TECHNICAL REPORT Evaluating for Suspected Child Abuse ...predispose to easy bruising/bleeding in some circumstances. This report reviews the rationale for the consid-eration of bleeding

TECHNICAL REPORT

Evaluating for Suspected Child Abuse: ConditionsThat Predispose to Bleeding

abstractChild abuse might be suspected when children present with cutaneousbruising, intracranial hemorrhage, or other manifestations of bleed-ing. In these cases, it is necessary to consider medical conditions thatpredispose to easy bleeding/bruising. When evaluating for the possi-bility of bleeding disorders and other conditions that predispose tohemorrhage, the pediatrician must consider the child’s presentinghistory, medical history, and physical examination findings beforeinitiating a laboratory investigation. Many medical conditions canpredispose to easy bleeding. Before ordering laboratory tests fora disease, it is useful to understand the biochemical basis and clinicalpresentation of the disorder, condition prevalence, and test character-istics. This technical report reviews the major medical conditions thatpredispose to bruising/bleeding and should be considered when eval-uating for abusive injury. Pediatrics 2013;131:e1357–e1373

INTRODUCTION

In the absence of known accidental mechanisms or medical causes,children with intracranial hemorrhage (ICH), cutaneous bruises, orother symptoms of bleeding might be suspected victims of child abuse.In such situations, physicians must often carefully evaluate for thepossibility of a bleeding disorder or another medical condition asa possible cause. In addition, because of the legal proceedings as-sociated with cases of potential abuse, physicians might feel compelledto rule out any theoretical possibility of a medical explanation for thechild’s findings despite clinical improbability. This can result in anexpensive and, in the case of young children with limited total bloodvolume, potentially harmful laboratory investigation of diminishedclinical value.

The list of congenital and acquired bleeding disorders that couldpotentially be confused with abusive injury is extensive: hemophilia,von Willebrand disease (VWD), disorders of fibrinogen, vitamin K de-ficiency, factor XIII and other factor deficiencies, thrombocytopenia,leukemia, aplastic anemia and other bone marrow infiltrative or failuresyndromes, and platelet function abnormalities, among others. Most ofthese conditions can present with mucosal bleeding, such as epistaxisand cutaneous bruising, but some (especially factor deficiencies) havebeen noted to present with isolated ICH, or can increase susceptibilityto severe ICH after minor trauma. Collagen disorders can also

Shannon L. Carpenter, MD, MS, Thomas C. Abshire, MD,James D. Anderst, MD, MS and the SECTION ON HEMATOLOGY/ONCOLOGY AND COMMITTEE ON CHILD ABUSE AND NEGLECT

KEY WORDSintracranial hemorrhage, inherited coagulation disorders,bruising, nonaccidental trauma

ABBREVIATIONSAP—α-2 antiplasminaPTT—activated partial thromboplastin timeBSS—Bernard-Soulier syndromeCNS—central nervous systemEDS—Ehlers-Danlos syndromeFFP—fresh-frozen plasmaGT—Glanzmann thrombastheniaICH—intracranial hemorrhageITP—immune thrombocytopeniaNARBDR—North American Rare Bleeding Disorders RegistryOI—osteogenesis imperfectaPAI-1—plasminogen activator inhibitor type 1PFA-100—platelet function analyzerPT—prothrombin timeVKDB—vitamin K deficiency bleedingVWAg—von Willebrand antigenVWD—von Willebrand diseaseVWF—von Willebrand factor

This document is copyrighted and is property of the AmericanAcademy of Pediatrics and its Board of Directors. All authorshave filed conflict of interest statements with the AmericanAcademy of Pediatrics. Any conflicts have been resolved througha process approved by the Board of Directors. The AmericanAcademy of Pediatrics has neither solicited nor accepted anycommercial involvement in the development of the content ofthis publication.

The guidance in this report does not indicate an exclusivecourse of treatment or serve as a standard of medical care.Variations, taking into account individual circumstances, may beappropriate.

All technical reports from the American Academy of Pediatricsautomatically expire 5 years after publication unless reaffirmed,revised, or retired at or before that time.

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predispose to easy bruising/bleedingin some circumstances. This reportreviews the rationale for the consid-eration of bleeding disorders andcollagen disorders as a cause of or ascontributing to ICH, bruising, or bleed-ing when child abuse is suspected, andaddresses several unsupported hy-potheses related to these issues.

CLINICAL APPROACH TO THEEVALUATION OF CONDITIONS THATPREDISPOSE TO BLEEDING IN THESETTING OF POSSIBLE ABUSE

In many children with bruising/bleeding concerning for abuse, theevaluation for medical conditionscausing or contributing to the findingsnoted on the physical examination canbe completed by assessing the child’spresenting symptoms, trauma history,medical history, family history, andmedications. Before engaging ina laboratory evaluation, physiciansshould consider the following:

1. The specific clinical characteristicsof the child’s findings, along witha previous history of bleeding orbruising. Family history of bleedingor bruising or a history of specificcoagulopathies and other condi-tions should be addressed.

2. The known presentations and prev-alence of the various bleedingdisorders, collagen disorders, orother medical conditions underconsideration.

3. The medical probability that a spe-cific medical condition might causeor contribute to the child’s bleed-ing or bruising.

4. The statistical characteristics ofthe proposed laboratory testing.

5. The history of the use of blood prod-ucts or other factor replacementproducts that might alter test results.

6. The associated costs of testing, bothfinancial and medical, such as theblood volume needed for testing.

7. The anticipated benefit of identify-ing conditions that might causebleeding or bruising.

CLINICAL CHARACTERISTICS

Nonintracranial Bleeding

The age and developmental capa-bilities of the child, history of trauma,and the location and pattern ofbruising often provide significant evi-dence in determining the presence ofabusive injury.1–5 In many cases, theconstellation of findings, taken inconjunction with the clinical history,can be so strongly consistent withabusive injury that a further labora-tory investigation for medical con-ditions is not warranted. For instance,in a verbal child with a patterned slapmark who describes being hit with anopen hand at the location of the slapmark, obtaining tests to rule outa bleeding disorder is unlikely toprovide useful information. However,because few data exist comparing thespecific clinical presentations ofbleeding disorders and abuse, insome cases, a laboratory evaluationmight be necessary to minimize thechances of a misdiagnosis. It also mustbe considered that the presence ofa bleeding disorder or other medicalcondition does not rule out abuse asthe etiology for bruising or bleeding.6

Other symptoms, such as hematemesis,7

hematochezia,8 and oronasal bleeding,can be caused by abuse or a bleedingdisorder.9–13 The relative frequenciesof abuse or coagulopathies presentingwith these symptoms should beconsidered, along with the patient ’shistory and any other medical find-ings, such as fractures, neglect, andother manifestations of bleeding/bruising, before ordering labora-tory tests. An increasing number offindings unrelated to bleeding dis-orders and consistent with abusedecrease the overall likelihood of

a coagulopathy or other medical condi-tion contributing to or causing bleedingor bruising. However, it is prudent toevaluate for bleeding disorders or othermedical causes in children who havepresenting symptoms that are not typi-cal of inflicted injury.

ICH

Multiple studies have assessed the rolesof history,14 clinical and radiographicfindings,15–22 and outcomes18,21,23,24 inmaking the diagnosis of abusive headtrauma. In a recent study of ICH inbleeding disorders, ICH was the pre-senting event in 19.2%.25 However, nostudies have addressed how to dif-ferentiate whether patients whopresent with ICH in the absence oftrauma or with a history of minimaltrauma have a bleeding disorder ei-ther causing or contributing to theclinical findings. No studies havesystematically compared the pre-sentation, clinical findings, patterns ofICH, or presence of retinal hemor-rhages between bleeding disordersand/or collagen disorders and abu-sive head trauma. Therefore, for chil-dren presenting with ICH but withoutother findings strongly suggestive ofabuse, such as fractures,26 significantabdominal trauma, burns, or pat-terned bruising, an evaluation forother medical conditions causing orcontributing to the findings is neces-sary. Additionally, physicians mustrecognize that although evidence ofold inflicted injury, such as healingfractures, could support the diagnosisof abuse, healing injuries may be un-related to recent bruising or ICH.Physicians must assess their owncomfort in making and supporting thediagnosis of abuse in the absence ofan extensive laboratory evaluation.

REVIEW OF BLEEDING DISORDERS

This section describes the significantbleeding disorders that may require

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further evaluation in cases of sus-pected abuse, including their commonpresentations, incidence of ICH, andthe method of diagnosis (Table 1).

Deficiency of Factor VIII or IX

Hemophilia A and B are attributable todeficiencies of factors VIII and IX, re-spectively. Factor VIII deficiency occursin approximately 1 in 5000 live malebirths. Factor IX deficiency is rarer,occurring in 1 in 20 000 live malebirths. Because of the X-linked re-cessive inheritance pattern of thesediseases, most patients affected withhemophilia are male. However, girlswho are carriers can have low enoughfactor VIII or IX levels to present withbleeding as a result of homozygousmutations or extreme inactivation ofthe normal X chromosome. Rarely,a phenotypic female can have only 1 Xchromosome and be affected with thedisease (ie, testicular feminization,Turner syndrome).27,28

Major bleeding sequelae of hemophiliainclude bleeding into joints and softtissues and ICH. The most commonsites of the initial bleeding episode inone series were post-circumcisionand intracranial.29 ICH in a child withhemophilia can occur as a result ofbirth trauma, in response to mildhead trauma, or spontaneously. ICH isestimated to occur in 5% to 12% ofpatients with hemophilia throughouttheir lives.25,30,31 A review of 57 epi-sodes of ICH in 52 patients with con-genital factor deficiencies showedintraparenchymal and/or intraven-tricular bleeding in 39 patients, sub-dural in 15, subarachnoid in 2, andcerebellar in 1. Most of these patients(38) had severe hemophilia. The me-dian age of presentation was 8 years(range, 1 month to 22 years). Theoverall prevalence of ICH in patientswith hemophilia in this study was9.1%.25 The largest series to date ofICH in hemophilia reported a rate of

2.7% over 5 years in a cohort of 3629patients with hemophilia, or 0.0054cases per year. Most of the cases inthis series were not the result oftrauma (78.4%). Most (69%) occurredin patients with severe hemophilia,and 18% occurred in those withmild hemophilia. Sites of hemorrhagewere intracerebral, subdural, sub-arachnoid, epidural, or unspecified.Trauma was implicated in all of theepidural hemorrhages, 36% of thesubarachnoid hemorrhages, 10% ofsubdural hemorrhages, and 3% of in-tracerebral hemorrhages.31 In a re-cent review of 97 patients withhemophilia who underwent a total of295 computed tomography scans forhead trauma, 9 (3%) were identifiedas having intracranial bleeding. Themean age of these patients was 3.7 ±4.1 years. Most of the bleeding inthese patients was subdural, althoughin 2 patients, bleeding was intra-parenchymal.32 A recent study of he-mophilia in the first 2 years of liferevealed 19.0% of first bleeding epi-sodes (n = 404) were head bleeding,of which 36.4% were ICH. Seventy-fivepercent of the ICH occurred in infantsyounger than 1 month of age, andmost of these were associated withdelivery. In contrast to the aforemen-tioned studies, the occurrence of ICHwas distributed across all severitiesof the disease.29

Approximately two-thirds of patientswho present with a diagnosis of he-mophilia have a positive family historyfor the disease. The one-third ofpatients without a family history ofhemophilia might represent newgerm-line mutations.29,33 Diagnosis ofhemophilia requires measuring factorVIII or IX activity level. Hemophilia iscategorized as severe if the factorlevel is <1%, moderate if the factorlevel is between 1% and 5%, and mildif the factor level is ≥5%. Sponta-neous bleeding is more common in

severe hemophilia. The activated par-tial thromboplastin time (aPTT) isprolonged in moderate and severecases, but can be normal in patientswith mild disease, depending on thelaboratory’s emphasis on detectingmild factor deficiencies. Factor VIII isalso an acute phase reactant and canbe elevated into the normal range inpatients with mild disease in re-sponse to trauma or inflammation.34

VWD

VWD is the most common heritablebleeding disorder, and typically pres-ents with mild to moderate mucocu-taneous bleeding. Low von Willebrandfactor (VWF) levels may occur in up to1% of the population, but fewer peoplemay present with symptoms (0.01% to0.1%). The current prevalence of VWDcan be difficult to ascertain becauserecent changes in consensus haveresulted in more specific diagnosticcriteria. The new criteria for diagnosisrequires VWF <30% (normal range,50% to 150%), resulting in fewerpeople with levels below the normalrange meeting diagnostic criteria.Individuals with bleeding symptomsand VWF levels between 30% and 50%create a diagnostic dilemma.35 In ad-dition, because the bleeding symp-toms of VWD are generally mild, thereare likely to be patients who have notcome to medical attention. On thebasis of the number of symptomaticcases seen by hematology specialists,the prevalence has been estimated tobe even lower than previously sug-gested (23 to 110 per million, or0.0023% to 0.01%), meaning that manyindividuals with low VWF levels mightnever manifest bleeding symptoms.36

The laboratory evaluation for, andcommon presentations of, the varioustypes of VWD are variable (Tables 2and 3). Type 1 VWD is the mostcommon form (approximately 80%)and is characterized by a normally




TABLE1

Common

TestingStrategies

forBleeding

Disorders

Condition

Frequency

Inheritance

ScreeningTests

SnandSp,%

PPVandNPV,%

Confirm

atoryTest

Factor

abnorm

alities/deficiencies

VWDtype

11per1000

ADPFA-100

Sn=79–96

aPPV=93.3

VWAg

b

VWFactivity

Sp=88–96

aNPV=98.2

VWmultim

eranalysis

Factor

VIIIactivity

VWDtype

2AUncommon

ADor

ARPFA-100

Sn=94–100a

PPV=93.3

VWAg

b

VWFactivity

Sp=88–96

aNPV=98.2

VWmultim

eranalysis

Factor

VIIIactivity

VWDtype

2BUncommon

ADPFA-100

Sn=93–96

aPPV=93.3

VWAg

b

VWFactivity

Sp=88–96

aNPV=98.2

VWmultim

eranalysis

Factor

VIIIactivity

VWDtype

2MUncommon

ADor

ARPFA-100

Sn=94–97

aPPV=93.3

VWAg

b

VWFactivity

Sp=88–96

aNPV=98.2

VWmultim

eranalysis

Factor

VIIIactivity

VWDtype

2NUncommon

AR,orcompound

heterozygote

aPTT

NANA

VWF-Factor

VIIIbindingassay

VWDtype

31per300000–1000000

AR,orcompound

heterozygote

PFA-100

Sn=94–100a

PPV=93.3

VWAg

b

Ristocetin

cofactor

Sp=88–96

aNPV=98.2

VWFmultim

eranalysis

Factor

VIIIactivity

Factor

IIdeficiency

(prothrombin)

26reported

cases,estim

ated

1per1–2million

aPTT,PT(m

aybe

norm

al)

Sn=variable

NAFactor

IIactivity

+/−

antigen

levels

Factor

Vdeficiency

1per1million

ARaPTT,PT

Sn=variable

NAFactor

Vactivity

Combinedfactor

V/factor

VIIIdeficiency

1per1million

ARaPTT>PT

Sn=variable

NAFactor

Vandfactor

VIIIactivities

Factor

VIId

eficiency

1per300000–500000

ARPT

Sn=variable

NAFactor

VIIactivity

Factor

VIIIdeficiency

1per5000

malebirths

X-linked

aPTT

Sn=variable

NAFactor

VIIIactivity

Factor

IXdeficiency

1per20

000malebirths

X-linked

aPTT

Sn=variable

NAFactor

IXactivity

Factor

Xdeficiency

1per1million

ARaPTT,PT,RVV

Sn=variable

NAFactor

Xactivity

Factor

XIdeficiency

1per100000

ARaPTT

Sn=variable

NAFactor

XIactivity

Factor

XIIIdeficiency

1per2–5million

ARClot

solubility

Sn=variable

NAFactor

XIIIactivity

Fibrinolyticdefects

APdeficiency

∼40

reported

cases

AREuglobin

lysistest

Sn=variable

NAAP

activity

PAI-1

deficiency

Very

rare

ARSn

=variable

NAPAI-1

antigen

andactivity

Defectsof

fibrinogen

Afibrinogenem

ia1per500000

ARPT,aPTT

Sn=high

NAFibrinogen

level

Hypofibrinogenem

iaLess

than

afibrinogenem

iaPT,aPTT

Sn=variable

NAThrombintim

e,fibrinogen

activity

Dysfibrinogenem

ia1permillion

Thrombintim

e,fibrinogen

level

Sn=variable

NAThrombintim

e,fibrinogen

antigen

andactivity

levelcomparison,

reptilase

time

Platelet

disorders

ITP

Age-related

NACBC

Sn=high

NAAntiplateletAb

(rarelyneeded)


functioning but decreased von Wille-brand antigen (VWAg), resulting in lowlevels of both VWAg and VWF activity.Type 1 VWD has a wide range ofbleeding severity and variable pene-tration among members of the samefamily. Type 2 VWD subtypes arecharacterized by abnormally func-tioning von Willebrand molecules andvariable bleeding severity. Type 3 VWDpresents with absence of VWF anda very low but detectable factor VIIIlevel. The bleeding in type 3 VWD canbe quite severe and can also includehemarthroses resulting from lowfactor VIII levels (Table 3).35

ICH has very rarely been reported inassociation with VWD. A single caseseries detailed 4 episodes of ICHthought to have occurred spontane-ously in patients with no previoushistory of VWD. Patient ages rangedfrom 18 to 65 years of age.37 There wasan additional report of ICH in a new-born child with type 3 VWD and si-multaneous sinovenous thrombosis.38

One case report implicated type 1VWD as a possible cause of subduralhematoma and retinal hemorrhages39;however, the laboratory findings inthat case report did not meet the di-agnostic criteria for definitive VWD,40

and child abuse was not completelyinvestigated, because no repeat skel-etal survey was performed. Largemass-effect ICH associated with minortrauma in children with VWD outsideof the typical age range for abusivehead injury has been reported.41,42

The extreme rarity of this pre-sentation and the questions sur-rounding the validity of VWD causingICH in some cases, indicate that VWDis not a typical cause of ICH.

The platelet function analyzer (PFA-100[Siemens Healthcare Diagnostics,Tarrytown, NY]) has been proposed asa screening test for VWD, and resultsare often abnormal in patients who areknown to have the disorder and have

VWF levels <30%. It is superior to thebleeding time because of ease oftesting but does not test for bloodvessel integrity and is affected bymedications, platelet count, and he-matocrit. The bleeding time is notrecommended for bleeding disorderscreening because of poor test char-acteristics and the invasive nature ofthe test.43 The utility of the PFA-100 asa screening tool for VWD has not beenestablished with population studies. Itcan be a useful tool as a preliminaryscreen for VWD or a platelet functiondefect, but if the result is normal andclinical suspicion remains high, otherspecific testing for these disordersshould be obtained. Abnormal resultsof the PFA-100 test should also promptfurther testing as well.35,40,44,45 It isimportant to realize that the PFA-100is not a diagnostic test for bleedingdisorders but rather acts as a quickscreen in situations in which morespecific testing is unavailable or willbe delayed. If access to specific test-ing is available, it might be rational toskip the PFA-100. Specific testing con-sists of VWAg, VW activity (also re-ferred to as ristocetin cofactor bysome laboratories), factor VIII activity,and often, von Willebrand multimeranalysis. Some practitioners also in-clude ristocetin-induced platelet ag-glutination and/or a collagen-bindingassay. Contributing to the difficulty ofdiagnosis, particularly for type 1 VWD,VWF levels increase in response tostress, pregnancy, and inflammationand exhibit significant variabilitywithin an individual. In addition, somepatients’ test results will fall belowthe lower limits of normal but abovethe current upper diagnostic cutoff(31% to 50%), creating a diagnosticdilemma.35 Because of these issuesand the lack of a single diagnostictest, the diagnosis of VWD might re-quire repeated testing and is bestaccomplished by a pediatric hematol-ogist.TA

BLE1

Continued

Condition

Frequency

Inheritance

ScreeningTests

SnandSp,%

PPVandNPV,%

Confirm

atoryTest

GTVery

rare

ARPFA-100

Sn=97–100

NAPlatelet

aggregationtesting

Flow

cytometry

BSS

Rare

ARPFA-100

Sn=100

NAPlatelet

aggregationtesting

Flow

cytometry

Platelet

release/

storagedisorders

Unknow

n,morecommon

than

otherplatelet

functiondisorders

variable

PFA-100

Sn=27–50

NAPlatelet

aggregationandsecretion

Electron

microscopy

Molecular

andcytogenetic

testing

AD,autosom

aldominant;AR,autosom

alrecessive;CBC,completebloodcell(count);NA,not

availableor

notapplicable;NPV,negativepredictivevalue;PPV,positivepredictivevalue;RVV,Russellviper

venom

(test);Sn,sensitivity;Sp,specificity;VW,

vonWillebrand;Ab,antibody.

aValues

derivedfrom

data

before

2008

NationalInstitutesof

Health

Consensusguidelines.S

nandSp

usingcurrentdiagnosticcutoffs

unknow

nbutwould

beexpected

tohave

higher

Spwith

lower

Sn.

bMay

bereasonable

toproceeddirectlyto

diagnostictestingdependingon

availability.Seeaccompanyingtechnicalreport

fordetaileddiscussion.25




Acquired von Willebrand syndrome isa rare phenomenon in pediatrics thatcan be associated with a number ofclinical disorders, such as vascularanomalies, Wilms tumor and othercancers, cardiovascular lesions, hy-pothyroidism, lymphoproliferative ormyeloproliferative disorders, storagedisorders, autoimmune illnesses,monoclonal gammopathies, and certainmedications. It has been estimated tooccur at a prevalence of 0.04% to 0.13%in the general population, although therate in pediatrics may be lower.46 It isusually caused by autoimmune clear-ance or inhibition of VWF, increasedshear stress causing consumption ofVWF, or adsorption of VWF to cell sur-faces. Laboratory tests used to diagnoseacquired VWD are the same as thoseused to diagnose the congenital disor-der. The addition of the von Willebrandpropeptide can help to distinguishbetween the 2 entities.46

Factor VII Deficiency

Factor VII deficiency is the only plasmacoagulation factor deficiency in whichthe prothrombin time (PT) alone isprolonged. The incidence is estimatedas 1 in 300 000 to 1 in 500 000. To date,more than 150 cases have beenreported. A quantitative factor VII de-termination by standard factor assaymethods provides a definitive di-agnosis. Homozygous patients usuallyhave less than 10 U/dL of factor VII.Heterozygous patients have factor VIIlevels between 40 and 60 U/dL andmight represent single or doubleheterozygous abnormalities. It is veryimportant to use age and gestational-related normal ranges, because factorVII is naturally low at birth.47

ICH has been reported in 4.0% to 6.5%of patients with factor VII deficiencyand usually occurs in those with se-vere disease (<1% factor activity),both spontaneously and as a result of

trauma.48,49 Central nervous system(CNS) bleeding was reported in 4.4%of factor VII–deficient patients asa presenting symptom in 1 registryand was found to occur in subjectsyounger than 6 months.49 Bleedingsymptoms can be extremely variable,and individuals can have minimalbleeding despite very low levels offactor VII. Using the most recent se-verity grading system, all patientswith CNS bleeding have severe dis-ease by definition.50 Intracranialbleeding in these patients has beenrecorded as intraparenchymal, in-traventricular, subdural, and tentorial,often accompanied with overlyingcephalohematoma and usually occur-ring soon after birth.48,51,52

It is also important to rule out ac-quired factor VII deficiency as a resultof vitamin K deficiency, liver disease, orconsumptive coagulopathy. Although inthese conditions, one would expect

TABLE 2 VWD Variants

Test Type 1 Type 2A Type 2B PT-VWD Type 2N Type 2M Type 3

VWF:Ag Low Low Low Low Low Low AbsentVWF:Act Low VWF:Act/VWF:Ag <0.5 Low Low Low VWF:Act/VWF:Ag <0.5 AbsentFVIII Low Nl Nl Nl Low Nl AbsentRIPA Nl Low Nl Nl Nl Low AbsentRIPA-LD Absent Absent Increased Increased Absent Absent AbsentFrequency 70%–80% 10%–12% 3%–5% 0%–1% 1%–2% 1%–2% 1%–3%Multimers Nl Small Small Small Nl Nl Absent

FVIII, factor VIII activity; Nl, normal; PT-VWD, platelet-type pseudo VWD; RIPA, ristocetin-induced platelet aggregation; RIPA-LD, low-dose ristocetin-induced platelet aggregation; VWF:Act, VWFactivity; VWF:Ag, VWF antigen. Reprinted with permission from Nichols WL, Hultin MB, James AH, et al. von Willebrand disease (VWD): evidence-based diagnosis and management guidelines,the National Heart, Lung, and Blood Institute (NHLBI) Expert Panel Reports (USA). Haemophilia. 2008;14(2):191.

TABLE 3 Common Bleeding Symptoms of Healthy Individuals and Patients With VWD

Symptoms Healthy Individuals(n = 500; n = 341;n = 88; n = 60), %

All Types of VWD(n = 264;

n = 1885),%

Type 1 VWD(n = 42;

n = 671), %

Type 2 VWD(n = 497), %

Type 3 VWD(n = 66;

n = 385), %

Epistaxis 4.6–22.7 38.1–62.5 53–61 63 66–77Menorrhagia 23.0–68.4 47–60 32 32 56–69Bleeding after dental extraction 4.8–41.9 28.6–51.5 17–31 39 53–70Ecchymoses 11.8–50.0 49.2–50.4 50 NR NRBleeding from minor cutsand abrasions

0.2–33.3 36 36 40 50

Gingival bleeding 7.4–47.1 26.1–34.8 29–31 35 56Postoperative bleeding 1.4–28.2 19.5–28 20–47 23 41Hemarthrosis 0–14.9 6.3–8.3 2–3 4 37–45Gastrointestinal tract bleeding 0.6–27.7 14 5 8 20

NR, not reported. Reprinted with permission from Nichols WL, Hultin MB, James AH, et al. von Willebrand disease (VWD): evidence-based diagnosis and management guidelines, theNational Heart, Lung, and Blood Institute (NHLBI) Expert Panel Reports (USA). Haemophilia. 2008;14(2):186.


more extensive coagulopathy, pro-longation of the PT is often the onlyfinding in the early stages of thesedisorders because of the short half-lifeof factor VII.

Factor XI Deficiency

Factor XI deficiency (also termed he-mophilia C) has an estimated fre-quency in the general population of 1in 100 000.53,54 Factor XI deficiencyoccurs more frequently in the AshkenaziJewish population; approximately0.2% of Ashkenazi Jewish people arehomozygous and 11.0% are heterozy-gous for this disorder.55

Bleeding in factor XI deficiency tends tobe mild and associated with trauma orsurgery. Bleeding symptoms oftencannot be predicted by the factor level.Serious spontaneous hemorrhage isuncommon, even in individuals withvery low factor levels.56 There was 1report of subarachnoid hemorrhagein a 53-year-old man with previouslyundiagnosed factor XI deficiency. Thispatient was also found to have cere-bral aneurysms.57

Laboratory screening tests reveala prolonged aPTT and normal PT,though the aPTT can be normal inheterozygous patients with mild de-ficiency. Other screening test resultsare normal. The specific assay forfactor XI is the definitive test for thisdeficiency. In homozygous individuals,factor XI activity ranges from <1 U/dLup to 10 U/dL. Severe deficiency isdefined as <15 U/dL.58 It is importantto compare results with age-matchednorms, because healthy ranges ininfants are lower than those inadults.59

Factor XIII Deficiency

Factor XIII acts to covalently cross-linkand stabilize fibrin. Because the PTand aPTT measure the production offibrin from fibrinogen and the actionof factor XIII is subsequent to the

formation of fibrin, these tests arenormal in factor XIII deficiency andtherefore cannot be used to screen forthis disorder. The clot solubility test,which is the most commonly used testto screen for factor XIII deficiency, isabnormal only in very severe defi-ciencies of factor XIII, typically withfactor XIII activities <3% of normal.This is the level most experts believeis necessary to cause spontaneousbleeding. A quantitative test for factorXIII exists.60,61

Deficiency of factor XIII is rare, oc-curring in only approximately 1 in 2 to5 million people. However, intracranialbleeding is a common manifestation ofthis disorder, occurring in up to one-third of those with the deficiency.60,62

Bleeding has been reported in sub-dural, intraparenchymal, and epidurallocations, although because mostregistries and case reports have notspecified the location of ICH, it is likelythat it has occurred in more disparatesites. ICH has been reported to occuroccasionally in patients with factorlevels >3%, and therefore, the di-agnosis can be missed if only the clotsolubility test is used.63–65 Other mani-festations of factor XIII deficiency areumbilical cord bleeding, muscle hema-tomas, and postoperative bleeding.62

Other Factor Deficiencies (FactorsII, V, Combined V and VIII, and X)

Prothrombin (Factor II) Deficiency

Homozygous prothrombin deficiencyoccurs at an estimated prevalence of 1in 1 to 2 million. The most commonbleeding presentation in homozygousand heterozygous patients is bleedinginvolving the skin and mucous mem-branes. In the North American RareBleeding Disorders Registry (NARBDR),11% of the subjects with factor II de-ficiency suffered a CNS complication(which included both ICH and ischemicstroke). In subjects with factor II levels<0.01 U/mL, the rate of ICH was 20%.66

Little description of these hemor-rhages exists, although case reportshave described subdural and epiduralhematomas.67–69 Homozygous patientscan also present with surgical ortrauma-induced bleeding.70 Hemarthro-ses occurred in 42%, and gastrointes-tinal bleeding in 12% of homozygoussubjects in one registry.71 Acquiredprothrombin deficiency can occur withvitamin K deficiency, liver disease,warfarin therapy, or overdose or in thesetting of connective tissue disorderswith accompanying lupus anticoagu-lant.70

The degree to which the PT and aPTTare prolonged varies from patient topatient, from a few seconds in somepatients to more than 60 secondsin others, and occasionally, thesescreening results can be in the normalrange.47,71 The diagnosis is estab-lished with a factor assay for func-tional prothrombin (FII), along withimmunologic tests for antigen levels ifnecessary.

Factor V Deficiency

Factor V deficiency is estimated tooccur in 1 in 1 million people. Bothhomozygous and heterozygous patientswith factor V deficiency typically havebleeding symptoms. Bleeding in ho-mozygous patients tends to be spon-taneous and occurs in the skin andmucous membranes, joints and mus-cles, genitourinary tract, gastrointes-tinal tract, and CNS. In the NARBDR,8% of homozygous patients presentedwith intracranial bleeding.66 Intrauterinesubdural hematomas have beenreported, as have spontaneous intra-parenchymal hemorrhages.72,73 Fifty-percent of heterozygous patientsalso had bleeding. Skin and mucousmembrane bleeding were the mostcommon manifestations, and noneexperienced ICH.66

Factor V can also be low in someplatelet disorders, because it is also




present in platelet α granules. In ad-dition, acquired factor V deficiencycan occur in patients with rheuma-tologic disorders or malignancies,patients using antimicrobial agents,or patients using topical bovinethrombin because of antibodies tofactor V.74

In factor V deficiency, the PT and aPTTare both prolonged. Abnormal bleed-ing time or positive PFA-100 result isreported in approximately one-thirdof patients, perhaps related to a de-ficiency of factor V in platelet αgranules.53 Other screening test re-sults are normal. Definitive diagnosisrequires a factor V assay.

Combined Factor V and Factor VIIIDeficiency

Combined deficiency of factor V andfactor VIII is rare, occurring in 1 in 1million people, with higher frequencyin populations in which consanguinityis more common. In this syndrome,factor V and factor VIII levels (bothantigen and activity) range from 5% to30% of normal.47,75 Bleeding is usuallymild to moderate. Patients typicallyhave easy bruising, epistaxis, and gumbleeding, as well as bleeding aftertrauma or surgery. Menorrhagia andpostpartum bleeding in affectedwomen have also been reported.Hemarthrosis can also occur. In-tracranial bleeding is rare but hasbeen reported in 1 patient of 46reported in the 2 largest registries ofthis disorder (27 and 19 subjects, re-spectively).76,77

Combined deficiency of factor V andfactor VIII is passed down in anautosomal-recessive fashion and isattributable to a mutation of a proteinof the endoplasmic reticulum–Golgiintermediate compartment (ERGIC 53)encoded by the LMAN1 gene. Thisprotein has been shown to be impor-tant in facilitating protein transportfrom the endoplasmic reticulum to

the Golgi apparatus. The decrease infactors V and VIII is, thus, attributableto defective intracellular transportand secretion unique to these 2 co-agulation factors.47 The PT and aPTTare prolonged in this disorder, withthe prolongation of aPTT out of pro-portion to that of the PT.

Factor X Deficiency

The prevalence of factor X deficiency is1 in 1 million in the general populationand more common in populationswith higher rates of consanguinity.47

It is passed down in an autosomal-recessive pattern. As many as 1 in500 people might be carriers of thedisorder.78 More severe deficiencywould be expected to present earlierin life. Heterozygous cases might beidentified incidentally by laboratorytests performed preoperatively or foranother purpose.79

In the NARBDR, most bleeding symp-toms in factor X deficiency were mu-cocutaneous, including easy bruising,followed by musculoskeletal bleeding.Intracranial bleeding occurred in 15%of the homozygous cohort, of which54% had a factor X level <0.01 U/ mL.This cohort had the highest rate of ICHin the study, compared with otherrare bleeding disorders. No heterozy-gous subjects experienced ICH.66 Se-verely affected patients also presentin the neonatal period with bleedingat circumcision, umbilical stumpbleeding, or gastrointestinal hemor-rhage.78 The Greifswald factor X de-ficiency registry, which enrollspatients from Europe and LatinAmerica, showed ICH in 21% of itscohort. ICH was reported only inpatients who were homozygous andcompound heterozygous.80

Severe liver disease can result in de-ficiency of all liver-produced factors,including factor X. Acquired factor Xdeficiency can also occur with amy-loidosis, cancer, myeloma, infection,

and use of sodium valproate. Acquiredinhibitors to factor X have also beenreported in association with upperrespiratory infections and burns andusually present with active bleedingfrom multiple body sites.78,80 Becauseof the frequency of the associateddiseases, acquired factor X deficiencyis actually fairly common. Althoughthe overall rate is unknown, this dis-order has been reported in up to 5%of patients with amyloidosis.78 There-fore, diagnosis of inherited factor Xdeficiency in the face of concomitantmedical diagnoses should be madecarefully and ideally with the assis-tance of a pediatric hematologist.

Both the PT and aPTT are usuallyprolonged and correct with a 1:1 mixwith normal plasma; however, with 2types of mutations, the PT is prolongedand the aPTT is normal, whereas theopposite is true in another variant.81

The Russell viper venom test is usuallyprolonged, although it can be normalin some variants.53 A factor X assay isthe definitive test, although it is im-portant to compare results with nor-mal levels for age and exclude vitaminK deficiency before confirming the di-agnosis.

Vitamin K Deficiency

Vitamin K is required to complete theposttranslational alteration of factorsII, VII, IX, and X and proteins C and S. Inthe absence of vitamin K, precursorproteins are synthesized by hepaticcells, but because γ-carboxyglutamicacid residues are absent, the calcium-binding sites are nonfunctional. De-ficiency of vitamin K results in inducedfunctional deficiencies of all of theseproteins. If the level of functionalproteins falls below 30 U/dL, bleedingsymptoms can result, and the PT and/or the aPTT will be prolonged.82

Vitamin K deficiency bleeding (VKDB) ismost often seen in newborn infants inthe first days of life (in infants who do


not receive vitamin K at birth). Becausetheir livers are still immature, syn-thesis of the vitamin K–dependentfactors in newborn infants is 30% to50% of adult levels. Almost all neo-nates are vitamin K deficient as a re-sult of poor placental transmission ofmaternal vitamin K and the lack ofcolonization of the colon by vitamin K–producing bacteria in the neonate,although not all infants will go on tohave VKDB without prophylaxis.

VKDB is divided into 3 subtypes: early,classic, and late. Early VKDB occursprimarily in infants of mothers whohave been on a vitamin K–blockingmedication, such as anticonvulsants,and usually occurs within hours to thefirst week of life. Classic-onset VKDBoccurs between the first week andfirst month of life and is largely pre-vented by prophylactic vitamin K ad-ministration at birth. Late VKDBoccurs from the first month to 3months after birth.83 This deficiency ismore prevalent in breastfed babies,because human milk contains lessvitamin K than does cow milk. It canbe precipitated by acquired or in-herited gastrointestinal tract disease.Infants with liver disease might alsobe susceptible.

Manifestations of VKDB are bleeding inthe skin or from mucosal surfaces,bleeding from circumcision, general-ized ecchymoses, large intramuscularhemorrhages, and ICH. Although VKDBis rare in countries that provide pro-phylaxis, more than 50% of infants withlate VKDB will present with ICH.82 VKDBis prevented in the United States byencouraging administration of vitaminK to all newborn infants. Althoughmost states have laws that requireadministration, some do not. Admin-istration of oral vitamin K prophylaxisreduces the incidence of late VKDBfrom 4.4 to 10.5/100 000 live births to1.5 to 6.4/100 000 live births.83 In-tramuscular vitamin K prophylaxis

prevents almost all cases of late VKDB;however, these can still occur, partic-ularly if there is an unrecognized un-derlying cause of vitamin K deficiency.Secondary VKDB can occur in thesetting of hepatobiliary disease,antimicrobial therapy, coumarolpoisoning/rat poison ingestion, biliaryatresia, and chronic diarrhea. ICH inthis setting is rare but does occur.84

Diagnosis of VKDB is the same re-gardless of underlying cause. Labora-tory tests show prolonged PT andpossibly aPTT for age. Specific factorassays for factors II, VII, IX, and X aremarkedly decreased. In patients whohave already received vitamin K astreatment or transfusion of plasma,measurement of proteins induced byvitamin K absence can confirm thediagnosis.82,84

Inherited combined deficiencies of vi-tamin K–dependent proteins occurwhen there is a mutation in theγ-glutamyl carboxylase gene or thevitamin K epoxide reductase complex.Fewer than 30 cases have beenreported. Bleeding symptoms rangefrom mild to severe, and ICH has beenreported. Some patients also havedysmorphic features or skeletaldefects.85

Defects of Fibrinogen

Abnormalities of fibrinogen can resultin complete lack of the protein (afi-brinogenemia), decreased levels(hypofibrinogenemia), or an abnor-mally functioning molecule (dysfi-brinogenemia). Clinical presentationsrange from mild to severe bleeding,and some patients have an increasedrisk of thrombosis as well, dependingon the causative mutation.86,87 Fibrin-ogen deficiencies can also be ac-quired in other medical disorders,such as liver disease or consumptivecoagulopathy.87

Severe disorders of fibrinogen resultin prolongation of PT and aPTT, but

milder disorders might be missed bythese screening tests. Thrombin timetests conversion of fibrinogen to fibrinand is more sensitive to both defi-ciencies and abnormalities of fibrino-gen than are PT and aPTT. Reptilasetime is similar to thrombin time, ex-cept that it is not affected by heparinand might help distinguish hypofi-brinogenemia from dysfibrinogenemiabecause of its slightly differentmechanism of action. One can alsomeasure the amount of fibrinogenantigen through a variety of methods.87

Most patients with dysfibrinogenemiaare asymptomatic. Bleeding, when it ispresent, is typically mild and triggeredby surgery or trauma, and thrombosiscan occur. The presence of a bleedingor thrombotic phenotype is dependenton the underlying mutation.88 One casereport of ICH and cephalhematomasin a child with suspected dysfi-brinogenemia has been published.The case in that report was unique inthat the patient had a long historyof bleeding and almost undetectablefibrinogen levels. In addition, the pa-tient appeared to inherit his diseasein a double heterozygous-recessivemanner from consanguineous parents,in contrast to most cases, which areautosomal dominant in nature.89

Overall, bleeding symptoms in afi-brinogenemia are variable and canrange from mild to life threatening. ICHhas been reported in patients withafibrinogenemia (5% to 10% ofpatients).90,91 Up to 85% of patientspresent in the neonatal period withumbilical cord bleeding.92

Defects of Fibrinolysis

Fibrinolysis refers to the breakdown ofthe fibrin clot and is directed byplasmin. Plasmin is generated fromplasminogen by the actions of plas-minogen activators. The inhibitors ofthis action are α-2 antiplasmin (AP,also known as α-2 plasmin inhibitor




and plasmin inhibitor), thrombin-activatable fibrinolysis inhibitor, andplasminogen activator inhibitor type 1(PAI-1). Deficiencies in AP and PAI-1have been described, although bothare rare.93,94

Patients with PAI-1 deficiency havebeen described as having mild tomoderate bleeding symptoms, such asepistaxis, menorrhagia, and delayedbleeding after surgery or trauma.Spontaneous bleeding is rare. Di-agnosis of PAI-1 deficiency can beproblematic in that the laboratoryassay used for diagnosis is inaccurateat low levels. Normal ranges often arereported beginning at 0, creatinga large crossover between thosepatients with an abnormality in PAI-1and healthy individuals. Only 2 of thereported deficiencies of PAI-1 havebeen correlated with an underlyinggenetic defect.94 In 1 large kindred inwhom a null mutation was identified,ICH and bleeding into joints werereported after mild trauma.95 ICH hasbeen reported in 2 adults in whom theonly underlying coagulation abnormal-ity identified was a low PAI-1 level. Oneadult also had osteogenesis imperfecta(OI).96,97

There have been approximately 40cases of AP deficiency reported in theliterature. AP deficiency is inherited inan autosomal-recessive pattern, al-though heterozygous patients can alsopresent with bleeding. Acquired de-ficiency has also been reported inpatients with liver disease, dissemi-nated intravascular coagulation, andacute promyelocytic leukemia. Homo-zygous patients tend to have severebleeding similar to that seen in factorXIII deficiency, although ICH has notbeen reported. Heterozygous patientscan have bleeding in response totrauma, surgery, or dental proceduresor can be asymptomatic.93,98 Intra-medullary hematomas of long bones,which can occur without a history of

trauma, are an unusual feature ofhomozygous AP deficiency.99,100 Simi-lar lesions have been seen in patientswith afibrinogenemia. A shortenedeuglobulin lysis time can be used asa screening test for AP deficiency.Definitive diagnosis requires mea-surement of AP antigen and activity.101

Congenital Platelet Abnormalities

Platelets interact with VWF to adhereto sites of vessel wall injury. Sub-sequent activation and aggregation ofplatelets, which includes the release ofgranular contents, leads to formationof a platelet plug. Congenital plateletdisorders can result in fewer platelets,abnormal function of platelets, ora combination of the two. There isa wide range in the presenting symp-toms of these disorders, from mildmucocutaneous bleeding to severe life-threatening hemorrhage.102

The most severe and best-characterizedplatelet function disorders are also therarest. These are the autosomal re-cessive disorders Bernard-Souliersyndrome (BSS) and Glanzmannthrombasthenia (GT). BSS resultsfrom absence or abnormal functionof the GP Ib-IX-V receptor, which isresponsible for platelet adhesion toVWF. Patients with BSS also commonlyhave mild thrombocytopenia with en-larged platelet size. In GT, the αIIβ3platelet integrin is abnormal ormissing, leading to impaired plateletaggregation, but the platelet count isnormal. In both of these disorders,significant mucocutaneous bleedingand ICH have been reported, althoughICH is rare, occurring in only 0.3%to 2.0% of patients with GT andeven less in those with BSS.103,104

The PFA-100 is a fairly reliablescreening mechanism for these di-agnoses (Table 1).102,103

Less well characterized but morecommon, the disorders of plateletsignaling and secretion result from

a variety of defects. Platelet activationleads to a conformational change inthe platelet and normally results insecretion of platelet granule contents,which recruits other platelets to thesite of injury. Without this response,platelets are unable to recruit otherplatelets. This group of disordersincludes Quebec platelet disorder,the MYH9-related disorders, Scottsyndrome, Hermansky-Pudlak syn-drome, Chediak-Higashi syndrome,and Wiskott-Aldrich syndrome. Mostbleeding with these disorders is mildand manifests as excessive bruising ormenorrhagia. The PFA-100 does notreliably screen for these disorders.105

More specific platelet aggregation andsecretion testing is required, and oc-casionally, electron microscopic ex-amination or genetic mutation testingis necessary to confirm the di-agnosis.102 All forms of genetic in-heritance have been reported. Mostpatients with these disorders presentwith mucocutaneous bleeding mani-festations or bleeding after surgery ortrauma. Bleeding symptoms are vari-able and dependent on the specificdefect. Joint bleeding can occur insome disorders. ICH has been reportedafter childbirth in neonates andtrauma in older individuals. Someplatelet function disorders are part ofsyndromes with associated physicalfindings. Individual review of theseentities is outside of the scope of thisreport.106,107 Of note, a variety ofmedications can lead to platelet dys-function (eg, nonsteroidal antiin-flammatory drugs, sodium valproate);therefore, a careful medication his-tory should be obtained before di-agnosing a congenital plateletabnormality.108 Acquired thrombocy-topenia, whether from medication,immune thrombocytopenia (ITP), ma-ternal ITP, or neonatal alloimmunethrombocytopenia, should be readilydiagnosed on the basis of a complete


blood cell count. The rate of ICH inpatients with idiopathic ITP is <1%.109

Vascular Disorders

Certain vascular disorders can pres-ent with bruising or bleeding. Twodisorders that might be confused forabuse are outlined. Discussion of allvascular disorders is outside of thescope of this report but can be foundelsewhere.110

Ehlers-Danlos

Ehlers-Danlos syndrome (EDS) con-sists of a group of genetically andclinically heterogeneous connectivetissue diseases that might be mistakenfor child abuse.111,112 The exact prev-alence of EDS is unknown but is esti-mated to be 1 in 5000.113 There are 6genetic subtypes, which differ in theunderlying biochemical defect, in-heritance pattern, and clinical symp-toms114; however, prominent bruisingand bleeding are seen in all sub-types.115 Mutations in collagen type I,type III, type V, or the genes involved inprocessing type I collagen result inmost EDS subtypes. The tendency tobleed and/or bruise in EDS is causedby an abnormal capillary structurewith deficiency of normal perivascularcollagen. Cutaneous blood vessels arepoorly supported and can rupturewhen subject to shearing forces. Testsfor bleeding disorders are generallynormal, except for the Hess test,which can be abnormal, indicatingcapillary fragility.115 Clinically, thedisorder manifests itself with easybruising, bleeding gums, prolongedbleeding after surgical procedures,and menorrhagia. When evaluatingchildren with possible abusive find-ings, pediatricians should assess forthe typical signs of EDS. Skin hyper-extensibility describes skin thatextends easily and snaps back afterrelease and is best tested at the volarsurface of the forearm.115 Widened,thin scarring often occurs at knees,

shins, elbows, and the forehead.115

Joint hypermobility is also often seen.

The vascular type of EDS, also knownas EDS type IV, particularly mightbe confused with child abuse.111

The precise prevalence is not knownbut has been estimated to be 1 in250 000.116,117 Both autosomal-recessiveand -dominant inheritance patterns,as well as sporadic mutations, havebeen described.118 The clinical di-agnosis is made on the basis of 4criteria: easy bruising; skin with visi-ble veins; characteristic facial fea-tures; and rupture of arteries, uterus,or intestines.114 The diagnosis is con-firmed by the demonstration thatcultured fibroblasts synthesize ab-normal type III procollagen moleculesor by the identification of a mutationin the gene for type III procollagen(COL3A1).119 Excessive bruising is themost common presentation, but othersevere complications, such as spon-taneous rupture of the bowel andhemorrhagic pneumothorax, can oc-cur. Vascular ruptures, including renalor splenic arteries, aneurysmal rup-ture, or stroke can also occur. ICH,including subdural hemorrhage, hasonly very rarely been described, andfindings would likely not be confusedwith those commonly seen in inflictedhead injury.118,120 Severe complica-tions are rare in childhood.116 Jointhypermobility is often limited to thesmall joints of the hands. Skin hy-permobility is typically not present,but the skin is often translucent,showing a visible venous pattern.121,122

The characteristic facial appearanceincludes prominent eyes, pinchednose, small lips, hollow cheeks, andlobeless ears.117,121

If clinical suspicion exists, the di-agnosis of most subtypes of EDS canbe evaluated with biochemical andmolecular analysis. Cultured skinfibroblasts can be used for gel elec-trophoresis of collagen types I, III,

and V. For the vascular subtype (EDStype IV), biochemical analysis of type IIIprocollagen identifies more than 95%of patients, whereas molecularscreening of the COL3A1 gene identi-fies up to 99% of mutations.117,119

OI

OI is a heterogeneous group of dis-eases characterized by bone fragility,dentinogenesis imperfecta, and adulthearing loss.123 OI has been associ-ated with easy bruising and ICH afterminimal or no trauma.124,125 Bleedingdiathesis in OI is thought to occur asa result of platelet dysfunction andcapillary fragility.126,127

Inheritance is generally autosomal-dominant, but autosomal-recessiveinheritance and new mutations areknown to occur. Most cases are theresult of mutations in COL1A1 andCOL1A2. At least 8 types of OI areknown to exist, and the prevalence isapproximated at 1 in 15 000 to 1 in20 000.128,129

Testing for OI by using DNA sequencingor collagen analysis is available. Sen-sitivities and specificities varydepending on the type of OI, but ap-proximately 90% of individuals with OItypes I, II, III, and IV (but none with OItypes V, VI, VII, or VIII) have an identi-fiable mutation in either COL1A1 orCOL1A2.125 Rare case reports have at-tributed multiple varieties of ICH, in-cluding subdural hematomas inchildren, to OI.130–134 Additionally, 3cases of relatively minor retinalhemorrhages coupled with subduralhematomas have been reported aftertrivial trauma in patients with OI type1.124 Despite these case reports, OI isa rare condition, and the occurrenceof subdural hematomas and/or retinalhemorrhages attributable to OI is ex-ceedingly rare.

Despite the reported associations ofOI with easy bruising, no large-scalestudies have characterized the




frequency and nature of bruising inchildren with OI or compared thesepatterns to nonabused children with-out OI or abused children. In childrenwith bruises only, in the absence ofother clinical indicators of OI, such asshort stature, blue sclera, wormian ordemineralized bones, or family history,it is generally not necessary to rule outOI via collagen or DNA testing.

Unsupported Hypotheses

Many alternative hypotheses havebeen proposed to explain bruising orbleeding concerning for abuse that arenot supported by scientific evidence. Itis outside of the scope of this reportto discuss all hypotheses of this na-ture. Two of the more common areintracranial findings concerning forabuse caused by the effects of vac-cines or by intracranial thrombosis.

Vaccines Mimicking Abusive HeadTrauma

Some have proposed that vaccinescause findings that might be confusedwith abusive head trauma.135–137 Thehypothesized mechanism is a combina-tion of ascorbate (vitamin C) depletionand foreign protein in vaccines causinga high histamine level, which thenleads to capillary fragility and venousbleeding. No scientific evidence existsto support the hypothesis that immu-nizations cause findings that might beconfused with inflicted trauma.

Intracranial Venous ThrombosisMimicking Abusive Head Trauma

The incidence of intracranial venousthrombosis in children is estimated tobe 0.67 cases per 100 000 children peryear.138 Of these, approximately 28%involve hemorrhagic venous in-farction; thus, the incidence of hem-orrhagic venous infarction is 0.19cases per 100 000 children per year.138

Common congenital associations in-clude factor V Leiden, prothrom-bin gene mutation, protein C or S

deficiency, and antithrombin de-ficiency. Other causes include infec-tions (eg, otitis media, mastoiditis,sinusitis), dehydration, and trauma.Affected infants typically present withseizures and diffuse neurologicsigns.138 No studies have systemati-cally compared characteristics of ICHresulting from intracranial thrombo-sis with characteristics of ICHresulting from trauma. A single studyevaluating nontraumatic intracranialvenous thrombosis detected no sub-dural hematoma in the study pop-ulation (n = 36).139 Additionally,bleeding from intracranial thrombosishas a typical appearance on magneticresonance imaging, including local-ized bleeding near the thrombus,typically in an intraparenchymal dis-tribution. This appearance is in con-trast to the typical presentingfeatures of deceleration head trauma,including thin-film subdural hemor-rhages involving the interhemisphericregion and the cerebral convexities.22

If there is concern for intracranialthrombosis, magnetic resonance ve-nography is the test of choice. Giventhe significant difference in appearanceof ICH as a result of intracranial venousthrombosis in comparison with ICH fromdeceleration trauma, confusion betweenthe 2 conditions should not exist.

INTERPRETATION OF TESTS

It should be noted that aPTT can befalsely prolonged in certain conditions,such as in the presence of a lupusanticoagulant, or can be prolongedand not indicate a true bleeding dis-order, such as in factor XII deficiencyor other contact factor deficiencies. Inaddition, patients who suffer a trau-matic brain injury often have a transientcoagulopathy that does not reflect anunderlying congenital disorder.140,141 Itshould also be noted that coagulationtests are very sensitive to specimenhandling and should be performed in

laboratories experienced with theseassays. Inappropriate handling com-monly leads to false-positive results.

Patients who have sustained sig-nificant trauma also might receivetransfusions of blood products. Fresh-frozen plasma (FFP) is prepared byseparating the liquid portion of bloodfrom the cellular portion after thecollection of whole blood or by col-lecting the liquid portion of blood byusing apheresis technique. By defini-tion, each milliliter of FFP contains 1unit of all normal coagulation factorsand inhibitors of coagulation, but ingeneral, 10 to 20 mL/kg will raisefactor levels only by 15% to 25%.142

Cryoprecipitate is prepared by thaw-ing FFP and refreezing the precipitate.It contains high concentrations of fi-brinogen, factor VIII, VWF, and factorXIII. Each coagulation factor has a dif-ferent half-life (Table 4). Therefore, theadministration of FFP or cryoprecipitatewill affect the investigation for a co-agulation factor deficiency differentlydepending on the factor being mea-sured.

FREQUENCY OF THE CONDITIONAND MEDICAL PROBABILITY

Specific data regarding the prevalenceof bleeding disorders within the pop-ulation of children with ICH or sub-dural hemorrhage are not available;however, there are data on the fre-quency of ICH as a result of specificbleeding disorders. If the prevalence ofa condition and the frequency of a par-ticular presentation of that conditionare known, a physician can constructthe probability of that specific condition(bleeding disorder) resulting in thespecific presentation (ICH):

PðBÞ ¼ PrevðAÞ× PrevðBjAÞ;

where B is ICH attributable to conditionA, P is probability, and Prev is prevalence.

For example, factor XIII deficiencyis extremely rare, occurring at an


upper limit estimated populationprevalence of 1 in 2 million; however,it can present with isolated in-tracranial bleeding in up to one-thirdof cases.59 The estimated probabilitythat factor XIII deficiency will cause anICH in a person in the population atlarge is:

ðPrevalence of factor XIII deficiencyÞ× ðPrevalence of ICH in factor XIII deficiencyÞð1=2 millionÞ× ð1=3Þ ¼ 1=6 million

Table 5 contains probabilities forcongenital bleeding disorders tocause ICHs in the population at large.

No calculation was made in situationsin which no reliable estimates ofprevalence of the condition or fre-quency of ICH exist. The most liberalprevalence and frequency numberswere used, so as to provide the upperlimits of probability.

CONCLUSIONS

In cases of suspected abuse involvingbruising and/or bleeding, physiciansmust consider the possibility of coa-gulopathies causing or contributing tothe findings. In many cases, the pos-sible coagulopathies can be effectivelyevaluated by a thorough history andphysical examination, and possibly bythe specific nature of the child’s find-ings; however, in some cases, a labo-ratory evaluation for coagulopathiesmight be necessary. The diagnosis ofa bleeding disorder does not auto-matically rule out the presence ofnonaccidental trauma. Because of thechronic nature of their disease, chil-dren with bleeding disorders may beat higher risk of abuse.143

Limited evidence exists comparingbruising and bleeding in children with

coagulopathies with child victims ofabuse. Conducting such studies wouldbe difficult, given the overall rarity ofcoagulopathies; however, large data-bases exist for rare hematologic con-ditions, and modification of thesedatabases to include factors, such aslocation of bruising or location/character of ICH, which would assistin discriminating between bleedingdisorders and abuse, would be benefi-cial. In the absence of such data,physicians must use existing data,including epidemiologic and clinicalfactors, in their decision-making pro-cess.

LEAD AUTHORSShannon L. Carpenter, MD, MSThomas C. Abshire, MDJames D. Anderst, MD, MS

SECTION ON HEMATOLOGY/ONCOLOGY,2012–2013Jeffrey Hord, MD, ChairpersonGary Crouch, MDGregory Hale, MDBrigitta Mueller, MDZora Rogers, MDPatricia Shearer, MDEric Werner, MD, Immediate Past Chairperson

FORMER EXECUTIVE COMMITTEEMEMBERSStephen Feig, MDEric Kodish, MDAlan Gamis, MD

LIAISONSEdwin Forman, MD–Alliance for ChildhoodCancer

CONSULTANTSShannon L. Carpenter, MD, MSThomas C. Abshire, MD

STAFFSuzanne Kirkwood, MS

COMMITTEE ON CHILD ABUSE ANDNEGLECT, 2010-2011Cindy W. Christian, MD, ChairpersonJames Crawford-Jakubiak, MDEmalee Flaherty, MDJohn M. Leventhal, MDJames Lukefahr, MDRobert Sege, MD, PhD

TABLE 4 Half-Lives of Coagulation Factors

Factor Half-Life Postinfusion, h

Fibrinogen 96–150II 60V 24VII 4–6VIII 11–12IX 22X 35XI 60XIII 144–300VWF 8–12

Reprinted with permission from Goodnight S, HathawayW. Disorders of Hemostasis and Thrombosis: A ClinicalGuide. 2nd ed. New York, NY: McGraw-Hill Professional;2001:497.

TABLE 5 Probabilities for Congenital Coagulopathies to Cause ICHa

Condition Prevalence of Condition,Upper Limits

Prevalence of ICH,Upper Limits

Probabilityb

VWD 1/1000 Extremely rare LowFactor II deficiency 1/1 million 11% 1/10 millionFactor V deficiency 1/1 million 8% of homozygotes 1/10 million

homozygotesCombined factors V and

VIII deficiency1/1 million 2% 1/50 million

Factor VII deficiency 1/300 000 4%–6.5% 1/5 millionFactor VIII deficiency 1/5000 males 5%–12% 1/50 000 malesFactor IX deficiency 1/20 000 males 5%–12% 1/200 000 malesFactor X deficiency 1/1 million 21% 1/5 millionFactor XI deficiency 1/100 000 Extremely rare LowFactor XIII deficiency 1/2 million 33% 1/6 millionAP deficiency 40 cases reported Not reported LowPAI-1 deficiency Extremely rare Common LowAfibrinogenemia 1/500 000 10% 1/5 millionDysfibrinogenemia 1/1 million Single case report Lowa The probability of having a specific bleeding disorder increases in the setting of a family history of that specific namedbleeding disorder or if the patient is from an ethnicity in which a specific bleeding disorder is more common (eg,Ashkenazi Jewish people and factor XI deficiency).b“Probability” indicates the probability that an individual in the general population would have the following specific

coagulopathy causing an ICH.




LIAISONSHarriet MacMillan, MD— American Academy ofChild and Adolescent PsychiatryCatherine Nolan, MSW — ACSW, Administrationfor Children, Youth, and Families, Office onChild Abuse & Neglect

Janet Saul, PhD — Centers for Disease Controland Prevention

CONSULTANTJames D. Anderst, MD, MS

STAFFTammy Piazza HurleySonya Clay

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DOI: 10.1542/peds.2013-0196 originally published online March 25, 2013; 2013;131;e1357Pediatrics

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Shannon L. Carpenter, Thomas C. Abshire, James D. Anderst and the SECTION ONEvaluating for Suspected Child Abuse: Conditions That Predispose to Bleeding

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DOI: 10.1542/peds.2013-0196 originally published online March 25, 2013; 2013;131;e1357Pediatrics

NEGLECTHEMATOLOGY/ONCOLOGY AND COMMITTEE ON CHILD ABUSE AND

Shannon L. Carpenter, Thomas C. Abshire, James D. Anderst and the SECTION ONEvaluating for Suspected Child Abuse: Conditions That Predispose to Bleeding

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ISSN: 1073-0397. 60007. Copyright © 2013 by the American Academy of Pediatrics. All rights reserved. Print the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois,has been published continuously since 1948. Pediatrics is owned, published, and trademarked by Pediatrics is the official journal of the American Academy of Pediatrics. A monthly publication, it


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TECHNICAL REPORT Evaluating for Suspected Child Abuse ...predispose to easy bruising/bleeding in some circumstances. This report reviews the rationale for the consid-eration of bleeding