LETTERS TO THE EDITOR
Bleeding disorders identified in blood
donors after quality control of fresh-frozen
plasma
Guidelines for the Blood Transfusion Services in the
United Kingdom state that 1% of donations used for
fresh-frozen plasma (FFP) must be tested for coagula-
tion FVIII:C activity (FVIII:C) and 75% of these must
have a level of greater than or equal to 0.70 IU/mL.1 In
the Northern Ireland Blood Transfusion Service (NIBTS)
donors who are found to have a FVIII:C of less than
0.50 IU/mL are referred on for further investigation.
There were a total of 57,409 whole blood donations
with 5392 units of FFP issued by NIBTS between April 1,
2012, and March 31, 2013. During this period 561 FFP com-
ponents were tested for FVIII:C. Six of these were found to
have FVIII:C of less than 0.5 IU/mL and three of these,
including one previously reported case, were subsequently
diagnosed with bleeding disorders.2 A 20-year-old male
who was donating for the third time in September 2012
was found on a subsequently drawn venous specimen to
have a FVIII:C of 0.34 IU/mL. Von Willebrand factor (VWF)
antigen and activity levels were normal. DNA sequence
analysis of the coding sequence of the F8 gene that enco-
des the FVIII protein identified a G-to-A substitution in
Exon 19 at Nucleotide 6089 (c.6089G>A) predicting the
substitution of serine at Codon 2030 by asparagine.3 This is
a known mutation associated with mild hemophilia A car-
ried by approximately 20% of patients with mild hemo-
philia A in Northern Ireland.
The second donor was a 61-year-old male donating
for the 26th time in March 2013 who was randomly
selected for FVIII:C screening for the first time. The level
of FVIII:C was found on a subsequently drawn venous
specimen to be 0.20 IU/mL. VWF antigen and activity lev-
els were normal and on genetic screening, no mutation
was identified in the F8 gene indicating that the patient
was not affected by mild hemophilia A. As an alternative
explanation of the low FVIII:C level and normal VWF anti-
gen and activity, he underwent further tests for Type 2N
von Willebrand disease (VWD). A VWF-FVIII binding
assay was abnormally low on testing. DNA sequence anal-
ysis of the VWF gene coding sequence identified the heter-
ozygous presence of two different mutations. The first was
a G-to-A substitution in Exon 20 at Nucleotide 2561
(c.2561G>A) predicting the substitution of arginine at
Codon 854 by glutamine (p.Arg854Gln), which is associ-
ated with Type 2N VWD.4 The second mutation was a sin-
gle base duplication (T) after Nucleotide 50 (c.50dupT)
resulting in a frameshift and leading to an in-frame termi-
nation signal 25 codons 30 (p.Leu17Phefs*25). This second
mutation results in a null VWF allele.
1482 TRANSFUSION Volume 56, June 2016
Both mild hemophilia and VWD can present later
in life at the time of a surgical challenge, trauma, or
incidental coagulation test findings in those who have
mild, absent, or unrecognized symptoms. Neither of
these donors had any personal history of signs or symp-
toms of a bleeding disorder or any relevant family his-
tory. It is reassuring that these donors did not report
any complications of venipuncture. Hemophilia almost
exclusively affects males and it is the plasma from male
donors that is in demand to reduce the risk of
transfusion-related acute lung injury. FVIII:C screening
would not detect hemophilia B as it is the F IX activity,
which is reduced. FFP is usually administered to
patients in doses of between 2 and 6 units and therefore
the clinical significance of one of these units having a
low FVIII:C may be negligible.
Data from the national hemophilia database indi-
cates that in Northern Ireland, where the total popula-
tion is 1,840,498, the prevalence of diagnosed mild
hemophilia A is 1 in 14,723, and the prevalence of VWD
is 1 in 12,961.5 There are a total of two cases of Type 2N
VWD in Northern Ireland. Out of the 561 FFP compo-
nents tested at NIBTS for FVIII:C between April 1, 2012,
and March 31, 2013, one donor was diagnosed with
Type 2N VWD and two donors were diagnosed with
mild hemophilia A. This includes a previously reported
case.2 These cases suggest that if every donor had a
screening test for FVIII:C performed this could poten-
tially detect significant numbers of previously undiag-
nosed bleeding disorders thus benefitting donors.
CONFLICTS OF INTEREST
The authors have disclosed no conflicts of interest.
Christopher J. McCauley1
e-mail: chris.mccauley@belfasttrust.hscni.net
Muhammad Mohsin1
Paul Winter2
Gary M. Benson2
1
Haematology Department
2
Northern Ireland Haemophilia and
Thrombosis Comprehensive Care Centre
Belfast City Hospital
Belfast, UK
doi: 10.1111/trf.13591
C 2016 AABB
V
REFERENCES
1. Joint UKBTS/NIBSC Professional Advisory Committee.
Guidelines for the blood transfusion services in the United
Kingdom. 8th ed. Norwich: TSO; 2013.

2. Mohsin M, Winter P, Murdock J, et al. Detection of haemo-
philia A during quality assurance of fresh frozen plasma.
Transfus Med 2013;23:206.
3. Structural Immunology Group. Factor VIII variant
disease [Internet]. 2014 Nov [cited 2015 Dec 9]. London:
University College London; Available from: http://www.
factorviii-db.org/.
4. Hampshire DJ. LOVD—Variant listings [Internet]. Leiden:
Leiden University Medical Center; 2004-2014; [cited 2015
Dec 9]. Available from: https://grenada.lumc.nl/LOVD2/
VWF/variants.php?action5search_unique&select_db5VWF.
5. Births [Internet]. Belfast: Northern Ireland Statistics and
Research Agency; 2014 [cited 2015 Dec 1]. Available from:
http://www.nisra.gov.uk/demography/default.asp8.htm.
Enhancing platelet transfusion safety: not a
one-size-fits-all approach
In December 2014 the Food and Drug Administration
(FDA) issued a draft guidance to blood collection agen-
cies and transfusion services describing the use of bac-
terial testing to enhance the safety and availability of
platelets (PLTs). The guidance expanded the current rec-
ommendations for bacterial testing of PLTs to include
secondary testing of PLTs after Day 3. In addition to
decreasing the possibility of transfusing a bacterially
contaminated unit in Day 4 or 5 PLTs, this new guid-
ance offered secondary testing as a mechanism to
increase PLT shelf life to Day 7 and thus improve sup-
ply. The FDA estimates that of the approximately 2 mil-
lion PLT transfusions annually, 75% occur in large-
volume transfusion services. These larger transfusion
services may elect to perform secondary testing to
extend the shelf life past Day 5. While the FDA esti-
mated the burden of this change on the 150 large-
volume transfusion services, there was no discussion
about the impact this guidance may pose to very small
transfusion services.1 This leaves approximately 500,000
PLT transfusions annually. According to the 2011
National Blood Collection and Utilization Report, based
on institutions reporting blood costs based on surgical
volume, there are approximately 800 institutions of our
size or smaller.
While it is possible that blood suppliers will per-
form secondary testing before shipping Day 4 or 5 PLTs
to smaller transfusion services or only send these small
institutions Day 3 or younger PLTs, there is no guaran-
tee that blood suppliers will offer testing or be able to
send a younger product. In addition, this is a change
from the current practice of sending small transfusion
services, especially those that do not maintain PLT
inventories, older product since the intent is for imme-
diate transfusion not stock.
LETTERS TO THE EDITOR
The burden for smaller transfusion services is
markedly different compared to larger services. For
example, some of the standard procedures performed in
larger transfusion services, such as the use of sterile
docking devices, are not commonly found in smaller
transfusion services. Introducing a new clinical test
requires several steps: training, competency for the
staff, validation of the test before implementation,
labeling, quality controls, and proficiency testing. For
small transfusion services with infrequent PLT transfu-
sions, maintaining all these elements for an infrequent
test can be challenging. Often, these laboratories do not
have a dedicated blood bank staff, especially during
weekend, evening, and night hours, utilizing rotating
staff for all laboratory testing, including blood bank
activities. Even though the rapid bacterial detection
devices are relatively quick and easy to use, validation
and ongoing proficiency testing is required. The possi-
bility of a positive test, especially a false-positive test,2,3
when only a single PLT product is received for transfu-
sion with no stock on hand, is an issue not usually
faced by larger transfusion services. Often oncology
patients travel to receive transfusion support during
therapy, and if there is no product available, they either
wait or need to return.
In December 2014, the FDA approved the first
pathogen inactivation method for apheresis PLT prod-
ucts. While not yet on the market, several blood suppli-
ers have indicated that they may implement this
technology and will be able to supply this product. If
approved as an acceptable alternative to testing for bac-
terial contamination, this product could offer a viable
strategy for smaller transfusion services. Additional ben-
efits for smaller transfusion services include protection
from graft-versus-host disease, eliminating the necessity
of ordering irradiated product (and additional charge)
and also providing protection against nonbacterial
pathogens, including viruses and protozoans (e.g., Babe-
sia). The estimated cost for this product of approxi-
mately $75 to $1254 per unit would be easily offset by
the costs for smaller services to maintain proficiency
plus the cost of the pan genera detection (PGD) test
and avoiding the potential additional cost for gamma
irradiation ($35/PGD test, potentially $70 if a repeated
test is required, and $45/unit additional cost we pay for
irradiation).5 If approved as an alternative to secondary
testing, pathogen-inactivated apheresis PLTs could be a
viable option for smaller transfusion services.
CONFLICT OF INTEREST
The authors have disclosed no conflicts of interest.
Nora Ratcliffe, MD1
e-mail: nora.ratcliffe@va.gov
Volume 56, June 2016 TRANSFUSION 1483