because a longer incubation also
increases the chances of contamina-
tion growth. “It’s a fine balance in
figuring out where you want to have
this cutoff.”
A seven-day incubation time was
more common in the ‘90s and 2000s,
he said, noting the transition to five
days was largely owing to better in-
strumentation and media. Was it time
to look at reducing the incubation in-
terval again with the Virtuo, which
held temperature at a more constant
rate and had improved media?
In their study, —continued on 20

SAFE SOLUTIONS
tory, having those specimens coming
in even if they wouldn’t get on the
machine for eight hours.”

A study of the impact of the Vir-

tuo system implementation at
Barnes-Jewish Hospital was pub- Even with minimal tube volumes,
lished in 2021 (Chavez MA, et al. J
Clin Microbiol. 2021;59[10]:e0061721). the potential for injury from manual

DECAPPING
The authors retrospectively reviewed decapping or manual
all blood cultures performed in 2018
(VersaTrek) and in 2019 (Virtuo) recapping is a
and compared positivity and con-
tamination rates. The positivity rate real possibility You have
increased from 8.1 percent before
Virtuo was implemented to 11.7 per-
known about
cent post-implementation. In its in- our Pluggo™
vestigation, the laboratory found a
spike post-implementation in what decappers
it considered to be contaminants, Dr.
Ransom said. Its first step was to Now
reeducate to ensure the new bottles available;
were collected properly.
Driving much of the increase, the KapSafe™
data showed, was a higher positivity
rate of the staphylococci. S. aureus Recappers
positivity, in particular, increased
from 1.5 percent of blood cultures pre-
in several
implementation to 3.4 percent of models
blood cultures post-implementation.
“It turns out that a big contributor to to fit any
this was that we were detecting bac-
RE volume needs
C AP
teria in the bloodstream longer than

PI N G
we were with our older system,” Dr.
Ransom said. The improved beads in
the new BacT/Alert bottles were
“probably inhibiting those antimicro-
bials a little better.”

Make your goal ZERO

Pre-implementation, a blood cul-
ture would be sent, and if it tested
positive, the patient would be treated.
“You may detect it that first time,
maybe a day later,” he said. Blood
cultures were drawn maybe two days
later. “But we were seeing a shift, and
repetitive stress injuries
overall we were detecting it on day
three and day four,” he said, which
worried providers initially. “A lot of
From the leader in bench-top solutions
education had to happen,” Dr. Ran- for automated decapping and recapping
som said. But there was no real impact
on patient health.
The microbiology team investi-
gated also whether a five-day incuba- Visit our website for additional information www.lgpconsulting.com
tion was still appropriate using the
Laboratory Growth Accommodates all major tube sizes
Virtuo system, an investigation
& Productivity 1.877.251.9246 and a variety of analyzer racks
prompted by what Dr. Ransom heard

Serving laboratories since 2002 | Contact us for literature and sales information
20 CAP TODAY | JANUARY 2023
Fig. 1. An overall algorithm
addressing the diagnosis of VWD
VWF levels refer to VWF antigen (VWF:Ag) and/or platelet-dependent VWF activity. The algorithm says VWF level 30 to 50 for simplicity; this refers to VWF levels of 0.30
to 0.50 IU/ml, with the caveat that the lower limit of the normal range as determined by the local laboratory should be used if it is <0.50 IU/ml. *Men and children,
referred to a hematologist and/or first-degree relative affected with VWD. BS, bleeding score; CBC, complete blood count; DDAVP, desmopressin; FVIII, factor FVIII; FVlll:C,
FVIII coagulant activity; PT, prothrombin time; PTT, partial thromboplastin time; r/o, rule out; TT, thrombin time; VWF:CB/Ag, ratio of VWF collagen binding to antigen;
VWF:FVIIIB, VWF FVIII binding.
Reprinted from Blood Advances, vol 5(1), James P, Connell N, Ameer B, et al. ASH ISTH NHF WFH 2021 guidelines on the diagnosis of von Willebrand disease, pages 280–300, Copyright 2021,
with permission from Elsevier.
Blood culture
continued from 19
Dr. Ransom and colleagues looked at
all blood cultures that came through
the central microbiology laboratory
(from fall 2018 to fall 2019) from the
five hospitals. They examined the
outcomes of all positive bottles and
time to positivity, defining TTP as the
time from when the bottles were
loaded onto the instrument to when
they came off and signaled positive.
Medical charts were reviewed for
patients with a bottle with TTP greater
than four days.
In studying the TTP of 13,592 posi-
tive bottles during the study period,
Dr. Ransom and colleagues found
76.74 percent of all positives (10,431
bottles) were detected within the first
24 hours. After day two, the positivity
rate was 93.56 percent; after day three,
97.07 percent, and after day four, 98.71
percent, “leaving just 175 bottles in
those final 24 hours,” he said.
They compared adult TTP data
(12,769 bottles) with pediatric data
(823 bottles) and the two data sets
“matched almost perfectly,” he said.
VWF activity assays develop
platelet
continued from 1
says ha
with the original ristocetin cofactor coeffici
assays are needed, said co-presenter ing to lo
Neil Harris, MD, clinical professor of tory rep
pathology, immunology, and labora- tin cofa
* tory medicine at the University of standar
Florida. Drs. Rollins-Raval and Harris first as
are members of the CAP Hemostasis mated
and Thrombosis Committee. ers, he s
When assessing a patient with a use a co
bleeding tendency for von Wille- contain
brand disease (VWD), Dr. Harris lets and
said, start with a CBC, “because it correct
could be a thrombocytopenia.” Pro-
thrombin time and partial prothrom-
bin time should be measured because
PT is not prolonged in VWD. “You’ll
want to look at fibrinogen and pos-
sibly the thrombin time as well,” he
said. If results of all are normal or
there’s an isolated prolonged PTT,
“you want to do the initial VWF Dr.Harr
screening assays,” which include
VWF antigen, VWF activity, and fac- better p
tor VIII activity. If one or more of try assa
these tests are abnormal, the patient not sub
should be referred for selected spe- The
cialized VWD studies, including von sis of V
Willebrand multimeric analysis ican So
(James PD, et al. Blood Adv. 2021;5[1]: tional
280–300; Nichols WL, et al. Haemo- Haemo
philia. 2008;14[2]:​171–232). Founda
The first VWF activity assay was Hemop
the ristocetin cofactor assay. “The the VW
original tests were done by optical VWF a
aggregometry and were really lab- (James
5[1]:280
levels
“If anything, it [TTP] was slightly A medical chart review of those 175 24 hours back or longer,” he said. VWD c
faster” in pediatric blood cultures: bottles (0.1 percent of all bottles and Since 90 percent of blood cultures said. “
76.55 percent positive in the first 24 1.3 percent of positive bottles) revealed are negative, the vast majority of the you’ve
hours, 95.75 percent positive at end 160 had no impact at all, with 38 noted bottles received in the laboratory are disease
of day two, 98.42 percent positive at in the record as contaminated—not a going to become final as negative one ity-to-a
day three, and 99.39 percent posi- surprising number, he said, given the day earlier, Dr. Ransom said. “That’s a platel
tive at day four, leaving only five cultures were from four days prior. earlier discharges for patients,” and which u
bottles becoming positive in the fi- The other 15 bottles had impact, but earlier deescalation of treatment—a cofacto
nal 24 hours. in some cases the impact was nega- plus for the patient, physician, and Willebr
S. aureus (3,893 bottles) and S. epi- tive—additional cultures or further laboratory. Another benefit: The re- gorithm
dermidis (1,248) grew quickly, and E. workup later deemed unnecessary or covery rate of the contaminant Cuti- simplic
coli (1,382) “was one of our most im- a delay in discharge, for example. “We bacterium spp. declined from 0.87 of 0.30 t
pressive organisms,” with 94.3 percent also had examples in which the pa- percent to 0.23 percent. If the contami- that th
found to be positive in the first 24 tient had already been discharged, nation rate or positivity rate is in- range
hours, the vast majority positive and the provider, then hearing there’s creased, “you also increase chances of laborat
within 16 hours, and 50 percent posi- a positive, had that patient go to the a central-line associated bloodstream than 0.
tive in 10 hours, he said. S. pneu- ED or to their primary care physician,” infection,” and many eyes in an insti- Per
moniae (192) grew exceptionally well: he said. By the most conservative es- tution are on that number, he said, more th
98.4 percent at day one, 100 percent at timate, fewer than 10 bottles were because such infections can affect re- mon ty
day two. Pseudomonas aeruginosa clinically actionable. imbursement. “This is something the quantit
(298) took a little longer than some of The study findings resulted in their hospital looks at very closely and you tio of le
the other organisms, “but still at the implementing a four-day incubation want to be sure you’re investigating with ty
end of day three, 98 percent; by the protocol. “Initially there was a lot of thoroughly.” n passes
end of day four, 99.3 percent.” hesitancy,” but once the data were and w
With so few positives in the final 24 made known, physicians asked, “How Amy Carpenter Aquino is CAP TODAY may be
hours, they asked, do they need them? quickly can we make this happen?” senior editor. Carey-Ann Burnham, PhD, may be
If those bottles are driving treatment Dr. Ransom said. They were given the D(ABMM), Melanie Yarbrough, PhD, lost som
and saving lives, he said, “we want to opportunity to request a five-day in- D(ABMM), D(ABCC), and the labora- These
maintain them or potentially extend cubation period. “Nobody calls the tory staff at Barnes-Jewish Hospital were monly,
our incubation time.” laboratory asking for that additional central to the studies reported. Thos
JANUARY 2023 page 20
 JANUARY 2023 | CAP TODAY 21

s developed tests using fixed reagent

platelets,” Dr. Harris said. These as-
VWF activity (0.30–.50 IU/mL) are
classified as “low VWF” if they have
need of additional testing, the 2021
guidelines suggest using either
cetin cofactor will give a low reading
even though there are no clinical con-
says had poor precision and a high no bleeding, he said. “But if they have VWF:factor VIII binding studies or sequences,” he said. “It’s an in vitro
ofactor coefficient of variation, he said, lead- bleeding they would be put in the targeted genetic testing for type 2N effect, not an in vivo effect, and can
esenter ing to low intraassay and interlabora- von Willebrand disease category.” variants. lead to the overdiagnosis of von Wil-
essor of tory reproducibility. “But the ristoce- Type 2N, Dr. Harris said, is the One of the problems with the ris- lebrand disease.” The polymorphism
labora- tin cofactor assay became the gold functional variant in which “von Wil- tocetin cofactor assay, Dr. Harris said, (present in the A1 domain) is found
rsity of standard simply because it was the lebrand factor does everything in its is the D1472H polymorphism, a com- in 63 percent of Blacks and 17 percent
d Harris first assay.” It has since been auto- normal capacity, except it lacks the mon VWF ristocetin-binding poly- of the white population.
mostasis mated on some coagulation analyz- ability to bind to factor VIII.” For morphism that reduces the apparent The guidelines suggest glycopro-
ers, he said, and those assays typically patients with suspected type 2N
CAP_Jan_Ad_Final_3.pdf 1 in activity.
12/22/22 10:23 When
AM it’s present, “the risto- tein (GP) 1bM or —continued on 22
with a use a commercially available reagent
Wille- containing lyophilized donor plate-
Harris lets and ristocetin. “If you have the
ause it correct coagulation analyzer, you can
a.” Pro- do it with a turbidi-
throm- metric analysis and
because you can measure
“You’ll the platelet aggluti-
nd pos-
ell,” he
nation and com-
pare it with calibra- Hematopathology is Complex.
mal or tors and controls,”

Your LIS Shouldn’t Be.

d PTT, he said. The auto-
l VWF Dr.Harris
mated assay, which
nclude is FDA cleared, has
nd fac- better precision than the aggregome-
more of try assay, but the limit of detection is
patient
ed spe-
ng von
not substantially improved.
The overall algorithm for diagno-
sis of VWD laid out in the 2021 Amer-
Your LIS Shouldn’t
Reduce turnaround times and workflow complexities with an easy to use
laboratory information system, NovoPath 360. Effortlessly manage cases, receive
real-time result notifications, automatically compile in-house and send out
nalysis
21;5[1]:
Haemo-
ican Society of Hematology, Interna-
tional Society on Thrombosis and
Haemostasis, National Hemophilia
Be.
results into one comprehensive report among many other capabilities.

Foundation, and World Federation of

ay was Hemophilia guidelines begins with
y. “The the VWF antigen, platelet-dependent
FISH
optical VWF activity, and factor VIII activity C

lly lab- (James PD, et al. Blood Adv. 2021;

Flow Cytometry 
5[1]:280–300) (Fig. 1, page 20). If VWF
M

levels are greater than 50 IU/dL,

Y

Morphology
aid. VWD can be ruled out, Dr. Harris CM

ultures said. “If it’s less than 30 percent,

Molecular
MY

y of the you’ve diagnosed von Willebrand CY

ory are disease, but the next step is the activ- CMY
Immunohistochemistry  
ive one ity-to-antigen ratio. We typically do K

“That’s a platelet-dependent VWF activity—

NGS
s,” and which up until now was the ristocetin
ment—a cofactor activity—divided by the von
an, and Willebrand factor antigen.” (The al-
The re- gorithm says VWF level 30 to 50 for
nt Cuti- simplicity; this refers to VWF levels
m 0.87 of 0.30 to 0.50 IU/mL, with the caveat
ontami- that the lower limit of the normal
e is in- range as determined by the local
ances of laboratory should be used if it is less
dstream than 0.50 IU/mL.)
an insti- Per this new algorithm, a ratio of
he said, more than 0.7 classifies the more com-
ffect re- mon type 1 VWD, caused by a partial NovoPath is redefining laboratory information systems. We are the
ing the quantitative deficiency of VWF. A ra- first SaaS-LIS to automate, track, simplify and complete
nd you tio of less than 0.7 classifies the patient complex cases from hematopathology to dermatopathology
igating with type 2 disease, which encom- faster than ever before. We are raising the bar with one-of-a-kind
n passes the qualitative VWF defects capabilities helping labs accession, diagnose and generate
and where “von Willebrand factor comprehensive reports.
TODAY may be present in normal amounts, it
m, PhD, may be reduced in some cases, but it’s See how the labs of tomorrow are operating with NovoPath 360 at
h, PhD, lost some function,” Dr. Harris said. www.NovoPath.com
labora- These are subclassified, most com-
tal were monly, as types 2A, 2B, 2M, and 2N.
Those with intermediate levels of

20 JANUARY 2023 page 21

22 CAP TODAY | JANUARY 2023
VWF activity assays
continued from 21
GP1bR, newer automated assays that
measure platelet-binding activity of
VWF, over the automated or nonau-
tomated ristocetin cofactor assay.
“They call it a suggestion rather than
a recommendation because the evi-
dence wasn’t very certain,” Dr. Har-
ris said. At the time the guidelines
were published neither of these as-
says was FDA cleared, but one
GP1bM assay received de novo FDA
approval in 2022.
The GP1bR assay works as fol-
lows: In the presence of ristocetin,
Table 1. Comparison of VWF activity assays for diagnosis of congenital VWD
Assay VWF:RCo
(aggregometry)
VWF ratio typing^
Sensitivity (%) 94
ratio 0.6
Specificity (%) 88
CV ~30%*
Reported LLOQ 10–20 IU/dL
FDA cleared^^ No; gold standard
Weaknesses Poor precision;
D1472H polymorphism; polymorphism;
Overestimation in 1/3 of LLOQ still high
type 2B (dx as type 1)
VWF ratio: VWF:Act/VWF; CV: coefficient of variation; LLOQ: lower limit of quantitation; ^Different ratio cutoffs (0.6, 0.7, 0.8) make it difficult to compare
accuracy of the different assays; *Decreased precision at lower levels of measurement; ^^All of the automated assays are CE marked; **Different
ristocetin concentration and recombinant GP1b
Higgins RA, et al. Am J Hematol. 2019;94(4):496–503; Boender J, et al. J Thromb
Haemost. 2018;16(12):2413–2424; Vangenechten I, et al. J Thromb Haemost.
2018;16(7):1268–1277; Sagheer S, et al. Haemophilia. 2016;22(3):e200–e207; Chen
D, et al. J Thromb Haemost. 2011;​9(10):1993–2002
patient VWF binds recombinant
wild-type GP1b attached by mono-
clonal antibodies to GP1b onto latex
or magnetic beads. “If you add risto-
cetin and patient von Willebrand
factor, the beads will agglutinate, and
this can be monitored by an immu-
noturbidimetric or chemiluminescent
assay.” The assay is not FDA cleared,
though some laboratories have devel-
oped their own versions of both the
GP1bR and GP1bM assays, he said.
“The GP1bM is a variation on the
same idea,” Dr. Harris said. “You have
a latex bead that’s coated with GP1b
by virtue of a bridging antibody, ex-
cept that the GP1b is a gain-of-func-
tion mutant which binds spontane-
ously to von Willebrand factor, to the
A1 domain. So it’s exactly the same as
the previous assay, except it doesn’t
require ristocetin.” (The “R” in GP1bR
stands for ristocetin, he noted, and the
“M” in GP1bM stands for mutant.)
The VWF antibody assay is FDA
cleared and gaining in popularity, Dr.
Harris said. “When somebody first
described this assay to me I said,
‘This can’t possibly work.’ But it does
work,” he said. Without ristocetin,
latex beads coated with monoclonal
antibodies against the VWF A1 do-
main agglutinate with the addition of
patient VWF. “I thought it wouldn’t
work because I thought it would only
pick up mutations in the A1 domain.
But it was explained to me—and this
was borne out by evidence—it also
picks up defects in multimerization.”
The antibody assay, which is avail-
able on some automated platforms,
“is a great screen to discriminate
patients with and without von Will-
ebrand disease.”
With the antibody assay, addi-
tional VWF activity tests are likely to
be needed for subclassification. “You
VWF:RCo VWF:GP1bR
(automated)
92 84
0.7 0.7
72 90
5–10%* 5–8%*
At least 10 IU/dL <5 IU/dL
Yes No
D1472H Not FDA cleared;
Not affected
by D1472H
polymorphism**
Boender, et al., compared all four assays, as well VWF:CB assay, finding all
had a high correlation overall but with individual patients showing consider-
able differences.
certainly need the multimers and you
may need collagen binding as well,”
he said. The VWF antibody assay has
similar sensitivity and specificity to
the ristocetin cofactor assay, though it
has comparatively increased precision
and a decreased coefficient of varia-
tion at lower levels. It typically uses a
VWF:Ab/VWF:Ag ratio of less than
0.7 to discriminate types 1 and 2,
“though people have used higher
ratios,” he said. “In our lab we run this
assay. If the activity comes out low or
less than 55 percent, we will reflex to
the ristocetin cofactor assay.”
The collagen-binding activity as-
say, rather than measuring binding
to platelets, measures binding to col-
lagen. Magnetic particles are coated
with a type III collagen triple-helical
peptide. “You mix that in with pa-
tient plasma and the von Willebrand
factor then binds onto the collagen,
and that binding is detected by a la-
beled antibody to von Willebrand
factor,” Dr. Harris said. The assay,
which is not FDA cleared, is an auto-
mated chemiluminescent assay. Lab-
oratory-developed ELISA-based as-
says also are available.
“Interestingly, the question has
come up: Should we be doing colla-
gen binding as well?” Dr. Harris
asked. In type 2 von Willebrand dis-
ease, he said, collagen binding is de-
creased. And there may be two vari-
eties of subtype 2M, he said: the col-
lagen-binding variant and the GP1b
variant. In the latter, VWF doesn’t
bind to glycoprotein 1b, “which is
what we usually think about with
type 2M.” In this subtype the platelet
binding activity-to-antigen ratio is
decreased, but the collagen-binding-
to-antigen ratio is normal. In the
collagen-binding variant, this is re-
versed (Favarolo EJ, et al. Haemo-
VWF:GP1bM VWF:Ab
92 100
0.7 0.8
85 92
~1%* 1–5%*
<5 IU/dL 19 IU/dL (≤3 IU/dL)
Yes Yes
High LLOQ without making
assay an LDT; may
overestimate VWF in type
2 (dx as type 1), but best
classification of type 2B
philia. 2021;27[1]:137–148; Favarolo
EJ, et al. Blood Adv. 2022;6[2]:416–
419). Other studies have identified
subtypes of the disease in which both
platelet binding and collagen binding
are decreased, he noted.
“So more studies are needed,” Dr.
Harris said. “There’s a risk of bias in
all studies due to case-control design.”
In addition, the assays have been used
to classify patients, as opposed to
making a new diagnosis of VWD.
And more FDA approvals are needed.
A fter the 2021 guidelines were
   published, the clinicians with
whom Dr. Rollins-Raval works began
to ask what they had never asked
before: What VWF activity assay
does the laboratory use? “So trying
to justify the assay that we had and
making sure it was a good assay for
our patient population—that’s where
I started down this rabbit hole.”
Dr. Rollins-Raval created a side-
by-side comparison of five of the von
Willebrand factor activity assays (ex-
cluding the collagen-binding assay)
(Table 1). “The first thing I noticed
was that we aren’t using the same
JANUARY 2023 page 22
ratios when we’re evaluating this,”
she said. The sensitivity and specific-
Brea
continue
ity of the five assays are relatively
similar, though the von Willebrand therapy
antibody activity appears superior in table m
that category, “at least based on the
study I reviewed and using that
higher ratio [0.8].” As expected, she
said, the manual ristocetin cofactor
T he u
  in r
The
assay (aggregometry) has the highest WF, et
coefficient of variation. “Automation this is n
has really helped with the precision associa
of these assays, and that’s across the directo
board,” she noted. With the ag- more a
gregometry assay the lower limit of juvant
quantitation, too, was a challenge, With
“and the automated ristocetin did apy (m
improve that some” but not as much standa
as the other three assays have positiv
(GP1bR, GP1bM, Ab). be dram
The manufacturer’s insert for the vant ch
VWF Ab assay gives a lower limit of vival at
quantitation of 19 IU/dL, “which is a profess
limitation,” Dr. Rollins-Raval said. pathol
“And if you lower that limit of quan- “which
titation, it does make it a laboratory- Eval
developed test.” The assay also may physici
overestimate VWF in type 2, “so we tumor
might have slightly higher activity cases, t
levels, which would then misdiag- neoadj
nose patients with type 1. But surpris- profess
ingly, among these assays it appears thology
to have the best classification of type Dees
2B” (increased VWF affinity for GP1b the pC
with increased platelet clearance). sponse
Though the major weakness with may no
the ristocetin cofactor assays is their and ins
relatively poor precision, “there’s also
the issue with both the automated
and the aggregometry assays of over-
detection or overdiagnosis” due to
VWF
continue
the D1472H polymorphism, she said.
In addition, “with the aggregometry out wh
assay it does seem there’s an overes- A su
timation of the activity level in some how re
studies of patients who have type 2B. tivity te
So they would be mistakenly diag- GP1bR
nosed as type 1 rather than type 2B, cofacto
which could be an issue, especially ity of r
with therapy.” manuf
In some studies, the GP1bR assay broad
has not been affected by the D1472H were d
polymorphism. “And that was ex- value f
plained by the authors—they’re us- guideli
ing a different ristocetin concentra-
tion in that assay, and they’re also
using, instead of a native GP1b or a
in-hous
Thromb
“And e
platelet GP1b, a recombinant GP1b. no disc
So that may explain why it’s not as activit
affected by the polymorphism.” fined,”
Boender, et al., in 2018 compared The
the four assays and the VWF colla- activity
gen-binding assay and found good sugges
overall correlation (Boender J, et al. J ate typ
Thromb Haemost. 2018;16[12]:​2413– diseas
2424). “But then if you look at indi- Though
vidual patients there was consider- 0.6, “ev
able difference,” she said. “So you don’t v
might need to look at your patient dealing
population to figure —continued on 23 And so
 JANUARY 2023 | CAP TODAY 23

g this,”
pecific-
Breast cancer specimens avoid axillary dissection. “That’s why we, the I-SPY
Pathology Working Group, started analyzing core
(The CAP Cancer and Pathology Electronic Re-
porting committees are evaluating emerging stan-
continued from 1
atively biopsies taken at 12 weeks into therapy to see if it dards in pathology reporting for breast cancer
ebrand therapy breast resections is direct, like a farm-to- can predict response and help determine the type following neoadjuvant therapy. Liaisons are in-
erior in table meal. of surgery or even avoid surgery altogether,” says volved in the AJCC Breast Working Group to en-
on the Dr. Sahoo, who is also director of breast pathology sure alignment with AJCC recommendations for
ng that
ed, she
ofactor
T he urgency around the matter has only grown
  in recent years.
The seminal paper came out in 2007 (Symmans
services at Clements University and Parkland Me-
morial hospitals, Dallas.
Moreover, if a patient has a pCR, “they know the
the standards.)
These specimens can be taxing. Pathologists’
experience so far has been mostly derived from
highest WF, et al. J Clin Oncol. 2007;25[28]:4414–4422). “So treatment worked,” says Dr. Sahoo, a welcome standards developed for cases seen in clinical tri-
mation this is not new,” says Uma Krishnamurti, MD, PhD, relief from the uneasy, sometimes years-long wait als, says Dr. Krishnamurti. This includes recom-
ecision associate professor, Yale School of Medicine, and to see if a treatment was effective. mendations from the Breast International Group–
oss the director, breast pathology service. “It’s just that None of these successes would have been pos- North American Breast Cancer Group collabora-
he ag- more and more centers have started giving neoad- sible without studying pathologic response assess- tion (Bossuyt V, et al. Ann Oncol. 2015;26[7]:
limit of juvant therapy.” ments. “It’s unusual that pathology is so central to 1280–1291).
llenge, With good reason. Neoadjuvant systemic ther- an advance for treatment,” says Dr. Bossuyt. With Among other things, the BIG-NABCG recom-
tin did apy (most typically chemotherapy) has become the so many patients now navigating neoadjuvant mendations addressed the various systems for
s much standard of care for triple-negative and HER2- therapy, she says, the number of pathologists see- identifying response to neoadjuvant therapy. “In-
s have positive early-stage breast cancers. The impact can ing these cases has also risen. “It’s not just the big stead of being subjective and saying ‘good,’ ‘excel-
be dramatic. Patients who have a pCR to neoadju- centers anymore,” she says. lent,’ or ‘poor,’ how do you have a more objective
for the vant chemotherapy have around a 90 percent sur- method of assessment?” says Dr. Krishnamurti.
limit of
hich is a
al said.
vival at 10 years, says Veerle Bossuyt, MD, assistant
professor, Harvard Medical School, and associate
pathologist, Massachusetts General Hospital,
A s Dr. Esserman’s own stark experience shows,
   however, the need for a standardized pathol-
ogy approach is paramount.
Though there are several options, “The MD Ander-
son residual cancer burden is an important way of
assessing response,” in large part because it uses
f quan- “which is incredible for these aggressive tumors.” Dr. Sahoo first published on these challenges and residual tumor size and residual tumor cellularity
ratory- Evaluating pathologic response also enables inconsistencies in 2009 (Sahoo S, et al. Arch Pathol in the breast as well as responses in the lymph
so may physicians to turn quickly to another regimen if a Lab Med. 2009;133[4]:633–642). Given the passage nodes.
“so we tumor is responding poorly to treatment. In some of years, “You’d think this is a dead topic,” she says. The online RCB calculator (https://bit.ly/RCB-calc)
activity cases, tumors will even continue to grow during Clearly, it isn’t. provides both score and class and “is an excellent
isdiag- neoadjuvant treatment, says Sunati Sahoo, MD, She revisited this topic with a recent paper (Sa- method” for predicting event-free five- and 10-year
surpris- professor of pathology and director of surgical pa- hoo S, et al. Arch Pathol Lab Med. Published online survival, Dr. Krishnamurti says. RCB-0 indicates a
ppears thology, UT Southwestern Medical Center, Dallas. Aug. 17, 2022. doi:10.5858/arpa.2022-0021-EP), in complete pathologic response; RCB-I is minimal
of type Deescalating treatment is another reason behind which the I-SPY Pathology Working Group offered residual disease; RCB-II, moderate residual disease;
or GP1b the pCR push. A person who has a complete re- its recommendations for handling these specimens. and RCB-III, extensive residual disease. “Within
nce). sponse to therapy in the breast and lymph nodes One hope, she says, is that the group’s work will each of these groups, as well as across groups, and
ss with may no longer need a mastectomy, for example, help pathologists as they await updated guidance for each receptor subtype, the RCB is a continuous
is their and instead choose breast-conserving surgery and from groups such as the CAP and the AJCC. parameter for prognosis,” —continued on 24
e’s also
omated
of over-
due to
VWF activity assays assay from one vendor and an anti-
gen assay from another, or a lab-de-
did work pretty well.” The VWF Ab
activity-to-antigen ratio range was
cent in 2015, 8 to 34.8 percent in 2020).
“It’s still not where we would like it,
continued from 22
he said. veloped test for one and a commer- 0.7–1.0, and the factor VIII range was but, for coagulation, it is improving.”
ometry out which assay to choose.” cial test for the other, “so it’s helpful 0.7–1.3. “So we’re using 0.7 for both.” The survey also found that the auto-
overes- A survey of laboratories that asked to validate this ratio in your own lab Testing a known bundle of VWD also mated ristocetin cofactor assay is now
n some how reference intervals for VWF ac- with the reagents you’re using.” would be helpful to verify that the 0.7 more common than the aggregome-
ype 2B. tivity testing were established for the Dr. Rollins-Raval’s laboratory per- cutoff works for distinguishing type try assay, and the most commonly
y diag- GP1bR, GP1bM, Ab, and ristocetin formed a study to verify that the 1 disease from type 2, she noted. used GP1b assay is the VWF Ab assay
ype 2B, cofactor assays found that the major- VWF activity-to- (83 percent of participants).
pecially

R assay
ity of respondents did not use the
manufacturer’s value. There was
broad variability in how intervals
D1472H were defined, with some taking a
was ex- value from the literature, some from
y’re us- guidelines, and others determined
centra- in-house (Hollestelle MJ, et al. Semin
re also Thromb Hemost. 2022;48[6]:739–749).
1b or a “And even in this survey there was
GP1b. no discussion about how the VWF
not as activity-to-antigen ratio was de-
m.” fined,” she said.
mpared The current guidelines for VWF
F colla- activity-to-antigen ratio verification
d good suggest 0.7 as the cutoff to differenti-
, et al. J ate type 1 and type 2 von Willebrand
]:​2413– disease, Dr. Rollins-Raval said.
at indi- Though some still suggest a cutoff of
nsider- 0.6, “even the FDA-cleared assays
So you don’t validate this, because you’re
patient dealing with two different assays.”
ed on 23 And some labs may use an activity
antigen and factor
VIII-to-VWF activ-
ity ratios, using cur-
rent reagents and
the local popula-
tion, were the same
as the published
Dr.Rollins-Raval
guideline ratio cut-
offs of 0.7. “We did
limit it to 20 male and 20 female do-
nors for measuring the VWF activity
and the antigen and factor VIII activ-
ity,” she said. “And then we calcu-
lated the ratios for these and found
the average and standard deviation
for each ratio,” with the lower limit
of each ratio range two standard de-
viations from the mean.
“Our acceptance criteria were that
it must agree within 15 percent of that
published cutoff for our lower limit
ratio,” she continued. “Fortunately, it
I n the September 2022 issue of
  Seminars in Thrombosis and He-
mostasis are several articles on exter-
nal quality assessment worldwide
for VWF testing. One finding from
a summary of the CAP’s proficiency
testing, which looked at samples sent
out for VWF antigen and activity
testing between 2015 and 2020, is that
the type of activity is changing over
time (Salazar E, et al. Semin Thromb
Hemost. 2022;48[6]:690–699).
“While in 2015 a lot of laboratories
were doing the ristocetin cofactor as-
say [50 percent], that’s starting to
decrease by 2020 [44 percent], and the
VWF GP1b activity assays are starting
to increase [28 percent and 45 percent,
respectively],” Dr. Rollins-Raval said.
“Interestingly, the coefficient of varia-
tion range is also starting to improve
a little bit,” she said (14.6 to 44.8 per-
More than 95 percent of partici-
pants who use the ristocetin cofactor
assay and more than 89 percent of
participants using the GP1b activity
assays gave the correct qualitative
interpretation (normal, type 1, or
type 2), Dr. Rollins-Raval said. The
GP1b activity means were consis-
tently higher than the ristocetin co-
factor means. “We’re not yet entirely
sure what that means—this is a rela-
tively limited study and some of
these samples were manufactured,
not patient samples,” she said. “But
if you have a higher activity assay
to antigen, you could be missing
some of your type 2s. So that is
something that we need to keep in
mind in the laboratory.” n
Charna Albert is CAP TODAY associate
contributing editor.

22 JANUARY 2023 page 23

24 CAP TODAY | JANUARY 2023
Breast cancer specimens
continued from 23
Dr. Krishnamurti says. The RCB has held up well
in multiple reproducibility studies; more recently,
Dr. Esserman says, a pooled analysis of more than
5,100 patients from 12 sites and trials showed RCB
score and class were independently prognostic in
all subtypes of breast cancer (Yau C, et al. Lancet
Oncol. 2022;23[1]:149–160). “It’s a very consistent
biomarker.”
The RCB website has links to graphical illustra-
tions for estimating the percentage of cancer cel-
lularity and to the pathol-
ogy protocol for macro-
scopic and microscopic
‘ These are not easy specimens for
assessment of RCB, and the pathologist to handle. But it’s also an biopsy of a tu-
thus walks pathologists opportunity where we add a lot of value.
through the intricacies of Veerle Bossuyt, MD
handling these specimens,
Dr. Krishnamurti says. Microscopically, residual
invasive tumor can extend beyond what is grossly
seen; the RCB calculator uses the primary tumor
bed area. “It explains what to do when your re-
sidual invasive tumor is present only in a small
portion of the grossly seen tumor bed,” she says.
Pathologists already do much of the heavy lifting
on these samples—histologic type, grading, tumor
size, single tumor versus multifocal, lymphovascu-
lar invasion. Plugging numbers into the RCB cal-
culator, Dr. Krishnamurti says, “is an extra few
minutes. Or not even that. You have the informa-
tion already; it’s certainly not tedious.”
Pathologists do have to calculate overall tumor
and invasive tumor cellularity; again, says Dr.
Krishnamurti, it’s a relatively easy task, one that
can be done in a matter of minutes if the specimen
was handled properly.
It’s worth the effort, says Dr. Esserman, who
agrees taking those extra steps up front isn’t par-
ticularly burdensome. “It’s a huge burden, how-
ever, if you don’t do it from the get-go. It matters
how much disease you have,” she says. The differ-
ence between RCB-0/I and RCB-II/III “is a mean-
ingful split” and will determine whether patients
will need additional therapy.
G iven the relative ease of using RCB, Dr. Bossuyt
  says the question she gets most often from her
clinical colleagues is: Why isn’t everyone doing it?
Pathologists are not required by current proto-
cols or guidelines to include RCB values in the
synoptic report or in the final diagnosis report, says
Dr. Krishnamurti; instead, many are reported using
phrases like “probable or definite response” and
“no definite response.”
Dr. Bossuyt suggests there remains a lack of
familiarity with it. “Maybe there’s an aura of it
being an ivory tower thing,” she adds. But once
pathologists start using it, these specimens be-
come less overwhelming. “The sign-outs become
much shorter, and you end up submitting fewer
sections.”
Dr. Sahoo empathizes with those who are start-
ing to see more neoadjuvant specimens, recalling
her early encounters with these cases. In 2004,
“When I started as a faculty, I was struggling, like
everyone else, with how to report these treated
carcinomas,” she says, given the lack of wide-
spread experience among pathologists. “And then
slowly it seemed like every day one was coming
into the lab.”
problems, just like everybody else.”
To be clear, even absent standardization, she
Onc
“the sec
Adding to their difficulties, she and her col- says, most of the work is done “very thoughtfully. says. T
leagues didn’t have reliable access to information But it takes several cycles of work, and you need But in m
through an electronic health record system. “We feedback,” especially as each new unusual situation mor th
didn’t know half the time—most of the time, actu- arises. “We need to be very clear why we want this percola
ally—that the person had been treated with che- paper to read as a recommendation. If we just keep says. A
motherapy” prior to surgery. What they did know going back and forth on the issues, they’re not go- tissue c
was that some of these tumors “looked weird,” as ing to be addressed.” there ar
Dr. Sahoo puts it. “So we learned to look for that She adds: “It’s pretty clear based on the pub- tify the
information in the patient’s chart when we sus- lished surveys that in academic centers in the And
pected it.” United States, we are not very consistent in the way and the
She also taught residents and fellows to look we report treated tumors. And some pathologists are not
closely at the are not aware there are certain important elements dle,” D
dates of core bi-
opsy. If a core
to include in the report.”
Even within her own group, she adds, disagree-
“But
of valu
ments can arise. What is the best way, for example, Hen
’ mor was done
several months
to measure tumor size post-therapy? “It’s not al-
ways easy,” Dr. Sahoo says. “Tu-
commu
The
earlier, she’d tell mor cells are often scattered hap- neoadju
them, they needed to think about the possibility of hazardly over the tumor bed. pens in
neoadjuvant therapy. “The person wasn’t sitting at Where do you put the ruler? Do Krishn
home doing nothing about it. A breast cancer freaks you go with the number of slices bed. A
everyone out,” Dr. Sahoo says. that have tumor, combine them, the righ
Things improved with the arrival of a more ro- or do you take one slide and mea- a clip i
bust EHR as well as adopting the RCB system by sure the largest focus?” involvi
the mid-2000s. For Dr. Sahoo, the latter has been a Surgeons and medical oncolo- Dr.Sahoo Plac
lifeline. “Currently, the majority of our breast can- gists also have a stake in these equally
cer patients who are eligible for adjuvant chemo- conversations, Dr. Esserman notes. “It’s not like the tum
therapy receive it neoadjuvantly,” she says. we’re just doing mastectomies and it doesn’t matter channe
Still, challenges remain. The grossing template what you find. It does matter. And so RCB is a way preven
at UTSW contains a field for neoadjuvant therapy: of standardizing evaluation of specimens. We don’t from re
yes/no. The first step is to track down that bit of let people use whatever MRI protocol they want. The
history. “I always check myself; so do my col- They have to follow a certain protocol because it’s node. “
leagues,” Dr. Sahoo says. “Even during frozen like a biomarker. RCB is a biomarker.” additio
sections of sentinel lymph nodes, I cannot rely on the lym
the surgeons to tell me if the patient had prior treat-
ment, so we proactively look for that history.”
Knowing the type of cancer (luminal versus triple
T he technical challenges can seem even more
  fraught for centers that are just starting to see
these specimens, Dr. Bossuyt says. Many neoadju-
found,”
compli
adds, a
negative versus HER2 positive) the patient had and vantly treated tumors today are easier for patholo- boards
the result of the prior biopsied node is extremely gists to assess, she says, than the advanced-stage, Whe
important, she says. “All this information helps me inoperable tumors that all centers were seeing adjuva
when I examine these treated nodes intraopera- before. subject
tively to help my surgeon colleague determine the A portion of neoadjuvant cases pathologists board d
next step in the axillary management.” encounter now are small lumpectomies, with rela- involvi
tively few sections. Submitting even one cross- before
D epending on the type of tumor, some might
  be completely gone from the breast and lymph
nodes when the pathologist sees the post-treatment
section will allow them to give a quantitative as-
sessment of residual tumor. “So then the treating
physician can have a conversation with the patient
remov
reveale
sentine
resection specimen. The only remaining evidence about the risks and benefits of additional treatment, negativ
might be the tumor bed. based on a precise estimate of their individual risk. “So m
Those are the easy cases, Dr. Sahoo says, and the “A lot of these specimens now are incredibly that wa
pathologist can confidently report there is no re- straightforward,” Dr. Bossuyt continues. “If you sied no
sidual tumor. get a small lumpectomy and sample it appropri- Anythi
When there is residual tumor, pathologists face ately, and there’s no more tumor left, you get to dioisoto
more forks in the road. What’s the best way to say, ‘No residual carcinoma, and the patient has a out, sh
measure that residual tumor? great prognosis.’ What could be better than that?” withou
Even as experience with these cases grows, stan- That’s one hand. What about the other? when w
dardization has lagged. Says Dr. Bossuyt: “There’s “These specimens are technically challenging, the lym
been a real ask from pathologists to figure this out.” and they’re very disorienting for pathologists,” Dr. receive
The recent I-SPY working group recommenda- Bossuyt says, “because we’re all used to all the
tions, Dr. Sahoo says, might nudge the conversa-
tion along. “It was time to revisit the topic when
the group acknowledged that things are not
important prognostic factors in breast cancer, and
when you give the chemotherapy first, they’re all
altered.”
I
“ n ord
  as a t
geon co
standardized.” That includes difficulty finding the tumor— that all
She and her coauthors started there, but discus- there’s no good correlation between imaging find- positiv
sions soon led to more in-depth discussion about ings and pathology findings. Imaging may be nega- she say
controversies in the field. Then came a leap of faith, tive with a lot of residual disease on pathologic have to
she says. “At the beginning, I have to tell you, most evaluation, or imaging may still see a lesion but there “Unles
of my colleagues wanted to just highlight the is no residual viable carcinoma microscopically. comple
JANUARY 2023 page 24
 JANUARY 2023 | CAP TODAY 25

Once the correct area is identified and sampled, leagues got ahead of the game, she says, and started
on, she “the second step is identifying tumor,” Dr. Bossuyt to localize the biopsied node prior to surgery with
htfully. says. That’s easy enough if a lot of tumor remains. radioactive seed to ensure removal of the node at
u need But in most cases, breast cancer is not a ball of tu- surgery, instead of relying on tracers (blue dye or
tuation mor that shrinks. Instead, the cancer will often radioisotope).
ant this percolate, so to speak, through normal tissue, she Enter that other C, communication.
st keep says. Areas with relatively normal-looking breast While wider adoption of EHRs has made things
not go- tissue can alternate with areas containing tumor. If easier for pathologists, Dr. Sahoo says, that’s not
there are few tumor cells left, it can be hard to iden- the end of the discussion. Surgeons and oncologists
he pub- tify them. might ask why the pathology report lacks the “y”
in the And often there are multiple areas of concern for treatment in the staging, for example, or ask
he way and the specimens are extremely complex. “So these pathologists to repeat a marker. Surgeons and on-
ologists are not easy specimens for the pathologist to han- cologists are clearly “keeping us on our toes,” she
ements dle,” Dr. Bossuyt says. says. “We are constantly making sure everything
“But it’s also an opportunity where we add a lot is addressed in the pathology report.”
sagree- of value.” But EHRs don’t automatically dispense informa-

One test,
xample, Hence the need for two Big C’s: clips and tion, either. As Dr. Bossuyt notes, neoadjuvant
not al- communication. specimens aren’t always labeled as such. For all
The first may be more straightforward. When breast specimens, “It’s really important to figure

one answer for

neoadjuvant treatment leads to pCR—which hap- out why we have these specimens.”
pens in most HER2-positive breast cancers, says Dr. At tumor board meetings, Dr. Krishnamurti says
Krishnamurti—it can be difficult to find the tumor conversations often revolve around multiple tumors.

total platelet
bed. A biopsy clip can help direct pathologists to Another challenge involves receptor profiles.
the right spot. At Yale, she says, the radiologists put At Yale, “We routinely repeat the ER, PR, and
a clip in the breast biopsy site, even in cases not HER2 on all neoadjuvant-treated specimens,” she

function
involving neoadjuvant therapy. says, “but by the international consensus you’re not
o
Placing a clip in the biopsied lymph node is required to repeat predictive markers unless the
equally important. Following neoadjuvant therapy, patient is in a trial or the oncologist requests it.”
not like the tumor can completely resolve, but the lymphatic Sometimes the tumor profile changes after treat-
matter channels may become fibrotic from the treatment, ment, however. Most often, receptors may be lost
s a way preventing the sentinel node dye or radioisotope or decrease, she says. Sometimes a new receptor,
We don’t from reaching its mark. which was not expressed before, now is, possibly
y want. The clip ensures that surgeons have the right due to tumor heterogeneity.
use it’s node. “When we give the frozen section report, in Dr. Esserman has her own spin on the impor-
addition to telling them whether there is tumor in tance of communication, and she doesn’t absolve
the lymph node, we also tell them that a clip was her surgeon colleagues of responsibility.
n more found,” says Dr. Krishnamurti. That can extend to “We use pathology tracking sheets,” she says.
g to see complicated cases involving multiple tumors, she “We’ve been doing this for years to make sure the
eoadju- adds, a not infrequent topic of discussion at tumor pathologist knows: Here’s where
atholo- boards. the tumor is located; what treat-
d-stage, When UT Southwestern began doing more neo- ment the patient had ahead of
seeing adjuvant chemotherapy, Dr. Sahoo recalls, the time; were they on I-SPY; treat-
subject of lymph nodes began to dominate tumor ment specifics; making sure the
ologists board discussions. One case still stands out for her, pathologist knows to look for the
th rela- involving a patient who had a positive lymph node clip in the tumor bed and where.
cross- before therapy; during the surgery, the surgeon “It’s essential to communicate T-TAS®01 PL Assay
tive as- removed sentinel lymph nodes. The pathology that to pathologists,” she says. Dr.Esserman
reating revealed residual tumor in the breast, while the “They can’t do their job unless Simple, affordable, rapid
patient sentinel lymph nodes that were removed were all you do that.” She developed the worksheet after
atment, negative. talking with pathologists about what they needed. whole blood test assesses
ual risk. “So my question was, ‘Where is that lymph node That also led to more standardization among her primary hemostasis under
redibly that was positive? How do we know that the biop- surgeon colleagues as far as marking specimens.
“If you sied node was removed?’” The surgeon’s response: “The more we can standardize what we do, the physiologic flow conditions
propri- Anything highlighted by the blue dye or hot (ra- easier it is for them.”
u get to dioisotopes) was removed. But as Dr. Sahoo pointed Likewise, the surgeons asked the pathologists to
nt has a out, she wasn’t certain which node was biopsied have a standard way of grossing specimens. “That Sensitive to antiplatelet
n that?” without seeing changes of a clip site. “So that’s lets me look down and say, OK, they went from
when we started putting a biopsy clip marker in medial to lateral, and I know where the margins are,” therapy and VWD types
enging, the lymph nodes if we know somebody’s going to says Dr. Esserman. “You’re trying to figure out, if
ts,” Dr. receive neoadjuvant chemotherapy.” you have to go back, where you have to go back.”
all the Now that pathologists no longer come to the OR
er, and
y’re all I
“ n order to do those things you have to work
as a team,” Dr. Sahoo says. She can tell her sur-
geon colleagues that even though she’s reporting
regularly, she says, “I ink my own specimens. I do
it in six colors because I want to make sure I know
the orientation. There’s no way for a pathologist to
Learn more at our
February 15 webinar
umor— that all the nodes are negative, it doesn’t mean the know that unless they come to the OR. And if
ng find- positive node is accounted for. At the same time, you’re not set up at your institution to do that, the
e nega- she says, they realize, I can’t rely on blue dye—I surgeons can be taught to ink the specimens.”
hologic have to specifically remove that positive lymph node. For the most complicated cases, she continues, 800.526.5224
ut there “Unless you do that, you can’t tell if the patient has “I’ve actually asked the pathologist to make a map
ally. complete pathologic response.” Her surgeon col- of the specimen—where it’s —continued on 26
diapharma.com

24 JANUARY 2023 page 25

26 CAP TODAY | JANUARY 2023
Breast cancer specimens
continued from 25
positive, where it’s not. On these complex cases, if
you sit down and talk to someone about it, and you
sort it out, you can figure out who really needs to
go back to the OR and who can avoid an unneces-
sary procedure.”
Handling these specimens is “a team sport,” Dr.
Esserman says. “First of all, it’s fun to work with
your colleagues if you know them and everybody
knows what their jobs are. There’s no
substitute for talking to each other.
And having some camaraderie and
saying, How can I make your job easier
so you can make my job easier?”
Talking to clinical colleagues “actu-
ally makes it more pleasant and more
rewarding for the pathologist,” says
Dr. Bossuyt. “Because you’re working
closely with your colleagues, and you
know what’s happening to the
patient.”
If it’s not clear by now, the com-
plexities of these specimens can
make pathology reports more byzan-
tine as well.
Say, for example, a pathologist
gets a request for Ki-67 analysis to see
if a patient would benefit from abe-
maciclib. The interpretation of the
Ki-67 result is dependent on whether
the specimen has been pretreated,
which may not be immediately clear
from the report, Dr. Bossuyt says.
“You can look at the ypT stage, but
that’s all the way at the end of the
report.” And while elements in cur-
rent reporting try to
address the neoadju-
vant setting, things
can still be confus-
ing, she says.
Among her con-
cerns: If there is no
residual tumor be-
cause it was removed Dr.Bossuyt
in the core biopsy,
“then information from the original
biopsy is added in the synoptic report.
In the neoadjuvant setting, that’s not
appropriate because the report for that
surgical specimen needs to have the
information at that point in time.” Dr.
Bossuyt would like more clarity: “This
is the information post-treatment.”
She’d also like to make it easier for
clinicians to identify in the report
whether there’s been a pCR. They
might read, for example, that there’s
no residual invasive carcinoma, then
encounter a note referring to, say,
lymphovascular invasion. “You’ll
stage it as ypT0, and that’s prominent
in the report,” Dr. Bossuyt says, “but
buried somewhere else is that it’s not
a pCR. It can be very confusing.”
Just as important is response in the
lymph nodes. It’s been an area of long-
standing confusion, she says. A report that indicates
no residual tumor, but that there is carcinoma in
the lymph nodes, is not a pCR—and it portends a
worse prognosis. “We need to clearly identify those
patients.” Moreover, she says, “In untreated speci-
mens, isolated tumor cells are less important.
They’re not going to affect prognosis or treatment
in a big way. But in the neoadjuvant setting, any
disease in the lymph nodes is important.”
Cellularity also plays a key role, says Dr. Esser-
man. “It can make the difference between more
J A N U A R
Cervical Health Awareness Month
This month, we recognize healthcare providers and laboratory professionals
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Thank You
for all you do
for women around the world.
chemotherapy or not.” But sampling and location
challenges muddy the picture for everyone.
Dr. Sahoo still encounters questions from her
colleagues on this, even after two decades of experi-
ence, tumor board discussions, and consistent use
of the RCB in addition to AJCC stage in their
reports.
She gives one example of how complicated these
cases can be. “Let’s say a case was reported out as
pT1a by AJCC staging criteria,” indicating a tumor
that is greater than 1 mm but less than or equal to
Y A commitment to patients and labs –
5 mm post-therapy. The pathologist had measured
the largest contiguous focus in the tumor bed,
which was 4 mm. But what if there are 10 or 20 foci
(“Who’s counting?” she asks), some of them with
single cells; what does that mean? “The surgeon
asks, ‘You say the tumor bed is 20 mm, but then
you say it’s pT1a. Which one is it?’”
With RCB in the report, pathologists can explain
that even though the tumor bed is 20 mm, the scat-
tered tumor cells only constitute 10 percent of tu-
mor cellularity (compared with 100 percent before
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treatment). “Versus if I say, ‘It’s a 20-mm area of
residual tumor but the cellularity is 80 percent.’”
Which, Dr. Sahoo says, indicates the neoadjuvant
treatment had minimal impact; on the other hand,
reporting a cellularity of one, five, or 10 percent
suggests a strong response, with only a few scat-
tered tumor cells remaining.
The current AJCC recommendation for doing T
stage is based on the largest contiguous focus, but
that can be hard to pin down. “How much stroma
do you need in between tumor clusters to call it
everywhere.
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JANUARY 2023 | CAP TODAY 27
contiguous or noncontiguous?” Dr. Sahoo asks.
“Nobody counts the number of foci,” she points
out. “After five or six sections, each slide could
have, say, five or 10 foci.” Totting them up “is not
practical,” nor would it be easy to explain their
size. “It is difficult for the oncologists to picture in
their mind what the residual tumor looks like from
reading a report, unless I am able to translate what
I see under the microscope in a standardized
manner.”
This is true of any organ system where the tumor
has been treated neoadjuvantly, she
adds. When the goal is to reduce the
tumor volume, and ideally make it
disappear, pathologists can be left
with the equivalent of a locked-room
mystery: “When you get the specimen,
you are trying to make sense of what
little is left—and how to tell the sur-
geon and the oncologist what is left,
given the entirety of what you see.”
Easier, perhaps, for poets to figure out
how to capture the sensation of moon-
light on a river.
Dr. Sahoo is sympathetic to the
demands placed on each group of
specialists. “You have three different
people—oncologist, pathologist, sur-
geon—doing three different things.”
Of the three, the pathologist is proba-
bly best positioned—like a baseball
catcher—to see everything that’s hap-
pening with the patient and to talk to
everyone involved.
D r. Sahoo reports that the vol-
ume of these samples has in-
creased to the point where, “believe
it or not, some weeks our first-year
residents will say, ‘I have not grossed
or seen a breast cancer that hasn’t
been treated with neoadjuvant chemo-
therapy yet.’” With untreated tumors
fast disappearing, so are the old ways
of looking at things.
If that’s astounding for pathologists,
it’s even more so for patients. But this
approach is demanding for them as
well, Dr. Bossuyt says.
“Instead of going to the surgeon
and having the tumor taken out, we’re
asking patients to not do that immedi-
ately,” she says. “And they get treat-
ment that is very difficult to tolerate.
Patients have to live with this tumor
for six months. Then they want to
know: ‘Was it helpful? How did the
tumor do?’” And when pathologists
can then offer a detailed, quantitative
response assessment, “Patients can do
something with that number.”
It’s true, agrees Dr. Esserman. Ulti-
mately, refining and standardizing the
approach will only make things better.
As she puts it, “That will let us get the
right drugs to the right people at the
right time.” ■
Karen Titus is CAP TODAY contributing
editor and co-managing editor.
28 CAP TODAY | JANUARY 2023
Volume? Space? Automation decisions in coagulation
Automation and point-of-care, reflex, and viscoelastic testing were some of what
came up when a group spoke with CAP TODAY publisher Bob McGonnagle in late
November about hemostasis testing. Also tossed in: Results reporting to the EHR,
which “can always be improved,” said Eric Salazar, MD, PhD, of University of
Texas Health San Antonio. And D-dimer, one of the pandemic’s “health care he-
roes,” said Nichole Howard of Diagnostica Stago.
Here’s what they said about all that and more. CAP TODAY’s guide to coagula-
tion analyzers begins on page 34.
Dr. Russell Higgins, what is top of mind as you
look at the field of hemostasis now? I put this
in two parts—the routine, high-volume,
largely heavily instrumented side and then the
specialty assay areas.
Russell Higgins, MD, professor,
clinical, University of Texas Health
San Antonio, and medical director,
University Health
System Pathology
Services: If we’re
talking about in-
strumentation, it’s
automation—track
systems, integra-
tion into larger
track systems, and Dr.Higgins
the automation that
goes in the box of coagulation ana-
lyzers, like HIL [hemolysis, icterus,
lipemia] modules. Those are chang-
ing. Coagulation is late to the game
in terms of incorporating HIL into
the workflow compared with chem-
istry, which has been doing this for
some time.
Dr. Eric Salazar, I’m going to ask you the same
question. I know you have a specialty in the
more esoteric components of the coagulation
cascade.
Eric Salazar, MD, PhD, associate
professor, clinical, University of Texas
Health San Antonio, and member,
CAP Hemostasis and Thrombosis
Committee: My top three answers are
automation, automation, and auto-
mation. In addition to what Dr. Hig-
gins said, we’re talking about ease of
use. The pandemic taught us that
we’re going to have shortages of
workers—we currently have short-
ages of medical laboratory scien-
tists—and supplies. There were
crunches during the pandemic such
that the easier the device was to use,
the more sustainable the whole pro-
cess. And that’s why we think about
automation not only for routine tests
but also for some of the more esoteric
tests that require manual processes.
Can we get these tests automated in
the event you need an esoteric test
more rapidly? The more automated
it is, the better it is for us so we don’t
need specialized medical laboratory
scientists.
As Dr. Higgins and I explored—
we recently wrote a chapter on auto-
mation and coagulation—when we
talk about automation we’re talking
not only about connecting the track
systems or the inside of the box, but
also about middleware and what the
software can do to make running the
tests easier.
Matt Modleski, what’s top of mind as you look
to coagulation testing and the laboratory and
in the networks and systems you work with?
Matt Modleski, executive vice
president of corporate/business devel-
opment, Orchard Software: As these
tests become better at the point of
care, we see a lot of testing moving
closer to the patient. Our two jobs as
a software company are, one, be
ready when a new test comes to mar-
ket so we can integrate it smoothly
into the lab. We need a little ad-
vanced warning if there are new ana-
lyzers coming so we can work on
interfaces and the things that make
bringing the new test and new ana-
lyzer to market easy.
The other is the location of testing,
point-of-care tests. That trend will
continue because it makes sense from
the perspective of the cost of other
health care. The closer we can get a
test result to the patient, when the
clinician wants it, the better the
chance of that patient getting the care
they need in a timely fashion and
staving off downstream costs. When
we think about coagulation, we’re
looking at the same four things we
look at with almost all testing, which
is: Is it going to move to point of care
or is it already there, and how effi-
cient is it? If there’s new technology
coming, are we ready for it? And as
those trends move, where is the big-
gest bang for the buck from a reim-
bursement or a patient treatment
perspective? Are we ready to help
that area of testing and treatment?
Ken Huffenus and Nichole Howard, both of
your companies offer a dedicated track and
automation for coagulation. That seems to be
efficient because if it’s all in one place, it’s
convenient for the medical laboratory scien-
tists. On the other hand, I suppose some labo-
ratory directors long to see coagulation tied
into the main core line and have coagulation
essentially imitating hematology, chemistry,
and immunoassay. Ken, you probably hear
from customers who want both solutions. Give
us your thoughts about this question around
automation.
Ken Huffenus, MBA, director of
marketing, hemostasis, Werfen: Dr.
Higgins’ comment about coagulation
being late to the automation game is
correct. Experts in the field were con-
cerned about what would happen to
the sample when it travels along a
total lab automation track to the ana-
lyzer and where the centrifugation
would be performed. In 2014–2015
we talked to customers about auto-
mation for coag testing and found
many were against any form of it,
other than automation within the
instrument itself. But that started to
change, even before the pandemic,
when we saw the shortage of well-
trained medical lab scientists. Then
E T
C
ID U
U D
Coagulation analyzers, pages 34–39
G O
R
P
the question was, how do we auto-
mate in the right way? That’s when
our hemostasis workcell concept
gained momentum. We said, let’s
make it dedicated and ensure that we
treat the sample the right way. With
HemoCell, we have only as much
automation as we need to get the
samples from entry into the lab to the
analysis, and the data back to the
laboratorian as quickly and efficiently
as possible.
Nichole, do you agree that the workstation
automation dedicated to coagulation is the
preference of more customers rather than
another solution?
Nichole Howard, MBA, director,
SNA marketing, Diagnostica Stago:
To your point earlier, there’s two
paths. There’s the high-volume, hy-
per-focused on coag path, for which
customers want a
dedicated solution.
We have that solu-
tion—it’s turnkey,
built in-house, and
we service and
manufacture it. It’s
tailor-made, you
Howard
can design it, and
it’s powered by dig-
ital solutions. It’s the challenges Ken
mentioned of coag being the last
added to the line and the coag blue-
top tube moving down the line, get-
ting shaken up. In that case, you have
sites that want the track, the automa-
tion in the instrument, and digital
solutions that help automate pro-
cesses. And Dr. Salazar or Dr. Higgins
can sit in their office right now and
look at results and review QC and be
empowered where they are.
On the flip side, we’ve also seen
double-digit growth of our automa-
tion installs on TLA lines over the past
few years. So we’re seeing both and
making sure we’re sensitive to meet-
ing customers where they are and
have the connections in place so when
a customer says I’m ready to go, their
analyzer can connect to that line.
Dr. Salazar, as a coauthor of a recent chapter
on the subject, did you come down on one side
or the other? Or do you recognize there are two
viable paths for automation in coagulation?
Dr. Salazar (UT Health): The ap-
proach is individualized. It depends
on your situation at your facility.
What are your volumes, what is
your space? Is your space set up to
put the analyzer where it needs
to be? That’s a huge limitation—
was the design appropriate
from the beginning? We’re de-
signing a lab now for the new UT
Health Hospital and coming across
this question of whether we go to-
ward TLA or keep analyzers sepa-
rate. Do we keep hematology and
coag separate from the chemistry
line? It’s a difficult question to an-
swer, highly individualized. With
the shortage of medical laboratory
scientists, the preference in general
is to move toward automation, in-
cluding coagulation.
While we’re talking about shortages, where
are we with blue-top tubes these days? Where
are you, Dr. Higgins, in terms of your supply
chain for coag tubes?
Dr. Higgins (UT Health): Blue-
top tubes never hit my shortage list.
But we have had shortages of EDTA,
purple-top tubes, and on and on. It
depends on where you are in the
country and who is taking care of
your supply and how closely they’re
looking at it. For instance, our out-
patient laboratories and hospital
were getting their supplies from
central supply, where the tubes are
managed. And they didn’t always
have a day-to-day communication
mechanism that could tell us how
much they had in stock and avail-
able. We had to ask every week, how
many tubes do you have? And they
had to check in several systems to
give us a number, and then we had
to translate that to how many days,
weeks, or months of supply we had.
We monitored that during COVID
and are still monitoring some of
those tubes.
—continued on 30
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30 CAP TODAY | JANUARY 2023
Coagulation
continued from 28
Nichole, can you tell us what the situation is
now nationally for blue tops?
Nichole Howard (Diagnostica
Stago): For a while we were having
almost weekly calls with BD to coor-
dinate efforts. Right now it’s pretty
calm; we’re not hearing much.
Ken, when we have the shortage we have of
phlebotomists or the situation in which sys-
tems are telling their nurses to stop drawing
blood because they’re too busy, is that having
an effect on the quality of draws, specifically
for coagulation studies?
Ken Huffenus (Werfen): We have
not heard of any recent changes in the
quality of draws.
From my perspec-
tive, one of the rea-
sons we focus on
preanalytics in he-
mostasis testing is
to make sure that
regardless of what
Huffenus
happened to the
sample before it
reached the lab, we have a way to
assess the quality of it during the ana-
lytical process and flag it if there is an
issue that may impact the result. That
preanalytical test-specific assurance
is really important.
Dr. Salazar, are you happy with the draw qual-
ity and the arrival of the specimens?
Dr. Salazar (UT Health): During
the pandemic when there were
crunches on nursing staff, we did not
notice a decline in the quality of the
specimens.
Improving the quality of the speci-
mens where I worked previously was
a major effort, especially in the ER.
There was a lot of effort to try to re-
duce, for example, hemolyzed sam-
ples coming from that area.
Right now if you don’t have an
HIL module with your coagulation
analyzer, it’s a manual process.
You’re looking at the sample, check-
ing for hemolysis, comparing it to
different pictures of a level of hemo-
lysis or lipemia, et cetera, and trying
to determine if it is a sample you can
reliably run. The more that analysis
can be automated, the better it is for
the lab.
From the perspective of the lab,
however, it is important to under-
stand, independent of what the ven-
dors tell you, what hemolysis, lipe-
mia, et cetera, do to the tests you’re
running. You probably should do
in-house validation to make sure you
understand how important it is. For
example, if I have a bleeding patient
in the OR and I get a hemolyzed
sample and need to run a PT/INR
and a fibrinogen, how important is it
if it’s a moderately hemolyzed sam-
ple? You need to know that for your
individual assays.
Nichole, do you have further comments about
specimen quality and preanalytic guarantees
coming from you and other vendors of coagu-
lation equipment?
Nichole Howard (Diagnostica
Stago): Dr. Salazar’s point is well made
in terms of understanding the impact
with your local patient population for
each of your assays. At the core of
every Stago analyzer is the viscosity-
based detection system with the me-
chanical clot. So knowing that we’re
not outside of the sample looking in,
whether you have H, I, or L, you are
able to actually live in that sample and
not have the interruptions that may
come from preanalytical issues.
Dr. Higgins, we talked about point of care
versus a core lab or a dedicated workcell for
coagulation automation. In the UT system, you
service many physicians and others in differ-
ent locations. How important is a point-of-care
strategy for you in your role?
Dr. Higgins (UT Health): In co-
agulation, it’s important for the war-
farin clinics. They like to provide a
point-of-care test so they can adjust
the medications onsite. Even though
we have direct oral anticoagulants
available that do not require monitor-
ing, about half the patients are still on
warfarin, so providing that INR at
point of care is a good service. Once
you start moving point of care into
the hospital, it becomes more diffi-
cult. The workhorses like INR and
PTT are costly to do at the point of
care—these are high-volume tests.
Also, there are limitations, at least in
the literature, that would make us
pause. For example, there’s one in-
strument that measures PT/INR that
has an electrochemical endpoint and
it’s completely insensitive to fibrino-
gen, so if you had somebody who
didn’t have any fibrinogen on the
hospital floor, that PT/INR would
tell you that patient is normal. A lot
of the PT/INR point-of-care tests are
indicated for warfarin monitoring
only, so it’s hard to know how those
tests perform in an ICU, where there
are many other considerations.
Dr. Salazar, we still have a lot of warfarin use
in this country despite the long-time avail-
ability of other oral anticoagulation agents.
How do you look at these therapeutic deci-
sions from your perch right now? Do you think
warfarin is overused or does it still have a
major place in treatment?
Dr. Salazar (UT Health): We’ve
seen a replacement of the use of war-
farin with direct oral anticoagulants,
with an increasing trend. There are
certain clinical scenarios where stud-
ies have shown that DOACs like di-
rect Xa inhibitors cannot replace war-
farin. A good example is a lupus an-
ticoagulant causing a thrombosis. We
still have to rely on warfarin in that
scenario because studies have shown
that the direct Xa inhibitors are not
effective enough. From the patient
perspective, moving to a direct Xa
inhibitor is tremen-
dously convenient.
At the same time,
we have to be aware
as a field that there
are clinical scenar-
ios where despite
the fact that we
don’t have to do Dr.Salazar
routine monitoring
for direct Xa inhibitors or DOACs in
general, it might be clinically useful.
We’ve looked at that closely and no-
ticed that what happens to an outpa-
tient might not necessarily apply to
the inpatient setting. If you have, for
example, a patient with renal failure
who is in the ICU or needs to transi-
tion to another anticoagulant, having
some understanding of a level could
be informative. From the laboratory
perspective, we have to make an as-
sessment—does that mean we need
to offer this kind of testing?
Ken, how much reflex testing is built into the
operation of your customers? Coagulation is
complex, difficult to understand. Are you see-
ing a greater demand for reflex testing?
Ken Huffenus (Werfen): Definitely.
When we originally designed the
ACL Top system, it had a lot of reflex
and rerun rules built in. But during
the early years of use, it was relatively
infrequent to do more than an auto-
mated rerun. That’s changed com-
pletely, primarily because we now
have data management solutions—
we have HemoHub—complementing
the analyzer software. It has capability
to build an algorithm not only to do a
reflex to one test but also to incorpo-
rate an entire workflow, and follow
that in an automated or manual fash-
ion. Bringing more control back to the
laboratorian to define those work-
flows in-depth has driven the increase
in the use of reflex testing.
Matt, can you speak to that? You’re often
caught in the middle between an instrument
vendor and a customer in a laboratory, and
they’re probably looking to you for help or
solutions. Are you seeing a lot of demand in
these kinds of cases?
Matt Modleski (Orchard): We
have a sophisticated rule set inside
our LISs that helps labs choose when
and how to reflex. It becomes an in-
dividual laboratory decision.
We typically don’t develop auto-
mation or an automation line until a
laboratory says, we’re buying this
from XYZ vendor, and they bring it
in. We will then work closely with the
vendor to develop that software
hardcoded into our LISs. We do a lot
of work with vendors pre-launch and
once the product is in the market-
place. It drives what we develop.
Nichole, tell us about reflex testing from your
perspective. What’s built into the analyzer and
the instrument solution and what is left to an
LIS or middleware vendor?
Nichole Howard (Diagnostica St-
ago): We’ve had our Max generation
analyzers in the field since 2013, and
each one comes connected to a mid-
dleware management system called
Coag Expert that has the ability to
build in rules. We like to work with
our customers so they can automate
the process and the standard operat-
ing procedures for testing. We’re
seeing it used frequently in lupus
testing, where you can build in the
International Society on Thrombosis
and Haemostasis guidelines so every-
thing flows end to end and you can
automate the process with the full
panel. We’re seeing it with factor VIII
and IX testing. Once you have well-
informed customers, leaders in the
industry who understand the testing,
then they are validating locally and
feel confident. It’s been powerful,
especially with the technologist short-
ages, to be able to have traveling
technologists come in and have less
of a learning curve.
Dr. Salazar, let’s go to the other end of the
testing process. Are you and your clinicians
and others happy with the way coagulation
test results are reported in the EHR?
Dr. Salazar (UT Health): We have
to be aware of whether we are con-
veying what we want to to our clini-
cians from the testing we’re doing.
Are the comments or interpretations
we’re making visible to them? Am I
happy with it? It can always be
improved.
One example is lupus anticoagu-
lant testing, because I’ve seen a few
different models for the way those
interpretations come across. Lupus
anticoagulant testing involves many
different tests and sometimes a long
interpretation. I get the feeling that
sometimes hematologists or clini-
cians are looking for a yes or no an-
swer, and sometimes we’re coming
up with inconclusive. From a clini-
cian’s perspective it’s tough to know
how to act on that, so we could work
on not just —continued on 32
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32 CAP TODAY | JANUARY 2023
Coagulation
continued from 30
standardizing but making sure it
comes across appropriately.
The second example is a little like
the elephant in the room for our con-
versation, and that’s viscoelastic test-
ing. A lot of clinicians are using vis-
coelastic testing in place of routine
testing and making important patient
decisions based on these curves and
parameters on the curves. Have we
as coagulation experts and laborato-
rians taken a close look at how clini-
cians are using that information and
are we appropriately interpreting
that for them? Those curves or dials
that viscoelastic platforms are pro-
ducing are sometimes difficult for the
clinician to access. It might be a PDF
that gets scanned in after the fact. It
might be an image that shows up
after the clinical information was
necessary. We need to look at this
area more closely.
Dr. Higgins, tell us more about viscoelastic
testing at the point of care. Is it ready for prime
time? Is it fully matured, is it understood?
What has been your experience?
Dr. Higgins (UT Health): We
don’t have a choice, because a lot of
this was direct marketed to surgeons
and anesthesiologists, and the TEG
[thromboelastography] showed up in
our ORs and we had to deal with it.
In my opinion the literature needs to
catch up. What are the triggers for
transfusion on this TEG for a particu-
lar surgery or scenario? The algo-
rithms I’ve seen that are designed
well end up needing a laboratory test
in the central lab to confirm, okay, the
maximum amplitude is low—is that
due to low platelets or fibrinogen? To
have an impact, we need to know
more. Surgeons and anesthesiologists
need an algorithm that they put to-
gether so they’re at least treating pa-
tients uniformly. That part is hard to
control. There may be software com-
ing down the line for some instru-
ments, and if so that would help. We
could, as a hospital, as a group, pro-
gram an algorithm and they could
use it to treat patients in a standard
way. But it’s like the Wild West at the
moment.
Nichole, your reaction to this?
Nichole Howard (Diagnostica
Stago): Our teams, our colleagues at
HemoSonics, a sister company, are
working together to understand this
because we are hearing the same—
this was sold at the surgeon or car-
diac level and now the lab is scram-
bling to try to deal with it. As vendors
it’s our job to facilitate those conver-
sations and get all the stakeholders to
the table to figure out a solution that
makes a difference in how we pro-
vide care and reduce the use of blood
products.
Ken, can you comment on this? I’m going to
throw in parenthetically that when we start to
see testing sold to nonpathologists and non-
laboratorians, troubles often arise.
Ken Huffenus (Werfen): The good
news for the laboratory is that Nich-
ole’s company and mine are getting
into the viscoelastic testing world
now. We have our ROTEM sigma
system for viscoelastic testing at the
point of care, with the hemostasis
expertise to understand what those
results mean. We leveraged the ex-
pertise from our laboratory hemosta-
sis team and brought it together with
the ROTEM team and we’ve found
that to be powerful. Now we can tell
the story, educate those in the labora-
tory and in the clinical settings about
what the results mean and how they
can help improve patient care and
blood usage.
Matt, can you comment on how these results
look in the EHR? Are you seeing a greater
sense of satisfaction with how the EHR is re-
porting lab tests overall?
Matt Modleski (Orchard): Of all
the testing regimens, this one seems
more complicated than the average
set of testing. What Dr. Salazar said
about results back
to the EHR is indic-
ative of what most
experts would say,
which is, we’re try-
ing to tell a sophis-
ticated story with
finite data. This is
Modleski
one of the times
when individual
data sets for hard data, without some
language around it, isn’t as helpful as
it could be. Most of the time we like
data and a hard number and a clear
set of yes/nos. This doesn’t lend itself
to that, so there’s room to improve
how the clinician receives the total
diagnosis.
Dr. Salazar, does coagulation testing and the
exploration of this complex science have
more to offer that we haven’t yet uncovered
completely? In other words, is there more
potential in coagulation testing than many
people might think?
Dr. Salazar (UT Health): Histori-
cally when we have thought about
coagulation testing, the way it has
been and continues to be applied of-
ten is a decision about whether we
should transfuse a patient—should
we give a blood product—or should
we change anticoagulation? On the
other hand, we learned during the
pandemic that one of the most impor-
tant biomarkers for COVID-19 sur-
vival was a D-dimer. So we’ve learned
that routine coagulation parameters
can be more than just a decision to
transfuse or to anticoagulate.
We can get into esoteric testing,
where you have esoteric biomarkers
or diagnostic parameters like an AD-
AMTS13 or a fibrinolysis marker
that’s not offered at many places and
may or may not be clinically relevant
under different scenarios. There’s a
lot of research now into long COVID,
and at least two studies suggest that
a coagulation parameter is perhaps
an important indicator of long CO-
VID, and that’s the ADAMTS13-to-
von Willebrand ratio. So the answer
to your question is yes, and more to
come. We’re learning a lot more.
Ken, do you have a closing comment on that
point?
Ken Huffenus (Werfen): Ken
Friedman [MD, of Versiti Blood Cen-
ter of Wisconsin and Medical College
of Wisconsin] presented an excellent
overview of parameters related to the
ADAMTS13–von Willebrand ratio
and what they might mean, during
the ISTH Congress in London last
July. This is available online at Wer-
fen Academy [academy.werfen.com]. As
far as what coagulation has to offer, I
go back to the pandemic, where he-
mostasis really shined. Prior to that,
when I’d say “hemostasis,” people
would ask if it’s clinical chemistry.
Now everyone knows, and they usu-
ally know about D-dimer testing too.
There’s more interest in these differ-
ent thrombotic complications. We see
adoption of a certain testing regimen,
and complementary care related to it,
in some areas of the world, and we
see a proliferation to the rest of the
world happening over time. From
where I sit, coagulation still has a lot
to offer.
Nichole, does coagulation and its study and
development still have much to offer?
Nichole Howard (Diagnostica
Stago): Yes. D-dimer is one of our
health care heroes in COVID-19.
When we saw the growth of D-dimer
through COVID, we expected things
to come down much faster than they
are. We’re not seeing patients being
hospitalized at the same rate; how-
ever, D-dimer numbers are still not
coming down as much. It will be in-
teresting to see how that shifts the
continuum of care in the next 12 to 18
months, especially when you think
about the data coming from Jeff Kline
[MD, of Wayne State University
School of Medicine] that highlights
underutilization of D-dimer and
overutilization of imaging in the ER
and how it changes an overall con-
tinuum of care [Kline JA, et al. Circ
Cardiovasc Qual Outcomes.
2020;13(1):e005753]. Also, how do we
manage using anti-Xa for its care
benefits, reduced dosage changes,
reduced length of stay, but also man-
age DOACs? There’s a lot of develop-
ment there.
Dr. Higgins, tell us more about the promise that
coagulation studies still have.
Dr. Higgins (UT Health): We’re
getting much better at what we do in
the coagulation lab, and some of it is
automation. Think about the ristoce-
tin cofactor assay—this is our classic
way of measuring the activity of von
Willebrand factor [VWF]. This was
done on a platelet aggregometer until
about 15 years ago. Now there are
automated von Willebrand activity
assays that can be put on instru-
ments. That’s huge for monitoring
patients who are on therapy in the
hospital. We don’t have enough MLS
staff to perform the old aggregometry
method every day, so putting it on
the instrument is a huge win. An-
other win is the availability of rapid
heparin-induced thrombocytopenia
testing on automated instruments—
getting those results rapidly not only
saves money in argatroban costs, it’s
better patient care.
The regulatory environment gets
in the way a little. For example, the
rest of the world had access to tests
like the von Willebrand factor glyco-
protein 1bM [VWF:GP1bM] assay
much earlier than the United States.
Guidelines recommend using these
newer automated tests [see related
story, page 1], but at the time they
weren’t available and certainly not on
every instrument and platform. Ad-
ditionally, the regulatory environ-
ment is such that new tests often get
approved only on a specific instru-
ment. Very recently, the FDA ap-
proved a VWF:GP1bM test on a few
Siemens and Sysmex instruments,
but it is not FDA approved on the
other manufacturers’ instruments.
My favorite approach is when com-
panies send tests to the FDA without
tying them to an instrument because
we can put them on our instruments
and my neighbors can put them on
theirs, regardless of the platform.
This approach was helpful for the
implementation of the bovine chro-
mogenic VIII assay in our laboratory,
which is another up-and-coming as-
say. So we’re making strides with
automation, and there are great as-
says coming out that help us take
care of patients. ■
 Better Tests = Better Patient Outcomes
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References
1. Soliman HM. Development of ionized hypomagnesemia is associated with higher mortality
rates. Crit Care Med 2003;31(4):1082-7.
2. Wilkes NJ et al. Correction of ionized plasma magnesium during cardiopulmonary bypass
reduces the risk of postoperative cardiac arrhythmia. Anesth and Analg 2002;95(4) 828-834.
3. Kobayashi M et al. Prognostic Value of Estimated Plasma Volume in Heart Failure in Three
Cohort Studies; Clin Res Cardiol 2019;108(5): 549-561.
4. Niedermeyer, et al. Calculated Plasma Volume Status Is Associated With Mortality in Acute
Respiratory Distress Syndrome. Critical Care Explorations: September 2021, V3(9):1-9.
5. Kim HK et al. Prognostic Value of Estimated Plasma Volume Status in Patients with Sepsis. J
Korea Med Sci 2020;9(37):1-10.
6. Mandelbaum T et al. Outcome of critically ill patients with acute kidney injury using the AKIN
criteria. Crit Care Med 2011;39(12):2659-2664.

Nova Biomedical FILE— NEW JANUARY 2023 page 33

34 CAP TODAY | JANUARY 2023 COAGULATION ANALYZERS

Part 1 of 6 Bio/Data Corp. Chrono-log Corp. Chrono-log Corp. Part 2 of

Mary Brown customer.service@biodatacorp.com Sal Pema sal@chronolog.com Sal Pema sal@chronolog.com
Horsham, PA Havertown, PA Havertown, PA
215-441-4000 or 800-257-3282 www.biodatacorp.com 610-853-1130 or 800-247-6665 www.chronolog.com 610-853-1130 or 800-247-6665 www.chronolog.com
Instrument name/First year sold Platelet Aggregation Profiler PAP-8E/2005 Optical Aggregation Systems Models 490 4+, 490 4+4/2017 Whole Blood Optical Lumi-Aggregation System 700-2, 700-4/2006 Instrume
List price/Model type $22,990/benchtop $11,268–$26,795/benchtop $19,909–$42,100/benchtop List price
Dimensions (H × W × D)/Weight/Instrument footprint 21.5–25.5 × 19.5 × 21.7 in./40 lbs./4 sq. ft. per each 4-channel module: 8.5 × 14 × 15 in./19.3 lbs./1.5 sq. ft. per each 2-channel module: 8.5 × 14 × 18 in./40 lbs./1.75 sq. ft. Dimensio
No. of units in clinical use in U.S./Outside U.S. (countries) >500/>300 (Canada, EEC, Middle East, Asia, Far East, North Africa) — — No. of un
Composition of installs: Hospital lab/Reference lab/Other 80%/15%/5% (unspecified) — — Composi
Targeted daily, monthly, annual test volume — — —
Operational type batch, random access discrete discrete Targeted
Country where analyzer designed/Manufactured U.S./U.S. U.S./U.S. U.S./U.S.
Company manufactures instrument yes (also sold by möLab, Sentinel Diagnostics, Werfen, Alpha yes (also sold via distribution partners) yes (also sold via distribution partners) Operation
Labs, Sysmex, Analis) Country w
Company
FDA-approved clotting-based tests — — —
FDA-approved chromogenic tests — — — FDA-app
FDA-approved immunologic tests ristocetin cofactor activity, HIT/HIPA, RIPA; others platelet agglutination with ristocetin platelet agglutination with ristocetin
Other FDA-approved tests platelet activation, spontaneous platelet aggregation, sticky LTA platelet aggregation, ristocetin cofactor assay whole blood impedance platelet aggregation, LTA platelet FDA-app
platelets, washed platelet aggregation, others aggregation, platelet dense granule ATP release, ristocetin
cofactor assay FDA-app
User-defined tests in clinical use — LTA platelet aggregation, ristocetin cofactor assay whole blood impedance platelet aggregation, LTA platelet
Other FD
aggregation, platelet dense granule secretion, ristocetin
User-defi
cofactor assay
Tests in development or awaiting FDA 510(k) clearance — — —
Tests in d
Methodologies supported turbidimetric, immunologic (agglutination, Ab-Ag tests) turbidimetric for measuring platelet aggregation in PRP and turbidimetric for measuring platelet aggregation in PRP and
Methodo
ristocetin cofactor assay ristocetin cofactor assay, impedance for measuring platelet
Number o
aggregation in whole blood
Number of different measured assays onboard simultaneously 255 4–8 2–4 Number o
Number of different assays programmed and calib. at one time 255 4–8 2–4 No. of use
No. of user-definable (open) channels/No. active simultaneously 8/8 4–8/4–8 2–4/2–4 Factor as
Factor assays require manual manipulation or dilutions yes (manual manipulation and dilutions) yes (manual dilutions) yes (manual dilutions) Test thro
Test throughput per hour/Assay run time 540 (up to 60 samples in throughput)/up to 8 hours 6 (24–48 tests in throughput)/5 min. minimum 6 (12–24 tests in throughput)/6 min. minimum
Design of sample-handling system manual manual manual Design o
Operates on whole blood or spun plasma spun plasma spun plasma whole blood and spun plasma
Reagent type open reagent system (liquid, lyophilized [reconstituted self-contained multiuse vials; open reagent system (liquid, self-contained multiuse vials; open reagent system (liquid, Operates
manually]) lyophilized [reconstituted manually]) lyophilized [reconstituted manually]) Reagent
Reagent barcode-reading capability yes, for all tests no no
No. of reagent containers held onboard/Reagents ready to use —/requires operator prehandling —/requires operator prehandling —/requires operator prehandling Reagent
Reagent lot tracking/Reagent inventory/Reagents refrigerated yes/no/no no/no/no no/no/no No. of rea
onboard Reagent
Reagents, consumables loaded without interrupting testing yes (reagents and consumables) yes (consumables) yes (consumables) onboar
Instrument uses proprietary or third-party reagents user’s option proprietary reagents proprietary reagents Reagents
Maximum time same lot number of reagents can be used 2 years 18 months–3 years 18 months–3 years Instrume
Maximum
Walkaway capability/Walkaway duration yes/8 specimens or 8 tests yes/5 min. or 4–8 specimens or 4–8 tests yes/6 min. or 2–4 specimens or 2–4 tests
Walkawa
Min.–max. specimen volume that can be aspirated at one time — 250–500 µL 225–500 µL
Min.–ma
Min. sample volume required for PT/PTT/Factor VIII activity — — —
Min. sam
Types of disposables used test cuvettes, micro stir bars, pipette tips, sample tubes and cuvettes, stir bars, pipette tips cuvettes, stir bars, disposable electrodes, pipette tips
Types of
caps
Primary t
Primary tube sampling supported/Pierces caps on primary tubes no/no no/no no/no
Accomm
Accommodates most standard tube sizes/Nonstandard sizes no/no no/no no/no
Sample b
Sample barcode-reading capability/Autodiscrimination —/yes no/no no/no
Auto track
Auto tracks product volume/Measures number of tests remaining no/no no/no no/no
Short sam
Short sample detection no no no
Clot dete
Clot detection as preanalytical variable in plasma sample no no no
Auto dete
Auto detects adequate reagents for aspiration or analysis no no no
Detection
Detection or quantitation for hemolysis, turbidity, icterus, lipemia detection for hemolysis, turbidity, icterus, lipemia no no
Dilutes p
Dilutes patient samples onboard no no no
Automati
Automatic rerun capability/Auto reflex testing capability no/no yes/no yes/no
Lag time
Lag time during which hypercoagulable sample not detected no no no
User can
User can adjust reagent volumes/Sample volumes yes/yes yes/yes yes/yes
User can
User can adjust No. of reagents/Sources of reagents yes/yes yes/yes yes/yes
User can
User can adjust incubation times/Reading times yes/yes yes/yes yes/yes
Read tim
Read time extended for prolonged clotting times — yes (selectable on menus) yes (selectable on menus)
Autocalib
Autocalibration/Calibrants stored onboard yes/no yes/no yes/no
Multipoin
Multipoint calibration supported/Recommended frequency yes/annually yes/annually yes/annually
Stat time
Stat time to complete all analytes/Throughput per hour for: • PT alon
• PT alone — — — • PT, PTT
• PT, PTT — — — • Fibrino
• Fibrinogen — — — • Factor
• Factor VIII activity assay — — — • D-dime
• D-dimer — — — Time del
Time delay from ordering stat to aspiration of sample — — — How labs
How labs get LOINC codes for results email query email query email query Onboard
Onboard real-time QC/Onboard software capability to review QC no/yes yes/no yes/no Informati
Information that can be barcode-scanned on instrument reagent lot No. barcode scanning not offered barcode scanning not offered
Compatible with laboratory automation systems no no no Compatib
Data-management capability/LIS or EHR systems interfaced onboard/none onboard/none onboard/none
Interface supplied by instrument vendor no no no Data-ma
Results transferred to LIS as soon as test time complete no no no Interface
Bidirectional interface capability no no no Results t
Remote servicing provided/UPS backup power supply no/no no/no no/no Bidirectio
Instrument connections to transfer information — — — Remote s
Interface standards supported — — — Instrume
Information transferred to data-management software — — —
Avg. time for basic user training 1.5 days (at customer site) — 1.5 days (at customer site) Interface
Approximate scheduled maintenance time weekly: 15 minutes; monthly: 30 minutes preventive maintenance and calibration by clinical engineering preventive maintenance and calibration by clinical engineering Informati
recommended annually recommended annually Avg. time
Maintenance records kept onboard no yes yes Approxim
Warranty with purchase/Annual service contract cost (24/7) yes/$2,050 yes/— (cost dependent on contract) yes/— (cost dependent on contract) Maintena
Warranty
Distinguishing features (supplied by company) 2-year instrument warranty; 3-year in-lab PC service; up to continuously monitors and regulates temperature and stirring; 3 instruments in 1: whole blood/impedance and PRP/LTA
9 reported test results per channel; hybrid annual calibration optical calibration can be performed by laboratory personnel aggregometer plus luminometer to measure platelet ATP Distingui
service using no-cost water samples; customized color-coding options release; continuously monitors and regulates temperature and
Note: a dash in lieu of an answer means company did not stirring; optical calibration can be performed by laboratory
personnel using no-cost water samples Note: a d
answer question or question is not applicable answer q

All information is supplied by the companies listed. The tabulation does not represent an endorsement by the CAP. All informa

JANUARY 2023 page 34

 COAGULATION ANALYZERS JANUARY 2023 | CAP TODAY 35

Part 2 of 6 Diagnostica Stago Diagnostica Stago Diagnostica Stago

Matthew Lyons matthew.lyons@us.stago.com Matthew Lyons matthew.lyons@us.stago.com John G. Chromczak john.chromczak@us.stago.com
Parsippany, NJ Parsippany, NJ Parsippany, NJ
com 800-222-2624 www.stago-us.com 800-222-2624 www.stago-us.com 800-222-2624 www.stago-us.com
00-4/2006 Instrument name/First year sold STA Compact Max/2013 STA Satellite/2010 STA-R Max/2015
List price/Model type $150,000/benchtop $58,935/benchtop $241,000/floor standing
1.75 sq. ft. Dimensions (H × W × D)/Weight/Instrument footprint 27.75 × 38.18 × 28.73 in./309 lbs./7 sq. ft. 27.4 × 21.1 × 25.5 in./72 lbs./4 sq. ft. 49.2 × 50.3 × 32.2 in./564 lbs./26.8 sq. ft.
No. of units in clinical use in U.S./Outside U.S. (countries) ~1,850/~4,100 (France, Spain, UK, Germany, Denmark, others) ~550/~2,100 (France, Spain, UK, Germany, Denmark, others) ~400/~1,800 (France, Spain, UK, Germany, Denmark, others)
Composition of installs: Hospital lab/Reference lab/Other ~96%/3%/1% (veterinary labs, pharmaceutical companies, ~98%/0/2% (veterinary labs, academic research) ~90%/7%/3% (veterinary labs, pharmaceutical companies,
academic research/educational labs) academic research/educational labs)
Targeted daily, monthly, annual test volume daily: >30 (moderate-volume laboratories); monthly: 900; daily: ~40; monthly: <900; annual: <13,000 daily: >100 (moderate- to high-volume laboratories);
annual: >5,000 monthly: >2,500; annual: >25,000
Operational type continuous random access random access continuous random access
Country where analyzer designed/Manufactured France/France France/France France/France
Company manufactures instrument yes yes yes
FDA-approved clotting-based tests PT, APTT, TT, fibrinogen, reptilase, factors, proteins C and S, PT, APTT, fibrinogen PT, APTT, TT, fibrinogen, reptilase, factors, proteins C and S,
lupus anticoagulant, DRVVT (screen and confirm) lupus anticoagulant, DRVVT (screen and confirm)
latelet FDA-approved chromogenic tests anti-FXa (UFH and LMWH), antithrombin, protein C, anti-FXa (UFH and LMWH), antithrombin anti-FXa (UFH and LMWH), antithrombin, protein C,
tocetin plasminogen, FVIII chromogenic plasminogen, FVIII chromogenic
FDA-approved immunologic tests D-dimer, antithrombin antigen, free protein S, total protein S, D-dimer D-dimer, antithrombin antigen, free protein S, total protein S,
vWF antigen (all microlatex) vWF antigen (all microlatex)
atelet
Other FDA-approved tests — — —
etin
User-defined tests in clinical use APCR, other clotting, chromogenic, and immunological tests — APCR, other clotting, chromogenic, and immunological tests
with user-defined applications with user-defined applications
Tests in development or awaiting FDA 510(k) clearance STA NeoPTimal protime reagent with ISI ~1.0 — STA NeoPTimal protime reagent with ISI ~1.0
RP and
Methodologies supported mechanical clot detection, chromogenic, immunologic (microlatex) mechanical clot detection, chromogenic, immunologic (microlatex) mechanical clot detection, chromogenic, immunologic (microlatex)
platelet
Number of different measured assays onboard simultaneously 80 80 200
Number of different assays programmed and calib. at one time 80 80 200
No. of user-definable (open) channels/No. active simultaneously 80/80 80/80 200/200
Factor assays require manual manipulation or dilutions — — —
Test throughput per hour/Assay run time 110 (2 tests in throughput)/4.6–7.3 min. (avg. 4.7 min.) 36 (3 tests in throughput for PT, APTT, fibrinogen)/4.6–7.3 200 (2 tests in throughput)/4.6–7.3 min. (avg. 4.7 min.)
min. (avg. 4.7 min.)
Design of sample-handling system continuous loading sample drawer with continuous random continuous sample loading with positive sample identification, rack with continuous specimen access
access removable sample carousel for 20 primary tubes
liquid, Operates on whole blood or spun plasma spun plasma spun plasma spun plasma
Reagent type self-contained single-use and multiuse vials; open reagent self-contained single-use and multiuse vials; open reagent self-contained single-use and multiuse vials; open reagent
system (liquid, lyophilized [reconstituted manually]) system (liquid, lyophilized [reconstituted manually]) system (liquid, lyophilized [reconstituted manually])
Reagent barcode-reading capability yes, for all tests yes, for all tests yes, for all tests
No. of reagent containers held onboard/Reagents ready to use 45/variable (reagent specific) 16/variable (reagent specific) 70/variable (reagent specific)
Reagent lot tracking/Reagent inventory/Reagents refrigerated yes/yes/yes (15°–19°C) yes/yes/yes (15°–19°C) yes/yes/yes (15°–19°C)
onboard
Reagents, consumables loaded without interrupting testing yes (consumables) yes (consumables) yes (consumables)
Instrument uses proprietary or third-party reagents user’s option (same capabilities when third-party reagents used) user’s option (same capabilities when third-party reagents used) user’s option (same capabilities when third-party reagents used)
Maximum time same lot number of reagents can be used 18 months 18 months 18 months
Walkaway capability/Walkaway duration yes/96 specimens or 12 tests yes/20 specimens or 12 tests yes/215 specimens or 32 tests
Min.–max. specimen volume that can be aspirated at one time 5–100 µL 5–100 µL 5–100 µL
Min. sample volume required for PT/PTT/Factor VIII activity 50 µL/50 µL/50 µL 50 µL/50 µL/50 µL 50 µL/50 µL/50 µL
s
Types of disposables used cuvettes, stir bars, cleaner solution cuvettes, stir bars, cleaner solution cuvettes, stir bars, cleaner solution
Primary tube sampling supported/Pierces caps on primary tubes yes/yes yes/no yes/yes
Accommodates most standard tube sizes/Nonstandard sizes yes/no yes/no yes/no
Sample barcode-reading capability/Autodiscrimination yes (Interleaved 2 of 5, UPC, Codabar)/— yes (Interleaved 2 of 5, UPC, Codabar)/no yes (Interleaved 2 of 5, UPC, Codabar)/—
Auto tracks product volume/Measures number of tests remaining yes/no yes/no yes/no
Short sample detection yes yes yes
Clot detection as preanalytical variable in plasma sample no no no
Auto detects adequate reagents for aspiration or analysis yes (aspiration and analysis) yes (aspiration and analysis) yes (aspiration and analysis)
Detection or quantitation for hemolysis, turbidity, icterus, lipemia — — —
Dilutes patient samples onboard yes yes yes
Automatic rerun capability/Auto reflex testing capability yes/yes yes/yes yes/yes
Lag time during which hypercoagulable sample not detected no no no
User can adjust reagent volumes/Sample volumes yes/yes yes/yes yes/yes
User can adjust No. of reagents/Sources of reagents yes/yes yes/yes yes/yes
User can adjust incubation times/Reading times yes/yes yes/yes yes/yes
Read time extended for prolonged clotting times yes (selectable on menus) yes (selectable on menus) yes (selectable on menus)
Autocalibration/Calibrants stored onboard yes/yes yes/yes yes/yes
Multipoint calibration supported/Recommended frequency yes/6 months yes/6 months yes/6 months
Stat time to complete all analytes/Throughput per hour for:
• PT alone <6 minutes/~150 specimens <6 minutes/~50 specimens <6 minutes/~320 specimens
• PT, PTT <6 minutes/~100 specimens <6 minutes/~40 specimens <6 minutes/~262 specimens
• Fibrinogen <6 minutes/~100 specimens <6 minutes/~40 specimens <6 minutes/~180 specimens
• Factor VIII activity assay <6 minutes/~60 specimens — <6 minutes/~180 specimens
• D-dimer 7 minutes/~60 specimens 7 minutes/~6 specimens 7 minutes/~150 specimens
Time delay from ordering stat to aspiration of sample <15 seconds <15 seconds <15 seconds
How labs get LOINC codes for results email query, LOINC codes available in STA Coag Expert email query email query, LOINC codes available in STA Coag Expert
Onboard real-time QC/Onboard software capability to review QC yes/yes yes/yes yes/yes
Information that can be barcode-scanned on instrument specimen identifier, reagent lot No., quality control ranges, specimen identifier, reagent lot No., quality control ranges, specimen identifier, reagent lot No., quality control ranges,
calibrator values calibrator values calibrator values
Compatible with laboratory automation systems no no yes (Stago, Abbott, Beckman Coulter, Cerner, Inpeco, Ortho,
Roche, Siemens)
Data-management capability/LIS or EHR systems interfaced onboard/Cerner, Meditech, Clinisys, SCC, McKesson, Epic onboard/Cerner, Meditech, Clinisys, SCC, McKesson, Epic onboard/Cerner, Meditech, Clinisys, SCC, McKesson, Epic
Interface supplied by instrument vendor contract dependent contract dependent contract dependent
Results transferred to LIS as soon as test time complete yes yes yes
Bidirectional interface capability yes (broadcast download and host query) yes (host query) yes (broadcast download and host query)
Remote servicing provided/UPS backup power supply no/yes no/yes no/yes
Instrument connections to transfer information data-management system, which in turn connects to LIS; directly to LIS data-management system, which in turn connects to LIS;
directly to LIS; directly to lab automation system directly to LIS; directly to lab automation system
Interface standards supported ASTM 1394-91, ASTM 1381 ASTM 1394-91, ASTM 1381 ASTM 1394-91, ASTM 1381
ngineering Information transferred to data-management software device unique identifier, patient ID, specimen ID, result, QC identifier device unique identifier, patient ID, specimen ID, result, QC identifier device unique identifier, patient ID, specimen ID, result, QC identifier
Avg. time for basic user training 3.5 days (at vendor office) 2.5 days (at vendor office) 3.5 days (at vendor office)
Approximate scheduled maintenance time weekly: <15 minutes; monthly: <15 minutes weekly: <15 minutes; monthly: <15 minutes weekly: <15 minutes; monthly: <15 minutes
Maintenance records kept onboard yes no yes
Warranty with purchase/Annual service contract cost (24/7) yes/— (cost dependent on contract) yes/— (cost dependent on contract) yes/— (cost dependent on contract)
TA
TP Distinguishing features (supplied by company) viscosity-based, mechanical clot detection; precalibrated D-dimer viscosity-based, mechanical clot detection; precalibrated viscosity-based, mechanical clot detection; precalibrated D-dimer
ure and and fibrinogen reagents, full complement of lupus anticoagulant D-dimer and fibrinogen reagents, 2-mL 24-hour quality and fibrinogen reagents, full complement of lupus anticoagulant
tory testing; STA Coag Expert and Coag.One data managers deliver full control for PT, APTT, fibrinogen; small footprint for low- testing; STA Coag Expert and Coag.One data managers deliver full
Note: a dash in lieu of an answer means company did not autoverification, repeat/reflex testing, auto upload of QC to peer throughput labs with limited space autoverification, repeat/reflex testing, auto upload of QC to peer
answer question or question is not applicable group group

All information is supplied by the companies listed. The tabulation does not represent an endorsement by the CAP.

e 34 JANUARY 2023 page 35

36 CAP TODAY | JANUARY 2023 COAGULATION ANALYZERS

Part 3 of 6 HemoSonics LLC LABiTec LAbor BioMedical Technologies GmbH LABiTec LAbor BioMedical Technologies GmbH Part 4 of
Jeff Light jlight@hemosonics.com M. Schramm info@labitec.de M. Schramm info@labitec.de
Durham, NC Ahrensburg, Germany Ahrensburg, Germany
401-741-3265 www.hemosonics.com 011-49-4102-47950 www.labitec.com 011-49-4102-47950 www.labitec.com
Instrument name/First year sold Quantra Hemostasis Analyzer/2019 CoaDATA 2004 and 4004/— CoaLAB 1000/— Instrume
List price/Model type —/portable, benchtop —/benchtop —/benchtop List price
Dimensions (H × W × D)/Weight/Instrument footprint 19 × 14 × 12 in./36 lbs./1 sq. ft. 10 × 13 × 3.5 in./8.6 lbs./0.92 sq. ft. 19.6 × 30.7 × 23.6 in./70.5 lbs./5 sq. ft. Dimensio
No. of units in clinical use in U.S./Outside U.S. (countries) >100/>100 (Germany, France, England, Spain, Austria, Japan, —/>1,500 (worldwide [except U.S., Canada]) —/— (worldwide [except U.S., Canada]) No. of un
Hong Kong, Australia, Italy, Portugal, Belgium) Composi
Composition of installs: Hospital lab/Reference lab/Other 10%/0/90% (point of care [operating room, ICU, stat lab, more]) — — Targeted
Targeted daily, monthly, annual test volume daily: 15–20; monthly: 1–200; annual: 1,200–2,400 — daily: 100–400; monthly: 2,000–8,000; annual: 24,000–95,000 Operation
Operational type random access, continuous random access batch batch, random access Country w
Country where analyzer designed/Manufactured U.S./U.S. Germany/Germany Germany/Germany Company
Company manufactures instrument yes (also sold via distribution partners in parts of Europe, Asia) yes (also sold via OEM distribution, local distributors) yes (also sold via OEM distribution, local distributors)
FDA-app
FDA-approved clotting-based tests QPlus cartridge: clot time, clot time with heparinase, clot time — —
ratio, clot stiffness, more; QStat cartridge: clot time, clot stability FDA-app
to lysis, clot stiffness, platelet contribution to clot stiffness, more
FDA-approved chromogenic tests — — —
FDA-approved immunologic tests — — — FDA-app
Other FDA-approved tests — — —
User-defined tests in clinical use — — — Other FD
Tests in development or awaiting FDA 510(k) clearance — — — User-defi
Methodologies supported clot detection, sonic estimation of elasticity via resonance clot detection, mechanical and optical; photometric with mechanical clot detection, mechanical and optical; photometric with mechanical Tests in d
(SEER) sonorheometry stirring, turbodensitometric; chromogenic; immunologic (photometric) stirring, turbodensitometric; chromogenic; immunologic (photometric) Methodo
Number of different measured assays onboard simultaneously 11 15 15 Number o
Number of different assays programmed and calib. at one time no calibration required 15 50 Number o
No. of user-definable (open) channels/No. active simultaneously — — 50/15 No. of use
Factor assays require manual manipulation or dilutions — yes (manual manipulation and dilutions) — Factor as
Test throughput per hour/Assay run time 5–6 (25–36 tests in throughput)/7–60 min. (avg. 12.5 min.) CoaDATA 2004: ~60 PT tests (1 test in throughput); CoaDATA 120 PT tests/— Test thro
4004: ~120 PT tests (1 test in throughput)/— Design o
Design of sample-handling system sealed room-temperature-stable cartridges accept a standard semiautomated analyzer with 2 and 4 channels cuvette ring, sample cups
3.2% citrate blue top tube, manually affixed to cartridge Operates
Operates on whole blood or spun plasma whole blood spun plasma spun plasma Reagent
Reagent type self-contained single-use cartridges (lyophilized [reconstituted self-contained single-use vials; open reagent system (liquid, self-contained single-use vials; open reagent system (liquid,
manually]) lyophilized [reconstituted manually]) lyophilized [reconstituted manually]) Reagent
Reagent barcode-reading capability yes, for all tests yes, for all tests yes, for some tests No. of rea
No. of reagent containers held onboard/Reagents ready to use 1 cartridge/yes 4/variable (reagent specific) 15/yes Reagent
Reagent lot tracking/Reagent inventory/Reagents refrigerated yes/no/no (20°–25°C) yes/—/no yes/yes/no onboar
onboard Reagents
Reagents, consumables loaded without interrupting testing no yes (reagents and consumables) yes (reagents) Instrume
Instrument uses proprietary or third-party reagents proprietary reagents user’s option user’s option (same capabilities when third-party reagents used) Maximum
Maximum time same lot number of reagents can be used — — —
Walkawa
Walkaway capability/Walkaway duration yes/~12.5 min. or 1 specimen or 5–6 tests no/— yes/22 samples plus 3 stat (reagent dependent) Min.–ma
Min.–max. specimen volume that can be aspirated at one time — 50–150 µL (total volume) 2–275 µL Min. sam
Min. sample volume required for PT/PTT/Factor VIII activity — 50 µL/50 µL/reagent dependent 50 µL/50 µL/assay dependent Types of
Types of disposables used single use cartridges, weekly cleaning cartridge, QC level 1 and 2 cuvettes, pipette tips, stir bars — Primary t
Primary tube sampling supported/Pierces caps on primary tubes yes/yes —/no yes/no Accomm
Accommodates most standard tube sizes/Nonstandard sizes yes/— no/no yes/no Sample b
Sample barcode-reading capability/Autodiscrimination yes/— yes/no yes (Interleaved 2 of 5, UPC, Codabar, Code 39, Code 128)/no Auto track
Auto tracks product volume/Measures number of tests remaining — no/no yes/yes Short sam
Short sample detection — no yes Clot dete
Clot detection as preanalytical variable in plasma sample — no no Auto dete
Auto detects adequate reagents for aspiration or analysis — no yes (aspiration and analysis) Detection
Detection or quantitation for hemolysis, turbidity, icterus, lipemia no detection for hemolysis, turbidity, icterus, lipemia no Dilutes p
Dilutes patient samples onboard no no yes Automati
Automatic rerun capability/Auto reflex testing capability no/no no/no yes/no Lag time
Lag time during which hypercoagulable sample not detected no no no User can
User can adjust reagent volumes/Sample volumes no/no yes/yes yes/yes User can
User can adjust No. of reagents/Sources of reagents yes/yes no/no yes/yes User can
User can adjust incubation times/Reading times no/variable yes/yes yes/yes Read tim
Read time extended for prolonged clotting times — no yes (selectable on menus) Autocalib
Autocalibration/Calibrants stored onboard — no/no yes/yes Multipoin
Multipoint calibration supported/Recommended frequency no calibration required yes/— yes/with lot change Stat time
Stat time to complete all analytes/Throughput per hour for: • PT alon
• PT alone — — <2 minutes/120 specimens • PT, PTT
• PT, PTT — — <5 minutes/71 specimens • Fibrino
• Fibrinogen fibrinogen contribution to clot stiffness: ~12.5 min./— — <5 minutes/50 specimens • Factor
• Factor VIII activity assay — — <6 minutes/— • D-dime
• D-dimer — — <6 minutes/— Time del
Time delay from ordering stat to aspiration of sample none — 3 minutes How labs
How labs get LOINC codes for results email query, included in Quantra implementation guide, functionality not provided functionality not provided Onboard
addressed during training Informati
Onboard real-time QC/Onboard software capability to review QC yes/yes no/no yes/yes Compatib
Information that can be barcode-scanned on instrument operator identifier, specimen identifier, reagent lot No., lot specimen identifier, reagent lot No. specimen identifier Data-ma
specific QC target ranges Interface
Compatible with laboratory automation systems no no no Results t
Data-management capability/LIS or EHR systems interfaced onboard/— no/— onboard/— Bidirectio
Interface supplied by instrument vendor yes yes (included in analyzer price) no Remote s
Results transferred to LIS as soon as test time complete yes yes yes Instrume
Bidirectional interface capability yes (broadcast download) no yes (host query)
Remote servicing provided/UPS backup power supply no/no no/no no/no
Instrument connections to transfer information directly to LIS; commercial middleware (RALS, Telcor, UniPOC, directly to LIS; directly to EHR data-management system, which in turn connects to LIS; Interface
Cobas Infinity, DI Data Innovations) directly to LIS Informati
Interface standards supported LIS: compliant to CLSI LIS02-A2; POC testing middleware: — LAN connection provides FTP result file transfer
compliant to CLSI POCT01-A2 Avg. time
Information transferred to data-management software device unique identifier, operator ID, patient ID, result, QC patient ID, result device unique identifier, patient ID, specimen ID, result Approxim
identifier, date and time of assay start, more Maintena
Avg. time for basic user training up to 5 days (approx. 2 days at vendor office) 1 day (at vendor office, on request) 3 days (at customer and vendor offices) Warranty
Approximate scheduled maintenance time weekly: 3 minutes; monthly: 12 minutes per shift: <1 minute; daily: <1 minute; weekly: <1 minute; per shift: 1 minute; daily: 3 minutes; weekly: 5 minutes;
monthly: <3 minutes monthly: 15 minutes Distingui
Maintenance records kept onboard yes no yes
Warranty with purchase/Annual service contract cost (24/7) yes/— (cost dependent on contract) yes/— yes/—
Distinguishing features (supplied by company) ultrasound measure of whole blood hemostasis directly advanced coagulation diagnostics by selectable dual easy-to-use, standalone device with small footprint; onboard
measures physical properties of a developing clot; wide range wavelength optics (405/750 nm) for each measuring channel; user and service software, no external PC required; optimized
of clinical indications with simplified interpretation allows for more sensitive to interferences from hemolysis, icteric, and for small to mid-sized labs Note: a d
Note: a dash in lieu of an answer means company did not better communication; novel technology allows for parameters lipemic samples; intuitive flexible user software; minimum answer q
answer question or question is not applicable not available in other systems, e.g. platelet contribution to clot maintenance, repair times, and costs (incl. printer)
All information is supplied by the companies listed. The tabulation does not represent an endorsement by the CAP. All informa

JANUARY 2023 page 36

 COAGULATION ANALYZERS JANUARY 2023 | CAP TODAY 37

Part 4 of 6 Siemens Healthineers Siemens Healthineers Siemens Healthineers

Aura Fucci aura.fucci@siemens-healthineers.com Aura Fucci aura.fucci@siemens-healthineers.com Aura Fucci aura.fucci@siemens-healthineers.com
Tarrytown, NY Tarrytown, NY Tarrytown, NY
914-631-8000 siemens-healthineers.us.com 914-631-8000 siemens-healthineers.us.com 914-631-8000 siemens-healthineers.us.com
Instrument name/First year sold BCS XP Analyzer/2006 BFT II Analyzer/1999 Sysmex CA-600 Series Systems/2012
List price/Model type $171,000/benchtop $8,500/benchtop CA-620: $42,000; CA-660: $55,000/benchtop
Dimensions (H × W × D)/Weight/Instrument footprint 37 × 49 × 25 in./330 lbs./8.5 sq. ft. 3.9 × 7.9 × 11.8 in./8.4 lbs./0.65 sq. ft. 22.5 × 19.5 × 19.5 in./94.6 lbs./3.1 sq. ft.
No. of units in clinical use in U.S./Outside U.S. (countries) >350/>1,000 (worldwide) —/— (worldwide) >2,000/>5,000 (worldwide)
Composition of installs: Hospital lab/Reference lab/Other — — —
Targeted daily, monthly, annual test volume daily: >300 daily: 1 daily: <25
00–95,000 Operational type continuous random access batch continuous random access
Country where analyzer designed/Manufactured Germany/Germany Germany/Germany Japan/Japan
Company manufactures instrument yes yes no (manufactured by Sysmex)
s)
FDA-approved clotting-based tests PT, APTT, fibrinogen, factors II, V, VII, VIII, IX, X, XI, XII, protein C, PT, APTT, fibrinogen PT, APTT, fibrinogen, factors VII, VIII, protein C, TT, batroxobin time
protein S, lupus, factor V Leiden, TT, batroxobin time
FDA-approved chromogenic tests antithrombin, protein C, Innovance free protein S antigen, — Sysmex CA-660 only: antithrombin, protein C, Innovance
plasminogen, Innovance heparin, factor VIII chromogenic, heparin
alpha-2-antiplasmin
FDA-approved immunologic tests Innovance VWF Ac, Innovance D-dimer, von Willebrand — Sysmex CA-660 only: Innovance D-dimer
factor-ristocetin cofactor assay
Other FDA-approved tests — — —
User-defined tests in clinical use — — —
mechanical Tests in development or awaiting FDA 510(k) clearance — — —
hotometric) Methodologies supported clot detection, optical; chromogenic; immunologic clot detection, mechanical and optical clot detection, optical; chromogenic; immunologic
Number of different measured assays onboard simultaneously >100 1 5
Number of different assays programmed and calib. at one time 99 3 7
No. of user-definable (open) channels/No. active simultaneously 7,999/>100 — 7/5
Factor assays require manual manipulation or dilutions — — —
Test throughput per hour/Assay run time 380 (1 test in throughput)/1–3 min. (avg. 5 min.) —/5 min. 60 (1 test in throughput)/1–3 min. (avg. 5 min.)
Design of sample-handling system continuous loading uncapped primary sample tubes and cups manual 10-tube position sample rack
in same rack; 10-tube position sample rack
Operates on whole blood or spun plasma spun plasma spun plasma spun plasma
Reagent type self-contained single-use vials; open reagent system (liquid, self-contained single-use vials; open reagent system (liquid, self-contained single-use vials; open reagent system (liquid,
m (liquid, lyophilized [reconstituted manually]) lyophilized [reconstituted manually]) lyophilized [reconstituted manually])
Reagent barcode-reading capability yes, for all tests no yes, for all tests
No. of reagent containers held onboard/Reagents ready to use 90/yes 4/yes 11/yes
Reagent lot tracking/Reagent inventory/Reagents refrigerated yes/yes/yes (15°C ± 2°C) no/no/no yes/yes/no (15°C ± 2°C)
onboard
Reagents, consumables loaded without interrupting testing yes (reagents and consumables) yes (reagents and consumables) no
Instrument uses proprietary or third-party reagents user’s option (same capabilities when third-party reagents used) proprietary reagents, third-party reagents, user’s option user’s option (same capabilities when third-party reagents used)
ents used) Maximum time same lot number of reagents can be used 1 year 1 year 1 year
Walkaway capability/Walkaway duration yes/100 specimens or up to 400 tests no/— yes/10 specimens or up to 50 tests
Min.–max. specimen volume that can be aspirated at one time 3 µL minimum — 5 µL minimum
Min. sample volume required for PT/PTT/Factor VIII activity 50 µL/50 µL/5 µL (standard) 50 µL/50 µL/— 50 µL/50 µL/5 µL (standard)
Types of disposables used rotors and wash solution cuvettes reaction tubes, CA clean I and II
Primary tube sampling supported/Pierces caps on primary tubes yes/no no/no yes/no
Accommodates most standard tube sizes/Nonstandard sizes yes/yes no/no yes/yes
Sample barcode-reading capability/Autodiscrimination yes/— no/— yes/—
e 128)/no Auto tracks product volume/Measures number of tests remaining yes/yes no/no yes/no
Short sample detection yes no yes
Clot detection as preanalytical variable in plasma sample no no no
Auto detects adequate reagents for aspiration or analysis yes (aspiration and analysis) no no
Detection or quantitation for hemolysis, turbidity, icterus, lipemia no no no
Dilutes patient samples onboard yes no yes
Automatic rerun capability/Auto reflex testing capability yes/yes no/no no/no
Lag time during which hypercoagulable sample not detected yes (PT and PTT: 7 seconds) no yes (PT: 7 seconds; PTT: 15 seconds)
User can adjust reagent volumes/Sample volumes yes/yes yes/yes yes/yes
User can adjust No. of reagents/Sources of reagents yes/yes yes/yes yes/yes
User can adjust incubation times/Reading times yes/yes yes/yes yes/yes
Read time extended for prolonged clotting times yes yes yes
Autocalibration/Calibrants stored onboard yes/yes no/yes no/yes
Multipoint calibration supported/Recommended frequency yes/6 months, per regulatory guidelines yes/6 months, per regulatory guidelines yes/6 months, per regulatory guidelines
Stat time to complete all analytes/Throughput per hour for:
• PT alone 5 minutes/380 specimens 1 minute/1 specimen 7 minutes/60 specimens
• PT, PTT 5 minutes/325 specimens — 8 minutes/24 specimens
• Fibrinogen 5 minutes/315 specimens 1 minute/1 specimen 7 minutes/60 specimens
• Factor VIII activity assay 5 minutes/280 specimens — 5 minutes/—
• D-dimer 5 minutes/— — 6 minutes/12 specimens
Time delay from ordering stat to aspiration of sample 1 minute — 1 minute
How labs get LOINC codes for results website website website
Onboard real-time QC/Onboard software capability to review QC yes/yes no/no yes/yes
Information that can be barcode-scanned on instrument operator identifier, specimen identifier, reagent lot No. — specimen identifier, reagent lot No.
Compatible with laboratory automation systems no no no
Data-management capability/LIS or EHR systems interfaced onboard/most major vendors no/no onboard/most major vendors
Interface supplied by instrument vendor contract dependent no contract dependent
Results transferred to LIS as soon as test time complete yes no yes
Bidirectional interface capability yes (host query) no yes (host query)
Remote servicing provided/UPS backup power supply no/yes no/no no/no
Instrument connections to transfer information data-management system, which in turn connects to LIS or commercial middleware (most major companies) data-management system, which in turn connects to LIS or
EHR; directly to LIS or EHR; directly to lab automation system; EHR; directly to LIS or EHR; directly to lab automation system;
commercial middleware (most major companies) commercial middleware (most major companies)
o LIS; Interface standards supported ASTM 1394-91, ASTM 1381, HL7 — ASTM 1394-91, ASTM 1381, HL7, CA-1000 protocol
Information transferred to data-management software device unique identifier, operator ID, patient ID, specimen ID, — device unique identifier, patient ID, specimen ID, result, QC
result, QC identifier, PSI checks identifier
Avg. time for basic user training varies at customer site, 3 days at vendor office Siemens PEPconnect online 2 days (at customer site)
ult Approximate scheduled maintenance time daily: 5 minutes; weekly: 10 minutes; monthly: 15 minutes daily: 1 minute daily: 8 minutes
Maintenance records kept onboard no no no
Warranty with purchase/Annual service contract cost (24/7) yes/— (cost dependent on contract) yes/— yes/— (cost dependent on contract)
tes;
Distinguishing features (supplied by company) user-definable calibration curve expiration and prewarning 2-channel micro reagent volume clot-based technology; opto- maximizes counter space with compact footprint in
alerts; user-definable barcode utility enables customizable mechanical detection accurate on lipemic, icteric samples; auto- low-volume labs; increases uptime and reduces service
reagent protocols; user-friendly Windows 10 software matic INR calculation, curve storage, built-in thermal printer; expenses; CA-620 system for routine clotting-based testing,
effective for low-volume testing, backup to larger systems CA-660 system for clotting, chromogenic, and immunologic
onboard testing
optimized
Note: a dash in lieu of an answer means company did not
answer question or question is not applicable

All information is supplied by the companies listed. The tabulation does not represent an endorsement by the CAP.

e 36 JANUARY 2023 page 37

38 CAP TODAY | JANUARY 2023 COAGULATION ANALYZERS
Part 5 of 6 Siemens Healthineers Siemens Healthineers Werfen Part 6 of
Aura Fucci aura.fucci@siemens-healthineers.com Aura Fucci aura.fucci@siemens-healthineers.com V. Shirley vshirley@werfen.com
Tarrytown, NY Tarrytown, NY Bedford, MA
914-631-8000 siemens-healthineers.us.com 914-631-8000 siemens-healthineers.us.com 781-674-3221 www.werfen.com
Instrument name/First year sold Sysmex CS-2500 System/2016 Sysmex CS-5100 System/2016 ACL AcuStar/2010 Instrume
List price/Model type $155,000/benchtop $205,000/floor standing —/benchtop List price
Dimensions (H × W × D)/Weight/Instrument footprint 27 × 30.6 × 35.2 in./242.5 lbs./7.5 sq. ft. 50.4 × 40.6 × 45.3 in./612.9 lbs./12.8 sq. ft. 21 × 34 × 24 in./170 lbs./10 sq. ft. Dimensio
No. of units in clinical use in U.S./Outside U.S. (countries) >500/>2,000 (worldwide) >100/>1,000 (worldwide) 5/196 (available in most countries) No. of un
Composition of installs: Hospital lab/Reference lab/Other — — 100%/0/0 Composi
Targeted daily, monthly, annual test volume daily: 25–300 daily: >300 daily: 20–150; monthly: 600–4,500; annual: 36,000–54,000 Targeted
Operational type continuous random access continuous random access random access Operation
Country where analyzer designed/Manufactured Japan/Japan Japan/Japan U.S./U.S. Country w
Company manufactures instrument no (manufactured by Sysmex) no (manufactured by Sysmex) no Company
FDA-approved clotting-based tests PT, APTT, fibrinogen, factors II, V, VII, VIII, IX, X, XI, XII, protein C, PT, APTT, fibrinogen, factors II, V, VII, VIII, IX, X, XI, XII, protein C, — FDA-app
lupus, factor V Leiden, TT, batroxobin time lupus, factor V Leiden, TT, batroxobin time
FDA-approved chromogenic tests antithrombin, protein C, Innovance free protein S antigen, antithrombin, protein C, Innovance free protein S antigen, — FDA-app
plasminogen, Innovance heparin, factor VIII chromogenic, plasminogen, Innovance heparin, factor VIII chromogenic,
alpha-2-antiplasmin alpha-2-antiplasmin FDA-app
FDA-approved immunologic tests Innovance VWF Ac, Innovance D-dimer Innovance VWF Ac, Innovance D-dimer HIT IgG, domain 1, anticardiolipin IgG, anticardiolipin IgM,
B2GPI IgG, B2GPI IgM
Other FDA-approved tests — — — Other FD
User-defined tests in clinical use platelet aggregation, anti-Xa rivaroxaban RUO platelet aggregation, anti-Xa rivaroxaban RUO — User-defi
Tests in development or awaiting FDA 510(k) clearance von Willebrand factor von Willebrand factor ADAMTS13, von Willebrand factor ristocetin cofactor, von Tests in d
Willebrand antigen
Methodologies supported clot detection, optical; chromogenic; immunologic clot detection, optical; chromogenic; immunologic immunologic (chemiluminescent) Methodo
Number of different measured assays onboard simultaneously 60 60 20
Number of different assays programmed and calib. at one time 60 60 20 Number o
No. of user-definable (open) channels/No. active simultaneously 80,000/60 80,000/60 0/0 Number o
Factor assays require manual manipulation or dilutions — — — No. of use
Test throughput per hour/Assay run time 180 (2 tests in throughput)/1–10 min. (avg. 5 min.) 400 (2 tests in throughput)/1–10 min. (avg. 5 min.) 60 (1 test in throughput)/30 min. Factor as
Design of sample-handling system continuous loading capped and uncapped primary sample tubes continuous loading capped and uncapped primary sample tubes samples loaded into carousel rack Test thro
and cups in same rack; 10-tube position sample rack × 5 and cups in same rack; 10-tube position sample rack × 10 Design o
Operates on whole blood or spun plasma spun plasma spun plasma spun plasma
Reagent type self-contained single-use vials; open reagent system (liquid, self-contained single-use vials; open reagent system (liquid, self-contained multiuse cartridges (liquid) Operates
lyophilized [reconstituted manually]) lyophilized [reconstituted manually]) Reagent
Reagent barcode-reading capability yes, for all tests yes, for all tests yes, for all tests
No. of reagent containers held onboard/Reagents ready to use 40/yes 40/yes 20/yes Reagent
Reagent lot tracking/Reagent inventory/Reagents refrigerated yes/yes/yes (10°C ± 2°C) yes/yes/yes (10°C ± 2°C) yes/yes/yes No. of rea
onboard Reagent
Reagents, consumables loaded without interrupting testing yes (reagents and consumables) yes (reagents and consumables) yes (reagents and consumables) onboar
Instrument uses proprietary or third-party reagents user’s option (same capabilities when third-party reagents used) user’s option (same capabilities when third-party reagents used) proprietary reagents Reagents
Maximum time same lot number of reagents can be used 1 year 1 year 6 months Instrume
Maximum
Walkaway capability/Walkaway duration yes/50 specimens or up to 500 tests yes/100 specimens or up to 1,000 tests yes/30 specimens or 280 tests
Min.–max. specimen volume that can be aspirated at one time 5 µL minimum 5 µL minimum 2–250 µL Walkawa
Min. sample volume required for PT/PTT/Factor VIII activity 50 µL/50 µL/5 µL (standard) 50 µL/50 µL/5 µL (standard) 50 µL/50 µL/50 µL Min.–ma
Types of disposables used reaction tubes, CA clean I and II reaction tubes, CA clean I and II cuvettes, trigger, solutions Min. sam
Primary tube sampling supported/Pierces caps on primary tubes yes/yes yes/yes yes/no Types of
Accommodates most standard tube sizes/Nonstandard sizes yes/yes yes/yes yes/no Primary t
Sample barcode-reading capability/Autodiscrimination yes/— yes/— yes/yes Accomm
Auto tracks product volume/Measures number of tests remaining yes/yes yes/yes yes/yes Sample b
Short sample detection yes yes yes Auto track
Clot detection as preanalytical variable in plasma sample yes yes no Short sam
Auto detects adequate reagents for aspiration or analysis yes (aspiration and analysis) yes (aspiration and analysis) yes (aspiration and analysis) Clot dete
Detection or quantitation for hemolysis, turbidity, icterus, lipemia detection and quantitation for hemolysis, turbidity, icterus, lipemia detection and quantitation for hemolysis, turbidity, icterus, lipemia — Auto dete
Dilutes patient samples onboard yes yes yes Detection
Automatic rerun capability/Auto reflex testing capability yes/yes yes/yes yes/yes Dilutes p
Lag time during which hypercoagulable sample not detected yes (PT: 7 seconds; PTT: 15 seconds) yes (PT: 7 seconds; PTT: 15 seconds) — Automati
User can adjust reagent volumes/Sample volumes yes/yes yes/yes no/no Lag time
User can adjust No. of reagents/Sources of reagents yes/yes yes/yes no/no User can
User can adjust incubation times/Reading times yes/yes yes/yes no/no User can
Read time extended for prolonged clotting times yes (selectable on menus) yes (selectable on menus) no User can
Autocalibration/Calibrants stored onboard no/yes no/yes no/no Read tim
Multipoint calibration supported/Recommended frequency yes/6 months, per regulatory guidelines yes/6 months, per regulatory guidelines yes/6 months Autocalib
Multipoin
Stat time to complete all analytes/Throughput per hour for:
• PT alone 5 minutes/180 specimens 5 minutes/400 specimens — Stat time
• PT, PTT 5 minutes/90 specimens 5 minutes/200 specimens — • PT alon
• Fibrinogen 5 minutes/180 specimens 5 minutes/201 specimens — • PT, PTT
• Factor VIII activity assay 5 minutes/— 5 minutes/— — • Fibrino
• D-dimer 5 minutes/90 specimens 5 minutes/202 specimens — • Factor
Time delay from ordering stat to aspiration of sample 1 minute 1 minute <1 minute • D-dime
How labs get LOINC codes for results website website functionality not provided Time del
Onboard real-time QC/Onboard software capability to review QC yes/yes yes/yes yes/yes How labs
Information that can be barcode-scanned on instrument operator identifier, specimen identifier, reagent lot No. operator identifier, specimen identifier, reagent lot No. specimen identifier, reagent lot No. Onboard
Compatible with laboratory automation systems no yes (Siemens Aptio Automation) no Informati
Data-management capability/LIS or EHR systems interfaced onboard/most major vendors onboard/most major vendors onboard/Meditech Compatib
Interface supplied by instrument vendor contract dependent contract dependent contract dependent Data-ma
Results transferred to LIS as soon as test time complete yes yes yes
Bidirectional interface capability yes (host query) yes (host query) yes (broadcast download and host query) Interface
Results t
Remote servicing provided/UPS backup power supply yes/yes yes/yes no/yes Bidirectio
Instrument connections to transfer information data-management system, which in turn connects to LIS or data-management system, which in turn connects to LIS or data-management system, which in turn connects to LIS;
EHR; directly to LIS or EHR; directly to lab automation system; EHR; directly to LIS or EHR; directly to lab automation system; directly to LIS; commercial middleware (Werfen, Beckman) Remote s
commercial middleware (most major companies) commercial middleware (most major companies) Instrume
Interface standards supported ASTM 1394-91, ASTM 1381 ASTM 1394-91, ASTM 1381 ASTM 1394-91
Information transferred to data-management software device unique identifier, operator ID, patient ID, specimen ID, device unique identifier, operator ID, patient ID, specimen ID, specimen ID
result, QC identifier, PSI checks result, QC identifier, PSI checks Interface
Avg. time for basic user training varies at customer site, 3 days at vendor office varies at customer site, 3 days at vendor office 4 days (at customer site) Informati
Approximate scheduled maintenance time daily: 5 minutes; weekly: 1 minute; monthly: 1 minute daily: 5 minutes; weekly: 1 minute; monthly: 1 minute daily: 5 minutes; weekly: 5 minutes Avg. time
Maintenance records kept onboard yes yes yes Approxim
Maintena
Warranty with purchase/Annual service contract cost (24/7) yes/— (cost dependent on contract) yes/— (cost dependent on contract) yes/— (cost dependent on contract)
Warranty
Distinguishing features (supplied by company) confidence: simultaneous multiwavelength detection and PSI confidence: simultaneous multiwavelength detection and PSI on-demand HIT IgG testing with results available in 30 Distingui
technology designed to ensure high-quality first-run results; technology designed to ensure high-quality first-run results; minutes; uses sensitive chemiluminescent technology,
operational efficiency: user-friendly software on Windows 10; operational efficiency: user-friendly software on Windows 10; improving sensitivity; reagents are ready to use with onboard
tilted reagent vials for efficiency; consistency: for multisite tilted reagent vials for efficiency; consistency: for multisite stability up to 12 weeks
Note: a dash in lieu of an answer means company did not patient monitoring, with sample result traceability for in-depth patient monitoring, with sample result traceability for in-depth Note: a d
answer question or question is not applicable audit capabilities audit capabilities answer q

All information is supplied by the companies listed. The tabulation does not represent an endorsement by the CAP. All informa

JANUARY 2023 page 38

 COAGULATION ANALYZERS JANUARY 2023 | CAP TODAY 39

Part 6 of 6 Werfen Werfen Werfen

V. Shirley vshirley@werfen.com V. Shirley vshirley@werfen.com V. Shirley vshirley@werfen.com
Bedford, MA Bedford, MA Bedford, MA
781-674-3221 www.werfen.com 781-674-3221 www.werfen.com 781-674-3221 www.werfen.com
Instrument name/First year sold ACL TOP 350/2016 ACL TOP 550 CTS/2016 ACL TOP 750 Series/2016
List price/Model type —/benchtop —/benchtop —/floor standing
Dimensions (H × W × D)/Weight/Instrument footprint 29 × 32 × 33 in./200 lbs./8 sq. ft. 29 × 43 × 35 in./312 lbs./14 sq. ft. 29 × 60 × 35 in./356 lbs./21 sq. ft.
No. of units in clinical use in U.S./Outside U.S. (countries) 1,309/3,700 (available in most countries) 737/3,400 (available in most countries) 737/3,200 (available in most countries)
Composition of installs: Hospital lab/Reference lab/Other 95%/5%/— 85%/12%/3% (pharmaceutical or medical device labs) 85%/12%/3% (pharmaceutical or medical device labs)
–54,000 Targeted daily, monthly, annual test volume daily: 20–150; monthly: 600–4,500; annual: 36,000–54,000 daily: 100–200; monthly: 3,000–6,000; annual: 36,000–72,000 daily: 200–400; monthly: 6,000–12,000; annual: 72,000–144,000
Operational type random access random access random access
Country where analyzer designed/Manufactured U.S./U.S. U.S./U.S. U.S./U.S.
Company manufactures instrument yes yes yes
FDA-approved clotting-based tests PT, APTT, fibrinogen, thrombin time, factor assays, lupus PT, APTT, fibrinogen, thrombin time, factor assays, lupus PT, APTT, fibrinogen, thrombin time, factor assays, lupus
anticoagulant (dRVVT and silica clotting time), protein S, protein C anticoagulant (dRVVT and silica clotting time), protein S, protein C anticoagulant (dRVVT and silica clotting time), protein S, protein C
FDA-approved chromogenic tests anti-Xa, apixaban, protein C, antithrombin, plasminogen, anti-Xa, apixaban, protein C, antithrombin, plasminogen, anti-Xa, apixaban, protein C, antithrombin, plasminogen,
plasmin inhibitor plasmin inhibitor plasmin inhibitor
FDA-approved immunologic tests high specificity D-dimer, standard D-dimer, heparin induced high specificity D-dimer, standard D-dimer, heparin induced high specificity D-dimer, standard D-dimer, heparin induced
n IgM, thrombocytopenia, von Willebrand factor antigen, von Willebrand thrombocytopenia, von Willebrand factor antigen, von Willebrand thrombocytopenia, von Willebrand factor antigen, von Willebrand
factor activity, free protein S, factor XIII antigen, homocysteine factor activity, free protein S, factor XIII antigen, homocysteine factor activity, free protein S, factor XIII antigen, homocysteine
Other FDA-approved tests — — —
User-defined tests in clinical use DOAC assays, chromogenic factor VIII DOAC assays, chromogenic factor VIII DOAC assays, chromogenic factor VIII
or, von Tests in development or awaiting FDA 510(k) clearance von Willebrand factor ristocetin cofactor, dabigatran, von Willebrand factor ristocetin cofactor, dabigatran, von Willebrand factor ristocetin cofactor, dabigatran,
rivaroxaban, apixaban rivaroxaban, apixaban rivaroxaban, apixaban
Methodologies supported clot detection, optical; chromogenic; immunologic clot detection, optical; chromogenic; immunologic clot detection, optical; chromogenic; immunologic
(immunoturbidimetric) (immunoturbidimetric) (immunoturbidimetric)
Number of different measured assays onboard simultaneously 30 30 30
Number of different assays programmed and calib. at one time 500 500 500
No. of user-definable (open) channels/No. active simultaneously 250/250 250/250 250/250
Factor assays require manual manipulation or dilutions — — —
Test throughput per hour/Assay run time 110 (1 test in throughput)/3–6 min. (avg. 4 min.) 240 (1 test in throughput)/3–6 min. (avg. 4 min.) 360 (1 test in throughput)/3–6 min. (avg. 4 min.)
Design of sample-handling system samples loaded into rack; system uses integrated sample barcode samples loaded into rack; system uses integrated sample barcode samples loaded into rack; system uses integrated sample barcode
reader to eliminate any post-draw sample misidentification reader to eliminate any post-draw sample misidentification reader to eliminate any post-draw sample misidentification
Operates on whole blood or spun plasma spun plasma spun plasma spun plasma
Reagent type self-contained multiuse vials; open reagent system (liquid, self-contained multiuse vials; open reagent system (liquid, self-contained multiuse vials; open reagent system (liquid,
lyophilized [reconstituted manually]) lyophilized [reconstituted manually]) lyophilized [reconstituted manually])
Reagent barcode-reading capability yes, for all tests yes, for all tests yes, for all tests
No. of reagent containers held onboard/Reagents ready to use 24/variable (reagent specific) 40/variable (reagent specific) 60/variable (reagent specific)
Reagent lot tracking/Reagent inventory/Reagents refrigerated yes/yes/yes yes/yes/yes yes/yes/yes
onboard
Reagents, consumables loaded without interrupting testing yes (reagents and consumables) yes (reagents and consumables) yes (reagents and consumables)
Instrument uses proprietary or third-party reagents user’s option (same capabilities when third-party reagents used) user’s option (same capabilities when third-party reagents used) user’s option (same capabilities when third-party reagents used)
Maximum time same lot number of reagents can be used 18 months 18 months 18 months
Walkaway capability/Walkaway duration yes/40 specimens or 800 tests yes/80 specimens or 800 tests yes/120 specimens or 800 tests
Min.–max. specimen volume that can be aspirated at one time 2–250 µL 2–250 µL 2–250 µL
Min. sample volume required for PT/PTT/Factor VIII activity 50 µL/50 µL/50 µL 50 µL/50 µL/50 µL 50 µL/50 µL/50 µL
Types of disposables used cuvettes, clean A/B, rinse cuvettes, clean A/B, rinse cuvettes, clean A/B, rinse
Primary tube sampling supported/Pierces caps on primary tubes yes/yes yes/yes yes/yes
Accommodates most standard tube sizes/Nonstandard sizes yes/yes yes/yes yes/yes
Sample barcode-reading capability/Autodiscrimination yes (Interleaved 2 of 5, Code 39, Code 128)/yes yes (Interleaved 2 of 5, Code 39, Code 128)/yes yes (Interleaved 2 of 5, Code 39, Code 128)/yes
Auto tracks product volume/Measures number of tests remaining yes/yes yes/yes yes/yes
Short sample detection yes yes yes
Clot detection as preanalytical variable in plasma sample yes yes yes
Auto detects adequate reagents for aspiration or analysis yes (aspiration and analysis) yes (aspiration and analysis) yes (aspiration and analysis)
Detection or quantitation for hemolysis, turbidity, icterus, lipemia detection and quantitation for hemolysis, turbidity, icterus, lipemia detection and quantitation for hemolysis, turbidity, icterus, lipemia detection and quantitation for hemolysis, turbidity, icterus, lipemia
Dilutes patient samples onboard yes yes yes
Automatic rerun capability/Auto reflex testing capability yes/yes yes/yes yes/yes
Lag time during which hypercoagulable sample not detected no no no
User can adjust reagent volumes/Sample volumes yes/yes yes/yes yes/yes
User can adjust No. of reagents/Sources of reagents yes/yes yes/yes yes/yes
User can adjust incubation times/Reading times yes/yes yes/yes yes/yes
Read time extended for prolonged clotting times yes (selectable on menus) yes (selectable on menus) yes (selectable on menus)
Autocalibration/Calibrants stored onboard no/no no/no no/no
Multipoint calibration supported/Recommended frequency yes/6 months yes/6 months yes/6 months
Stat time to complete all analytes/Throughput per hour for:
• PT alone <3 minutes/110 specimens <3 minutes/240 specimens <3 minutes/360 specimens
• PT, PTT <6 minutes/55 specimens <6 minutes/90 specimens <6 minutes/165 specimens
• Fibrinogen <3 minutes/60 specimens <3 minutes/78 specimens <3 minutes/108 specimens
• Factor VIII activity assay 8 minutes/38 specimens 8 minutes/77 specimens 8 minutes/100 specimens
• D-dimer 5 minutes/55 specimens 5 minutes/75 specimens 5 minutes/100 specimens
Time delay from ordering stat to aspiration of sample none none none
How labs get LOINC codes for results functionality not provided functionality not provided functionality not provided
Onboard real-time QC/Onboard software capability to review QC yes/yes yes/yes yes/yes
Information that can be barcode-scanned on instrument specimen identifier, reagent lot No. specimen identifier, reagent lot No. specimen identifier, reagent lot No.
Compatible with laboratory automation systems no no yes (HemoCell, Beckman, Siemens, Abbott, Thermo Fisher, others)
Data-management capability/LIS or EHR systems interfaced onboard/Cerner, CompuLab, CPSI, HBOC, HMS, McKesson, onboard/Cerner, CompuLab, CPSI, HBOC, HMS, McKesson, onboard/Cerner, CompuLab, CPSI, HBOC, HMS, McKesson,
Meditech, Novius, SMS, SCC, Clinisys, Vista Meditech, Novius, SMS, SCC, Clinisys, Vista Meditech, Novius, SMS, SCC, Clinisys, Vista
Interface supplied by instrument vendor contract dependent contract dependent contract dependent
Results transferred to LIS as soon as test time complete yes yes yes
Bidirectional interface capability yes (broadcast download and host query) yes (broadcast download and host query) yes (broadcast download and host query)
o LIS;
kman) Remote servicing provided/UPS backup power supply yes/yes yes/yes yes/yes
Instrument connections to transfer information data-management system, which in turn connects to LIS; data-management system, which in turn connects to LIS; data-management system, which in turn connects to LIS;
directly to LIS; commercial middleware (Beckman) directly to LIS; commercial middleware (Beckman) directly to LIS; directly to lab automation system; commercial
middleware (Beckman)
Interface standards supported ASTM 1394-91 ASTM 1394-91 ASTM 1394-91
Information transferred to data-management software specimen ID specimen ID specimen ID
Avg. time for basic user training 9 days (5 days at customer site, 4 days at vendor office) 14 days (10 days at customer site, 4 days at vendor office) 14 days (10 days at customer site, 4 days at vendor office)
Approximate scheduled maintenance time daily: <5 minutes; weekly: <10 minutes daily: <5 minutes; weekly: <10 minutes daily: <5 minutes; weekly: <10 minutes
Maintenance records kept onboard yes yes yes
Warranty with purchase/Annual service contract cost (24/7) yes/— (cost dependent on contract) yes/— (cost dependent on contract) yes/— (cost dependent on contract)
30 Distinguishing features (supplied by company) FDA 510(k) approved; improves patient care, lab efficiencies, FDA 510(k) approved; improves patient care, lab efficiencies, FDA 510(k) approved; improves patient care, lab efficiencies,
gy, and costs; supports lab’s policy on sample acceptance with and costs; supports lab’s policy on sample acceptance with and costs; supports lab’s policy on sample acceptance with
onboard quantitative HIL, sample fill detection, aspiration errors (clots); quantitative HIL, sample fill detection, aspiration errors (clots); quantitative HIL, sample fill detection, aspiration errors (clots);
best-in-class reagents; liquid format for PT/APTT (10-day liquid format for PT/APTT (10-day onboard stability), high liquid format for PT/APTT (10-day onboard stability), high
Note: a dash in lieu of an answer means company did not onboard stability), high specificity D-dimer, on-demand HIT specificity D-dimer, on-demand HIT testing specificity D-dimer, on-demand HIT testing
answer question or question is not applicable testing

All information is supplied by the companies listed. The tabulation does not represent an endorsement by the CAP.

e 38 JANUARY 2023 page 39

40 CAP TODAY | JANUARY 2023
Clinical Pathology
Selected Abstracts
Use of whole blood real-time
PCR testing to diagnose
early Lyme disease
Borrelia burgdorferi is the leading
cause of Lyme disease in the United
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States, with approximately 35,000
new cases reported to the CDC each
year. The agency recommends a two-
tiered approach to testing. The first
tier is a sensitive enzyme immunoas-
say (EIA) targeting B. burgdorferi
Editor: Deborah Sesok-Pizzini, MD, MBA, chief medical officer, Labcorp Diagnos-
tics, Burlington, NC, and adjunct professor, Department of Clinical Pathology and
Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania,
An
Philadelphia.
Editor
Fellow
antibodies and the second is an im- newer molecular testing techniques
munoblot specific for immunoglobu- may improve the limit of detection
PhD,
lin M (IgM) or immunoglobulin G and, therefore, extend the diagnostic
Hospit
Monte
(IgG) antibodies. However, orthogo- testing window, further enhancing
nal EIA in a modified two-tiered the utility of molecular testing for
testing (MTTT) algorithm can replace early Lyme disease. The authors con-
the second tier of testing. The two- cluded that WB-RTPCR will identify
Analy
tiered approach to Lyme disease di- additional cases of Lyme disease that injury
agnosis has a sensitivity of 66 to 78 would have been missed with serol- Radioe
percent and specificity of 95 to 99 ogy alone. In addition, WB-RTPCR pregna
percent. Direct molecular testing for and serologic testing for Lyme dis- target h
B. burgdorferi DNA in whole blood ease could be most appropriately zation.
also has high specificity for early utilized in situations involving un- injury s
Lyme disease diagnosis, but spiro-
chetemia in early Lyme disease usu-
characteristic erythema migrans rash
or an absence of such rash in those
spheres
patholo
ally lasts only several days after infec- with a recent history of tick bites. a study
tion. The authors conducted a study Pratt GW, Platt M, Velez A, et al. Utility of
proven
to assess the impact of concurrent whole blood real-time PCR testing for the diag- therapy
molecular and serologic testing for nosis of early Lyme disease. Am J Clin Pathol. the inc
2022;158:327–330.
early Lyme disease and determine resin-b
the utility of whole blood real-time Correspondence: Dr. George Pratt at george.w.pratt@ (TheraS
polymerase chain reaction (WB-RT- questdiagnostics.com spheres
PCR) in assisting with the diagnosis. cally co
They performed a retrospective ana- Assessment of neurofilament from 1
lysis of 33,199 blood specimens that
were concurrently evaluated with
light chain levels in patients clinical
sies we
WB-RTPCR and an antibody capture
enzyme immunoassay (ACEIA)
with ICANS
Neurofilament light chain, a bio-
therapy
cent) ca
method (group A). An additional 56
pairs of specimens from a separate
marker of neuronal injury, is elevated
in several neurodegenerative dis-
duoden
percent
data set were retrospectively identi- eases, including Alzheimer disease ing fou
fied and analyzed at both initial and and multiple sclerosis, and in acute rounde
follow-up testing time points to de- concussion. Patients receiving an ing 4 to
termine if seroconversion occurred infusion of cellular products are at A singl
(group B). Lastly, 2,526 specimens risk for neuronal injury and may de- cent gla
that were evaluated by molecular velop immune effector cell-associated eter. Hi
testing and the MTTT EIA serology neurotoxicity syndrome (ICANS). 14 (70
methods were analyzed (group C). Approximately 40 to 60 percent of clearly
The authors found that 1,379 of the patients will develop ICANS after body g
33,199 results in group A were posi- chimeric antigen receptor (CAR) T-
tive for early Lyme disease when cell therapy. Symptoms of ICANS
tested concurrently with ACEIA and
WB-RTPCR. Of this latter group,
range from encephalopathy to apha-
sia to cerebral edema. Grade three or
Clini
continue
1,179 were found to be positive via higher ICANS can cause significant
serology, 131 via molecular testing, morbidity and mortality. While fewer perform
and 69 via both testing methods. Of than 10,000 patients are treated annu- examin
the 56 pairs of specimens in group B, ally with cellular therapy, the indica- had det
20 pairs initially were found to be tions for such therapy are growing include
positive via serology, 17 via molecu- rapidly. Neurofilament light chain the stu
lar testing, and 10 via both methods, (NfL) may be elevated before or after sympto
while nine were negative by both infusion of cellular products and ob- ment. N
methods. The 47 pairs that were posi- served up to five days prior to peak points:
tive for Lyme disease were serology- ICANS. Determining whether NfL lymph
positive on follow-up testing. In the elevations in ICANS occur before or one, th
2,526 specimens evaluated in group after infusion is important for iden- accurac
C, 358 results were consistent with tifying high-risk patients and deter- using r
early Lyme disease. Of these, 308 mining whether neuroaxonal injury classifi
were found to be positive via serol- is latent or a result of treatment. The eling w
ogy, 31 via molecular testing, and 19 authors conducted a study to quan- associa
via both methods. The data showed tify serial NfL levels in patients un- potenti
that WB-RTPCR in clinically sus- dergoing cellular therapy, and they oncolog
pected cases of early Lyme disease examined the association between se- of expo
can identify an infection that serology rial NfL levels, ICANS, and potential results
alone would miss. Furthermore, risk factors. They —continued on 41 grade o
JANUARY 2023 page 40
 JANUARY 2023 | CAP TODAY 41

agnos-
gy and
vania,
Anatomic Pathology ever, this can be challenging due to sampling and
fixation issues and shared morphological fea-
tures. The authors conducted a study involving
Selected Abstracts surgically resected tumors diagnosed as primary
small cell carcinoma (SCLC; n=129) and large-cell
Editors: Rouzan Karabakhtsian, MD, PhD, professor of pathology and director of the Women’s Health Pathology neuroendocrine carcinoma (LCNEC; n=27). Tu-
Fellowship, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, NY; Shaomin Hu, MD,
hniques mor sections were immunohistochemically
PhD, staff pathologist, Cleveland Clinic; S. Emily Bachert, MD, breast pathology fellow, Brigham and Women’s
tection stained with Rb1, cyclin D1, and p16 using tissue
Hospital, Boston; and Amarpreet Bhalla, MD, assistant professor of pathology, Albert Einstein College of Medicine,
gnostic Montefiore Medical Center. microarray. The expression patterns of the pro-
ancing teins were compared between SCLC and LCNEC
ing for to identify the discriminatory pattern. All mark-
ors con- curred in only three (15 percent) cases. In a retro- ers had high diagnostic accuracy, with Rb1 being
dentify
Analysis of gastrointestinal tract spective review of GI tissue obtained postprocedure the highest, followed by p16 and cyclin D1. The
ase that injury from yttrium-90 from 784 sequential patients treated with Y-90 mi- majority of SCLC had the pattern Rb1-/p16+/
h serol- Radioembolization therapy uses yttrium-90-im- crospheres, three (0.4 percent) patients exhibited cyclin D1-, and more than half of LCNEC had
RTPCR pregnated resin or glass microspheres to selectively resin microspheres upon histologic examination. the pattern Rb1+/p16-/cyclin D1+. Overall, the
me dis- target hepatic lesions via transarterial radioemboli- No cases involving glass-based Y-90 were identified expression pattern Rb1- and cyclin D1- was
riately zation. Occasional cases of gastrointestinal (GI) tract (P = 0.0078) despite 630 (80 percent) patients having strongly associated with the diagnosis of SCLC,
ng un- injury secondary to nontargeted delivery of micro- received glass radioembolization. This increased while the expression pattern Rb1+ and/or cyclin
ns rash spheres have been reported, but large descriptive risk of secondary sphere dissemination is likely D1+ was strongly associated with LCNEC. P16
n those pathology series are lacking. The authors conducted related to the increased number of particles required did not further discrimination. Use of this simpli-
ites. a study to assess the pathologic sequelae of biopsy- per activity for resin versus glass microspheres. The fied expression pattern led to a diagnostic accu-
Utility of
proven GI injury secondary to yttrium-90 (Y-90) authors concluded that Y-90 microspheres may be racy of 97.3 percent. The heterogeneity of Rb1,
the diag- therapy. They also sought to identify differences in found in the GI tract years after initial liver-targeted cyclin D1, and p16 expression was insignificant
n Pathol. the incidence and features of GI injury between therapy and, when present, are often associated in SCLCs compared with LCNECs. The authors
resin-based (SIR-Spheres, Sirtex) and glass-based with mucosal ulceration. This finding is less likely concluded that use of Rb1, cyclin D1, and p16
ge.w.pratt@ (TheraSphere, Boston Scientific Corp.) Y-90 micro- to be encountered in patients who received Y-90 IHC can distinguish between SCLC and LCNEC
spheres. The authors identified 20 cases of histologi- radioembolization using glass microspheres. with a high degree of accuracy. Notably, the
cally confirmed mucosal injury associated with Y-90 Feely M, Tondon R, Gubbiotti M, et al. Gastrointestinal tract injury by
Rb1-/cyclin D1- pattern in a given tumor sample
ament from 17 patients and assessed the corresponding yttrium-90 appears largely restricted to resin microspheres but can would confirm the diagnosis of SCLC. The results
clinical and pathologic sequelae. The mucosal biop- occur years after embolization. Am J Surg Pathol. 2022;46:1234–1240. could be extrapolated to routine diagnostic
ents sies were obtained from one to 88 months after Y-90 samples, such as core biopsies, bronchial biop-
Correspondence: Dr. Raul S. Gonzalez at rgonzal5@bidmc.harvard.edu
therapy (median, five months). Seventeen (85 per- sies, and cytology samples.
a bio- cent) cases were gastric and the remainder were Papaxoinis G, Bille A, McLean E, et al. Comparative study of Rb1,
levated duodenal. Endoscopic ulceration was seen in 16 (80 Comparison of Rb1, cyclin D1, and p16 cyclin D1 and p16 immunohistochemistry expression to distinguish
ve dis- percent) cases and mucosal erythema in the remain- IHC expression for distinguishing lung small-cell carcinoma and large-cell neuroendocrine carcinoma.
Histopathology. 2022;81(2):205–214.
disease ing four. Nineteen (95 percent) cases showed
n acute rounded, dark blue to purple microspheres measur- SCLC and LCNEC of lung Correspondence: Dr. D. Nonaka at dnonaka@msn.com
ing an ing 4 to 30 µm, consistent with resin microspheres. Large-cell neuroendocrine carcinoma and small —continued on 42
are at A single case demonstrated intramucosal translu- cell lung carcinoma are high-grade neuroendo-
may de- cent glass microspheres measuring 26 µm in diam- crine tumors and share several fundamental
ociated eter. Histologic evidence of ulceration was found in features. Because the tumors may respond to
CANS). 14 (70 percent) cases, and the microspheres were different treatment modalities and show
cent of clearly intravascular in six (30 percent). A foreign unique molecular alterations, distinguishing
S after body giant cell reaction to the microspheres oc- between the two is clinically relevant. How-
AR) T-
ICANS
o apha-
hree or
Clinical abstracts lymphodepletion and CAR T-cell infusion (87.6
pg/mL) compared with those who did not de-
continued from 40
nificant velop ICANS (29.4 pg/mL). Baseline NfL levels
e fewer performed a retrospective two-center study that predicted development of ICANS with a high
d annu- examined plasma NfL levels in 30 patients who degree of accuracy (area under the ROC curve,
indica- had detailed medical and treatment histories that 0.96), sensitivity (0.91), and specificity (0.95). Of
rowing included risk factors. The authors excluded from interest, NfL levels remained elevated across all
t chain the study patients with dementia and severe time points up to 30 days post-infusion. Baseline
or after symptomatic central nervous system involve- NfL levels correlated with ICANS severity but
ASCENT | 4
®

and ob- ment. NfL levels were measured at seven time not with the other potential risk factors. The au-
to peak points: baseline (prelymphodepletion), during thors demonstrated that the risk of developing Process, review, and release GC/LC-MS results
er NfL lymphodepletion, and at post-infusion days ICANS is associated with preexisting neuronal
efore or one, three, seven, 14, and 30. The prediction injury that can be quantified with plasma NfL
r iden- accuracy for developing ICANS was modeled levels. Preinfusion NfL levels may help identify Elevate your impact in the lab
d deter- using receiver operating characteristic (ROC) those patients most at risk for ICANS. Additional
l injury classification. Univariate and multivariate mod- studies should address whether NfL can serve as Accelerate the release of high confidence results, and
nt. The eling were also performed to determine the a predictive biomarker for early preemptive or gain additional insight, with ASCENT.
o quan- association between NfL levels, ICANS, and prophylactic intervention.
nts un- potential risk factors related to demographics, Butt OH, Zhou AY, Caimi PF, et al. Assessment of pretreatment
nd they oncologic history, neurologic history, and history and posttreatment evolution of neurofilament light chain levels in
ween se- of exposure to neurotoxic therapies. The study patients who develop immune effector cell-associated neurotoxicity
syndrome. JAMA Oncol. doi:10.1001/jamaoncol.2022.3738
otential results showed that patients who developed any See the benefits for yourself:
ed on 41 grade of ICANS had elevated NfL levels before Correspondence: Dr. Omar H. Butt at omarhbutt@wustl.edu n indigobio.com/ascent
Questions | 317.493.2400 | ascent@indigobio.com

40 JANUARY 2023 page 41

42 CAP TODAY | JANUARY 2023

Anatomic abstracts
continued from 41
Assessment of left-sided ulcerative
colitis with a cecal/periappendiceal
patch of inflammation
Ulcerative colitis is characterized by continuous
mucosal inflammation of the rectum, extending
uninterrupted to a variable portion of the colon
proximally. However, in some patients with distal
colitis, a distinct pattern of skip (so-called patch)
inflammation involves the cecum or appendiceal
orifice, or both. The clinical significance of the proxi-
mal patch of inflammation in ulcerative colitis (UC)
continues to be debated, and data are limited or
contradictory. The authors identified 102 adults who
had left-sided UC with a cecal/periappendiceal
patch and 102 control subjects who had left-sided
UC only. They compared them based on clinico-
pathologic characteristics and disease outcomes. In
multivariate analysis, patients with a patch were
younger (median age, 31 versus 41 years; P=0.004)
and more likely to have rectosigmoid involvement
only (58.8 versus 28.4 percent; P<0.001) compared
with patients without a patch. During follow-up,
patients with a patch were more likely to eventually
be diagnosed with Crohn disease (9.8 versus 1.0
percent; P=0.022) and show proximal extension of
inflammation (35.6 versus 10.0 percent; P=0.021).
However, they showed no differences in rates of
neoplasia, colectomy, or pharmacotherapy escalation
compared with the other patient group. Kaplan-
Meier analysis confirmed that patients with a biopsy
diagnosis of cecal/periappendiceal patch were more
likely to show proximal disease extension (P<0.001)
and be diagnosed with Crohn disease (P=0.008). The
authors concluded that cecal/periappendiceal skip
inflammation in left-sided UC occurs more often in
younger patients and those with rectosigmoid in-
volvement and is associated with proximal disease
extension and, in a small fraction of cases, a change
of diagnosis to Crohn disease. However, it does not
portend increased risk of neoplasia, pharmaco-
therapy escalation, or subsequent colectomy in this
patient group compared with patients who had
left-sided UC only.
Albayrak NE, Polydorides AD. Characteristics and outcomes of left-
sided ulcerative colitis with a cecal/periappendiceal patch of inflam-
mation. Am J Surg Pathol. 2022;46:1116–1125.
Correspondence: Dr. Alexandros D. Polydorides at alexandros.polydorides@
mountsinai.org
Use of FOXC1 biomarker for
triple-negative breast cancer
diagnosis and classification
The authors conducted a study to investigate the
diagnostic utility of the IHC-based FOXC1 test in
breast cancer subtyping and evaluate the correla-
tion between FOXC1 expression and clinicopatho-

Shorts on Standards logic parameters in triple-negative breast cancer.

FOXC1 expression was evaluated using IHC in a
cohort of 2,443 breast cancer patients. Receiver
Now out: ISO 15189 new edition on operating characteristic (ROC) curves were used to
assess the ability of FOXC1 expression to predict
quality and competence the triple-negative phenotype and identify the best
The CAP has 30 official liaisons to various organizations who attend scientific meetings or designate others cutoff value. FOXC1 expression was correlated with
to do so. Here is a report from two outbound liaisons to ISO working group 1 quality and competence in the the clinicopathologic parameters of triple-negative
medical laboratory.
breast cancer. The expression rate of FOXC1 in such
William J. Castellani, MD; Frank Schneider, MD cancer was significantly higher than in other sub-
The fourth edition of the International Organization for Standardization’s ISO 15189, Medical Laboratories— types. The area under the ROC curve confirmed
Requirements for Quality and Competence, was published at the end of 2022. This international standard, ad- the high diagnostic value of FOXC1 for predicting
opted as an accreditation standard by many countries around the world, applies principles of quality management the triple-negative phenotype. The cutoff value of
to the clinical laboratory and has general requirements for competent performance of testing. In the United one percent showed a maximized sum of sensitivity
States, ISO 15189 has been implemented voluntarily by close to 100 laboratories as an adjunct to CLIA ’88 regula- and specificity. FOXC1 expression was significantly
tions or CAP accreditation. associated with aggressive tumor phenotypes in
This revised version of ISO 15189 is organized differently to align with other ISO “conformity assessment triple-negative breast cancer. Furthermore, FOXC1
standards” (documents used to assess management systems and testing laboratories). It includes some required expression was primarily observed in invasive
harmonized elements but still recognizes the unique focus and purpose of the clinical laboratory. breast carcinoma of no special type and metaplastic
The new version of ISO 15189 places greater emphasis on the needs of the patient and risk management. It carcinoma but rarely in invasive carcinoma with
also expands on measurement uncertainty and traceability and incorporates point-of-care testing.
apocrine differentiation. Correspondingly, FOXC1
Patients are typically removed from direct involvement with the laboratory after providing the sample. Their
expression was significantly associated with the
needs are addressed through other “users” of the laboratory—that is, the caregiver taking care of them and
ordering the tests. Throughout the new edition, the ultimate service to the patient has been made explicit and expression of basal markers but was negatively
emphasized. correlated with apocrine-related markers in triple-
The revised standard reflects the emphasis that ISO 9001:2015, Quality Management Systems—Requirements, negative breast cancer. The authors concluded that
places on addressing risks. “Risk-based thinking” (referred to in ISO 15189 as risk management) is a foundational FOXC1 is a highly specific marker for the triple-
aspect of the management system in ISO 15189, not only in understanding the risks inherent in day-to-day ac- negative phenotype. Moreover, FOXC1 may serve
tivities but also in addressing future harm when issues (nonconformities) arise. As such, it supplants “preventive as an additional diagnostic marker in the histologic
action” as an ongoing process for addressing these issues. An example of risk management in ISO 15189 is and molecular subclassification of triple-negative
mislabeled specimens, including “clinically critical or irreplaceable sample[s],” an issue that clinical laboratories breast cancer in future studies.
well understand. ISO 22367, Medical Laboratories—Application of Risk Management to Medical Laboratories
Li M, Lv H, Zhong S, et al. FOXC1: A specific biomarker for triple-
(CAP TODAY, https://bit.ly/SoS_052020), serves as an excellent resource for managing risk in clinical laboratories. To
negative breast cancer diagnosis and classification. Arch Pathol Lab
this end, it is accepted that a laboratory in compliance with ISO 9001 covers many, though not necessarily all, Med. 2022;146(8):994–1003.
of the quality requirements of ISO 15189.
Earlier versions of the standard introduced requirements for measurement uncertainty and traceability. Correspondence: Dr. Wentao Yang at yangwt2000@163.com
Measurement uncertainty addresses the likely range around a quantitative result that the “true” value actually
is. Traceability focuses on how to ensure that the result for a given test today can be compared to the result for
that test last year and the result that may be obtained next year. Both concepts are addressed in greater detail Have a pathology or
in this edition.
This ISO 15189 revision, though holding close to quality and competence requirements in earlier editions of lab medicine-related question?
the standard, represents a useful evolution to address how clinical laboratories serve their users with a primary Do you have a question related to pathology
focus on patient care. This standard identifies supplemental ISO documents that were developed to assist labo- and laboratory medicine practice? If so, and if
ratories in understanding and complying with these requirements. ■ it is likely to be of interest to others in labora-
tories, send it to CAP TODAY’s Q&A column
Dr. Castellani, formerly professor of pathology at Penn State Hershey College of Medicine, is a member of the CAP Standards Com- (srice@cap.org). We’ll forward it to experts for a
mittee, CAP accreditation interregional commissioner, and member of the CAP Checklists Committee. Dr. Schneider, also a member reply. If the question and answer are featured
of the Standards Committee, is associate professor, Department of Pathology and Laboratory Medicine, Emory University School
of Medicine, and scientific director, cancer tissue and pathology shared resource, Winship Cancer Institute of Emory University.
in the column, the only name published will be
that of the person who answered the question.
 JANUARY 2023 | CAP TODAY 43

Molecular Pathology
disease
change
oes not
rmaco-
y in this
Selected Abstracts
ho had Editors: Donna E. Hansel, MD, PhD, division head of pathology and laboratory medicine,
MD Anderson Cancer Center, Houston; James Solomon, MD, PhD, assistant professor,
mes of left-
Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York; Erica
of inflam- Reinig, MD, assistant professor and medical director of molecular diagnostics, University
of Wisconsin-Madison; Marcela Riveros Angel, MD, molecular genetic pathology fellow,
Department of Pathology, OHSU; Andrés G. Madrigal, MD, PhD, assistant professor,
olydorides@ clinical, Ohio State University Wexner Medical Center, Columbus; Maedeh Mohebnasab,
MD, assistant professor of pathology, University of Pittsburgh; and Alicia Dillard, MD,
clinical pathology chief resident, New York-Presbyterian/Weill Cornell Medical Center.
TCEAL1 loss of function: cause
of a rare X-linked dominant
neurodevelopmental syndrome
ate the An international group of scientists
test in and clinicians identified the molecular
correla- cause of a rare neurodevelopmental
opatho- syndrome affecting children world-
cancer.
HC in a
eceiver
wide. This discovery was made pos-
sible through such publicly available
online databases as MyGene2, Gene-
used to Matcher, and Matchmaker Exchange,
predict which match genotypic profiles with
he best phenotypic profiles of rare diseases.
ed with The causative gene underlying this
egative novel neurodevelopmental syndrome
in such is TCEAL1 (transcription elongation
er sub- factor A-like 1), a single coding-exon
firmed gene that encodes a nuclear phospho-
dicting protein, TCEAL1, involved in tran-
alue of scriptional regulation. TCEAL1 is lo-
nsitivity cated on the X chromosome in a region
ficantly known as the Xq22.2 sub-band, which
ypes in is approximately 1.2 Mb. Disruptions
FOXC1 in this sub-band have been associated
nvasive with other neurological diseases. In
aplastic particular, a span within the Xq22.2
ma with sub-band containing six contiguous
FOXC1 genes, including TCEAL1, has been
ith the associated with emerging early onset
atively neurological disease trait (EONDT),
n triple- which affects 46,XX females. EONDT
ed that consists of hypotonia at birth, neurobe-
triple- havioral abnormalities, severe intel-
y serve lectual disability, and mild dysmor-
stologic phic facial features. The authors
egative searched online databases to deter-
mine if a single gene within the afore-
for triple-
mentioned region of the X chromo-
athol Lab some was responsible for an unde-
fined monogenic neuro­devel­op­men­tal
disorder. In the study, four males and
three females with de novo loss-of-
function TCEAL1 variants were iden-
tified. Their clinical features resembled
those of EONDT patients harboring
n? contiguous deletions involving
logy TCEAL1 and the adjacent gene PLP1,
nd if including developmental delay/intel-
ora- lectual disability, neurobehavior ab-
umn normalities, and dysmorphic cranio-
or a facial features. Additional features that
ured characterize the novel TCEAL1 loss-
ll be of-function disorder include hypoto-
tion. nia, stereotypic movement disorder,
and abnormal gait or nonambulatory
status. A subset of patients showed
abnormal myelination, structural brain
anomalies, or seizures. Furthermore,
some patients had ocular, gastrointes-
tinal, or immune system abnormali-
ties. Overall, the female patients had
milder symptoms than the male pa-
tients, which supports a role for
TCEAL1 gene dosage in the observed
variation in disease severity. An eighth
patient, who was male, had a mater-
nally inherited TCEAL1 missense
variant and presented with a different
set of clinical features, which included
neuromuscular features in the absence
of developmental delay/intellectual
disability or dysmorphic craniofacial
features, potentially suggesting an al-
ternate molecular mechanism. Mo-
lecular mechanisms involving the
Xq22.1-Xq22.2 region may contribute
to the multiple, though rare, neurologi-
cal disorders associated with this chro-
mosomal region. Genomic instability
of the Xq22.1-Xq22.2 region may be
due to such factors as increased repeat
sequences, copy number variants
(CNV), intergenic microdeletions, and
the effect of X-chromosome inactiva-
tion in females. Unfortunately, stan-
dard screening methods may not de-
tect microdeletions of TCEAL1. Given
the genomic instability in Xq22.1-
Xq22.2, the authors propose applying
DNA sequencing and CNV assess-
ment to this region.
Hijazi H, Reis LM, Pehlivan D, et al. TCEAL1 loss-
of-function results in an X-linked dominant neu-
rodevelopmental syndrome and drives the neuro-
logical disease trait in Xq22.2 deletions. Am J Hum
Genet. 2022. https://doi.org/10.1016/j.ajhg.2022.10.007
Correspondence: Dr. Elena V. Semina at esemina@
mcw.edu or Dr. James R. Lupski at jlupski@bcm.edu
Single-cell multiomics of
human clonal hematopoiesis:
revelations about mutations
As people age, a subset of blood cells
will acquire cancer-associated muta-
tions without a diagnosis of blood can-
cer. Because this condition, known as
clonal hematopoiesis, can be a precur-
sor of hematologic malignancy, it is of
increasing clinical and scientific inter-
est. Clonal hematopoiesis, in turn, can
be subclassified based on peripheral
blood cell counts and the characteristics
of precursor bone marrow cells. The
clonal stem cells harboring somatic
alterations are often of the myeloid lin-
eage and produce erythrocytes, granu-
locytes, or megakaryocytes as they
mature. There is significant overlap
between the mutations seen in clonal
hematopoiesis and those seen in acute
myeloid leukemia (AML). However,
patients with frank malignancy often
harbor additional acquired mutations
or genomic aberrations that lead to cells
becoming cancerous. Consequently,
while patients with clonal hematopoi-
esis have an increased risk of progress-
ing to frank malignancy, this may or
may not occur, and the role these low-
level mutations play in tumorigenesis
is unclear. The authors performed a
detailed analysis of the genomic and
epigenomic changes involved in clonal
hematopoiesis by applying multiomics
to single-cell analysis and compar-
ing clonal and normal background
stem cells from the same patients. Stem
cells were obtained from patients with
clonal hematopoiesis harboring a mu-
tation in codon R882 of the epigenetic
modifying gene DNA methyltransfer-
ase 3α (DNMT3A). This is a common
and well-characterized mutation seen
in AML and clonal hematopoiesis. In
gene-expression profiling, clonal and
nonclonal stem cells demonstrated
a similar degree of gene expression.
Interestingly, stem cells harboring the
DNMT3A R882 mutation were en-
riched in the megakaryocytic-erythroid
progenitor cell populations. Compared
to nonclonal stem cells, DNMT3A
R882 clonal stem cells showed in-
creased expression of genes previously
associated with leukemia stem cells,
genes involved in proinflammatory
signaling, and genes associated with
megakaryocytic-erythroid hemato-
poiesis, consistent with dysregulation
of megakaryocytic-erythroid stem-cell
lineages. To further understand the
implications of the DNMT3A R882
alteration, the authors used a single-
cell multimodal approach, evaluating
DNA methylation, RNA sequencing,
and targeted somatic genotyping, to
assess the molecular landscape of the
abnormal cells. DNMT3A R882-mu-
tated stem cells, unlike nonmutated
stem cells, showed an overall decrease
in methylation status across the ge-
nome, similar to previous findings
about genomic hypomethylation in
AML. A large subset of the hypometh-
ylated genes in DNMT3A R882 stem
cells are associated with cell-lineage
differentiation and are regulated by a
different epigenetic regulator, PRC2,
which is suggestive of orchestrated,
multilayered epigenetic dysregula-
tion. Single-cell gene-expression pro-
filing of DNMT3A R882 stem cells
showed increased expression of key
hematopoietic transcription factors,
including MYC/MAX, HIF1A/ARNT,
USF1/2, and KLF1. Notably, the in-
creased expression correlated with
selective hypomethylation of sequence-
specific CpG motifs in DNMT3A R882
stem cells, suggesting an underlying
mechanism, which parallels findings
for AML. Overall, this elegant study
demonstrates the utility of a single-cell
multiomics approach to investigating
the cellular dynamics of gene control
in stem cells with cancer-associated
mutations.
Nam AS, Dusaj N, Izzo F, et al. Single-cell multi-
omics of human clonal hematopoiesis reveals that
DNMT3A R882 mutations perturb early progeni-
tor states through selective hypomethylation. Nat
Genet. 2022;54:1514–1526.
Correspondence: Dr. Irene Ghobrial at irene_ghobrial@
dfci.harvard.edu or Dr. Dan A. Landau at dlandau@
nygenome.org n
People
News of CAP member
awards, appointments, elections
The photography collection of Leonard
Yenwongfai, MD, MS, a third-year pa-
thology resident at the University of
Kentucky College of
Medicine, was se-
lected for display at
the Arts in Health-
Care North Gallery
located in the Ken-
tucky Clinic, part of
the UK hospital. His
collection of flowers
and insect life is titled Dr.Yenwongfai
“Patterns and Pollina-
tors” and was born of concern for a friend
who had been diagnosed in 2020 at UK
with bulbar amyotrophic lateral sclerosis
and missed spending time outdoors. Dr.
Yenwongfai took the photos and sent
them to his friend to keep her connected
to nature from inside her home. The mis-
sion of the UK Arts in HealthCare pro-
gram is to create a healing environment
through visual and performing arts and
other programming. See the full story
about Dr. Yenwongfai and some of his
photos at captodayonline.com.
Ulysses G. J. Balis, MD, is the first
professor to be named to the newly estab-
lished endowed pro-
fessorship in pathol-
ogy informatics at the
University of Michi-
gan, where he is the
A. James French pro-
fessor of pathology
informatics. Dr. Balis
is director of the Uni-
Dr.Balis versity of Michigan’s
Division of Pathology
Informatics, the computational pathology
laboratory section, and the pathology
informatics fellowship program.
If you are a member of the CAP, send news
of appointments, elections, awards, and
other professional honors to srice@cap.org.

42 JANUARY 2023 page 43

44 CAP TODAY | JANUARY 2023
Maximum allowable total blood draw volumes (mL)

Q&A
In a 24-hour period In a 30-day period
Affected Healthy Affected Healthy
Body Wt. Body Wt. Total blood 2.5% of total 3% of total 5% of total 10% of total
(kg) (lbs) volume (mL) blood volume blood volume blood volume blood volume
Editor: Frederick L. Kiechle, MD, PhD
1 2.2 100 2.5 3 5 10
2 4.4 200 5 6 10 20
Dr. Kiechle is consultant, clinical pathology, Cooper City, Fla. Submit your inquiries
3 6.6 240 6 7.2 12 24
to Sherrie Rice, srice@cap.org. Questions that are of general interest will be answered.
4 8.8 320 8 9.6 16 32
5 11 400 10 12 20 40

Q. I am updating our procedure for days or length of hospitalization.2 6 13.2 480 12 14.4 24 48
7 15.4 560 14 16.8 28 56
blood draw volume limits and using Guidelines for minimal risk for pe-
8 17.6 640 16 19.2 32 64
So You’re Going to Collect a Blood Speci- diatric blood sample volume limits 9 19.8 720 18 21.6 36 72
men: An Introduction to Phlebotomy, 15th range from one to five percent of 10 22 800 20 24 40 80
edition, by Frederick L. Kiechle, MD, PhD, total blood volume within 24 hours 11–15 24–33 880–1200 22–30 26.4–36 44–60 88–120
as a guide. The chart in the manual lists up to 10 percent of total blood vol- 16–20 35–44 1280–1600 32–40 38.4–48 64–80 128–160
volume limits for a single blood draw at ume over eight weeks.2 Sick children 21–25 46–55 1680–2000 42–50 50.4–60 64–100 168–200

2 cc/kg. Other charts online list 2.5 cc/ have lower limits, with a maximum 26–30 57–66 2080–2400 52–60 62.4–72 104–120 208–240
31–35 68–77 2480–2800 62–70 74.4–84 124–140 248–280
kg and a maximum milliliters per 30-day of 3 mL/kg post-neonatally within
36–40 79–88 2880–3200 72–80 86.4–96 144–160 288–320
period that is twice the single blood draw 24 hours or 3.8 percent of total blood
41–45 90–99 3280–3600 82–90 98.4–108 164–180 328–360
(5 cc/kg). I am going to use 2 cc/kg and volume.2 Whole blood volume may 46–50 101–110 3680–4000 92–100 110.4–120 184–200 368–400
add a column for maximum milliliters in a be calculated for adults using BV =  51–55 112–121 4080–4400 102–110 122.4–132 204–220 408–440
30-day period at 4 cc/kg. 0.3669 × h3 + 0.03219 × w + 0.6041 for 56–60 123–132 4480–4800 112–120 134.4–144 224–240 448–480
The phlebotomists are confused about men and BV = 0.3561 × h3 + 0.3308 ×  61–65 134–143 4880–5200 122–130 146.4–156 244–260 488–520
whether a single blood draw means every w + 0.1833 for women (BV = blood 66–70 145–154 5280–5600 132–140 158.4–168 264–280 528–560

day of the patient’s admission or if you volume in liters, h = height in meters, 71–75 156–165 5680–6000 142–150 170.4–180 284–300 568–600

would take the single blood draw and only w = body weight in kilograms).3 In 76–80 167–176 6080–6400 152–160 182.4–192 304–360 608–640
81–85 178–187 6480–6800 162–170 194.4–204 324–340 648–680
allow the remainder of the 30-day limit. healthy adults, the maximum blood 86–90 189–198 6880–7200 172–180 206.4–216 344–360 688–720
You could essentially draw the single draw should be 10.5 mL/kg or 550 91–95 200–209 7280–7600 182–190 218.4–228 364–380 728–760
blood draw volume limit on day one and mL, whichever is less over an eight- 96–100 211–220 7680–8000 192–200 230.4–240 384–400 768–800
the remainder on day two. Please clarify. week period (https://bit.ly/UofM-drawvol).
Policies and recommendations on clinicians, and others. 2. Howie SRC. Blood sample volumes in child

A. This question addresses the
accuracy of the table titled
“Recommended volume limits for a
single blood draw” on page 10 of the
cited reference.1 The table uses 2 cc/
kg or 2 mL/kg in a 24-hour period
to determine the maximum recom-
mended blood draw in milliliters
based on the patient’s weight. Note:
This maximum volume is based on
a 24-hour period. The table does
not define the maximum cumula-
tive draw volume allowed per 30
safe blood sample volume limits for
pediatric patients2 vary from 2.5
mL/kg per day (not exceeding 4
mL/kg per day) (https://bit.ly/SEAchild-
drawvol), or 2.5 percent of total blood
volume for sick patients or three
percent of total blood volume for
healthy individuals (https://bit.ly/UPenn-
drawvol), or 2.4 mL/kg or three per-
cent of total blood volume per 24-
hour period.4 These recommenda-
tions will vary by practice location
based on input from laboratorians,
The table, from the University of
Pennsylvania (https://bit.ly/UPenn-drawvol),
is a good example of how the table
in the 2017 reference1 could be modi-
fied. With no updated version of the
phlebotomy manual planned, this
information should be useful in de-
veloping local guidelines for maxi-
mum blood draw volumes for 24
hours or longer.
1. Kiechle FL. So You’re Going to Collect a Blood
Specimen: An Introduction to Phlebotomy. 15th
ed. CAP Press; 2017.
health research: review of safe limits. Bull World
Health Organ. 2011;89(1):46–53.
3. Nadler SB, Hidalgo JH, Bloch T. Prediction of
blood volume in normal human adults. Surgery.
1962;51(2):224–232.
4. Peplow C, Assfalg R, Beyerlein A, Hasford J,
Bonifacio E, Ziegler AG. Blood draws up to 3% of
blood volume in clinical trials are safe in children.
Acta Paediatr. 2019;109(5):940–944.
Frederick L. Kiechle, MD, PhD
Editor, CAP TODAY Q & A Column
Chief Medical Officer
Boca Biolistics reference laboratory
Pompano Beach, Fla.
Member, CAP Publications Committee

Q. An oncologist contacted the labora-

tory to ask if our standard estradiol
immunoassay was appropriate to monitor
her breast cancer patients who are on an
aromatase inhibitor. What should I say?
breast cancer. AI therapy can reduce
already low E2 concentrations in
these patients to <1 pg/mL.1,2 AI
therapy failure, on the other hand, is
associated with E2 concentrations in
the 5–20 pg/mL range.3 Therefore,
bias, according to results reported in
the CAP Accuracy-Based Programs
Survey. Finally, immunoassays are
subject to interference by drugs such
as fulvestrant and the aromatase in-
hibitor exemestane.7,8 In summary,
estradiol should be monitored not only during
the peri-menopausal period but also the post-
menopausal period at the time of aromatase inhibi-
tor administration. World J Surg Oncol. 2009;7:88.
6. HoSt/VDSCP: Certified Participants. Centers for
Disease Control and Prevention. https://www.cdc.gov/
labstandards/hs_certified_participants.html

A. Mass-spectrometry–based as-
says are preferred for measur-
ing estradiol (E2) in populations
where low concentrations are ex-
pected, such as in males, postmeno-
pausal females, prepubertal children,
and those receiving estrogen-sup-
pressing medications or therapies.
Comparing the E2 reference interval
for postmenopausal females (ap-
proximately <10 pg/mL) to that of
premenopausal females (15–350 pg/
mL, depending on the phase of the
menstrual cycle) illustrates what con-
centrations could be considered low.
Aromatase inhibitors (AIs) reduce
the production of estrogen and are
used in postmenopausal women
with hormone-receptor–positive
E2 is used as a potential biomarker to
guide treatment decisions in these
patients.
The most common methods for
measuring E2 are immunoassays and
liquid chromatography-mass spec-
trometry (LC-MS) methods. The
lower limit of quantitation (LLOQ) of
immunoassays is approximately 5–30
pg/mL compared to <1–5 pg/mL for
LC-MS.4,5 For a laboratory to be certi-
fied by the CDC Hormone Standard-
ization Program, the total allowable
error of its estradiol assay must be
± 2.5 pg/mL for samples ≤ 20 pg/
mL.6 This is problematic for immu-
noassays, which generally have rela-
tively high LLOQs. In addition, im-
munoassays demonstrate positive
LC-MS assays are preferred for popu- 7. Owen LJ, Monaghan PJ, Armstrong A, et al. Oes-
tradiol measurement during fulvestrant treatment
lations with low E2 concentrations. for breast cancer. Br J Cancer. 2019;120(4):404–406.
1. Dixon JM, Renshaw L, Young O, et al. Letrozole
8. Mandic S, Kratzsch J, Mandic D, et al. Falsely ele-
suppresses plasma estradiol and estrone sulphate
vated serum oestradiol due to exemestane therapy.
more completely than anastrozole in postmeno-
pausal women with breast cancer. J Clin Oncol.
Ann Clin Biochem. 2017;54(3):402–405.
2008;26(10):1671–1676. Brian Harry, MD, PhD
Assistant Professor of Pathology
2. Handelsman DJ, Gibson E, Davis S, Golebiowski
University of Colorado Anschutz
B, Walters KA, Desai R. Ultrasensitive serum estra-
diol measurement by liquid chromatography-mass Medical Campus
Aurora, Colo.
spectrometry in postmenopausal women and mice.
J Endocr Soc. 2020;4(9):bvaa086. Member, CAP Accuracy-Based
3. Faltinová M, Vehmanen L, Lyytinen H, et al.
Programs Committee
Monitoring serum estradiol levels in breast cancer Joely Straseski, PhD, DABCC
patients during extended adjuvant letrozole treat- Professor of Pathology
ment after five years of tamoxifen: a prospective
University of Utah School of Medicine
trial. Breast Cancer Res Treat. 2021;187(3):769–775.
Section Chief, Clinical Chemistry
4. Bertelsen BE, Kellmann R, Viste K, et al. An ultra- Medical Director, Endocrinology
sensitive routine LC-MS/MS method for estradiol ARUP Laboratories
and estrone in the clinically relevant sub-picomolar Salt Lake City, Utah
range. J Endocr Soc. 2020;4(6):bvaa047. Member, CAP Accuracy-Based
5. Nagao T, Kira M, Takahashi M, et al. Serum Programs Committee

JANUARY 2023 page 44


Newsbytes
Editors: Raymond D. Aller, MD, & Dennis Winsten
How to make data in charts
and graphs ‘more consumable’
The acclaimed film composer John
Powell said, “Communication works
for those who work at it.” A senti-
ment to which Yonah Ziemba, MD,
adhered when communicating data
via charts, graphs, and tables during
his pathology fellowship—benefiting
himself and others.
“In pathology, our data is deeper
and richer, so if we get better at pre-
senting our data, we will have a very
important seat at the table,” says Dr.
Ziemba, assistant professor in the
Department of Pathology and Labo-
ratory Medicine, Northwell Health,
New Hyde Park, NY.
During his pathology fellowship
at Northwell, he explains, “I started
noticing that everyone realizes when
they need help accessing data, be-
cause if you don’t have it, you don’t
have it. But not everyone realizes
when they need help with how to
present the data.”
This led Dr. Ziemba to research
data visualization for his own presen-
tation purposes and to help col-
leagues redesign their charts and
graphs to be easier to understand and
more impactful. Over time, he devel-
oped a set of tips to help pathologists
avoid common data-visualization
mistakes.
Darci Block, PhD, laboratory direc-
tor for the central clinical laboratory
at Mayo Clinic, attended Dr. Ziem-
ba’s data-visualization presentation
at the Association of Pathology Infor-
matics’ 2022 Pathology Informatics
Summit. She was sufficiently im-
pressed that she invited him to speak
at a recent clinical chemistry grand
rounds at Mayo Clinic.
“Our goal when we publish data
should be to accurately represent it
but also to make it more consum-
able,” Dr. Block says. “The improve-
ments he suggests make data more
consumable, which is, in turn, going
to help people better appreciate the
message of the presentation or
publication.”
Following are common data-visu-
alization mistakes in pathology, ac-
cording to Dr. Ziemba, and tips for
avoiding them.
Multiple axes. One of the most
visually confusing components of a
graph are vertical axes on the left and
right sides displaying different types
of measurements, Dr. Ziemba says.
This often occurs when two represen-
tations are superimposed, such as
when a line graph showing the
monthly percentage of pathology
reports processed within a two-day
turnaround is superimposed on a bar
chart listing total pathology cases
each month. While it sometimes
makes sense to superimpose data, he
continues, requiring people to draw
a mental line to one side of the chart
and then another mental line to the
other side is too much to ask.
The simple solution: Label the line
graph and bar chart directly, Dr.
Ziemba says. If there were 137 pathol-
ogy cases in February, for example,
place the number 137 above or inside
the February bar in the chart. This
way, people viewing the chart do not
have to draw imaginary lines to the
side of the page to try to figure out
Fig. 1. Simplifying content of graphs
300
Case volume per month
200
100
0
Jan Feb
GI
H&N
Prostate
At left, a double-axis graph with a legend and axes labels, which has a significant cognitive load. At right, a double-axis graph in which the legend has been replaced with
color-coded descriptors and the axes labels with numerals on the corresponding visual elements to allow viewers to absorb the information with less cognitive effort.
the height of the February bar. Label
key data points in the line graph in a
similar manner, he says (Fig. 1).
The legend. A legend might seem
like a helpful way to identify various
elements in a chart or graph, but it
forces viewers to look away from a
graphic to find the labels they need,
Dr. Ziemba says. Instead, he advises,
color code and label each component.
If, for example, a pathologist labeled
a green slice of pie “chemistry” and
a blue slice of pie “hematology” in a
pie chart of pathology test volumes,
the viewer could quickly and easily
digest the information without hav-
ing to scan the legend to determine
what each color represents.
The process of looking back and
forth from a chart to a legend requires
conscious effort, Dr. Ziemba says.
This conflicts with the data-visualiza-
tion goal of designing charts with
preattentive attributes, which are
features that people will automati-
cally understand before they realize
they are paying attention.
Three-dimensional displays.
While three-dimensional imagery
may make figures in a chart pop from
the page, it can also create visual
distortion, Dr. Ziemba warns. Imag-
ine if a 3D pie chart were lying on the
ground. A 21 percent slice of pie in
the foreground would look signifi-
cantly larger than a 21 percent slice
on the far side of the pie (Fig. 2).
In a similar man-
ner, “if you are look-
ing down from the
top of the Empire
State Building at the
other skyscrapers,”
he says, “they sud-
denly don’t look as
tall as they did when Dr.Ziemba
you were on the
sidewalk. It’s the same type of thing.”
Bar charts can also be distorted by
3D graphics, Dr. Ziemba says. When
bars are rendered in 3D, the depth of
a pillar can appear to add to its height,
making it harder for viewers to dis-
cern where the top of the bar ends.
Long vertical labels. Bar graphs
are often displayed as a group of
Compliance rate
37%
215 cases per month
Mar Apr May
Thyroid
Jun Jul Aug Sep
Liver
GYN Breast Jan
Jan
Compliance rate
Fig. 2. Avoiding 3D distortion
At left, use of three-dimensional graphics distorts the slices of the pie chart, making the green slice appear
larger than the identically sized yellow slice. At right, the lack of 3D graphics makes it clear that the yellow and
green slices of the pie chart are the same size.
vertical bars, but when each bar has
a long textual label, the graphic may
benefit from a horizontal orientation,
Dr. Ziemba says. If each bar in a bar
graph represents the number of cases
of a specific disease—plasma cell
leukemia, mantle cell lymphoma, and
pure red cell aplasia, for example—it
could be difficult to fit each disease
name under a vertical bar in a graph.
By turning the graph on its side, long
disease names can run horizontally
to the left of horizontal bars and still
allow room for the varying lengths of
the bars (Fig. 3, page 46).
JANUARY 2023 page 45
JANUARY 2023 | CAP TODAY 45
Default software settings. People
often assume the default graph set-
ting in a software program is the best
visual choice, but that’s not always
the case, Dr. Ziemba says. Microsoft
Excel’s default setting, for example,
uses a visually jarring blue and or-
ange color combination in bar
graphs. The text is too small, and the
bars are spaced so far apart that it’s
hard for viewers to see the big pic-
ture that the graph is trying to create,
he adds.
The Microsoft Excel default setting
also floats a chart name in the white
space above the chart bars and does
not label axes. The location of the
chart name can be distracting and
usually must be removed for medical
journals, which tend to put the chart
names in the captions, Dr. Ziemba
says. Furthermore, the lack of axes
labels can cause ambiguity. “Always
have axes labels,” he continues,
“which often eliminate the need for a
chart title.”
90% compliance rate
60%
70% Prostate
349
Breast
GYN
259 H&N
196 Liver
137 132 127
Thyroid
88
57
GI
Feb
Feb Mar
Mar Apr
Apr May
May Jun
Jun Jul
Jul Aug
Aug Sep
Sep
The inappropriate pie chart. One
thing that a pie chart can do better
than any other graphic is illustrate
when one element is greater than all
the other elements in the chart com-
bined, Dr. Ziemba says. “In a bar
chart, you would not easily see that
the biggest bar is bigger than every-
thing else combined, but the reason
you can see that in a pie chart is be-
cause your eye is drawn to the angle
at the center,” he explains.
Yet pie charts underperform in
many situations. For example, it is
not advisable —continued on 46
 46 CAP TODAY | JANUARY 2023

Newsbytes that represents a single data point

within text instead of burying it in a
continued from 45
chart that readers will have to deci-
to place two pie charts side by side pher. “Don’t show data just because
for comparison purposes because you have it,” he cautions.
similar elements do not appear next Most importantly, consider
to each other, Dr. Ziemba says. Pie charts and graphs to be tools for
charts also should not be used for telling a story with data, Dr. Ziemba
data with a linear progression, such says. Pathologists should keep the
as age. Ages should be displayed in differing perspectives and needs of
a line from youngest to oldest. Fur- viewers in mind when telling that
thermore, he adds, cutting pie charts story.
into too many pieces reduces their These tips can help pathologists
visual impact. “reduce the cognitive load” of their
Too much data. While graphs and visual data representations, Dr.
charts can be visually stimulating, it Ziemba says. “When it comes to spot-
is possible to provide viewers with ting trends and understanding the
too much information in such for- significance of the data on display,”
mats, Dr. Ziemba says. Therefore, it he adds, “you want viewers to in-
is often better to state information stantly see it.” —Renee Caruthers
Fig. 3. Rethinking bar graph orientation
240
240
207
204 207
204
175
150 158 Plas mablast i c lymlymphoma
106
131 132
91
70
70
I
54
54
CompuGroup Medical Medicus network of health care orga-
nizations and consultants selling its
acquires Medicus LIS solutions.”
CompuGroup Medical US has pur- Medicus’ LIS team will become
chased Medicus Laboratory Informa- part of CompuGroup Medical US,
tion Systems from Diagnostic Sys- which offers a product portfolio that
tems Consulting. includes the CGM LabDaq, CGM
Medicus is a provider of labora- SchuyLab, and CGM AP Easy labora-
tory-management software, middle- tory information systems.
ware, and laboratory consulting ser- CompuGroup Medical, 800-359-0911
vices. The company has installed its
Medicus LIS in more than 1,000 labo-
ratories nationwide.
FTC updates tool to assist
“The acquisition of Medicus will mobile app developers
further enable CompuGroup Medical The Federal Trade Commission has
to grow its relationships with large, released an update to the online, in-
value-added resellers in the U.S. teractive Mobile Health Apps Tool,
health care market,” according to a which provides developers of mobile
CGM press release. “CGM will also health applications with information
be able to leverage the expansive about federal laws relevant to design-
ing, marketing, and distributing such
products.
PlasPlasma
ma cell leukemia
cell leukemia - 25
25
The tool provides a list of ques-
WalWaldenstroms
d enst roms disease
tions to help users assess whether
disease - 54
54
specific federal laws apply to the
Plasmablastic phoma - 70
70
apps they are developing based on
MantMantle
le cellcell
lymphoma
lymphoma 91
91
what the tool will do, how it will be

■ I
25
25 Pure red cell aplasia 106 used, how users will get it, and who
Essential thrombocythaemia
Essential thrombocythaemia 131
131 will use it. It addresses the FTC Act
..
...

...
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...
...

..

mia
ma
a

ma
s
l..

asi

osi
n.
ic .

pho
ms

and FTC health breach notification

pho

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ell
ial
ell

Langerhans c ell hist ioc ytosis

kae

132
cel

Langerhans cell histiocytosis

a pl

132
fibr
gki

cyt
ast

sc
ent
ac

tro

lym
ym

leu
ntle

Hod

elo
ell

pho
abl

han
sm

Ess

rule; Health Insurance Portability and

ens

Classical Hodgkin lymphoma 150

ar l
dc

Classical Hodgkin lymphoma

my

150
ell
kitt
Ma
sm

lym
Pla

cal
ger
ld

e re

ry c
cul

Bur
ar y
Pla
Wa

Accountability Act privacy, security,

ssi

Pro
Lan

Pri mary myelof

Primary ibrosis
myelofibrosis 158
li

158
Hai
Pur

Fol
Prim
Cla

Follie ular lymphoma

Follicular lymphoma
Prolymphocyti c leukemia
Prolymphocytic leukemia
Burkit t lymphoma
Burkitt lymphoma
Hairy cellcell
Hairy leukaemia
leukaemia
Switching a bar chart’s orientation from a vertical layout (left) to a horizontal layout (right) can add more space for necessary text and improve visualization.
Laboratory Medical Direction Workshop
May 4–5, 2023
Northfield, IL
Grow your skills and become a more effective laboratory medical director
Join a select group of your peers for an expert-led 1.5 day workshop that will prepare you
to lead a successful laboratory and build high-functioning teams. Get ready to succeed as
a highly qualified laboratory medical director.
Learn more at learn.cap.org or 800-323-4040 option 1
© 2022 College of American Pathologists. All rights reserved. 0025185.1122
175
175 and breach notification rules; Federal
204
204 Food, Drug, and Cosmetic Act; 21st
207
207
Century Cures Act health IT and in-
240
240
formation-blocking provisions; ONC
Cures Act final rule; and Children’s
Online Privacy Protection Act.
“Whether you are a developer
new to mHealth, focusing on differ-
ent users than you have with prior
mHealth products, or are building
innovative features into an existing
app focused on the same kinds of
users, the Mobile Health Apps Tool
can serve as a sort of ‘trail guide’ to
these federal laws centered on infor-
mation governance and federally
required protections for information
related to an individual’s health, as
well as the safety and effectiveness of
medical devices—which some mobile
health apps might be,” according to
an ONC Health IT Buzz blog post.
The ONC noted that developers of
mobile health apps may also be sub-
ject to federal and state laws that are
outside the scope of the Mobile
Health Apps Tool.
The tool was revised as part of a
collaborative effort between the FTC,
Health and Human Services’ Office
of the National Coordinator and Of-
fice for Civil Rights, and the FDA.n
Dr. Aller practices clinical informatics in
Southern California. He can be reached at
raller@usc.edu. Dennis Winsten is founder
of Dennis Winsten & Associates, Health-
cap.org care Systems Consultants. He can be
reached at dwinsten.az@gmail.com.

0025185_LMD_CT_ad.indd 1
JANUARY 2023 page 46
11/16/22 12:00 PM
 JANUARY 2023 | CAP TODAY 47

Classified Advertising
MICHIGAN

FACULTY POSITION
Senior Staff Pathologist
NEUROPATHOLOGY
Henry Ford Department of Pathology and Laboratory Medicine is seeking an ABP neuropathology board
certified neuropathologist to lead the Clinical Neuropathology Section. The successful candidate will be
accomplished in diagnostics, education and clinical investigation. The position is fortified by partner-
ships with clinicians and scientists of the Henry Ford Neuroscience Institute, ranked among the top 10%
of neuroscience centers nationally. It is home to the Hermelin Brain Tumor Center and provides unique
access to the largest brain tumor biorepository with combined informatics database in the US. Henry
Ford is a major participant in the National Cancer Institute’s Adult Brain Tumor Consortium, performing
innovative phase 1 and 2 clinical trials.
The Henry Ford Health System, Detroit, is the largest healthcare delivery system in Southeast Michigan,
the 6th largest site for graduate medical training in the US, and the 3rd largest source of NIH research
funding in Michigan. The Pathology Department is a Lean managed enterprise and the largest ISO 15189
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center. The Pathology product line oversees laboratory testing at 5 system hospitals, 30 clinic delivery
sites with 40 senior staff pathologists and clinical scientists, complemented by 750 technical staff, han-
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report to the Vice-Chair for Anatomic Pathology.
Interested applicants should submit CV, a statement describing
previous accomplishments and future direction, with names of 3
references to:
Richard Zarbo, MD, DMD
Chairman, Department of Pathology and Laboratory Medicine
Henry Ford Hospital
2799 West Grand Blvd,
Detroit MI 48202
Rzarbo1@hfhs.org
Henry Ford Health
Senior Staff Community Hospital Pathologist
Henry Ford Jackson Hospital
Henry Ford Pathology and Laboratory Medicine seeks to fill a community hospital senior
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Jackson is a 475-bed acute-care hospital serving central Michigan offering comprehensive
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fellowships in Medical Genetics and Informatics.
Applicants for this anatomic pathology position must be expert in general surgical
pathology, and should submit CV, and statement of interest with 3 references to:
Richard J. Zarbo, M.D., DMD
CHAIRMAN, PATHOLOGY AND LABORATORY
MEDICINE
Henry Ford Hospital
2799 West Grand Blvd,
Detroit MI 48202
Rzarbo1@hfhs.org
Richard J Zarbo, MD
Senior Vice President and KD Ward Chair
Pathology and Laboratory Medicine
Henry Ford Health System
Detroit, MI 48202
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PRODUCTS AND SERVICES

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Pathology and Laboratory Medicine
Henry Ford Health System
Detroit, MI 48202
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For information on placing a classified advertisement, please call 888-489-1555

48 CAP TODAY | JANUARY 2023
Marketplace
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General Data launches
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General Data Healthcare launched its
LaserTrack Flex cassette printer. The Flex
has a footprint of 13” L × 19” W and a
capacity that starts at 480 cassettes, with
each magazine holding 80 cassettes; it can
be upgraded to hold
up to 800 cassettes. The
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EKF handheld hemoglobin
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EKF Diagnostics’ DiaSpect handheld
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storage for 4,000 tests and QC results,
as well as the capability to provide a
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DiaSpect is CE-IVD marked and
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EKF Diagnostics, 830-249-0772
Santé, Vanguard
Healthcare Staffing
announce partnership
Santé Consulting and Vanguard Health-
care Staffing announced a partnership
in which the companies will provide
recruiting support for anatomic and clini-
cal laboratories.
“The demand for medical and clinical
lab techs, pathologists, and executives will
only continue to increase. Anything that
we can do as recruiters to streamline the
hiring process for our clients is essential,”
Rich Cornell, founder and president of
Santé Consulting, said in a joint press
release. “Employers get the benefit of hav-
ing their jobs posted on two job boards
and in both of our proprietary databases.
Candidates and employers will continue
to have only one contact per opening.”
The companies will also comarket their
services at various conferences this year.
Santé Consulting, 833-522-5627
Vanguard Healthcare Staffing, 973-756-5080
FDA clears HemoSonics
Quantra with QStat cartridge
HemoSonics has received FDA 510(k)
clearance for the Quantra hemostasis
system with QStat cartridge. The clear-
ance of the QStat cartridge expands the
Quantra system’s indications for use
to include trauma and liver transplant
procedures.
“The Quantra hemostasis system
with QStat and QPlus cartridges will
assist more clinicians in determin-
ing which specific blood products are
needed to rapidly treat individual
patients,” Bruce Spiess, MD, medi-
cal director of HemoSonics, said in
a company press release. “It has the
potential to positively impact patient
outcomes for hundreds of thousands
of trauma patients and thousands of
liver transplant recipients each year by
optimizing blood product usage and
conserving critically low blood supplies.”
The Quantra system uses sonic esti-
mation of elasticity via resonance (SEER)
sonorheometry, an ultrasound technolo-
gy, to measure the coagulation properties
of a whole blood sample. The Quantra
with QPlus and QStat cartridges is com-
mercially available in the United States,
Europe, Australia, New Zealand, Japan,
and Hong Kong.
HemoSonics, 800-280-5589
ZeptoMetrix launches
NATtrol MS2 bacteriophage
stock
ZeptoMetrix launched its NATtrol MS2
bacteriophage quantitative stock, intend-
ed for use as an internal process control
for rt-PCR assays.
Bacteriophage MS2 is a virus that in-
fects Escherichia coli and other members
of the Enterobacteria family. NATtrol
inactivation of MS2 results in a refriger-
ator-stable, whole organism stock solu-
tion, the company says, which shows
increased reproducibility and lot-to-lot
consistency over live MS2. The product
is for research use only.
ZeptoMetrix, 716-882-0920
FDA clears Simplexa
Congenital CMV Direct assay
DiaSorin announced it has received FDA
510(k) clearance for its Simplexa Con-
genital CMV Direct kit. The molecular
diagnostic test enables direct detection

of cytomegalovirus DNA in saliva swab
and urine specimens from babies 21 days
old or younger. It is the first kit to receive
FDA clearance for CMV detection from
both saliva swab and urine specimens.
The assay is designed for use with the
Liaison MDX instrument.
DiaSorin, 562-240-6500
Verichem reference
materials for cholesterol
assays
Verichem Laboratories offers liquid-
stable, ready-to-use clinical reference
materials intended for calibration and
calibration verification procedures for to-
tal cholesterol and high- and low-density
lipoprotein assays.
The Matrix Plus Total Cholesterol Ref-
erence kit, along with an optional level F,
contains total cholesterol values ranging
from 40 to 750 mg/dL and is stable for
21 months when stored at 2° to 8°C. The
HDL Cholesterol Verifier kit is stable for
14 months when stored at −15° to −25°C
and can be frozen and thawed for up to
10 cycles, without affecting concentra-
tion accuracy or test performance, the
company says. The serum-like formula-
tion contains a blend of highly purified
human source material and bovine
biologicals in sa-
line. The materials are protein
based and free of azides, glycols, and
surfactants.
Verichem Laboratories, 800-552-5859
SeraCare BRCA NGS
reference material
LGC SeraCare announced the availability
of its Seraseq FFPE BRCA1/2 LGR Refer-
ence Material intended for use with next-
generation sequencing assays or ampli-
fied nucleic-acid–based methods that
identify somatic and germline variants
in BRCA1 and BRCA2 genes. The refer-
ence material contains 20 DNA variants
in the genomic background of GM24385.
One 10-μm formalin-fixed, paraffin-em-
bedded curl is provided per vial.
LGC SeraCare, 508-244-6400
Thermo Fisher launches
TrueMark infectious
disease panels
Thermo Fisher Scientific launched its
TrueMark Infectious Disease Research
Panels. The analytically sensitive, du-
plexed TaqMan assays are performed on
pre-spotted and dried-down plates that
include microorganism-specific patho-
gens, using real-time PCR techniques,
which enables rapid and accurate detec-
tion for investigating microorganisms
that cause respiratory, vaginal, urinary,
gastrointestinal, and sexually transmitted
diseases. The predefined and customiz-
able panel options allow researchers
to choose from more than 90 different
bacterial and viral strain assays to gen-
erate results within four hours of taking
the samples. Testing can be done from
nasopharyngeal swabs or nasopharyn-
geal aspirate; vaginal, genital, and lesion
swabs; or urine samples.
The samples can be prepared using
workflows that use the Applied Biosys-
tems MagMax viral/pathogen kits auto-
mated on a KingFisher purification sys-
tem instrument and mixed with Applied
Biosystems multiplex master mix onto a
96- or 384-well plate. The panels are for
use on QuantStudio qPCR systems and
provide easy-to-read results with the
Applied Biosystems QuantStudio Design
and Analysis software v2.6.
The panels are for research use only,
not for use in diagnostic procedures.
Thermo Fisher Scientific, 800-556-2323
Bio-Rad launches blood
screening controls in Europe
Bio-Rad Laboratories has announced
that Exact Diagnostics HBV, HCV, and
HIV-1 screen controls are available in
Europe. The controls are designed to
monitor the performance of blood do-
nor screening assays and are calibrated
against the Third WHO International
Standard for HBV (NIBSC code 10/264)
and HIV-1 (10/152) and the Fourth WHO
International Standard for HCV (06/102).
The products are made of whole viruses
in a citrate plasma matrix to ensure lot-
to-lot reproducibility, have an 18-month
shelf life from date of manufacture when
stored at −20°C or below, and are stable
for 24 hours when stored at 2° to 8°C.
Bio-Rad, 510-741-1000
Spot Imaging introduces
sample-tracking solutions
Spot Imaging has introduced three in-
struments for sample tracking and stor-
age designed to address staffing short-
ages and storage inefficiencies. BlocDoc
automatically captures images of cut
blocks and raw slides for electronic shar-
ing and tracking. The PathTracker scans
cassettes and slide transport containers in
bulk, scanning 150 cassettes in less than
25 seconds, and uploads the information
to the PathTracker and laboratory infor-
mation system. PathArchiv is a file-room
sample management system for blocks
and slides that can trace samples by case,
loan status, location, or age.
Spot Imaging, 586-731-6000
Roche announces
collaboration with Pfizer
Roche has entered into a collaboration
with Pfizer to help patients access re-
sources and locate information about
COVID-19 testing, available treatment
options, high-risk factors that increase
the chance of progressing to severe
COVID-19, and ways to seek timely
care. People can learn why early testing
is important at symptom onset, which
health conditions increase the risk of
progressing to severe COVID-19, and
what treatment options are available on
covid19knowmore.com, a Pfizer website. The
Pilot COVID-19 At-Home Test, distrib-
uted in the U.S. by Roche and manufac-
tured by SD Biosensor, will include a QR
code that directs people to the website.
Roche Diagnostics, 800-428-5074
FDA authorizes PerkinElmer
Eonis kit for SMA screening
in newborns
PerkinElmer announced that the FDA
has authorized the marketing of its Eonis
SCID-SMA
assay kit
for in vitro diagnostic use by certified
laboratories for the detection of spinal
muscular atrophy and severe combined
immunodeficiency in newborns. This is
the first FDA-authorized assay for SMA
screening in newborns in the United
States, the company says, and is part of
the company’s Eonis platform. The Eonis
platform is a robust, flexible system that
uses real-time PCR technology to screen
for SMA and SCID using a single dried
blood spot sample.
PerkinElmer, 203-925-4602
QuidelOrtho, Runda
form joint venture to
develop assays
QuidelOrtho will form a joint venture
between Ortho Clinical Diagnostics Trad-
ing, a subsidiary of QuidelOrtho, and
Shanghai Medconn Biotechnology, a
subsidiary of Shanghai Runda Medical
Technology, to develop and manufacture
assays in China for QuidelOrtho’s Vitros
platform. Following a successful assay
pilot program, the companies expect to
begin developing a broader set of assays
early this year in parallel with building
out the joint venture organization in the
Shanghai and Beijing areas.
QuidelOrtho, 800-828-6316 Q
CAP TODAY (ISSN 0891-1525) is published monthly
by the College of American Pathologists, 325 Wau-
kegan Road, Northfield, IL 60093. Subscriptions:
$100 U.S. (single copy: $20), $125 Canada (single
copy: $25), $225 foreign
(single copy: $30). Periodi-
cals postage paid at Win-
netka, Ill., and at additional
mailing offices. POSTMASTER: Send address
changes to CAP TODAY , 325 Wau kegan Road,
Northfield, IL 60093-2750. Mailed under Canada
Post International Publication Mail Sales Agree-
ment Number 40016906.
Printed in U.S.A. ISSN 0891-1525
JANUARY 2023 | CAP TODAY 49
Put It on the Board
continued from 50
Qiagen developed to identify patients
with NSCLC who have a KRAS G12C
mutation, is instrumental in determin-
ing who may benefit from treatment
with Krazati. The drug is indicated for
the treatment of adult patients with
KRAS G12C-mutated locally ad-
vanced or metastatic NSCLC, as de-
termined by an FDA-approved test,
who have received at least one prior
systemic therapy.
De novo classification
granted to HLA typing test
for use as CDx
The Food and Drug Administration
granted de novo classification to
Thermo Fisher’s SeCore CDx HLA
Sequencing System for use as a com-
panion diagnostic with Kimmtrak
(tebentafusp-tebn), Immunocore’s
T-cell receptor therapy for HLA-
A*02:01-positive adults with meta-
static or unresectable uveal melano-
ma. The marketing authorization
makes the SeCore CDx HLA Se-
quencing System the only commer-
cially available HLA typing compan-
ion diagnostic.
Kimmtrak, the only FDA-ap-
proved T-cell receptor therapy for
metastatic or unresectable uveal mel-
anoma, is indicated for adults who
are HLA-A*02:01 positive. The
SeCore CDx HLA Sequencing System
was used to identify HLA-A*02:01-
positive patients for enrollment in
Kimmtrak clinical trials. Q
INDEX TO ADVERTISERS
Abbott, pages 2, 8
BioMérieux, pages 7, 40
Diagnostica Stago, page 29
Diapharma Group, page 25
Hologic, pages 5, 26–27
Indigo Bioautomation,
pages 41, 48
LGP Consulting, page 19
Nova Biomedical, page 33
NovoPath, page 21
Quidel, page 17
Siemens Healthineers, page 31
Streck, page 11
Sysmex, page 52
TechLab, page 4
Werfen, page 51
 50 CAP TODAY | JANUARY 2023
Put It on the Board
AMP reports on use of
guidelines for sequence
variants in cancer
The Association for Molecular Pa-
thology last month released a report
on somatic variant classification us-
MAKE MEANINGFUL
CONNECTIONS
The CAP is a place for thought leaders to come together and
move the science forward. The CAP provides a mechanism
for pathologists—from all walks of life and coming from all
different perspectives—to bring their experiences to one
place. There’s no other setting or organization that allows
for pathologists that are very passionate about various
disciplines to come together.
— RAJESH C. DASH, MD, FCAP
30322_CT_Dash_Testimonial_Ad4_I_StdA_Final.indd 1
ing 2017 standards and guidelines
for interpreting and reporting such
variants, which were a consensus
recommendation of the AMP, CAP,
and American Society of Clinical
Oncology.
The new report is based on variant
Join or renew at cap.org
© 2022 College of American Pathologists. All rights reserved. 30322.0122
interpretation challenges and a
guideline implementation survey
conducted by an AMP working
group (Li MM, et al. J Mol Diagn.
Published online Dec. 9, 2022.
doi:10.1016/j.jmoldx.2022.11.002).
The group’s aim was to identify clas-
sification inconsistencies and evalu-
ate barriers to implementing the 2017
standards and guidelines (Li MM, et
al. J Mol Diagn. 2017;19[1]:4–23).
JANUARY
1/13/22 12:58 PM
In the guidelines, the AMP, CAP,
and ASCO proposed a tiered system
to categorize somatic sequence vari-
ants. In tier one are variants with
strong clinical significance; tier two,
variants with potential clinical signifi-
cance; tier three, variants of unknown
clinical significance; and tier four,
variants deemed benign or likely
benign (most commonly representing
rare germline variants with no known
cancer association).
There were 134 participants in the
variant interpretation challenge, and
86 percent correctly differentiated
clinically significant variants from
variants of uncertain significance and
benign/likely benign variants. More
than 70 percent agreed in judging the
potential for germline variants. Sev-
enty-one percent of respondents to
the implementation survey (157/220)
implemented the guidelines for vari-
ant classification and more than 90
percent of them used the recommend-
ed tier-based reporting system.
FDA clears Roche’s CSF
assays for Alzheimer’s
Roche’s Elecsys beta-Amyloid (1-42)
CSF II (Abeta42) and Elecsys Phos-
pho-Tau (181P) CSF (pTau181) assays
have received Food and Drug Ad-
ministration 510(k) clearance. The
Elecsys AD CSF Abeta42 and pTau181
assays (used as a pTau181/Abeta42
ratio) measure beta-amyloid and tau
proteins in adults 55 and older evalu-
ated for the disease. Both assays are
traceable to reference materials.
The ratio of these biomarkers
(pTau181/Abeta42) is consistent with
a negative beta-amyloid PET scan if
the result is less than or equal to the
cutoff (negative), and with a positive
beta-amyloid PET scan if the result is
above the ratio cutoff (positive).
Abeta42 and pTau181 assays are
intended to be used in addition to
other clinical diagnostic evaluations
to determine whether a person has
Alzheimer’s. A positive pTau181/
Abeta42 ratio result in CSF does not
establish a diagnosis of Alzheimer’s
disease.
FDA approves CDx to
Krazati in NSCLC
The Food and Drug Administration
approved Qiagen’s Therascreen
KRAS RGQ PCR kit as a companion
diagnostic test to Mirati Therapeutics’
drug Krazati (adagrasib) for non-
small cell lung cancer.
Qiagen and Mirati announced their
cooperation in May 2021. The tissue-
based KRAS companion diagnostic
assay, which —continued on 49
2023 page 50
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Sysmex_ShadowAD_FINAL _CAP.indd 2
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