Bleeding Disorders in Congenital SyndromesSusmita N. Sarangi, MD, Suchitra S. Acharya, MD

Bleeding Disorders and Thrombosis Program, Cohen

Children’s Medical Center of New York, New Hyde Park,

New York

Drs Sarangi and Acharya contributed to the

conceptualization, content, and composition of the

manuscript and approved the fi nal manuscript as

submitted.

DOI: 10.1542/peds.2015-4360

Accepted for publication Aug 15, 2016

Address correspondence to Suchitra S. Acharya,

MD, Bleeding Disorders and Thrombosis Program,

Cohen Children’s Medical Center of New York, 269-

01 76th Ave, Suite 255, New Hyde Park, NY 11040.

E-mail: sacharya@northwell.edu

PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online,

1098-4275).

Copyright © 2017 by the American Academy of

Pediatrics

FINANCIAL DISCLOSURE: The authors have

indicated they have no fi nancial relationships

relevant to this article to disclose.

FUNDING: No external funding.

POTENTIAL CONFLICT OF INTEREST: The authors

have indicated they have no potential confl icts of

interest to disclose.

Children with congenital syndromes

with multiple anomalies need a

multidisciplinary approach to

their care, along with continued

surveillance for rare manifestations

such as a bleeding diathesis, which

may not be evident at diagnosis. This

accompanying bleeding diathesis

due to thrombocytopenia or other

coagulation defects may be a part of

the syndrome that is not routinely

addressed. Consequently, this may go

unrecognized in these children until

they face hemostatic challenges, which

is not uncommon (given the number

of corrective surgeries performed

for the congenital defects) in this

population leading to unanticipated

surgical bleeding. Counseling for these

families should include discussions

regarding potential spontaneous or

trauma-related bleeding associated

with these syndromes that can

evolve over time. This review aims

to highlight congenital syndromes

where hemostatic defects have been

reported, aid the treating primary care

physician (PCP) to adequately workup

these patients as part of surveillance

or before scheduled procedures

and recommends guidelines for

appropriate and timely referral to the

hematologist.

Achieving hemostasis is a complex

process starting with endothelial

injury that results in platelet plug

formation, which is then strengthened

by deposition of fibrin formed

by the proteolytic coagulation

cascade. Platelets initially attach

to subendothelial collagen and

von Willebrand factor (vWF) via

glycoproteins VI and 1bα (GPVI,

GPIbα). This leads to activation of

platelets releasing Thromboxane

A2 (TxA2) and conforming the

glycoprotein IIb/IIIa (GPIIb/IIIa)

receptor on the platelet surface into

its high affinity state, which now

binds to fibrinogen and vWF. This

further leads to release of platelet

granule contents (fibrinogen, Factor

V, platelet factor 4, Calcium, ADP,

ATP, serotonin, vWF) leading to an

extremely procoagulant surface and

abstractPediatricians provide a medical home for children with congenital

syndromes who often need complex multidisciplinary care. There are

some syndromes associated with thrombocytopenia, inherited platelet

disorders, factor deficiencies, connective tissue disorders, and vascular

abnormalities, which pose a real risk of bleeding in affected children

associated with trauma or surgeries. The risk of bleeding is not often an

obvious feature of the syndrome and not well documented in the literature.

This makes it especially hard for pediatricians who may care for a handful

of children with these rare congenital syndromes in their lifetime. This

review provides an overview of the etiology of bleeding in the different

congenital syndromes along with a concise review of the hematologic

and nonhematologic clinical manifestations. It also highlights the need

and timing of diagnostic evaluation to uncover the bleeding risk in these

syndromes emphasizing a primary care approach.

STATE-OF-THE-ART REVIEW ARTICLEPEDIATRICS Volume 139 , number 2 , February 2017 :e 20154360

To cite: Sarangi SN and Acharya SS. Bleeding

Disorders in Congenital Syndromes. Pediatrics.

2017;139(2):e20154360

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SARANGI and ACHARYA

platelet aggregation. The stage is

now set for the cascade of serine

proteases (factors V, VII, VIII, IX, X,

XI, XII, XIII) activated by the release

of tissue factor, which culminate in

the cleaving of thrombin to form

an insoluble fibrin mesh leading

to a stable clot at the site of injury.

With the many players involved in

coagulation, it can be seen how the

clinical bleeding phenotype can be

modified by gene–gene interactions

by improving or worsening the

integrity of clot formation directly

or indirectly. Therefore, this review

will focus on congenital syndromes

associated with quantitative

(thrombocytopenia) and qualitative

platelet function defects (ie, defects

in platelet generation or defects at 1

or more levels of platelet activation)

and coagulation factor deficiencies.

It will also highlight congenital

syndromes where bleeding can

result from defects in the underlying

connective tissue or anatomic

malformations that increase

predisposition to bleeding. It will

further discuss basic evaluation of

these patients on the basis of a high

index of suspicion and highlight what

phenotypes need specialist referral

for both health maintenance and

prevention of surgical bleeding and

discuss general treatment principles.

Table 1 and Supplemental Tables 5

and 6 summarize the key features of

the congenital syndromes discussed

in this review.

COMMON CONGENITAL SYNDROMES ASSOCIATED WITH A BLEEDING DIATHESIS

Chromosomal Syndromes

A fault in chromosome distribution

during cell division leads to

aneuploidy, which can be associated

with thrombocytopenia but is rarely

severe. Hohlfeld et al 6 in a study of

5194 fetal blood samples (17 to 41

weeks) reported 4.7% samples (247

samples) with thrombocytopenia

(platelet counts <150 000/μL), out

of which 17% (43 samples) were

due to chromosomal anomalies. The

prevalence was 54% in Trisomy

13, 86% in Trisomy 18, 31% in

Turner syndrome, and 6% in

Trisomy 21–Down syndrome (DS).

However, Hord et al 7 reported mild

to moderate thrombocytopenia

(platelet counts 40 000–100 000/

μL) in 28% of neonates with DS. The

exact mechanism is not known, but

is thought to be due to decreased

platelet production, from chronic

fetal hypoxia, which also leads to

intrauterine growth retardation. 8

DS (Trisomy 21) is also associated

with other hematologic findings,

such as polycythemia, neutropenia,

abnormal circulating blasts,

erythroblastosis, and giant platelets. 9

Approximately 10% of neonates with

DS have transient myeloproliferative

disorder, which can present with

isolated thrombocytopenia or

thrombocytosis, leukocytosis, or

persistent peripheral blood blasts.

These abnormal blood cells will self-

resolve in most infants by 3 months

after birth; however, 20% can have

more progressive disease. Both

transient myeloproliferative disorder

and myeloid leukemia associated

with DS (ML-DS), which presents

at 1 to 4 years of age, have somatic

mutations in the megakaryocyte

erythroid transcription factor

GATA-1. 10, 11 ML-DS has a preceding

myelodysplastic phase with patients

presenting with progressive

anemia and thrombocytopenia,

which then develops into leukemia.

DS-associated acute lymphoblastic

leukemia develops after age 4 years,

presenting with cytopenias, and often

lower platelet counts than ML-DS

patients. Therefore, all DS patients

should have a complete blood cell

count at birth and if found to have

any hematologic abnormalities

should be referred to hematology.

Other trisomies such as Trisomy 13

and Trisomy 18 have very distinct

clinical patterns ( Table 1),

and the diagnosis is usually

made soon after birth. Although

survival beyond infancy is rare, life

expectancy is improving. Recognizing

thrombocytopenia is important

because these conditions have

associated cardiac, respiratory, and

craniofacial anomalies that may need

corrective or palliative surgeries.

Surgical planning in these patients

needs a multidisciplinary team with

screening blood work to identify

thrombocytopenia, which if present

will need platelet transfusions pre-

and postoperatively depending upon

the complexity of the surgery guided

by the hematologist.

Turner syndrome (45, X) can

be associated with transient

thrombocytopenia (31% of patients 6)

in the newborn period. Due to the

single functional X chromosome, girls

can inherit X-linked conditions like

hemophilia, but this has only very

rarely been described. 12 Therefore,

prolonged bleeding events warrants

referral to a hematologist for workup.

Gastro-enteral bleeding can occur in

Turner syndrome due to associated

inflammatory bowel disease or

often unrecognized intestinal

telangiectasias (incidence of 7%). 13

DiGeorge syndrome (22q11.2 del)

is the most common micro deletion

syndrome with associated mild

macrothrombocytopenia in 30%

of patients resulting from deletion

of the contiguous GP1BB gene in

the deleted Chromosome 22q11

locus, which codes for the subunit

of the platelet adhesion receptor. 1

Immune dysfunction is common in

these patients and it is estimated

that immune thrombocytopenic

purpura is 200 times more common in

these patients as compared with the

general population. 14, 15 These platelet

abnormalities need to be identified

early on and specifically before

corrective cardiac surgeries. Close

collaboration with a hematologist

before these surgeries will help avert

bleeding complications.

Noonan syndrome is a relatively

common autosomal dominant

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PEDIATRICS Volume 139 , number 2 , February 2017

multisystem disorder with

a prevalence of 1 in 1000 to

2500 individuals. Patients with

Noonan syndrome with germ-line

mutations in PTPN11 need to be

monitored for the development

of myeloproliferative disorder or

juvenile myelomonocytic leukemia. 16

Prevalence of bleeding disorders

in Noonan syndrome has been well

described (ranging between 50%

and 89%) if positive bleeding history

or abnormal hemostatic laboratory

values are considered, whereas it

ranges between 10% and 42% if both

history and laboratory values are

considered. 17 – 22 Thrombocytopenia

is not reported as commonly;

however, platelet function defects

are frequent with a prevalence of

27%. 2 Up to 37% of these patients

can have factor XI deficiency while

von Willebrand disease and mixed

factor deficiencies are also reported. 2

Due to the complex phenotype,

a significant proportion of these

patients need surgical procedures.

A reasonable screening process can

begin with obtaining a platelet count,

prothrombin time (PT), activated

partial thromboplastin time (aPTT),

and Factor XI levels at a minimum

even in the absence of bleeding

symptoms and if there is a significant

bleeding history to include platelet

function testing and testing for other

components of the clotting cascade in

consultation with the hematologist.

Connective Tissue Disorders

Easy bruising and bleeding are

prominent manifestations of

heritable collagen disorders

with Ehlers-Danlos syndrome

3

TABLE 1 Features of Congenital Syndromes Associated With Thrombocytopenia

Disorder Incidence Clinical Features Incidence of Thrombocytopenia When to Refer to Hematology

Trisomy 21 1 in 660 Cognitive impairment, hearing

issues, thyroid issues, heart

defects, gastroenteral atresias,

cataracts

7–28%a All patients with any hematologic

abnormalities

Trisomy 13 1 in 5000 Cleft lip and palate, polydactyly,

rocker bottom feet, cutis aplasia,

omphalocele, VSD, PDA, neural

tube defects

54%a (All patients had platelet counts

>100 000/μL)

Platelet count <150 000/μL

Trisomy 18 1 in 5000 Dolichocephaly, micrognathia,

overriding fi ngers, cardiac septal

defects, horse shoe kidney,

psychomotor retardation, feeding

issues

86%a (20% with platelet counts 50 000–

100 000/μL)

Platelet count <150 000/μL

Turner

syndrome

1 in 2500 Coarctation of aorta, aortic stenosis,

short stature, ovarian failure,

horseshoe kidney, cubitus valgus,

low posterior hairline, webbed

neck

31%a (18% with platelet counts 50 000–

100 000/μL)

Platelet count <100 000/μL or between

100 000 and 150 000/μL and needs

surgery

DiGeorge

syndrome

1 in 4000 Typical facies, thymic abnormalities,

hypocalcemia, velopharyngeal

insuffi ciency, conotruncal cardiac

defects, tetralogy of Fallot,

truncus arteriosus, aortic arch

anomalies

30% 1 (Usually mild

macrothrombocytopenia)

Platelet count <150 000/μL and/or

rapidly falling platelet counts in the

context of viral illness should be

referred to rule out ITP

Noonan

syndrome

1 in 1000–2500 Facial dysmorphism, cardiac

anomalies, short stature, bony

and genital anomalies.

6.2% 2 (27% have platelet function defects) Any patient with thrombocytopenia

and all patients before surgery to

evaluate platelet function and other

components of clotting cascade.

Wiskott–Aldrich

syndrome

1 in 4 million Microthrombocytopenia, eczema,

immune defects

Microthrombocytopenia is universal

feature (platelet counts 5000–50 000/

μL) 3

Refer all patients. Also refer to

Immunology.

Cornelia de

Lange

syndrome

1 in 10 000 Growth retardation, synophrys,

limb abnormalities and cognitive

impairment

35% (15/43 patients) with platelet counts

<100 000 4 (16% had ITP with majority

progressing to chronic ITP; 11% had

transient thrombocytopenia)

Check platelet count at diagnosis

and every 5 years if asymptomatic.

Platelet count <100 000 or rapidly

falling platelet count refer to

hematology to rule out ITP

Jacobsen

syndrome

1 in 100 000 Dysmorphogenesis of hands and

feet, frequent cardiac defects and

cognitive impairment

Macrothrombocytopenia (88.5%)

with varying degrees of platelet

function defects (platelets with

giant α granules, storage pool

defects and delayed maturation of

megakaryocytes) 5

Any patient with thrombocytopenia

and all patients before surgery to

evaluate platelet function.

PDA, patent ductus arteriosus; VSD, ventricular septal defect. a Prevalence data from fetal samples (Hohlfeld et al 6).

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SARANGI and ACHARYA

(EDS) being the most prevalent.

Although collagen proteins are

an integral part of capillary

scaffolding, they also contribute

to platelet activation, adhesion,

and aggregation. EDS is a clinically

and genetically heterogeneous

group of conditions with varying

degrees of skin hyperextensibility,

joint hypermobility, delayed

wound healing, and atrophic skin

scarring. There are 5 subtypes with

a combined prevalence rate of 1

in 5000 individuals. Type IV EDS

(vascular type) carries the gravest

prognosis affecting medium and large

sized vessels. It can initially present

as easy bruising and gum bleeding,

but depending on the vessels affected

can have bleeding from every

possible site of the body, including

fatal intraabdominal bleeding. 23 The

other subtypes of EDS manifest with

soft, fragile hyperextensible skin

along with joint dislocations and

bony abnormalities. 23 The diagnosis

is often challenging in children,

especially when there is no family

history and can lead to extensive

hemostasis-related bleeding

workups, which are often normal.

In the office setting, clinicians can

use the Beighton scoring system

( Fig 1) for evaluation of joint

hypermobility and refer patients

with high scores to the geneticist

for further evaluation and

confirmatory genetic testing. 24, 25

Capillary fragility is common among

all subtypes with variable degrees

of platelet function defects and

coagulation factor deficiencies

(factors VIII, IX, XI, XII, and XIII)

being reported. 23 Desmopressin

has been shown to reduce bleeding

risk and postoperative bleeding

in pediatric patients with EDS,

suggesting that a weakened platelet

collagen interaction underlies

the bleeding tendency in EDS. 26

Therefore, individuals with suspected

or confirmed diagnosis of EDS with

any bleeding symptoms or planned

surgical procedures should be

referred to a hematologist.

Abnormalities in Vasculature

Hereditary hemorrhagic

telangiectasia (HHT) or Osler–

Weber–Rendu syndrome is a

common autosomal inherited

disorder with altered defects in

vascular integrity with an incidence

of 1 in 5000 individuals. The

underlying genes ENG, ACVRL1,

SMAD4 encode proteins leading

to elevated expression of vascular

endothelial growth factor. 27 This

leads to characteristic clinical

manifestations of dilated and

tortuous postcapillary venules

(telangiectasias) without intervening

capillaries, which have a higher

propensity to bleed due to inherently

elevated perfusion pressures. In HHT,

telangiectasias can develop in the

nasal mucosa within the first decade

and worsen with age, presenting with

severe and recurrent nosebleeds.

While evaluating significant and

prolonged epistaxis in a pediatric

patient, the PCP should inquire

about bleeding from other sites,

presence of anemia and gastro-

enteral bleeding, and strokes related

to arterio venous malformations

among close family members. It

4

FIGURE 1The Beighton Scoring system for joint hypermobility. Degree of mobility assessed by passive maneuvers in 5 joints. Total score: 0–9. Hypermobility score: ≥5. (Figure reproduced with permission from Arthritis Research UK; http:// www. arthritisresearch uk. org)

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PEDIATRICS Volume 139 , number 2 , February 2017

might be difficult to make a diagnosis

in childhood as characteristic

telangiectasias are often not present

until later or present as benign-

looking mucocutaneous red spots

that go unnoticed by providers.

The Curacao Criteria ( Table 2) is a

validated scoring system developed

to help elucidate a diagnosis of HHT

as nosebleeds and telangiectasias are

common in the general population. 28, 29

Otorhinolaryngologists should be

consulted early on in a child with

prolonged recurrent nose bleeds to

look for these telangiectasias without

which the diagnosis may be missed

until a later encounter with a life-

threatening bleeding episode.

RARE CONGENITAL SYNDROMES ASSOCIATED WITH A BLEEDING DIATHESIS

Inherited Platelet Disorders

Many of the inherited

thrombocytopenias are clinically

mild and may go unrecognized

unless faced with hemostatic

stressors such as menses, surgery,

trauma, or childbirth. 30 A thorough

bleeding history is a crucial

component in the evaluation of

these patients, including obtaining

previous blood counts if available.

Particularly, time should be devoted

to eliciting the family history with

special attention to hemostatic

stressors, such as menorrhagia,

bleeding after teeth extractions,

blood transfusions after surgery, or

unexplained anemia. Platelet counts

should be determined in family

members with bleeding symptoms.

The pattern of bruising and bleeding

disproportionate to trauma should

raise suspicion for nonaccidental

trauma even in patients in whom

congenital platelet disorders are

suspected. 31 The use of standardized

bleeding assessment tools is very

useful in this setting. The Pediatric

Bleeding Questionnaire identified

high bleeding scores (>96% of

patients) in a cohort of 23 patients

with known inherited platelet

disorders. 32

Supplemental Table 5 outlines

the various features of inherited

thrombocytopenic syndromes. The

underlying molecular defect can be

restricted to platelets alone, or in

some cases can involve other cells

thereby resulting in multisystem

dysfunction. Evaluation of the

patient and the family for presence

of immunodeficiency, hearing loss,

albinism, and renal findings will point

to an underlying syndromic cause of

thrombocytopenia. This is further

complicated by the fact that all

components of the syndrome may not

be present in affected individuals and

therefore a high index of suspicion is

key to their diagnoses. While working

up these patients, it is important

to collect fresh blood samples

with citrate as the anticoagulant

to eliminate the phenomenon

of pseudothrombocytopenia.

Automated platelet counters are not

accurate in the presence of macro

or micro thrombocytopenia and

manual inspection of peripheral

smears under Giemsa or Wright

stain provide important information

regarding platelet number, size, and

granularity. After recognition of

these syndromes, further diagnostic

evaluation of platelet disorders needs

careful preparation (a nontraumatic

blood draw to preserve component

proteins of the coagulation

cascade), specimen handling,

and interpretation and should be

carried out in conjunction with an

experienced hematologist who can

accurately interpret the clinical and

laboratory findings. Although light

transmission aggregometry and

its modification lumiaggregometry

are used for initial screening for

platelet function defects, there are

limitations of standardization and

reproducibility. However, it can

help identify platelet adhesion or

aggregation defects, platelet granule

release defects on the basis of which

further confirmatory testing can be

carried out.

Wiskott–Aldrich syndrome is a

rare autosomal recessive disorder

due to defects in the WASP gene

(Xp 11.22) with an incidence of 4

per million live births. 3 The clinical

features classically include the

triad of microthrombocytopenia

(platelet counts 5000–50 000/

μL) presenting as bruising and

purpura in the neonatal period,

eczema that develops around

infancy and immune defects with

recurrent sinopulmonary infections

in midchildhood. A high index of

suspicion should prompt referral to

a hematologist who may recommend

splenectomy to ameliorate

bleeding symptoms associated with

thrombocytopenia or bone marrow

transplantation, which is usually

curative ( Table 1 and Supplemental

Table 6).

Bone Marrow Failure Syndromes

Thrombocytopenia in inherited

bone marrow failure syndromes

(IBMFS) presents as a component of

progressive marrow failure, which

is the hallmark of these syndromes.

Thrombocytopenia may present in

the neonatal period in congenital

amegakaryocytic thrombocytopenia

and thrombocytopenia with

absent radii (TAR) manifesting

as petechial bleeding and rarely

leading to catastrophic intracranial

5

TABLE 2 The Curacao Diagnostic Criteria for

HHT

Criteria Defi nition

Epistaxis Spontaneous, recurrent

nosebleeds

Telangiectasias Multiple, at characteristic

sites (lips, oral cavity,

fi ngers, nose)

Visceral

involvement

Pulmonary, liver, cerebral,

spinal, or gastrointestinal

vascular malformations

Family history A fi rst-degree relative with

defi nite HHT

Diagnostic criteria

Defi nite HHT 3 or 4 criteria are present

Probable HHT 2 criteria are present

HHT unlikely Only 1 criterion is present

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SARANGI and ACHARYA

hemorrhage. Unlike other IBMFS,

the thrombocytopenia in TAR

improves after infancy and may rise

to levels safe to perform surgery,

suggesting that nonlife-threatening

procedures could be delayed until

after infancy. Fanconi anemia

presents with thrombocytopenia as

the first hematologic manifestation

during midchildhood, whereas in

Shwachman–Diamond syndrome it

appears later, having been preceded

by neutropenia for variable amounts

of time. 33 Supplemental Table 6

outlines the various IBMFS that

have thrombocytopenia as part of

the syndrome. The pathognomonic

physical features can aid in

recognizing the underlying IBMFS,

but it is important to realize that

half of these patients may not be

recognized until adulthood. 34

Chromosomal Disorders

Cornelia De Lange syndrome

(heterozygous mutation of NIPBL

gene) is an autosomal dominant

rare inherited disorder that can

have transient thrombocytopenia

at birth. 35 More recently a higher

incidence of chronic immune

thrombocytopenia (ITP) in these

patients has also been described

(see Table 1). 4 Self-injurious

behavior is often a component of

the syndrome that compounded

with thrombocytopenia can lead

to an increased risk of intracranial

bleeding. It has been proposed to

get platelet counts for these patients

at diagnosis, with any unusual

bleeding symptoms and at 5 yearly

intervals if asymptomatic and refer

to hematology for severe bleeding

symptoms. 4

Jacobsen syndrome (11q

syndrome) is perhaps the most well

described congenital syndrome

with thrombocytopenia that

poses significant morbidity to

affected children. The clinical

phenotype is variable with

macrothrombocytopenia a frequent

(88.5% of patients) feature of the

syndrome and a number of other

platelet abnormalities described,

including platelet function defects

( Table 1). 36 – 38 It is important to

recognize that abnormal platelet

function usually persists despite

resolution of thrombocytopenia in

some patients. Therefore, formal

platelet function testing with a plan

for platelet transfusions are indicated

before major procedures despite

normal platelet counts.5

Other Congenital Disorders

Storage disorders such as Gaucher

disease and Niemann–Pick disease

present with splenomegaly either

due to direct splenic infiltration or

portal hypertension. While caring

for these patients, it is important

to keep in mind that platelets can

pool and sequester inside the

abnormally enlarged spleen, which

can lead to acute life-threatening

thrombocytopenia. Von Gierke

disease (glycogen storage disease 1)

has been shown to have associated

platelet function defects. 39 Once

these disorders are diagnosed, it

would be important to obtain a

baseline platelet count and refer to a

hematologist for bleeding symptoms

or before a surgical procedure

for a comprehensive evaluation

of the bleeding phenotype and

recommendations for surgery.

GENERAL GUIDELINES FOR HEALTH MAINTENANCE AND MANAGEMENT OF BLEEDING SYMPTOMS

Newborn Period

Thrombocytopenia is encountered

fairly commonly (up to 25%

of admitted newborns) in the

NICUs with rates increasing with

prematurity. 40 The challenge lies

in identifying which of these can

stem from an underlying inherited

disorder. Fetal platelets are found in

circulation by ∼5 weeks of gestation

and start reaching adult values by

22 weeks. 41 The diagnostic approach

should be based on the gestational

age, onset of thrombocytopenia (<72

hours indicating likely placental,

perinatal factors; >72 hours

indicating postnatally acquired

infections), and the clinical status

of the newborn (sick versus well

appearing). Karyotype testing should

be done in all obviously dysmorphic

infants with thrombocytopenia.

Inherited causes of thrombocytopenia

are in general rare and rarely

present in the newborn period. If a

clear family history is present, the

hematologist should be consulted

to guide appropriate timing of

confirmatory testing and help

manage thrombocytopenia in

the neonatal period. This should

include a comprehensive delivery

plan with contraindication for

instrumental delivery, vacuum,

or use of fetal scalp monitoring.

Early onset thrombocytopenia

<72 hours, presence of macro-

thrombocytes in the smear, limb

abnormalities, and platelet counts

usually >50 000/ μL are good

clues pointing to an underlying

inherited defect. In the setting of a

well appearing infant with isolated

thrombocytopenia and absence of

any other features, it is reasonable

to treat for immune-mediated causes

of thrombocytopenia (neonatal

alloimmune thrombocytopenia)

until platelet antigen incompatibility

can be demonstrated between

mother and infant serologically.

Most allo or auto antibodies against

neonatal platelets clear from the

circulation over time with platelet

counts normalizing within 1 to 2

weeks in most infants. Persistence

of thrombocytopenia beyond 8 to 12

weeks 42 after birth should warrant a

hematology consult especially in the

absence of any immunologic factors

or genetic syndromes.

Infancy and Beyond

The reader is referred to health

supervision guidelines for various

genetic syndromes, which are a

useful resource for physicians

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PEDIATRICS Volume 139 , number 2 , February 2017

involved in the care of these

children. 43 – 46 Periodic hematologic

screening has been recommended

in Noonan syndrome, DS, Turner

syndrome, and Jacobsen syndrome as

outlined in previous sections.

The comprehensive care of children

and adolescents with syndromes

mentioned in this review should

include careful attention to oral

hygiene to prevent gum bleeding,

hormonal control of menstrual

bleeding, and avoidance of

medications such as aspirin and

nonsteroidal anti-inflammatory

analgesics. Dental procedures should

ensure good local hemostasis with

fibrillar collagen products along

7

TABLE 3 Management of Common Bleeding Symptoms With Identifi ed Platelet/Coagulation Defects

Symptom General and Preventive

Measures

Associated With Platelet

Defect

Associated With Coagulation

Factor Defi ciency

Interventions Useful for Severe Symptoms

Epistaxis Place patient in sitting

position with neck forward.

Firmly compress tip of nose

for 20 min.

Local application of

hydrophilic powder such

as NasalCeasea

Local application of

hydrophilic powder such

as NasalCeasea

Bleeding lasting >10 min despite hemostatic

measures, >5 episodes per year: refer

to ENT for electrocauterization, nasal

packing for persistent or profuse

bleeding.

Daily saline nasal lubrication

and humidifi cation of room

air.

Aminocaproic acid 50–100

mg/kg/dose every 6 h

× 7 d

Aminocaproic acid 100 mg/

kg/dose every 6 h × 7 d

HHT patients may need laser ablation or

embolization

Do not: Stick toilet paper,

cotton balls in nose as can

dislodge clot

Desmopressinb intranasal

spray 150 μg/dose: 2

sprays for adult, and 1

spray for <50 kg child

rVIIa (used in Glanzmann thrombasthenia

refractory to platelet transfusions)—

referral to hematology dose: 90 μg/kg

with dose repeated every 2–6 h 3Do not: squeeze bony part of

nose as no blood vessels

here

Oral mucosal

bleeding

(spontaneous)

Ensure good dental hygiene

and periodic dental

cleanings

Oral and/or systemic

aminocaproic acid. Can

use oral swish for 2

min and spit but not as

effective

Oral and/or systemic

aminocaproic acid. Can

use oral swish for 2

min and spit but not as

effective

Platelet and/or blood transfusions as

indicated for platelet defect

Compression with gelatin

sponge

Compression with gelatin

sponge

For coagulopathy: Factor concentrates (FI,

II, VII, VIII, IX, XIII defi ciencies) or FFP or

cryoprecipitat (rich in FVIII, FI, VWF, and

FXIII)

FFP only choice for FV, FXI defi ciencies in the

United States.

Menorrhagia Hormonal regulation Tranexamic acid orally

15–25 mg/kg TID or 10

mg/kg IV TID for serious

bleedingc

Factor concentrates (FI, II,

VII, VIII, IX, XIII defi ciencies)

or FFP or cryoprecipitate

(rich in FVIII, FI, VWF, and

FXIII)

Co-manage with gynecology

Platelet and/or blood

transfusions

FFP only choice for FV, FXI

defi ciencies in the United

States

High dose estrogen therapyc until bleeding

ceases followed by taper and oral

contraception

Blood transfusion Progesterone impregnated intrauterine

devices (eg, Mirenad)

Bruising/minor

lacerations

Protective cushions/pads

as indicated. Rarely if

compromising may need

specifi c treatment

Use of tropical thrombin for oozing and

minor lacerations.

Life-threatening

bleeding (CNS, GI

bleeding)

Avoid contact sports, wear

helmets/protective devices

as indicated in conditions

with severe defi ciencies.

Platelet and/or blood

transfusions

Factor concentrates (FI, II,

VII, VIII, IX, XIII defi ciencies)

or FFP or cryoprecipitate

(rich in FVIII, FI, VWF, and

FXIII)

Refer to hematology to help guide use

of various products like rVIIa and

concentrates

Immediate evaluation to rule

out intracerebral bleeding.

Treat fi rst, image once

stabilized.

FFP only choice for FV, FXI

defi ciencies in the United

States

Blood transfusion

CNS, central nervous system; GI, gastrointestinal; IV, intravenously; TID, 3 times per day.a Catalina Healthcare, Mendon, NY.b Also useful in connective tissue disorders.c Concomitant use of estrogen and tranexamic acid carries a black box warning due to increased risk of thrombosis and if used should be separated by 4 hours.d Bayer Healthcare Pharmaceuticals, Whippany, NJ.

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SARANGI and ACHARYA

with other indicated systemic

hemostatic therapy because of

abundance of fibrinolysis in the

mouth. Children with a high risk of

bleeding should avoid contact sports,

heavy exercise, or isometric exercise

and wear protective pads to avoid

deep hematomas and bruising. 26

Nonweight bearing exercises such as

aqua therapy should be encouraged

to promote a healthy lifestyle. Some

of these children can have restrictive

diets and vitamin K and vitamin C

may need to be supplemented, the

deficiencies of which can aggravate

the underlying bleeding disorder.

Common bleeding symptoms and

their management are addressed in

Table 3.

Antifibrinolytic agents (ε amino

caproic acid and tranexamic acid)

inhibit plasmin activity, thereby

strengthening clot formation and

can be used for prevention of minor

trauma-induced or minor surgical

bleeding especially involving mucosal

surfaces that are rich in fibrinolytic

enzymes in areas such as the mouth,

nose, uterus, and gastrointestinal

tract. Desmopressin (1-deamino-

8-D arginine vasopressin) increases

platelet aggregation by increasing

plasma levels of vWF and factor VIII,

thus improving platelet adhesion

and function. It has been shown

to be useful in various platelet

secretion and granule defects, EDS

and Noonan syndromes, where it

can improve platelet function and

promote hemostasis. 26, 47 – 49 Both

1-deamino-8-D arginine vasopressin

and/or antifibrinolytic agents

can be used as monotherapy or

adjuvant therapies to more definitive

treatment. Hemostasis therapy

should be tailored on the basis of

the underlying hemostatic defect,

severity of bleeding symptoms, or

hemostatic challenge of planned

surgery and results of the bleeding

evaluation. Although platelet

transfusion seems straightforward,

the development of alloantibodies

may cause platelet refractoriness

and therefore should be reserved

for serious bleeding symptoms.

In some cases, judicious and

tailored use of fresh-frozen plasma

(FFP), cryoprecipitate, and rVIIa

may be indicated. The use of

rVIIa is approved in Glanzmann’s

thrombasthenia where it improves

platelet aggregation and fibrin and

thrombin generation.50 Point of care

devices, such as thromboelastogram,

which can quantify global hemostasis

and monitor response to therapeutic

agents, are increasingly being

explored in clinical settings such as

trauma and surgery, 51 which can

provide improved bleed management

and patient outcomes. Further

studies are needed to evaluate

the impact of thromboelastogram

to improve patient outcomes in

bleeding disorders.

GUIDELINES FOR MANAGEMENT BEFORE SURGICAL PROCEDURES

Patients suspected to have a

congenital syndrome with a

bleeding diathesis (symptomatic

or asymptomatic) must have a

sequential evaluation at least 2 to 4

weeks before a scheduled surgical

procedure as proposed in Fig 2.

Bleeding assessment tools are useful

to get a standardized bleeding

history and calculate bleeding scores,

8

FIGURE 2Suggested approach to sequential presurgical evaluation for children with congenital syndromes with known or suspected bleeding diathesis. The laboratory workup should start with an initial screen and a more exhaustive workup can be done in conjunction with the hematologist on the basis of known hemostatic defects for the specifi c congenital syndrome and the bleeding phenotype of the individual patient. aBleeding phenotype: prolonged (>10 min), persistent (>5 episodes/year) nose bleeds, petechiae with minor trauma, bleeding while brushing teeth, heavy menstrual bleeding, prolonged bleeding after tooth eruption or extractions; prolonged bleeding after a procedure requiring a red cell transfusion, >1 cm bruises especially palpable in nature after minor trauma. bHigh risk procedures: craniosynostosis surgery, multiple teeth extraction especially wisdom teeth, plastic or vascular procedures, cardiac procedures, scoliosis surgery, neurosurgery, liver or kidney biopsy. cLow risk procedures: simple dental extraction, bronchoscopy, central venous catheter removal, cutaneous biopsy, GI endoscopy with biopsy, laparoscopic abdominal surgery. dInclude factor XI levels in patients with Noonan syndrome.

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PEDIATRICS Volume 139 , number 2 , February 2017 9

TABL

E 4

The

Com

pon

ents

an

d S

cori

ng

of t

he

Ped

iatr

ic B

leed

ing

Qu

esti

onn

aire

Sym

pto

m/S

core

–1

01

23

4

Epis

taxi

s—

No

or t

rivi

al (

≤5 p

er y

ear)

>5

per

yea

r or

>10

min

du

rati

on

Con

sult

atio

n o

nly

Pac

kin

g, c

aute

riza

tion

, or

anti

fi b

rin

olyt

ics

Blo

od t

ran

sfu

sion

, rep

lace

men

t

ther

apy,

or

des

mop

ress

in

Cu

tan

eou

s—

No

or t

rivi

al (

≤5 p

er y

ear)

>1

cm a

nd

on

tra

um

aC

onsu

ltat

ion

on

ly—

—

Min

or w

oun

ds

—N

o or

tri

vial

(≤5

per

yea

r)>

5 p

er y

ear

or >

5 m

in

du

rati

on

Con

sult

atio

n o

nly

or

ster

i-

stri

ps

Su

rgic

al h

emos

tasi

s or

anti

fi b

rin

olyt

ics

Blo

od t

ran

sfu

sion

, rep

lace

men

t

ther

apy,

or

des

mop

ress

in

Ora

l cav

ity

—N

oR

epor

ted

at

leas

t on

ceC

onsu

ltat

ion

on

lyS

urg

ical

hem

osta

sis

or

anti

fi b

rin

olyt

ics

Blo

od t

ran

sfu

sion

, rep

lace

men

t

ther

apy,

or

des

mop

ress

in

Gas

troi

nte

stin

al t

ract

—N

oId

enti

fi ed

cau

seC

onsu

ltat

ion

or

spon

tan

eou

s

Su

rgic

al h

emos

tasi

s,

anti

fi b

rin

olyt

ics,

blo

od

tran

sfu

sion

, rep

lace

men

t

ther

apy

or d

esm

opre

ssin

—

Toot

h e

xtra

ctio

nN

o b

leed

ing

in a

t le

ast

2 ex

trac

tion

s

Non

e d

one

or n

o b

leed

ing

in 1

ext

ract

ion

Rep

orte

d, n

o co

nsu

ltat

ion

Con

sult

atio

n o

nly

Res

utu

rin

g, r

epac

kin

g, o

r

anti

fi b

rin

olyt

ics

Blo

od t

ran

sfu

sion

, rep

lace

men

t

ther

apy,

or

des

mop

ress

in

Su

rger

yN

o b

leed

ing

in a

t le

ast

2 su

rger

ies

Non

e d

one

or n

o b

leed

ing

in 1

Rep

orte

d, n

o co

nsu

ltat

ion

Con

sult

atio

n o

nly

Su

rgic

al h

emos

tasi

s or

anti

fi b

rin

olyt

ics

Blo

od t

ran

sfu

sion

, rep

lace

men

t

ther

apy,

or

des

mop

ress

in

Men

orrh

agia

—N

oR

epor

ted

or

con

sult

atio

n

only

Anti

fi b

rin

olyt

ics

or

con

trac

epti

ve p

ill u

se

D&

C o

r ir

on t

her

apy

Blo

od t

ran

sfu

sion

, rep

lace

men

t

ther

apy,

des

mop

ress

in, o

r

hys

tere

ctom

y

Pos

tpar

tum

No

ble

edin

g in

at

leas

t

2 d

eliv

erie

s

No

del

iver

ies

or n

o

ble

edin

g in

1 d

eliv

ery

Rep

orte

d o

r co

nsu

ltat

ion

only

D&

C, i

ron

th

erap

y or

anti

fi b

rin

olyt

ics

Blo

od t

ran

sfu

sion

,

rep

lace

men

t th

erap

y, o

r

des

mop

ress

in

—

Mu

scle

hem

atom

a—

Nev

erP

ostt

rau

ma,

no

ther

apy

Sp

onta

neo

us,

no

ther

apy

Sp

onta

neo

us

or t

rau

mat

ic,

req

uir

ing

rep

lace

men

t

ther

apy

or d

esm

opre

ssin

Sp

onta

neo

us

or t

rau

mat

ic r

equ

irin

g

surg

ical

inte

rven

tion

or

blo

od

tran

sfu

sion

Hem

arth

rosi

s—

Nev

erP

ostt

rau

ma,

no

ther

apy

Sp

onta

neo

us,

no

ther

apy

Sp

onta

neo

us

or t

rau

mat

ic,

req

uir

ing

rep

lace

men

t

ther

apy

or d

esm

opre

ssin

Sp

onta

neo

us

or t

rau

mat

ic r

equ

irin

g

surg

ical

inte

rven

tion

or

blo

od

tran

sfu

sion

Cen

tral

ner

vou

s sy

stem

—N

ever

——

Su

bd

ura

l, an

y in

terv

enti

onIn

trac

ereb

ral,

any

inte

rven

tion

Oth

era

—N

oR

epor

ted

Con

sult

atio

n o

nly

Su

rgic

al h

emos

tasi

s,

anti

fi b

rin

olyt

ics

or ir

on

ther

apy

Blo

od t

ran

sfu

sion

, rep

lace

men

t

ther

apy,

or

des

mop

ress

in

Rep

rin

ted

wit

h p

erm

issi

on f

rom

Bow

man

M, R

idd

el J

, Ran

d M

L, T

oset

to A

, Silv

a M

, Jam

es P

D. E

valu

atio

n o

f th

e d

iagn

osti

c u

tilit

y fo

r vo

n W

illeb

ran

d d

isea

se o

f a

ped

iatr

ic b

leed

ing

qu

esti

onn

aire

. J T

hro

mb

Ha

emos

t. 2

009;

7(8)

: Tab

le S

1. —

, sco

re n

ot

avai

lab

le f

or t

his

par

ticu

lar

syst

em.

a In

clu

des

pos

tcir

cum

cisi

on, u

mb

ilica

l stu

mp

, cep

hal

hem

atom

a, m

acro

scop

ic h

emat

uri

a, p

ostv

enip

un

ctu

re, a

nd

con

jun

ctiv

al h

emor

rhag

e.

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SARANGI and ACHARYA

which can help recognize individual

bleeding risk. The components of the

Pediatric Bleeding Questionnaire are

presented in Table 4 for review. 52

A thorough head to toe physical

examination to identify and uncover

bleeding risk should focus on

hyperextensibility, telangiectasias,

palpable bruises, splenomegaly,

ecchymoses, and petechiae. All

medications and alternative therapies

(including herbal preparations)

should be carefully reviewed, and

any medications known to affect

hemostasis should be discontinued or

substituted. A basic workup should

include a complete blood count,

PT, and aPTT with mixing studies

(when PT/aPTT are prolonged),

which helps distinguish a clotting

factor deficiency from nonspecific

coagulation inhibitors. In syndromes

with known qualitative platelet

defects, platelet function analysis

(PFA-100), which has replaced the

bleeding time, should be included as

part of the initial workup if available.

Further testing should be guided by

a pediatric hematologist who can

then order confirmatory testing.

Knowledge of the underlying platelet

abnormality can guide further

platelet function testing because the

use of specific platelet agonists can

limit the amount of blood drawn in

pediatric patients. A multidisciplinary

team involving the surgeon,

hematologist, and anesthesiologist

should tailor a treatment plan before

surgery for these patients with the

judicious use of platelets and other

blood components to avoid allo-

immunization especially because

patients with clinical syndromes

may require more than 1 corrective

procedure. The risk of bleeding due

to any underlying thrombocytopenia

in part depends upon the nature

of the surgery, critical need

for maintaining postoperative

hemostasis and promoting healing,

and individualized target platelet

count depending upon the type

of surgery. Regional anesthesia

and epidural catheters may be

contraindicated depending on the

level of thrombocytopenia and other

hemostatic defects.

CONCLUSIONS

Abnormalities in hemostasis

leading to clinical bleeding are an

often unidentified component of

many congenital syndromes. These

abnormalities are important for the

PCP to recognize and anticipate,

thereby prompting timely referral

to the hematologist to adequately

manage these patients to prevent

catastrophic bleeding.

ABBREVIATIONS

aPTT:  activated partial thrombo-

plastin time

DS:  Down syndrome

EDS:  Ehlers-Danlos syndrome

FFP:  fresh-frozen plasma

HHT:  hereditary hemorrhagic

telangiectasia

IBMFS:  inherited bone marrow

failure syndromes

ITP:  immune thrombocytopenia

ML-DS:  myeloid leukemia associ-

ated with Down

syndrome

PCP:  primary care physician

PT:  prothrombin time

TAR:  thrombocytopenia with

absent radii

vWF:  von Willebrand factor

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originally published online January 6, 2017; Pediatrics Susmita N. Sarangi and Suchitra S. Acharya

Bleeding Disorders in Congenital Syndromes

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