Bleeding Disorders Anjali A. Sharathkumar and Steven W. Pipe … · 2013-03-01 · Bleeding Disorders Anjali A. Sharathkumar, MD,* Steven W. Pipe, MD* Author Disclosure Drs Sharathkumar

DOI: 10.1542/pir.29-4-1212008;29;121Pediatrics in Review

Anjali A. Sharathkumar and Steven W. PipeBleeding Disorders

http://pedsinreview.aappublications.org/content/29/4/121located on the World Wide Web at:

The online version of this article, along with updated information and services, is

Pediatrics. All rights reserved. Print ISSN: 0191-9601. Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 2008 by the American Academy of published, and trademarked by the American Academy of Pediatrics, 141 Northwest Pointpublication, it has been published continuously since 1979. Pediatrics in Review is owned, Pediatrics in Review is the official journal of the American Academy of Pediatrics. A monthly

at UNIV OF CHICAGO on February 13, 2013http://pedsinreview.aappublications.org/Downloaded from

http://pedsinreview.aappublications.org/content/29/4/121

http://pedsinreview.aappublications.org/

Bleeding DisordersAnjali A. Sharathkumar,

MD,* Steven W. Pipe,

MD*

Author Disclosure

Drs Sharathkumar and

Pipe did not disclose

any financial

relationships relevant

to this article.

Objectives After completing this article, readers should be able to:

1. Discuss the physiology of hemostasis.2. Describe the clinical features suggestive of an underlying bleeding disorder.3. Develop a diagnostic algorithm for evaluating patients who are suspected of having

bleeding disorders.4. Recognize the inheritance and clinical management of the commonly encountered

bleeding disorders.

Overview of HemostasisHemostasis refers to the process whereby bleeding is halted in a closed circulatory system.Understanding the physiology of hemostasis allows the clinician to identify children whohave both inherited and acquired abnormalities of hemostasis, guide laboratory investiga-tions, and facilitate effective therapeutic interventions.

In response to an injury (Fig. 1), local vasoconstriction reduces blood flow to limit orprevent bleeding. Primary hemostasis describes the subsequent interaction between plate-lets, von Willebrand factor (vWF), and the vessel wall to form a platelet plug at the site ofvascular injury. vWF, a large multimeric plasma glycoprotein that is synthesized and storedin endothelial cells and megakaryocytes, is released at the site of vascular injury. CirculatingvWF also binds and stabilizes factor VIII (FVIII). Exposed subendothelial elements, suchas collagen, serve as a binding site for vWF, which, in turn, mediates platelet adherence tothe area of injury. Platelet receptors, vWF, and fibrinogen mediate platelet-plateletinteractions, leading to aggregation, activation, secretion of platelet granules, and addi-tional platelet aggregation. The platelet plug that ensues contributes to bleeding cessationbut is unstable. Thus, for stability, the platelet plug must be reinforced by the formation ofan organized fibrin clot through the activation of the blood coagulation system orsecondary hemostasis.

Blood coagulation involves a cascade of activation reactions. At each stage, a precursorprotein (eg, FX) is converted to an active protease (eg, FXa) in the presence of calcium anda phospholipid surface that is provided by damaged endothelium and platelets.

Coagulation is initiated through the “extrinsic pathway.” Following injury, the dam-aged endothelium expresses tissue factor (TF). TF binds to FVII and forms the TF/FVIIacomplex, which activates FIX and FX. FXa activates prothrombin to thrombin, the centralmediator of coagulation. Thrombin has many functions within coagulation as well as otherphysiologic pathways. However, its prime function in hemostasis is to convert solublefibrinogen into insoluble fibrin. These fibrin monomers polymerize in the vicinity of theprimary platelet plug and are strengthened further through cross-linking by FXIII.However, the initial FXa and thrombin generated through the extrinsic pathway areinadequate to form an effective fibrin clot. Therefore, a feedback loop, the “intrinsicpathway,” also is activated by thrombin. Thrombin can activate FXI, which, in turn,activates FIX to FIXa. This reaction further enhances FXa and thrombin generation. Thismerger of the extrinsic and intrinsic pathways has been called the “common pathway.” Inaddition, thrombin activates two key cofactors of coagulation, FVIII and FV. FVIIIa is acofactor for FIXa, enhancing its proteolytic activity on FX by several orders of magnitude.FVa is a cofactor for FXa, which enhances the proteolytic activity of FXa on prothrombin.

*Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, Mich.

Article hematology

Pediatrics in Review Vol.29 No.4 April 2008 121



This effect ultimately produces a burst of thrombin for-mation sufficient for effective hemostasis. The physio-logic significance of this amplification loop in hemostasisis exemplified by the severe bleeding manifestations as-sociated with a deficiency of one of its components (eg,FVIII deficiency resulting in hemophilia A).

Physiologic inhibitors of coagulation regulate eachstep of the hemostatic process. Within the extrinsicpathway, tissue factor pathway inhibitor binds to andinhibits the action of TF/FVIIa and FXa. Protein C isactivated by thrombin to activated protein C that, alongwith its cofactor protein S, proteolytically inactivatesFVIIIa and FVa, thereby inhibiting the intrinsic pathway.

Antithrombin is the key inhibitorof the common pathway, formingcomplexes with FXa and thrombin.Following formation of the fibrinclot, a fibrinolytic pathway medi-ated by plasmin regulates the size ofthe clot and ultimately facilitates itsdissolution.

The plasma kallikrein/kinin sys-tem includes FXII, prekallikrein,and FXI. These proteins also areknown as the “contact system” be-cause FXII autoactivates when as-sociated with a negatively chargedsurface such as a glass tube. Theautoactivation of FXII results inprekallikrein activation and addi-tional amplification of FXII, pro-ducing subsequent activation ofFXI, which can contribute to acti-vation of the intrinsic pathway.However, deficiencies of FXII andprekallikrein are not associatedwith bleeding. Therefore, this sys-tem cannot be a physiologic one forhemostasis, but it is useful clinicallyin the activated partial thrombo-plastin time (PTT) to evaluatecomponents of the intrinsic path-way.

The Influence of Age on theCoagulation SystemMost coagulation factors are foundin the fetus by the 10th week ofgestation, with synthesis predomi-nantly by the liver. Protein produc-tion increases with gestational age

and through the first year of postnatal life when theplasma activity for most coagulation factors becomescomparable with that of adults. In the immediate post-natal period, concentrations of vitamin K-dependent co-agulation proteins (prothrombin, FVII, FIX, and FX)and the inhibitors protein C and protein S are approxi-mately 50% of adult values. In contrast, values for fibrin-ogen, FVIII, FV, FXIII, and inhibitors are similar to orincreased above adult values. Concentrations of vWF areincreased at birth and for the first several postnatalmonths. In the clinical setting, the results of variouscoagulation assays need to be interpreted according toage-appropriate normal ranges.

Figure 1. The coagulation system. F�factor, vWF�von Willebrand factor, TFPI�tissuefactor pathway inhibitor. Coagulation inhibitors are indicated in red.

hematology bleeding disorders

122 Pediatrics in Review Vol.29 No.4 April 2008



Evaluation of a Child Who Has a BleedingDisorderChildren who have bleeding disorders often present ini-tially to their pediatricians with suspicious signs, abnor-mal screening laboratory results from a presurgical eval-uation, or a known family history. Whereas severebleeding disorders such as hemophilia often present inthe first year after birth, less severe bleeding disorders,such as von Willebrand disease (vWD) or a plateletfunction abnormality, may be clinically silent for yearsuntil a major hemostatic challenge occurs. Careful assess-ment of the medical and the family history, attention topertinent physical findings, and discretionary use of lab-oratory resources are required to reach a likely diagnosisand initiate definitive therapy.

Clinical EvaluationA systematic approach employing the following ques-tions can help to reach a more precise clinical diagnosis.

AM I DEALING WITH A BLEEDING DISORDER? Typicalpresentations include easy bruisability, mucosal bleeding(epistaxis; menorrhagia; oral, genitourinary, or rectalbleeding), unexpected surgical hemorrhage, and deep-tissue bleeding into muscles and joints. Because many ofthese signs can be common in childhood, the challengefor the pediatrician is to decide when additional evalua-tion is warranted. The significance of any particularbleeding sign is enhanced when seen in combinationwith other bleeding signs or when evaluated in relationto the presence or absence of associated trauma.

Bruising in children first must be differentiated fromextrinsic causes such as child abuse, which is more com-mon than hemophilia. Inflicted trauma is most likely tomanifest over the calvarium, the chest, the back, and thelong bones and may retain the outlines of the instrument.Bruises associated with a defect in primary hemostasisusually are located over areas of typical childhoodtrauma, such as the bony protuberances of the extremi-ties or the spinous processes along the back, typically aresuperficial, and are in multiple stages of resolution. Pete-chiae may suggest platelet dysfunction or vWD. In gen-eral, bruises that are not limited to the distal extremities,are larger than a quarter coin, and are associated withhematomas and bruising out of proportion to the mech-anism of injury are more indicative of an underlyinghemostatic disorder. Intramuscular hematomas may bemore difficult to see, but they cause swelling of themuscle group and pain with use of the muscle. Hemar-throsis (bleeding into a joint) causes joint effusion,warmth, and pain with passive movement of the joint and

is a common feature of hemophilia. For young children,refusal to walk or use the affected limb may be the onlyapparent sign.

Epistaxis is a common childhood complaint and mostlikely is due to local factors such as drying of the nasalmucosa, trauma, or allergic rhinitis. However, amongpatients referred to a pediatric hematology clinic forrecurrent epistaxis, 25% to 33% are diagnosed as having ableeding disorder. Epistaxis requiring an emergency de-partment visit, occurring in both nostrils, and occurringin association with other bleeding signs and a familyhistory of similar bleeding increases the likelihood of anunderlying bleeding disorder.

Menorrhagia may be the presenting sign in an adoles-cent girl who has a bleeding disorder and often can occurwith the first cycle at menarche. Menorrhagia frequentlyis associated with anemia and a suboptimal quality of life.A pictorial blood flow assessment chart can be used in theoffice to provide a semiquantitative assessment of men-strual blood loss. Frequent pad changes (�2 h fre-quency), menses lasting more than 7 days, or more thanone menstrual period per month all are consistent withmenorrhagia. In 2000, the American College of Obstet-rics and Gynecology recommended that women whohave menorrhagia be evaluated for vWD. Platelet func-tion disorders and other coagulopathies also are frequentcauses of menorrhagia.

Surgical bleeding in children is associated most oftenwith circumcision, tonsillectomy, and dental extractions.In addition to uncontrolled bleeding in the surgical field,bleeding in an affected individual may extend beyond thesurgical site (ie, drains, vascular access), with associatedpoor wound healing and infection. The need for trans-fusion during or after surgery that normally does notcause significant blood loss can suggest an underlyingbleeding disorder. Bleeding after tonsillectomy or ade-noidectomy often is delayed until 7 to 10 days postoper-atively when there is an underlying bleeding disorder.

WHAT IS THE CLINICAL PHENOTYPE OF THE BLEEDING?Mucosal bleeding characterized by easy bruisability, ep-istaxis, menorrhagia, petechiae, and oozing from surgicalwounds is most consistent with a defect in primary he-mostasis. The pediatrician should consider defects inplatelets, vWF, or the vessel wall. On the other hand,deep-tissue bleeding (hematomas, joint and muscle hem-orrhages) and “delayed” surgical bleeding are more sug-gestive of a coagulation factor abnormality. The mostcommon disorder in this group is hemophilia, but otherrare clotting factor deficiencies can occur.





IS IT CONGENITAL OR ACQUIRED? Inherited severebleeding disorders present most often during the neona-tal period or early childhood. Circumcision bleeding,umbilical stump bleeding, cephalohematomas, and sub-galeal hemorrhages following delivery all may occur inotherwise healthy infants but are cardinal manifestationsof underlying bleeding disorders. Hence, these signsalways should be evaluated with a high degree of suspi-cion. The incidence of neonatal intracranial hemorrhageamong boys who have hemophilia is estimated to be ashigh as 3%, but may be as high as 25% in patients whohave FXIII deficiency. Diagnosis of a bleeding disorderin this setting is urgent because specific replacementtherapy is required to prevent extension of the hemor-rhage.

Only two thirds of patients who have hemophilia havea positive family history of the condition. Therefore, ahigh degree of suspicion is required, even with a negativefamily history. Because hemophilia is an X-linked disor-der, the history should focus on maternal cousins, uncles,and the grandfather. Some rare platelet function disor-ders (eg, Glanzmann thrombasthenia) and clotting fac-tor deficiencies (eg, FXIII deficiency) are autosomalrecessive, and their incidence is increased in consang-uineous unions. The common inherited bleeding disor-ders (eg, vWD and mild plateletfunction abnormalities) usually areinherited in an autosomal domi-nant pattern. However, even thesemore common bleeding disorderscan have variable expression andmay be more likely to manifest infemales because of gynecologic andobstetric experiences (eg, postpar-tum hemorrhage).

IS THERE ANY UNDERLYING SYS-TEMIC DISEASE OR DRUG EXACER-BATING BLEEDING? Acquiredbleeding disorders should be con-sidered in patients who have anunderlying medical illness or aretaking concurrent medications.A primary hemostatic defect maybe attributed to medications thathave well-known antiplatelet ad-verse effects (eg, aspirin and othernonsteroidal anti-inflammatorydrugs [NSAIDs]), but many medi-cations used to treat a variety ofdisorders can have unappreciated

effects on platelet function and should be investigated.Underlying medical disorders may cause a bleeding phe-notype due to thrombocytopenia or uremia. A coagula-tion factor abnormality may be a manifestation of liverdisease, vitamin K deficiency, or disseminated intravascu-lar coagulation (DIC).

Laboratory EvaluationAn appropriate and reliable laboratory approach, encom-passing first-line (screening) and second-line (specific)testing, is essential to screen, diagnose, and monitorpatients who have bleeding diatheses (Fig. 2). The avail-able clinical assays also can be grouped according towhether they evaluate components of primary hemostasisor coagulation factors.

CLINICAL ASSAYS FOR EVALUATING PRIMARY HEMO-STASIS. A complete blood count and evaluation of theperipheral blood smear usually constitute the requiredfirst step. The bleeding time is the historical screeningtest for defects of primary hemostasis, but low sensitivityand specificity in children limit its utility. Newer plateletfunction analyzers (PFAs) are now available in clinicallaboratories but cannot be relied on to identify all pa-tients who have vWD or platelet function defects, and

Figure 2. Laboratory evaluation of bleeding disorders. CBC�complete blood count,F�factor, PFA�platelet function analyzer, PT�prothrombin time, PTT�activated partialthromboplastin time, RIPA�ristocetin-induced platelet aggregation, vWD�von Wille-brand disease, vWF�von Willebrand factor, vWF:RCo�ristocetin cofactor activity.





their routine use remains controversial. Therefore, whenthese disorders are considered, specific testing (vWFindices, platelet aggregation studies) should be per-formed.

CLINICAL ASSAYS FOR EVALUATION OF COAGULATIONFACTOR FUNCTION. The prothrombin time (PT) andactivated PTT are coagulation screening tests performedon citrated plasma. The PT is reported commonly alongwith the International Normalized Ratio (INR) to adjustfor different reagent sensitivities. The PT is a measure ofthe extrinsic (FVII) and common pathway (FV, FX,prothrombin, fibrinogen) clotting factors. The PTTmeasures the contact system (prekallikrein, FXII) as wellas the intrinsic (FVIII, FIX, FXI) and common pathwayclotting factors. Sensitivities of various PT and PTTreagents vary and may yield normal values in the presenceof mild factor deficiencies. Therefore, specific factor as-says should be performed for patients who are stronglysuspected of having a bleeding disorder. An understand-ing of the relationships among the PT; PTT; and theintrinsic, extrinsic, and common pathways helps guideadditional specific factor assays (Fig. 2).

The terminal event for both the PT and PTT assays isthe conversion of soluble fibrinogen to insoluble fibrin.Because neither of these tests assesses the activity ofFXIII, a specific FXIII assay must be requested to preventmissing this rare but important coagulation factor defi-ciency.

Incidental detection of a prolonged PTT occurs com-monly in the primary care setting; such prolongationoften is found in children who have no history of bleed-ing. This finding usually can be attributed to a lupusanticoagulant (LA), antibodies that arise transiently, of-ten in association with infections, and are directedagainst proteins that bind phospholipid surfaces. Despitemarked prolongations of the PTT, such antibodies donot cause bleeding; paradoxically, they have been linkedwith some thrombotic complications in childhood.However, in most children, the LA antibodies are un-complicated and disappear over several weeks, with anaccompanying normalization of the PTT. Rarely, LA isassociated with an antibody directed against prothrom-bin, which can lead to an accompanying prothrombindeficiency manifested by both a prolonged PT and PTT.This subgroup of affected patients can present with acutebleeding problems but also can exhibit a transient clinicalcourse. LA can be confirmed by a mixing study in whichpatient plasma is mixed 1:1 with normal plasma and thePTT is measured. If a clotting factor deficiency is present,the PTT completely corrects to within the normal range.

However, in the presence of an LA, the PTT remainsprolonged.

Normal reference ranges for the PT and PTT arewider in newborns, reflecting relative immaturity of thevitamin K pathway. Published reference ranges for coag-ulation assays for newborns of different gestational agesare available. Laboratory methods and standards differamong institutions; local age-matched reference rangesshould be used when available.

Inherited Bleeding Disorders of PrimaryHemostasis

von Willebrand DiseasevWD is the most common genetic bleeding disorder. Itaffects both sexes, and the prevalence is estimated to be ashigh as 1%. Three primary vWD types should be distin-guished: type 1 (70% to 80% of cases) and type 3 (rare)are characterized by partial and virtually complete defi-ciency of vWF, respectively; type 2 vWD reflects a qual-itative defect in vWF function (Table 1). Clinical presen-tations vary substantially, depending on the subtype andseverity, and manifestations range from mild mucocuta-neous bleeding to hemarthroses.

Due to the heterogeneity of vWF defects and externalvariables (such as blood group and other physiologicmodifiers) that can influence vWF concentrations in thecirculation, diagnosing vWD can be difficult. The bleed-ing time can be normal in affected patients. vWD isdiagnosed most often if the patient satisfies three criteria:1) a positive bleeding history, 2) reduced levels of vWFactivity (ristocetin cofactor [RCo] activity), and 3) apositive family history suggestive of vWD. The vWF:RCoassay is the most useful tool for screening patients, butother assays are required to distinguish among the vari-ous subtypes. These other tests include vWF antigen,FVIII activity, vWF multimer analysis, ristocetin-induced platelet aggregation at low concentrations ofristocetin (seen with Type 2B), and blood typing.

Because vWF is an acute-phase reactant, concentra-tions increase with stress, exercise, acute inflammatoryprocesses, and pregnancy and during the menstrual cycle.The plasma concentration of vWF also is modified byother determinants such as blood group and race. Theplasma vWF antigen values for individuals who have typeO blood are 25% lower than in pooled normal plasma,leading to a greater likelihood of diagnosis in those whohave type O blood. In contrast, those who have type ABblood have concentrations averaging 25% higher thanpooled plasma. African American women tend to havevalues 15% higher than white women. When clinicalsymptoms or family history suggest vWD, a single nega-





Tab

le1.

von

Will

ebra

ndDi

seas

eFe

atur

esTy

pe1

Type

2ATy

pe2B

Type

2NTy

pe2M

Type

3

Defe

ctPa

rtia

lqua

ntita

tive

defic

ienc

yw

ithno

rmal

stru

ctur

ean

dfu

nctio

nof

vWF

Qua

ntita

tive

and

qual

itativ

ede

fect

with

loss

ofH

MW

M

2af

finity

ofvW

Fto

plat

elet

mem

bran

eGP

Ib/IX

/Vco

mpl

ex

2af

finity

ofvW

Ffo

rFV

IIIm

imic

king

hem

ophi

liaA

Qua

litat

ive

defe

ctw

ithre

tent

ion

ofH

MW

M

Com

plet

ede

ficie

ncy

ofvW

F

Patt

ern

ofbl

eedi

ngM

ucoc

utan

eous

Muc

ocut

aneo

usM

ucoc

utan

eous

Muc

ocut

aneo

us,

soft

tissu

e,jo

int

Muc

ocut

aneo

usM

ucoc

utan

eous

,so

fttis

sue,

join

tIn

herit

ance

ADAD

ADAR

ADAR

Blee

ding

time

and/

orPF

A-10

0N

or1

1N

or1

NN

or1

1

Plat

elet

coun

tN

NN

or2

NN

NFa

ctor

VIII

activ

ityN

or2

Nor2

Nor2

2(d

iscr

epan

tlylo

wco

mpa

red

tovW

Fan

tigen

)

Nor2

Mar

kedl

y2

vWF

Antig

en*

22

Nor2

NN

or2

Mar

kedl

y2

Rist

ocet

inco

fact

orac

tivity

(vW

F:RC

o)*2

2N

or2

N2

(dis

crep

antly

low

com

pare

dto

vWF

antig

en)

Mar

kedl

y2

Rist

ocet

in-i

nduc

edpl

atel

etag

greg

atio

nw

ithlo

wdo

seof

risto

cetin

Abse

ntAb

sent

Pres

ent

Abse

ntAb

sent

Abse

nt

vWF

mul

timer

anal

ysis

NAb

senc

eof

HM

WM

Abse

nce

ofH

MW

MN

NAb

sent

Resp

onse

toDD

AVP

Good

Varia

ble

Wor

seni

ngof

thro

mbo

cyto

peni

aGo

odvW

Fre

spon

se;

poor

FVIII

activ

ityre

spon

se

Varia

ble

Non

e

AD

�au

toso

mal

dom

inan

t,A

R�

auto

som

alre

cess

ive,

DD

AV

P�de

smop

ress

inac

etat

e,H

MW

M�

high

-mol

ecul

arw

eigh

tm

ultim

ers,

PFA

�pl

atel

etfu

nctio

nan

alyz

er,

vWF�

von

Will

ebra

ndfa

ctor

,1

�pr

olon

ged,2

�de

crea

sed,

N�

norm

al*L

abor

ator

yin

terp

reta

tion

ofvo

nW

illeb

rand

fact

orco

ncen

trat

ions

shou

ldbe

eval

uate

din

the

cont

ext

ofth

epa

tient

’sbl

ood

grou

p





tive test does not rule out the diagnosis; repeated labo-ratory measurements often are needed.

Two primary options are available to treat spontane-ous bleeding episodes and for bleeding prophylaxis: des-mopressin (DDAVP) and transfusional therapy withplasma-derived vWF products. DDAVP is the treatmentof choice for most patients who have type 1 vWD and asubset of patients who have types 2A and 2M vWD. Thishemostatic agent raises endogenous vWF plasma con-centrations two- to fourfold and causes a similar rise inFVIII activity. Because peak values can be achievedwithin 1 hour after administration, the agent is useful forsurgical prophylaxis.

Prior to considering DDAVP for treatment, aDDAVP challenge test should be performed by measur-ing vWF indices before and after the administration ofDDAVP. The dose of DDAVP is 0.3 mcg/kg for intra-venous use and 150 to 300 mcg via the intranasal route.DDAVP can be safely administered daily for several daysin a row. The major adverse effects associated with its useinclude facial flushing, headache, tachycardia, and hypo-natremia. Due to the risk of hyponatremic seizures,DDAVP should be used with utmost caution in youngchildren (�2 y of age) and children undergoing surgicalprocedures associated with significant blood loss. Simul-taneous use of antifibrinolytic agents (e-aminocaproicacid, 50 mg/kg q 6 hours; tranexamic acid, 25 mg/kg q4 to 6 hour) helps to stabilize the clot by preventingplasmin-mediated clot lysis.

For patients who have the more severe type 3 and inmost patients who have type 2 disease, DDAVP is inef-fective or is contraindicated, usually necessitating the useof plasma concentrates containing both FVIII and vWF.Virally inactivated products always should be used ratherthan cryoprecipitate. These agents are dosed in vWF:RCo units (1.5% plasma increase for every 1 IU/kginfused). vWF-containing concentrates also should beconsidered for patients whose disease is mild and whohave failed to have their bleeding controlled withDDAVP or antifibrinolytic agents. Adolescent girls pre-senting with menorrhagia as their primary bleeding man-ifestation may have bleeding controlled with oral contra-ceptives as well as DDAVP.

Platelet Function DisorderThrombocytopenia is another important cause of bleed-ing manifestations in children, but the approach to thisproblem is beyond the scope of this review. Plateletfunction disorders may be congenital or acquired andcommonly present with spontaneous mucocutaneousbleeding or bleeding after hemostatic challenge (eg,

trauma, surgery). Acquired disorders are most common.Antiepileptic medications (eg, valproate) and antidepres-sants can cause functional impairment of platelets. Anti-platelet agents such as aspirin cause platelet inhibition forthe entire life span (�5 to 7 d) of the platelet; otherNSAIDs inhibit platelets as long as the drug is present.Systemic disorders such as uremia, congenital heart dis-ease, liver failure, and leukemia also can lead to plateletfunction defects. Any possible acquired causes for plate-let dysfunction should be ruled out before an inheritedcause is considered.

Congenital platelet disorders are less common and arecomprised of inherited defects in receptors critical toplatelet adhesion and aggregation, defects in signalingmolecules that impair platelet secretion, and defects inplatelet metabolism. The clinical presentation is variablebut usually manifests with mild mucocutaneous bleed-ing. Patients in whom the disorders are suspected may bescreened in vivo for a prolonged bleeding time or ex vivousing a PFA. Platelet aggregometry tests platelet aggre-gation and secretion responses to a variety of agonists.Some disorders exhibit structural abnormalities underlight or electron microscopy.

The bleeding symptoms in hereditary platelet disor-ders often can be ameliorated with DDAVP and anti-fibrinolytic agents, although certain severe disorders (eg,Bernard-Soulier syndrome and Glanzmann thrombas-thenia) may require platelet transfusions. Recently, re-combinant FVIIa (rFVlla) has been shown to be effectivein controlling bleeding in patients who have these moresevere platelet function defects. Such use of this agent hasnot been approved yet by the United States Food andDrug Administration.

Congenital Deficiency of CoagulationProteins

HemophiliaHemophilia A and B result from deficiency or dysfunc-tion of FVIII or FIX, respectively. The incidence ofhemophilia A is estimated to be 1 in 5,000 male birthsand that of hemophilia B is estimated at 1 in 30,000 malebirths. Because the genes for both FVIII and FIX arelocated on the X chromosome, hemophilia primarilyaffects males, although females may be symptomaticcarriers. All the female offspring of an affected male areobligate carriers. Carrier females have a 50% chance ofpassing the affected chromosome to their male offspring.Clinical severity, corresponding factor concentrations,and clinical signs are elaborated in Table 2. The typicalpresentation is excessive bleeding after circumcision.However, with fewer families choosing circumcision, this





early bleeding challenge often is missed. Later presenta-tions in infancy can include severe mucosal bleeding fromtongue or gum injuries and prominent bruising, withhematomas over both the trunk and extremities. Theclassic bleeding manifestations of severe hemophilia, se-vere soft-tissue bleeding and hemarthroses, typically donot begin until the child becomes ambulatory, mostlyafter the first birthday.

Those who have hemophilia usually have a prolongedPTT, with normal PT, platelet count, and bleedingtime/PFA testing. The diagnosis is confirmed by analysisof FVIII or FIX activity. FVIII activity already is at“adult” values at birth. However, because FIX is a vita-min K-dependent factor, FIX concentrations typically arelow in the newborn period. Follow-up FIX activityshould be measured after 4 to 6 months of age to confirma diagnosis of mild hemophilia B. Mild reductions inFVIII also should prompt measurement of vWF concen-trations to rule out vWD.

Patients who have hemophilia can be treated withepisodic or prophylactic infusions of factor concentrates.In developed countries, most children who have severehemophilia are treated with prophylactic therapy to pre-vent the chronic complications associated with frequentjoint bleeding and to prevent life-threatening bleeding.Much of the treatment is home-based after the parents,caregivers, and eventually the patient learn venipuncturetechnique.

Due to concerns about transfusion-transmitted dis-eases in the past and an increasing demand for factorconcentrates worldwide, most pediatric patients in thedeveloped world now are treated with recombinant-derived FVIII and FIX concentrates. RecombinantFVIII concentrates produce a 2% rise in plasma FVIIIconcentration for every 1 IU/kg infused. Current re-combinant FIX concentrates produce about an 0.8% risein plasma FIX concentration for every 1 IU/kg infused.Target replacement should aim for a 50% correction of

the plasma value for most hemorrhages. However, re-placement for major hemorrhages (head and neck, ab-dominal, intracranial) should aim for 100% plasma val-ues. Perioperative management always should beconducted in consultation with a pediatric hematologist.

Following treatment with FVIII concentrates, up to30% of patients who have hemophilia A develop antibod-ies (called inhibitors) against FVIII, usually within thefirst 50 exposures. The incidence of inhibitors is lower inhemophilia B (1% to 3%). Most inhibitors are detectedduring routine surveillance, but such antibodies mayseriously complicate the treatment of bleeding events orsurgery if the inhibitor emerges during the treatment.Patients who have inhibitors usually are unresponsive tofactor concentrates but can be treated with “bypassing”agents, such as rFVIIa or activated prothrombin complexconcentrates.

The care of patients who have hemophilia within anetwork of specially trained hemophilia treatment cen-ters has greatly reduced the mortality and morbidity onceassociated with this condition. Patients whose disease issevere now can expect a lifespan similar to that of healthymales who have little to no joint disease as adults.

Prenatal diagnosis options for women known to becarriers for hemophilia include: 1) noninvasive fetal sexdetermination by ultrasonography and 2) invasive testingby chorionic villus sampling or amniocentesis for specificdiagnosis. Due to the greatly enhanced quality of lifewith current hemophilia therapy, most women currentlyopt for noninvasive fetal sex determination facilitated byultrasonography in the second trimester. This allows forappropriate decisions regarding delivery options and ac-celerated diagnostic testing in the newborn period.

Rare Congenital Bleeding DisordersAdditional rare congenital coagulation bleeding disor-ders that have autosomal recessive inheritance includedeficiencies/dysfunction of coagulation factors V, VII,

Table 2. Clinical Classification of HemophiliaClassification Severe Moderate Mild

FVIII or FIX activity <1% 1% to 5% 6% to 30%Frequency 50% to 70% 10% 30% to 40%Cause of bleeding Spontaneous Minor trauma, rarely

spontaneousMajor trauma, surgery

Frequency of bleeding 2 to 4 times/mo 4 to 6 times/y UncommonPattern of bleeding Joint, soft tissue, bleeding

after circumcision,neonatal intracranialhemorrhage

Joint, soft tissue � bleedingafter circumcision, �neonatal intracranialhemorrhage

Joint, soft tissue, � bleedingafter circumcision





X, XI, XIII, and fibrinogen. Affected patients presentwith prolongations of the PT or PTT or both, with theexception of FXIII, as mentioned earlier. In addition,there are rare inherited disorders of fibrinolysis in whichpatients exhibit excessive fibrinolytic activity that com-promises clot stability. Clinicians should consider a con-nective tissue disorder (eg, Ehlers-Danlos syndrome) ifsignificant mucocutaneous bleeding is accompanied bynormal laboratory study results.

Acquired Bleeding DisordersThe most common causes of bleeding encountered inclinical practice are due to acquired systemic disorders.Abnormal hemostasis in liver disease involves a variety ofmechanisms, including impaired hepatic synthesis, acti-vation of both coagulation and fibrinolytic systems, lossof hemostatic proteins into ascitic fluid, concurrent vita-min K deficiency, thrombocytopenia, and platelet dys-function. Management of coagulopathy due to hepaticdysfunction should include replacement of coagulationfactors with fresh frozen plasma (FFP) or cryoprecipitate,vitamin K replacement, and platelet transfusions.

Acquired vitamin K deficiency should be suspected inchronically ill children who have malabsorption syn-dromes such as cystic fibrosis, biliary atresia, and celiacdisease. Hemorrhagic disease of the newborn (HDN) isattributed to hepatic immaturity in the synthesis of vita-min K-dependent clotting factors. Generally, affectedinfants have been delivered at home and have not re-ceived prophylactic vitamin K injections. HDN can betreated with intramuscular or oral vitamin K. Uremia andcardiopulmonary bypass and extracorporeal membraneoxygenation circuits can cause bleeding through bothqualitative and quantitative platelet defects. In addition,during cardiopulmonary bypass, the concentrations ofboth coagulant proteins and inhibitors of coagulationdecrease significantly due to hemodilution. These disor-ders can be treated with FFP and platelet transfusions.DDAVP can aid in improving bleeding symptoms inchildren who have renal failure. However, close monitor-ing of fluid and electrolyte balance is required to avoidhyponatremia in this population.

DIC is a consumptive coagulopathy that involvessimultaneous activation of coagulation and the fibrino-lytic system. This presentation most often is accompa-nied by prolongations of coagulation screening tests,thrombocytopenia, and elevated concentrations of fibrindegradation products (eg, D-dimer). In addition to pro-

viding supportive therapy through replacement of coag-ulation factors with FFP and platelets, correction of theunderlying cause (sepsis, malignancy, trauma) is the pri-mary aim of management.

Acquired inhibitors to coagulation proteins such asFVIII or FIX are rare in children. Acquired vWD hasbeen reported in children who have congenital heartdiseases with right-to-left shunt due to rapid clearance oflarge vWF multimers. For children who have Wilmstumor, adsorption of vWF on malignant cells can lead toacquired vWD.

Coagulopathy in children who have acute promyelo-cytic leukemia has been shown to be associated withDIC. Treatment with FFP, platelets, and antifibrinolyticagents may be required to control bleeding in suchpatients.

SummaryThe general pediatrician remains the “front line” for theidentification of congenital and acquired bleeding disor-ders. Prompt and accurate diagnosis is critical to ensuretimely and appropriate therapy and to avoid potentiallylife-threatening complications. Detection involves acareful and focused history and physical examination aswell as diagnostic screening studies. Knowledge of avail-able therapies is helpful in emergent situations, evenwhen a rare disorder is suspected. A pediatric hematolo-gist should be consulted once patients are identified toaid in diagnosis and to recommend long-term manage-ment.

Suggested ReadingHayward CPM, Rao AK, Cattaneo M. Congenital platelet disor-

ders: overview of their mechanisms, diagnostic evaluation andtreatment. Haemophilia. 2006;(suppl 3):128–136

Lippi G, Franchini M, Guidi GC. Diagnostic approach to inheritedbleeding disorders. Clin Chem Lab Med. 2007;45:2–12

Mannucci PM. How I treat patients with von Willebrand disease.Blood. 2001;97:1915–1919

Mannucci PM, Tuddenham EG. The hemophilias: from royal genesto gene therapy. N Engl J Med. 2001;344:1773–1779

Peyvandi F, Kaufman RJ, Seligsohn U, et al. Rare bleeding disor-ders. Haemophilia. 2006;(suppl 3):137–142

Useful Web SitesNational Hemophilia Foundation: www.hemophilia.org/resources/handi/htm

Safety checklist for young children: http://parentcenter.babycenter.com/general/72315.html





PIR QuizQuiz also available online at www.pedsinreview.org.

6. Which of the following clinical features is most likely to be associated with a benign condition?

A. Bleeding 7 days after a tonsillectomy.B. Bruises over the bony prominences of the extremities, both proximal and distal.C. Epistaxis (worse in winter).D. Hemarthrosis.E. Menstrual bleeding that lasts 8 days.

7. Which of the following coagulation factors is measured exclusively by the activated partial thromboplastintime?

A. Factor V.B. Factor VII.C. Factor VIII.D. Factor X.E. Factor XIII.

8. You are evaluating a 15-year-old girl who has had heavy periods since menarche at age 13 years. Herperiods are regular, but she experiences heavy bleeding that lasts for 8 to 9 days with each cycle. Shedenies other bleeding. Her mother reports a similar menstrual history. Her physical examination findings arenormal. Laboratory evaluation reveals a normal platelet count, prothrombin time, and partialthromboplastin time with a normal bleeding time. Of the following, which is the most likely diagnosis inthis patient?

A. Bernard-Soulier syndrome.B. Factor VIII deficiency.C. Hemophilia B.D. Systemic lupus erythematosus.E. von Willebrand disease.

9. A 3-year-old boy comes to your office with a limp. He reports falling while playing tag with his brotherearlier that day. His medical history is unremarkable except for prolonged bleeding after circumcision. Thereis no family history of bleeding. His physical examination reveals a tender, large, bluish mass in the leftquadriceps muscle, which his mother says has enlarged quickly over the last few hours. You suspect ableeding disorder. Of the following, which is the most likely bleeding disorder in this patient?

A. Acute lymphoblastic leukemia.B. Factor XIII deficiency.C. Hemophilia A.D. Immune thrombocytopenic purpura.E. von Willebrand disease.





DOI: 10.1542/pir.29-4-1212008;29;121Pediatrics in Review

Anjali A. Sharathkumar and Steven W. PipeBleeding Disorders

ServicesUpdated Information &

http://pedsinreview.aappublications.org/content/29/4/121including high resolution figures, can be found at:

References

http://pedsinreview.aappublications.org/content/29/4/121#BIBL

This article cites 3 articles, 1 of which you can access for free at:

Subspecialty Collections

of_blood_neoplasmshttp://pedsinreview.aappublications.org/cgi/collection/disorders_Disorders of Blood/Neoplasmsfollowing collection(s): This article, along with others on similar topics, appears in the

Permissions & Licensing

/site/misc/Permissions.xhtmltables) or in its entirety can be found online at: Information about reproducing this article in parts (figures,

Reprints/site/misc/reprints.xhtmlInformation about ordering reprints can be found online:



Documents

Bleeding Disorders Anjali A. Sharathkumar and Steven W. Pipe … · 2013-03-01 · Bleeding Disorders Anjali A. Sharathkumar, MD,* Steven W. Pipe, MD* Author Disclosure Drs Sharathkumar