ORIGINAL

ARTICLES
The Evaluation of Hematologic Screening and Perioperative Management
in Patients with Noonan Syndrome: A Retrospective Chart Review
Benjamin Briggs, MD1,2,3, Dipal Savla, MD1, Nanda Ramchandar, MD, MPH1,3,4, David Dimmock, MBBS MS3,
Dzung Le, MD, PhD5, and Courtney D. Thornburg, MD, MS1,2,6

Objectives To assess the potential impact of using screening recommendations for bleeding disorders in patients
with Noonan syndrome on perioperative bleeding complications.
Study design We performed a retrospective, single-site cohort study; patients were identified by query of the
electronic medical record. All patients with a clinical diagnosis of Noonan syndrome over a 10-year period were
included. Data on surgeries, hematologic evaluation, bleeding symptoms, and bleeding complications were ex-
tracted. Surgeries were graded as major or minor.
Results We identified 101 patients with Noonan syndrome, 70 of whom required surgery for a total of 164 proced-
ures. Nine patients (9/70; 12.8%) had bleeding complications, occurring in those without comprehensive testing or
perioperative intervention and undergoing major or dental surgery. Based on these findings, the risk of a bleeding
complication for patients with Noonan syndrome who did not have comprehensive testing or perioperative interven-
tion was 6.2% (95% CI 2.3%-10.1%), indicating the number needed to treat or screen would be 16 to prevent 1
bleeding complication (95% CI 9.9-43.9). The majority of patients had either no or incomplete evaluation (59 of
101; 58.4%).
Conclusions With proper evaluation and management, the bleeding risk in patients with Noonan syndrome can
be minimized. Efforts are needed to address the knowledge and implementation gap in this evaluation. (J Pediatr
2020;-:1-5).

N
oonan syndrome is an autosomal-dominant condition with an estimated incidence of 1 in 1000 to 1 in 2500 individ-
uals1 and is associated with multiple anomalies with variable expressivity.2 Approximately 80% of clinically diagnosed
patients will have disease-causing variants in genes of the RAS/mitogen-activated protein kinase pathway: PTPN11,
SOS1, RAF1, RIT1, KRAS, NRAS, BRAF, MAP2K1, RRAS, RASA2, A2ML1, LZTR1, and SOS2.3 Phenotypic features include
hypertelorism, broad forehead, ptosis, broad neck, structural heart disease such as pulmonary stenosis and hypertrophic car-
diomyopathy, cryptorchidism, chest wall deformity, and short stature. Bleeding disorders, defined as either bleeding symptoms
or abnormal coagulation testing, are also a common feature of Noonan syndrome.4 Identification of the subset of patients with
a bleeding disorder is important because many of the associated defects require surgical or procedural interventions that inher-
ently challenge the patient’s hemostatic system. Postoperative bleeding complications have been seen in 4.5%-20% of patients
with Noonan syndrome.5,6
Determination of the prevalence of bleeding disorders in Noonan syndrome is difficult because authors have quoted figures
ranging from 20%7 to 92%.8 A likely source of this discrepancy concerns the depth of hematologic testing performed, potential
ascertainment bias, and how bleeding disorders are defined in the various studies. The most clinically relevant definition of a
bleeding disorder would be the presence of bleeding symptoms, abnormal hemostatic laboratory results, or both,4 as bleeding
complications have been reported in patients with bleeding symptoms but normal laboratory results9,10 and in patients with
abnormal laboratory results but no bleeding symptoms.11,12
Peer-reviewed guidelines have advised routine clinical screening for bleeding
disorders be performed in all patients with Noonan syndrome.2,3,13 The recom-
mendation is for all patients to receive Tier 1 testing, which includes a bleeding
1 2
history, a screening complete blood count with differential, a prothrombin time From the Department of Pediatrics, Division of
Hematology and Oncology, University of California San
(PT), and an activated partial thromboplastin time (aPTT) time at diagnosis and 3
Diego, La Jolla; Rady Children’s Institute of Genomic
4
Medicine, San Diego; Division of Infectious Disease, and
after 6-12 months of age if initial screen was performed in infancy. If the patient 5
Department of Pathology, University of California San
6
Diego, La Jolla; and Hemophilia and Thrombosis
has bleeding symptoms or abnormal screening results, then Tier 2 screening Treatment Center, Rady Children’s Hospital San Diego,
San Diego, California
The views expressed in this article are those of the au-
thor(s) and do not necessarily reflect the official policy or
aPTT Activated partial thromboplastin time position of the Department of the Navy, Department of
EMR Electronic medical record Defense, or the US Government. The authors declare no
conflicts of interest.
PT Prothrombin time
RCHSD Rady Children’s Hospital San Diego 0022-3476/$ - see front matter. ª 2020 Elsevier Inc. All rights reserved.
https://doi.org/10.1016/j.jpeds.2020.01.048

1
THE JOURNAL OF PEDIATRICS  www.jpeds.com Volume -  - 2020

should occur in consultation with a hematologist to include based on a false-positive screening test, an abnormal PT or
specific factor activity (factor XI, XII, IX, VIII, and von Wil- aPTT with no further evaluation was considered an abnormal
lebrand factor) and platelet dysfunction (by way of platelet Tier 1 test with incomplete evaluation but not a bleeding dis-
aggregation). Preoperative screening should include both order unless the previous criteria was met. One abnormal
first- and second-tier testing in consultation with a hematol- value on Tier 1 testing with previous normal results or
ogist. Aspirin, aspirin-containing products, and nonsteroidal normal findings on repeat analysis was considered as negative
anti-inflammatory drugs, which interfere with platelet func- Tier 1 test. Surgeries and procedures were tabulated and
tion, should be avoided if possible. graded as major or minor (Table I; available at www.jpeds.
It has been suggested that appropriate tests are not being com) based on the work by Solimeno et al.15 If more than
performed routinely in clinical practice.14 Published guid- 1 procedure occurred under the same anesthesia, it was
ance on the treatment of bleeding complications and the considered a single surgical episode and was assigned the
management of the perioperative patient with Noonan syn- category of the most invasive procedure. A bleeding
drome has been suggested but never evaluated.6 We present complication was defined as documentation of significant
the results of a single-institution, 10-year retrospective study bleeding, prolonged bleeding, or bleeding that required
of coagulation screening and perioperative management in blood products or surgical intervention to stop.
patients with Noonan syndrome. Patients are classified based
on published recommendations for coagulation testing and Statistical Analyses
further characterized by bleeding phenotype, laboratory ab- Descriptive statistics were used to characterize the demo-
normalities, and clinically diagnosed bleeding disorders.14 graphic, clinical, and laboratory features of the study cohort.
We assess how screening for bleeding disorders in patients The Fisher exact test was performed for categorical data with
with Noonan syndrome impacted perioperative bleeding a P value of <.05 considered statistically significant.
complications.
Results
Methods Of 2.1 million charts, 115 were identified by the search
defined in the methods, 14 of which the diagnosis of Noonan
The study protocol was approved by the Human Research syndrome could not be confirmed or a different diagnosis
Protections Program at the University of California San was found, giving a total of 101 patients to be investigated
Diego (Project #181821XL). The study included patients (Table II).
who received care at Rady Children’s Hospital San Diego
(RCHSD) from September 1, 2008, to October 13, 2018.
RCHSD is the largest children’s hospital in California, with
520 licensed beds and more than 18 000 admissions per
year. In 2014, RCHSD provided care to 196 905 children. It Table II. Demographics of patients with Noonan
provides comprehensive pediatric medical services to San syndrome
Diego, Riverside, Imperial, and Orange Counties, which
Demographics n = 101
have a combined population of 9 million, caring for
more than 90% of the children in San Diego County. Patients Female 41 (40.6%)
Male 60 (59.4%)
were identified by searching the electronic medical record Age range* 5 mo to 32 y
(EMR) Epic Hyperspace (Epic Systems Corp, Verona, Wis- Mean (SD) 12.1 y (7.2 y)
consin), which also pulled data from the previous EMR, Race
White 55 (54.5%)
ChartMaxx (Health IT Outcomes, Erie, Pennsylvania) in Black/African American 4 (4%)
the dates defined with a SNOMED CT query for the term Asian 5 (5%)
“Noonan’s syndrome” (Concept Code 20582406). Individual Pacific Islander 2 (2%)
Other 33 (32.7%)
medical records were then manually reviewed to obtain de- Unknown 2 (2%)
mographic, clinical, and laboratory data. Patients were Ethnicity
included if they had a clinical diagnosis of Noonan syndrome Non-Hispanic 47 (46.5%)
Hispanic/Latino 54 (53.5%)
documented in their EMR and were seen at our institution Molecular diagnosis n = 40 (39.6%)
during the study period. Charts in which the diagnosis of PTPN11 mutation 28 (70%)
Noonan syndrome could not be confirmed in the medical re- SOS1 mutation 3 (7.5%)
RIT1 mutation 2 (5%)
cord were not included for further analysis. Data were BRAF mutation 2 (5%)
abstracted from the EMR. KRAS mutation 2 (5%)
For this report, a bleeding disorder was defined as docu- SHOC2 mutation 2 (5%)
MAP2K2 mutation 1 (2.5%)
mentation of bleeding symptoms, an abnormal Tier 2 labora- No molecular diagnosis (negative or no test) 61 (60.4%)
tory test, persistently low platelet count on Tier 1 testing, or a RASopathy panel negative 5 (5%)
clinical diagnosis of a bleeding disorder. To eliminate the risk No testing 56 (55.4%)
of inaccurately categorizing a patient with a bleeding disorder *On October 13, 2018.

2 Briggs et al
- 2020 ORIGINAL ARTICLES

Twenty-eight patients had no documentation of hemato-

logic testing, 31 had incomplete testing, and 42 had Tier 1 Table IV. Association of bleeding symptoms with
testing; 24 patients had both Tier 1 and Tier 2 testing. perioperative bleeding complications in patients with
Twenty-eight patients had a bleeding disorder as defined, Noonan syndrome
and Table III (available at www.jpeds.com) shows the Perioperative No perioperative
specific features of these patients. Eight patients came to Bleeding bleeding bleeding
symptoms complication complication P value
attention for bleeding symptoms other than perioperative
Easy bruising 7/9 (78%) 9/61 (14.8%) <.01
bleeding and were seen by hematology. The etiology of Gum bleeding 3/9 (33%) 2/61 (3.2%) .01
bleeding disorders in our cohort included platelet function Epistaxis 3/9 (33%) 1/61 (1.6%) .01
defect (8), mild deficiencies in factor VII (2), IX (2), XI Menorrhagia* 1/2 (50%) 0/12 .14
(3), low von Willebrand factor (6), and thrombocytopenia *Evaluation limited to girls of age 10 years or older.
(7). Eight patients had a mixed bleeding disorder. Twenty-
four patients had documented bleeding symptoms. The
presence of bleeding symptoms, with the exception of intervention was 6.2% (95% CI 2.3%-10.1%), and no
menorrhagia, had a statistically significant association with patients with negative testing or who received perioperative
operative bleeding complications (Table IV). intervention had bleeding complications. This would
Of the 16 patients seen by hematology with a positive indicate the number of patients needed to treat or screen
workup, 11 (69%) had a clear emergency care/surgical for a bleeding disorder would be 16 to prevent 1 bleeding
plan, 2 had no plan yet as they have not had a follow-up visit complication (95% CI 9.9-43.9), although a larger
since testing was completed, 1 had no emergency care plan, multicenter study would be required to confirm this.
and for 2 it was unclear due to incomplete records. Five of
the 11 patients with emergency care plans went on to have Discussion
successful surgeries without bleeding complication
(Table V; available at www.jpeds.com). The remaining 6 The results of this study demonstrate that patients with
patients have not yet had surgery. Noonan syndrome who had coagulation evaluation and
Seventy patients required surgery or a procedure for a total perioperative management in line with peer-reviewed rec-
of 164 surgical episodes, with 53 categorized as major surgery ommendations2,3,13 had lower perioperative bleeding than
and 111 categorized as minor.15 The types of surgeries and patients without recommended evaluation. The majority
procedures were as follows: 38 cardiac (23.2%), 29 urologic of patients with Noonan syndrome seen at our institution,
(17.1%), 21 dental surgeries (12.8%), 18 orthopedic surgeries however, had either no evaluation or an incomplete evalua-
(11%), 15 abdominal (9.1%), 15 ear, nose, and throat (9.1%), tion (59 of 101; 58.4%). A similar deficit was found in a pub-
10 ophthalmologic surgeries (6.1%), 7 endoscopies (4.2%), 7 lished cohort of patients with Noonan syndrome, in which
neurosurgical (4.2%), 2 dermatologic surgeries (1.2%), 1 47% of their patients had no screening coagulation studies
placement of an indwelling cardiac catheter, and 1 lung bi- before surgery.5 Together, these findings suggest a
opsy. Nine patients (9/70; 12.8%) had bleeding complica-
tions, all occurring in those who did not have Tier 2 testing
or perioperative intervention and who had major surgery
or dental procedure. Of note, 5 of 17 dental procedures
(29.4%) which occurred without Tier 2 testing or periopera- Table VI. Preoperative evaluation and perioperative
tive intervention had bleeding complications. bleeding complications for 164 surgical episodes in
Five patients with bleeding complications saw hematology patients with Noonan syndrome
subsequently and were diagnosed with a bleeding disorder. Bleeding
Two of the 9 patients with bleeding complications had seen Preoperative complications/ Total bleeding
hematology previously and been diagnosed with a bleeding screening Surgical surgical complications/total
categories category episodes surgical episodes
disorder but did not have perioperative intervention to miti-
Positive Tier 1 or 2 Major 2/4 (50%) 9/145 (6.2%)
gate complications. Both of these patients went on to have testing with no Minor 2/7 (28.6%)
subsequent procedures with perioperative intervention suc- perioperative
cessfully preventing bleeding complications. Two of the 9 pa- intervention
Negative Tier 1 testing Major 1/15 (6.7%)
tients with bleeding complications have no documentation of Complete blood count Minor 1/35 (2.9%)
having seen a hematologist to date. Six patients saw a hema- only in 42/50 (84%)
tologist preoperatively and had a negative workup and un- No Tier 1 or 2 testing Major 1/27 (3.7%)
Minor 2/57 (3.5%)
derwent a combined 14 procedures without bleeding Negative Tier 1 Major 0/5 ( ) 0/19 ( )
complication. Table VI outlines the preoperative and 2 testing Minor 0/9 ( )
evaluation and perioperative bleeding complications in the Positive Tier 1 or 2 Major 0/1 ( )
testing Minor 0/4 ( )
164 surgical episodes. Based on these findings, the risk of a with perioperative
bleeding complication for patients with Noonan syndrome intervention
who did not have Tier 1 and 2 testing or perioperative
The Evaluation of Hematologic Screening and Perioperative Management in Patients with Noonan Syndrome: A 3
Retrospective Chart Review
THE JOURNAL OF PEDIATRICS  www.jpeds.com
knowledge and implementation gap in the evaluation and
management of bleeding disorders in patients with Noonan
syndrome.
We agree with the recommendations to obtain a bleeding
history and screening coagulation studies (PT, aPTT, and
platelet count) in all patients with Noonan syndrome. In
addition, our findings underscore the importance of clini-
cians asking about bleeding symptoms, optimally with a
bleeding risk assessment tool validated for patients with
Noonan syndrome. Such inquiries could be initiated by
any provider caring for patients with Noonan syndrome.
If abnormalities are found or surgery is planned, then
referral to a specialist in the management of bleeding disor-
ders should occur to facilitate in-depth evaluation and
minimize future risk. Indeed, our cohort suggests that nega-
tive findings on Tier 1 and 2 testing would indicate very low
risk for bleeding complications; no complications in this
group of 14 procedures. Abnormal findings on Tier 1 or 2
testing, however, would indicate a high risk of bleeding
complications, as they occurred in 4 out of 11 surgical epi-
sodes (36.3%) being performed without perioperative inter-
vention. We also demonstrate that this can be avoided with
proper perioperative management. In addition, we see that
patients with Noonan syndrome undergoing major surgery
or dental surgery are at the greatest risk.
There are several limitations to this investigation,
including the retrospective nature in a single site, which
makes it difficult to assess whether patients had any docu-
mentation of bleeding symptoms, additional workup per-
formed, or bleeding complications occurring elsewhere.
Furthermore, practice patterns may vary based on institu-
tion, limiting the generalizability of our findings. Because
we are a large referral center servicing a large geographic
area, however, we think the contributions of these limitations
are less. Also, with so few of our patients having comprehen-
sive laboratory workup, it is difficult to make conclusions
about the bleeding risk for patients who may have abnormal
laboratory results but no bleeding symptoms. Although our
cohort was not powered to prove a statistically significant
decrease in bleeding complications in the group of patients
with negative preoperative screening or perioperative man-
agement for those with an identified bleeding disorder, it is
encouraging to note that none of our patients who had nega-
tive Tier 1 and 2 testing or perioperative management when
indicated had bleeding complications. The feasibility of
achieving a study powered to prove such a difference retro-
spectively would be challenging at a single site, and a prospec-
tive study would raise ethical concerns for those with positive
bleeding workup.
Historical data and current peer-reviewed guidelines were
developed before the widespread availability of DNA
sequencing for Noonan syndrome. Therefore, we used a clin-
ical diagnosis as the inclusion criteria for our study. Hemato-
logic evaluation is indicated for all patients clinically or
molecularly diagnosed with Noonan syndrome. In our
cohort, only 39.6% of the patients with a documented clinical
4 Briggs et al
Volume -
diagnosis of Noonan syndrome had a molecular etiology
identified. This reflects local practices of not seeking molec-
ular confirmation when a dysmorphologist is confident in
the diagnosis. Therefore, in this historical cohort, we are un-
able to establish whether particular genetic etiologies are
more or less likely to lead to a bleeding disorder.
It is possible that the lower incidence of bleeding disorders
in our study compared with previous work is a result of
incomplete evaluation in our series. In addition, our platelet
aggregation is performed with a 10-fold greater concentra-
tion of collagen and a 5-fold greater concentration of ADP
when compared with that used by Artoni et al,8 which could
explain our lower incidence of platelet function disorders.
Furthermore, we do not use U46619 or thrombin receptor–
activating peptide in our platelet aggregation but do use
high- and low-dose ristocetin and epinephrine. Finally, the
inconclusive workup for one of our patients with bleeding
symptoms (Patient 21) suggest that additional testing may
be indicated for some patients, to include factor XIII
activity or urea clot lysis screen and tissue plasminogen acti-
vator and plasminogen activator inhibitor-1 antigen and
activity testing to complete the evaluation of their bleeding
symptoms.
Laboratory abnormalities are often mild and individually
do not easily explain the bleeding symptoms exhibited by
patients with Noonan syndrome. Mild abnormalities in
combination, however, could explain the bleeding pheno-
type, and current knowledge does suggest a potential deficit
in all stages of coagulation: primary hemostasis, secondary
hemostasis, and fibrinolysis. Artoni et al8 underscored de-
fects in primary hemostasis, with 83% of their patients hav-
ing abnormal platelet aggregation. Thrombocytopenia and
von Willebrand disease also are seen at rates greater in
Noonan syndrome than would be expected for the normal
population, being seen in 6% and 5% of patients, respec-
tively.4,13-15,16,17 Defects in secondary hemostasis occur
from deficiencies in factor II, V, VII, VIII, IX, XI, XII,
and XIII.8,14,18-20 Finally, fibrinolysis also may be involved
as suggested by a study21 that found a low plasminogen
activator inhibitor-1 to tissue plasminogen activator ratio
in patients with Noonan syndrome, suggestive of increased
fibrinolysis. Perhaps abnormalities in all stages of coagula-
tion could explain the bleeding phenotype in Noonan syn-
drome, as mixed disorders are common.4,14
In conclusion, bleeding disorders are an important pheno-
type in Noonan syndrome of which all providers caring for
these patients should be aware. Our work suggests that,
with proper evaluation, the bleeding risk in patients with
Noonan syndrome can be mitigated. Further efforts are
needed, however, to address the knowledge and implementa-
tion gap in the evaluation of bleeding risk for patients with
Noonan syndrome. Finally, larger studies with comprehen-
sive evaluation for bleeding disorders, coupled with detailed
surgical classification, are needed to identify the patients
with Noonan syndrome at the greatest risk of bleeding
complications. n
- 2020
Submitted for publication Oct 17, 2019; last revision received Jan 2, 2020;
accepted Jan 21, 2020.
Reprint requests: Benjamin Briggs, MD, 3020 Children’s Way, MC 5035, San
Diego, CA 92123. E-mail: bbriggs@rchsd.org
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5. Perez Botero J, Ho TP, Rodriguez V, Khan SP, Pruthi RK, Patnaik MM.
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7. Allanson JE. Noonan syndrome. J Med Genet 1987;24:9-13.
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et al. Hemostatic abnormalities in Noonan syndrome. Pediatrics
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in Noonan syndrome. Scand J Plast Reconstr Surg Hand Surg 2005;39:
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The Evaluation of Hematologic Screening and Perioperative Management in Patients with Noonan Syndrome: A
Retrospective Chart Review
ORIGINAL ARTICLES
10. Tofil NM, Winkler MK, Watts RG, Noonan J. The use of recombinant
factor VIIa in a patient with Noonan syndrome and life-threatening
bleeding. Pediatr Crit Care Med 2005;6:352-4.
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patient with Noonan’s syndrome. J Oral Maxillofac Surg 1994;52:
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12. Grange CS, Heid R, Lucas SB, Ross PL, Douglas MJ. Anaesthesia in a
parturient with Noonan’s syndrome. Can J Anaesth 1998;45:332-6.
13. Roberts AE, Allanson JE, Tartaglia M, Gelb BD. Noonan syndrome. Lan-
cet 2013;381:333-42.
14. Nugent DJ, Romano AA, Sabharwal S, Cooper DL. Evaluation of
bleeding disorders in patients with Noonan syndrome: a systematic re-
view. J Blood Med 2018;9:185-92.
15. Solimeno LP, Escobar MA, Krassova S, Seremetis S. Major and minor
classifications for surgery in people with hemophilia: a literature review.
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17. Leebeek FWG, Eikenboom JCJ. Von Willebrand’s disease. N Engl J Med
2016;375:2067-80.
18. Sharland M, Patton MA, Talbot S, Chitolie A, Bevan DH. Coagulation-
factor deficiencies and abnormal bleeding in Noonan’s syndrome. Lan-
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19. Singer ST, Hurst D, Addiego JE. Bleeding disorders in Noonan syn-
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Oncol 1997;19:130-4.
20. Witt DR, McGillivray BC, Allanson JE, Hughes HE, Hathaway WE,
Zipursky A, et al. Bleeding diathesis in Noonan syndrome: a common as-
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5
THE JOURNAL OF PEDIATRICS  www.jpeds.com
Table I. Surgical categorization
Major surgery
Acetabuloplasty, appendectomy, arthrodesis, cardiac surgery,
cholecystectomy, cranioplasty, craniotomy, epiphysiodesis,
nephrectomy, osteotomy, pyloromyotomy, dental extraction (if
number of teeth specified and greater than 3), spinal fusion,
tethered cord release, ureteroureterostomy, xyphoidectomy
5.e1
Volume -
Minor surgery
Cardiac catheterization, endoscopy, colonoscopy, orchiopexy, hernia repair, strabismus
surgery, dental procedure (if extraction but the number of not specified),
adenoidectomy, needle lung biopsy, hardware removal, circumcision, cochlear
implant placement, cystoscopy, frontalis suspension, G-tube placement, lipoma
resection, myringotomy tube insertion, pilomatrixoma resection, central venous
catheter placement, tendon release, ptosis repair, subungual exostosis,
dacryocystorhinostomy, tonsillectomy
Briggs et al
- 2020 ORIGINAL ARTICLES

Table III. Patients with Noonan syndrome and a bleeding disorder

Patients’ information Bleeding symptoms Tier 1 coagulation testing Tier 2 coagulation testing
Patient 8 Easy and excessive bruising, PT 11.4-15.7 Fibrinogen 566
Age: 22 y postoperative bleeding aPTT 30.9-42 FVIII 80-98
Sex: male Plt 85-165 FIX 56-70
Genotype: unknown FXI 46
Hematology evaluation: yes FXII 58
Surgery: yes VWF:Ag 84-96
VWF:RCo 77-90
Not Done: Plt Ag
Patient 9 Blood, platelet, fresh-frozen plasma, PT 16.1-20.7 Fibrinogen 94-316
Age: 20 y and cryoprecipitate transfusion given aPTT 33-40 Not done: VWF:Ag,
Sex: male intraoperatively for bleeding Plt 89-157 VWF:RCo, factor activities, Plt Ag
Genotype: unknown
Hematology evaluation: no
Surgery: yes
Patient 12 Menorrhagia, easy bruising PT 12.5 Fibrinogen 286
Age: 19 y aPTT 32 FVIII 85
Sex: female Plt 279-324 VWF:Ag 51
Genotype: PTPN11 VWF:RCo 46
Hematology evaluation: yes VWF multimers reduced
Surgery: no Not done: Plt Ag
Patient 13 Epistaxis PT 14.3* FVIII 75
Age: 19 y aPTT 35 FIX 76
Sex: male Plt 124-150 FXI 75
Genotype: RIT1 FXII 59
Hematology evaluation: yes VWF:Ag 51
Surgery: yes VWF:RCo 43
Plt Ag: ADP 74, Col 55, AA 59,
Rist HD 65, Rist LD 0, Epi 62
Patient 21 Gum bleeding, easy bruising, PT 11.6 VWF:Ag 55
Age: 16 y postoperative bleeding, menorrhagia aPTT 31 VWF:RCo 59
Sex female Plt 185- 217 VWF multimers normal,
Genotype: unknown Plt Ag: ADP 62, Col 61, AA 73,
Hematology evaluation: yes Rist HD 82, Rist LD 0, Epi 55
Surgery: yes
Patient 31 None listed PT 12.8-17.8 Fibrinogen 194-585
Age: 14 y aPTT 34-44 Not Done: VWF:Ag, VWF:RCo,
Sex: female Plt 66-165 factor activities, Plt Ag
Genotype: unknown
Hematology evaluation: no
Surgery: yes
Patient 35 Epistaxis, gum bleeding, easy bruising, PT 11.8-15, Fibrinogen 290
Age: 12 y postoperative bleeding aPTT 34-38, FVII 81
Sex: female Plt 68-212 FVIII 87
Genotype: PTPN11 VWF:RCo 64
Hematology evaluation: yes VWF:Ag 66
Surgery: yes Not Done: Plt Ag
Patient clinically diagnosed with a
platelet aggregation defect
Patient 45 Easy bruising PT 11.1 FVIII 81
Age: 15 y aPTT 35 FIX 85
Sex male Plt 234-279 FXI 57
Genotype: PTPN11 FXII 94
Hematology evaluation: yes VWF:RCo 52
Surgery: yes VWF:Ag 62
VWF multimers normal
Plt Ag: ADP 43, Col 68, AA 52,
Rist HD 74, Rist LD 0, Epi 17
Patient 52 Menorrhagia PT 12.7 FVIII 122
Age: 21 y aPTT 30.7 FXIII 96
Sex: female Plt 259-286 VWF:RCo 76
Genotype: PTPN11 VWF:Ag 83
Hematology evaluation: yes Plt Ag: ADP 62, Col 60, AA 62,
Surgery: no Rist HD 65, Rist LD 0, Epi 58
Not Done: FVII

(continued )

The Evaluation of Hematologic Screening and Perioperative Management in Patients with Noonan Syndrome: A 5.e2
Retrospective Chart Review
THE JOURNAL OF PEDIATRICS  www.jpeds.com Volume -

Table III. Continued

Patients’ information Bleeding symptoms Tier 1 coagulation testing Tier 2 coagulation testing
Patient 55 Hematemesis PT 13.3-14.2 Fibrinogen 346
Age: 16 y aPTT 39-43 Not done: VWF:Ag, VWF:RCo,
Sex: male Plt 210-339 Factor activities, Plt Ag
Genotype: unknown
Hematology evaluation: no
Surgery: no
Patient 56 Easy bruising, Plt 168-358 Not done
Age: 9 y postoperative bleeding
Sex: female
Genotype: unknown
Hematology evaluation: no
Surgery: yes
Patient 57 Epistaxis Plt 271 Not done
Age: 22 y
Sex: male
Genotype: unknown
Hematology evaluation: no
Surgery: no
Patient 58 Easy bruising PT 12.6 FVII 59
Age: 9 y aPTT 40.1 FVIII 89
Sex: male Plt 183-301 FIX 67
Genotype: unknown FXI 84
Hematology evaluation: yes XII 36
Surgery: yes VWF:RCo 113
VWF:Ag 107
Plt Ag: ADP 67, Col 59,
AA 59, Rist HD 69,
Rist LD 0, Epi 63
Patient 61 Easy bruising, Platelets and PT 11.6, FVIII 71
Age: 8 y fresh frozen plasma aPTT 31.7 VWF:RCo 46
Sex: female given intraoperatively for bleeding Plt 178-433 VWF:Ag 71
Genotype: unknown Not done: Plt Ag
Hematology evaluation: yes
Surgery: yes
Patient 68 Easy bruising Not done Not done
Age: 8 y
Sex: male
Genotype: PTPN11
Hematology evaluation: no
Surgery: yes
Patient 71 Epistaxis, excessive and PT 11.4 FVIII 81
Age: 8 y easy bruising, aPTT 38.5 FIX 85
Sex: male postoperative bleeding Plt 286 FXI 108
Genotype: unknown FXII 50
Hematology evaluation: yes VWF:RCo 45
Surgery: yes VWF:Ag 55
Plt Ag: ADP 58, Col 51, AA 61,
Rist HD 64, Rist LD 0, Epi 61
Patient 73 Easy bruising Plt 188 Not done
Age: 13 y Not done: PT, aPTT
Sex: female
Genotype: unknown
Hematology evaluation: no
Surgery: yes
Patient 76 Subdural hemorrhage PT 13.5 FXI 72
Age: 7 y aPTT 31.5 Not done: VWF:Ag, VWF:RCo
Sex: female Plt 271 and Plt Ag
Genotype: unknown
Hematology evaluation: yes
Surgery: yes
(continued )

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Table III. Continued

Patients’ information Bleeding symptoms Tier 1 coagulation testing Tier 2 coagulation testing
Patient 78 Easy bruising Not done Not done
Age: 12 y
Sex: female
Genotype: PTPN11
Hematology evaluation: no
Surgery: no
Patient 80 Postoperative bleeding PT 13.4-18.5 Plt Ag documented as moderately
Age: 5 y aPTT 35-44 s decreased response to all agonists
Sex: female Plt 86-154 VWF:Ag and VWF:RCo documented
Genotype: unknown as normal, factor activities
Hematology evaluation: yes documented as normal
Surgery: yes
Patient 89 Easy bruising, PT 11.4 FIX 80
Age: 4 y postoperative bleeding aPTT 39 FXI 91
Sex: female Plt 292-686 FXII 105
Genotype: SOS1 VWF:Ag 66
Hematology evaluation: yes VWF:RCo 55
Surgery: yes Plt Ag: ADP 60, Col 54,
AA 54, Rist HD 66, Rist
LD 0, Epi 58
Plasminogen activity 110
PAI-1 12
TPA 8.5
Patient 90 Gum bleeding, easy bruising PT 12.5 aPTT 32.1 FVIII 59-104
Age: 32 y BT 11 - >20 VWF:Ag 73-106
Sex: female Plt 175-196 VWF:RCo 40-114
Genotype: unknown VWF multimers reduced
Hematology evaluation: yes Plt Ag documented as
Surgery: yes normal to all agonists
Patient 92 History of abnormal Not done Not done
Age: 27 y coagulation studies
Sex: female
Genotype: unknown
Hematology evaluation: no
Surgery: yes
Patient 95 Easy bruising, gum bleeding, PT 13.5 aPTT 38 FVIII 121
Age: 14 y postoperative bleeding Plt 165-232 FIX 79
Sex male FXI 67
Genotype: PTPN11 FXII 42
Hematology evaluation: yes VWF:Ag 130
Surgery: yes VWF:RCo 97
VWF multimers normal
Plt Ag: ADP 37, Col 53, AA 53,
Rist HD 59, Rist LD 0, Epi 24
Patient 100 Epistaxis, gum bleeding, PT 17.2 aPTT 38 FVII 26
Age: 9 y postoperative bleeding Plt 375 FVIII 71
Sex: male FIX 46
Genotype: unknown FXI 61
Hematology evaluation: yes FXII 77
Surgery: yes VWF:Ag 58
VWF:RCo 51
Plt Ag: ADP 67, Col 58, AA 65,
Rist HD 69, Rist LD 0, Epi 59
Patient 109 Easy bruising, subdural PT 12.1 aPTT 30.0 FVII 64
Age: 5 y hemorrhage Plt 491 FVIII 103
Sex: male VWF:Ag 81
Genotype: unknown VWF:RCo 64
Hematology evaluation: yes Not done: Plt Ag
Surgery: yes
(continued )

The Evaluation of Hematologic Screening and Perioperative Management in Patients with Noonan Syndrome: A 5.e4
Retrospective Chart Review
THE JOURNAL OF PEDIATRICS  www.jpeds.com Volume -

Table III. Continued

Patients’ information Bleeding symptoms Tier 1 coagulation testing Tier 2 coagulation testing
Patient 110 None listed PT 14.0* aPTT 53 Fibrinogen 198
Age: 2 y Plt 410 FVIII 63
Sex: female FIX 38
Genotype: unknown Not done: VWF:Ag, VWF:RCo, FXI, Plt Ag
Hematology evaluation: no
Surgery: no
Patient 115 None listed Plt 72-123 Not Done: VWF:Ag, VWF:RCo,
Age: 5 mo Not done: PT, aPTT factor activities, Plt Ag
Sex: male
Genotype: unknown
Hematology evaluation: no
Surgery: no

AA, arachidonic acid; BT, bleeding time; Col, collagen; Epi, epinephrine; FVII, factor VII activity; FVIII, factor activity VIII; FIX, factor IX activity; FXI, factor XI activity; FXII, factor XII activity; PAI-1,
plasminogen activator inhibitor; Plt, platelet; Plt Ag, platelet aggregation; Rist HD, ristocetin 1.5 mg/mL; Rist LD, ristocetin 0.5 mg/mL; tPA, tissue plasminogen activator; VWF:Ag, von Willebrand
factor antigen; VWF:RCo, von Willebrand factor activity.
Bold values indicate abnormal results.
Normal ranges: Plt 140-440 thousand mL, PT 9.7-12.5 s or 11.4-14.0 s if * (done at different laboratories), aPTT 25-34 s, fibrinogen 160-425 mg/dL, VWF:Ag 60%-160%, VWF:RCo 55%-150%, VWF
multimers, FVII 60%-150%, FVIII 55%-140%, FIX 65%-135%, FXI 75%-165%, FXII 60%-140%. Plt Ag: agonists–ADP 20 mM >60%, Col 0.19 mg/mL >60%, AA 0.5 mg/mL >65%, Rist HD >75%,
Rist LD <15%, Epi 0.1 mg/mL >60%. Plasminogen activity 65%-176%, PAI-1 4-43 ng/mL, tPA £12.8 ng/mL, BT 0-7 min.

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Table V. Perioperative management in patients with Noonan syndrome and bleeding disorders
Patients Bleeding disorder diagnosis Surgery performed Perioperative management Outcome
Patient 8 Thrombocytopenia Tooth extraction Aminocaproic acid 2 g every 6 hours as needed for bleeding Minimal blood loss
Patient 35 Platelet function defect Tooth extraction Platelet transfusion, aminocaproic acid 2 g every 6 hours for 7 days Minimal blood loss
Thrombocytopenia
Patient 58 Platelet function defect Tooth extraction Aminocaproic acid 2 g every 6 hours as needed for bleeding Minimal blood loss
Patient 61 Von Willebrand Disease Cranioplasty Platelets and fresh frozen plasma Minimal blood loss
Patient 109 No diagnosis Tooth extraction Platelet transfusion with severe blood loss—not needed Minimal blood loss

The Evaluation of Hematologic Screening and Perioperative Management in Patients with Noonan Syndrome: A 5.e6
Retrospective Chart Review