13
Rare Bleeding Disorders in Children: Identication and Primary Care Management abstract Bleeding symptoms are common in healthy children but occasionally may indicate an underlying congenital or acquired bleeding diathesis. The rare bleeding disorders (RBDs) comprise inherited deciencies of coagulation factors I (congenital brinogen deciencies), II, V, VII, X, XI, and XIII and combined factor deciencies, most notably of factors V and VIII and of vitamin Kdependent factors. These disorders often man- ifest during childhood and may present with recurrent or even seri- ous or life-threatening bleeding episodes, particularly during the neonatal period. Accordingly, primary care and other nonhematologist pediatric providers should be familiar with the clinical presentation and initial evaluation of these rare disorders. Bleeding manifestations generally vary within the same RBD and may be indistinguishable from 1 RBD to another or from other more common bleeding disorders. Serious bleeding events such as intracranial hemorrhage may be her- alded by less serious bleeding symptoms. The results of initial coagu- lation studies, especially prothrombin time and activated partial thromboplastin time, are often helpful in narrowing down the poten- tial factor deciency, with factor XIII deciency being an exception. Con- sultation with a hematologist is advised to facilitate accurate diagnosis and to ensure proper management and follow-up. The approach to bleeding episodes and invasive procedures is individualized and depends on the severity, frequency, and, in the case of procedures, likelihood of bleeding. Prophylaxis may be appropriate in children with recurrent serious bleeding and specically after life-threatening bleed- ing episodes. When available, specic puried plasma-derived or recombinant factor concentrates, rather than fresh frozen plasma or cryoprecipitate, are the treatment of choice. Pediatrics 2013;132:882892 AUTHOR: Suchitra S. Acharya, MD Bleeding Disorders and Thrombosis Program, Cohen Childrens Medical Center of New York, New Hyde Park, New York; and Hofstra North Shore-Long Island Jewish School of Medicine, Hempstead, New York KEY WORDS blood coagulation factor deciencies, blood coagulation disorders, hemorrhage, pediatrics, blood coagulation tests ABBREVIATIONS APTTactivated partial thromboplastin time ARautosomal recessive FFPfresh frozen plasma FIbrinogen FIIfactor II FIXfactor IX FVfactor V FVIIfactor VII FVIIIfactor VIII FXfactor X FXIfactor XI FXIIfactor XII FXIIIfactor XIII HAhemophilia A HBhemophilia B ICHintracranial hemorrhage PCCprothrombin complex concentrate PTprothrombin time RBDrare bleeding disorder VKCFDvitamin Kdependent clotting factor deciency Dr Acharya contributed to the conceptualization, content, and composition of the manuscript and approved the nal manuscript as submitted. www.pediatrics.org/cgi/doi/10.1542/peds.2012-3662 doi:10.1542/peds.2012-3662 Accepted for publication Jul 31, 2013 Address correspondence to Suchitra S. Acharya, MD, Bleeding Disorders and Thrombosis Program, Cohen Childrens Medical Center of New York, 269-01 76th Ave, Suite 255, New Hyde Park, NY 11040. E-mail: [email protected] PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). Copyright © 2013 by the American Academy of Pediatrics FINANCIAL DISCLOSURE: The author has indicated she has no nancial relationships relevant to this article to disclose. FUNDING: No external funding. POTENTIAL CONFLICT OF INTEREST: The author has indicated she has no potential conicts of interest to disclose. 882 ACHARYA by guest on July 16, 2015 pediatrics.aappublications.org Downloaded from

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Page 1: Rare Bleeding Disorders in Children: Identi cation and ... · Rare Bleeding Disorders in Children: Identification and Primary Care Management abstract Bleeding symptoms are common

Rare Bleeding Disorders in Children: Identification andPrimary Care Management

abstractBleeding symptoms are common in healthy children but occasionallymay indicate an underlying congenital or acquired bleeding diathesis.The rare bleeding disorders (RBDs) comprise inherited deficiencies ofcoagulation factors I (congenital fibrinogen deficiencies), II, V, VII, X, XI,and XIII and combined factor deficiencies, most notably of factors V andVIII and of vitamin K–dependent factors. These disorders often man-ifest during childhood and may present with recurrent or even seri-ous or life-threatening bleeding episodes, particularly during theneonatal period. Accordingly, primary care and other nonhematologistpediatric providers should be familiar with the clinical presentationand initial evaluation of these rare disorders. Bleeding manifestationsgenerally vary within the same RBD and may be indistinguishable from1 RBD to another or from other more common bleeding disorders.Serious bleeding events such as intracranial hemorrhage may be her-alded by less serious bleeding symptoms. The results of initial coagu-lation studies, especially prothrombin time and activated partialthromboplastin time, are often helpful in narrowing down the poten-tial factor deficiency, with factor XIII deficiency being an exception. Con-sultation with a hematologist is advised to facilitate accurate diagnosisand to ensure proper management and follow-up. The approach tobleeding episodes and invasive procedures is individualized anddepends on the severity, frequency, and, in the case of procedures,likelihood of bleeding. Prophylaxis may be appropriate in children withrecurrent serious bleeding and specifically after life-threatening bleed-ing episodes. When available, specific purified plasma-derived orrecombinant factor concentrates, rather than fresh frozen plasma orcryoprecipitate, are the treatment of choice. Pediatrics 2013;132:882–892

AUTHOR: Suchitra S. Acharya, MD

Bleeding Disorders and Thrombosis Program, Cohen Children’sMedical Center of New York, New Hyde Park, New York; andHofstra North Shore-Long Island Jewish School of Medicine,Hempstead, New York

KEY WORDSblood coagulation factor deficiencies, blood coagulationdisorders, hemorrhage, pediatrics, blood coagulation tests

ABBREVIATIONSAPTT—activated partial thromboplastin timeAR—autosomal recessiveFFP—fresh frozen plasmaFI—fibrinogenFII—factor IIFIX—factor IXFV—factor VFVII—factor VIIFVIII—factor VIIIFX—factor XFXI—factor XIFXII—factor XIIFXIII—factor XIIIHA—hemophilia AHB—hemophilia BICH—intracranial hemorrhagePCC—prothrombin complex concentratePT—prothrombin timeRBD—rare bleeding disorderVKCFD—vitamin K–dependent clotting factor deficiency

Dr Acharya contributed to the conceptualization, content, andcomposition of the manuscript and approved the finalmanuscript as submitted.

www.pediatrics.org/cgi/doi/10.1542/peds.2012-3662

doi:10.1542/peds.2012-3662

Accepted for publication Jul 31, 2013

Address correspondence to Suchitra S. Acharya, MD, BleedingDisorders and Thrombosis Program, Cohen Children’s MedicalCenter of New York, 269-01 76th Ave, Suite 255, New Hyde Park, NY11040. E-mail: [email protected]

PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).

Copyright © 2013 by the American Academy of Pediatrics

FINANCIAL DISCLOSURE: The author has indicated she has nofinancial relationships relevant to this article to disclose.

FUNDING: No external funding.

POTENTIAL CONFLICT OF INTEREST: The author has indicatedshe has no potential conflicts of interest to disclose.

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Mild bleeding symptoms are fairly com-mon in children and do not always in-dicate an underlying bleeding disorder.Epistaxis and easy bruising have beenreported in 39% and 24% of children,respectively.1 Easy bruising may be re-lated to “normal” childhood activity andvaries in prevalence by motor develop-mental stage, with bruising reportedin 61% to 90% of children aged 2 to10 years.2 Other factors causing bleedingin children include anatomic abnormal-ities that contribute to serious bleedingevents, such as intracranial, gastroin-testinal, or genitourinary bleeds, andheavy menstrual bleeding3,4 in adoles-cent girls resulting from immaturity ofthe hypothalamic-pituitary-ovarian axisand anovulation.5 The pooled rate ofbleeding after tonsillectomy, a commonpediatric procedure, has been reportedas 3.3% in patients without bleedingdisorders.6

The identification of the child with path-ologic bleeding may therefore prove dif-ficult, given the relative frequency ofnonpathologic bleeding and similaritiesbetween pathologic and nonpathologicbleeding. Common bleeding sites (eg,skin and mucous membranes) are sim-ilar, and whereas bleeding often occursspontaneously in the setting of bleedingdisorders, affected individuals may ini-tially present with bleeding only aftertrauma or surgery or, in girls, at men-arche. Conversely, childrenwith bleedingdisorders may tolerate certain hemo-static challenges without seemingly ex-cessive bleeding, only to present withpathologic bleeding later in life. Factorsthatmayhelpindifferentiatingpathologicversus nonpathologic bleeding includeageatfirstepisode; frequency,extent,andduration of bleeding; personal historyof recurrent spontaneous or procedure-related bleeding or heavy menstrualbleeding in girls,5,7 especially if accom-panied by other bleeding; and familyhistory of bleeding or known bleeding di-atheses (Table 1). Nonaccidental trauma

must also be considered in childrenwith unexplained or excessive bleedingsymptoms.2,8 Specifically, any bruisingin a nonmobile child must be viewed aspathologic and may indicate eithera bleeding disorder or nonaccidentaltrauma.2,8 In children who are mobile,bruising away from bony prominences,particularly on the face, head, or neck,is especially suggestive of nonaccidentaltrauma.2,8

Pathologic bleeding occurs in the settingof congenital or acquired abnormalitiesin normal hemostasis, which consists of3 basic processes: primary hemostasis,culminating in the formation of a plateletplug; secondary hemostasis, comprisingthe processes of coagulation (ie, fibrinformation) and clot stabilization; andfibrinolysis.9,10 Primary hemostatic dis-orders affecting children, namely quan-titative and qualitative abnormalitiesof platelets and von Willebrand factor,are reviewed elsewhere,10–14 as aredisorders of excessive fibrinolysis.7,9,12

Secondary hemostatic disorders en-compass congenital or acquired defi-ciencies of clotting factors. Among thosecongenital disorders, hemophilia A (HA)

and hemophilia B (HB) are the mostcommon, resulting from deficiencies offactor VIII (FVIII) and factor IX (FIX), re-spectively. HA and HB are primarilyinherited as X-linked recessive disor-ders and together affect ∼1 in 5000live male births per year in the UnitedStates, with HA accounting for ∼80% ofcases.15 The clinical hallmarks of HAand HB are musculoskeletal and softtissue bleeding,16 the former of whichmay lead to debilitating arthropathy. InHA and HB, bleeding risk and pheno-type correlate with plasma levels of thedeficient factor in most cases.16,17

Inherited deficiencies of other coagu-lation factors that may manifest withbleeding occur much less commonlyand are thus collectively referred to as“rare” bleeding disorders (RBDs). TheRBDs consist of inherited quantitativeor functional deficiencies of factors I (ie,fibrinogen [FI]), II (FII), V (FV), VII (FVII), X(FX), XI (FXI), and XIII (FXIII) and com-bined factor deficiencies, most notablyof FV and FVIII and of vitamin K–dependent factors. Given the congeni-tal nature of these conditions, theymay present with bleeding in infancy or

TABLE 1 Initial Features Suggestive of Pathologic Bleeding in Children

Age-relatedBleeding (eg, umbilical stump bleeding, ICH, excessive and prolonged bleeding postcircumcision or after

heel stick or intramuscular injection) during neonatal periodPalpable and multiple bruises in infants and older children who are not independently mobilePersistent palpable bruising in an older mobile child

Spontaneous bleeding in the absence of anatomic causesPersonal history ofRecurrent (especially excessive and spontaneous) mucocutaneous bleedingAtypical bleeds (eg, hemarthroses, retroperitoneal bleeding), whether spontaneous or provokedExcessive or prolonged bleeding after hemostatic challenges (ie, trauma, dental procedures, or surgery)Menorrhagia in adolescent girls: menstrual bleeding for.7 d3 or.80-mL blood loss per menstrual cycle

(as evidenced by soaking through a pad or tampon within 1 h or change of pads or tampons every hour,or passage of large [.1.1-inch diameter] clots)4

Traumatic bleeding that is out of proportion to or inconsistent with reported injury (consider nonaccidentaltrauma)

Family history ofRecurrent bleeding symptomsExcessive or prolonged bleeding after trauma or invasive proceduresKnown or suspected bleeding diatheses

Physical findingsMultiple bleeding stigmataPhysical findings suggestive of specific underlying causes (eg, petechiae in platelet disorders, jaundice in

liver disease, hypermobility, vascular malformations, musculoskeletal abnormalities)Pallor/anemia

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childhood. Although severe RBDs mayinitially present with serious bleedingcomplications such as intracranial hem-orrhage (ICH), such events may be oc-casionally heralded by less seriousbleeding symptoms.18 Recognizing thehistorical and laboratory features thatsuggest the presence of an RBD isparamount, to optimize prompt consul-tation with a hematologist for definitivediagnosis, treatment, and long-termfollow-up of affected infants and chil-dren. However, identification of thesedisorders is challenged by their rarity,their variable and often indistinguish-able clinical presentations, and a fre-quent lack of family history to suggestan inherited bleeding disorder. Whereasmuch is known (and written12,16) aboutthe clinical presentation and manage-ment of HA and HB in children, similarinformation pertaining to RBDs is rel-atively limited in general as well as inthe pediatric literature, largely due tothe small numbers of identified chil-dren with these disorders. This reviewsummarizes the clinical presentations,diagnosis, and basic management ofRBDs in children for the nonhematologistpediatric provider, with an emphasis ona primary care approach.

EPIDEMIOLOGY AND CLINICALPRESENTATION

Features that distinguish RBDs from themost common inherited bleeding dis-orders, HA and HB, are summarized inTable 2.16,17,19–27 RBDs encompass 3% to5% of all inherited coagulation disordersoverall19,25 and, specifically, in children.20

With a prevalence of 1 symptomatic per-son per 500 000 population,28 FVII de-ficiency is the most common RBD,constituting 30% to 50% of various RBDsincluded in published series,19,20,22,25,26,29,30

followed by FXI deficiency, which accountsfor 23% to 39% of RBDs in various multi-national registries.19,25,26 The least com-mon RBDs are FII and FXIII deficiencies,with a prevalence of ∼1 per 2 million

each,25,26 and vitamin K–dependent clot-ting factor deficiency (VKCFD), of which,30 cases were reported as of 2008.31

Inheritance

Most RBDs are considered autosomalrecessive (AR); however, in all but VKCFDand combined FV/FVIII deficiency, het-erozygotes (whonumber 1 perevery 350to 700 individuals7) may have varyingdegrees of corresponding factor de-ficiency that render an unpredictablepropensity for bleeding, especially inFVII and FXI deficiencies. Whereas theoccurrence of symptomatic hetero-zygotes contradicts an AR pattern ofinheritance, the prevalence of most ofthese RBDs is increased where con-sanguinity is commonplace, similar toother AR conditions.21,22,27 In addition,a family history of bleeding is oftenlacking. Combined FV/FVIII deficiencyand VKCFD, which are caused by muta-tions in genes outside those encodingthe coagulation factors themselves, aretrue AR disorders in that heterozygoteshave normal factor levels and are thusasymptomatic. Strictly non-AR RBDs in-clude FXI deficiency (autosomal withvariable penetrance) and dysfibrino-genemia (autosomal dominant).

There are no inherent race- or ethnicity-based propensities for specific RBDs,with the exception of FXI deficiency,which is especially prevalent amongAshkenazi Jews; 1 of every 450 is af-fected32,33 and 8% are heterozygotes,34

accounting for a higher incidence ofsevere disease, in particular, in thisgroup.35 In addition, FII deficiency wasfound to disproportionately affect La-tinos in a survey of 58 North Americanhemophilia treatment centers.20

Clinical Manifestations of RBDs

Common Bleeding Symptoms

Bleeding propensity varies widelyamong individuals affected by RBDs,fromno symptoms (45.8%of 489 peoplewith RBDs in a European series26) to

life-threatening bleeding. However, whenaccounting for patients across all agesand genotypes, the most common bleed-ing manifestation of RBDs overall ismucocutaneous bleeding.20,22,25–27 Thischaracteristic may make it difficult toclinically distinguish RBDs from plate-let disorders or von Willebrand diseaseor from nonpathologic bleeding. Thatsaid, in contrast to nonpathologic bleed-ing, RBD-related bleeding is often spon-taneous. Alternatively, RBDsmay presentwith excessive bleeding after a hemo-static challenge. For example, bleedingafter procedures such as circumcisionor heel stick in the neonatal period anddental extractions later in childhood isa symptom common to all RBDs,12,36,37

although the historical absence of bleed-ing after these challenges does notnecessarily exclude an RBD.

Site-Specific Bleeding Symptoms

Thepresentationof individualRBDsmaybe diverse. In general, serious bleeding(eg, ICHormusculoskeletal or umbilicalcord bleeding) is rare in FV and FXIdeficiencies,25,38 as is spontaneousbleeding in FXI deficiency.32,39 Bleedingphenotype iswidely heterogeneous in FV,FVII, and FXI deficiencies and, in contrastto HA and HB, correlates poorly withfactor activity level. Specifically, a recentreview documented a poor correlationbetween clinical severity and coagulantactivity in FV and FVII deficiencies and nocorrelation between clinical severity andcoagulant activity in FXI deficiency, evenat undetectable or moderately reduced(,20%) levels.24 In particular, severeFVII deficiency may be asymptomatic or,in contrast, may present with seriousbleeding events (eg, ICH) in infancy.28,40

In deficiencies of FI, FII, FX, and FXIII,clinical severity strongly correlates withfactor levels.24 The bleeding phenotypein FI deficiency (afibrinogenemia) maybe similar to that in moderate or severeHA or HB; however, umbilical cordbleeding and mucosal bleeding areamong the most common bleeding

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symptoms.41 Severe FII deficiencypresents early in life with mucosal andmusculoskeletal bleeding and ICH.42

Serious bleeding events such as um-bilical cord bleeding, ovulatory hemo-peritoneum, and hemarthrosis arerelatively common in FII deficiencyrelative to other RBDs.36 Similarly, FXand FXIII deficiencies are generallycharacterized by early onset of seri-ous or life-threatening bleeding epi-sodes, such as ICH or umbilical cordbleeding.22,26 The latter is virtuallypathognomonic of FXIII deficiency andis often delayed, given the role of FXIIIin stabilizing clots.

Althoughmore common in certain RBDs,serious bleeding events may occur invirtually any RBD and may therefore notalways distinguish 1 RBD from anotheror from other bleeding disorders, forthat matter. For example, umbilical cordbleeding may occur in conditions otherthan FX and FXIII deficiencies, includingHA, HB, and other RBDs.22,25,35,36,43,44

Likewise, ICH has been described in theneonatal period in severe deficienciesof FII, FV, and FVII and in VKCFD,31,42,45,46

although ICH is especially common inFX and FXIII deficiencies; ICH has beenreported in as many as 20% of indi-viduals with FX deficiency44,47,48 and asmany as 30% of those with FXIII de-ficiency,49–51 in which ICH is the maincause of death and disability.23,49 Oth-er life- and limb-threatening bleedingevents, such as ovulatory hemoper-itoneum and hemarthroses, have beenreported, most frequently in FII, FX, andFXIII deficiencies.36,37 FX deficiency hasbeen associated with various non–coagulation-related abnormalities,including thrombocytopenia-absentradius syndrome, mitral valve prolapse,hypertrophic cardiomyopathy, and hy-percholesterolemia.52 FV deficiency issometimes confused with FV Leiden. FVdeficiency is an inherited disordercharacterized by low levels of FV dueto mutations in the FV gene, which

preclude the synthesis of this proco-agulant protein. Therefore, individualswith FV deficiency have an increasedrisk of excessive bleeding. FV Leiden, onthe other hand, is a genetic thrombo-philia wherein a defect in the FV genemakes FV resistant to inactivation byanticoagulant protein C, thus increasingthe risk of clotting events such as deepvein thrombosis, pulmonary embolus,and miscarriages.

Bleeding in Women With RBDs

Menorrhagia is the most commonbleeding symptom in women withbleeding disorders, including RBDs.53

Approximately 50% of women affectedby all RBDs report menorrhagia.25

Menarche may be the first significanthemostatic challenge encountered bygirls with RBDs, but data regarding theprevalence of RBDs among adolescentgirls with menorrhagia are limited.53

Menorrhagia is likely underreported inadolescents on the whole5 and con-stitutes a “hidden” source of bleeding,making it difficult to identify withoutdisclosure by the patient or explicitquestioning by clinicians. Factors sug-gestive of menorrhagia are presentedin Table 1.3–5 The presence of structurallesions (eg, leiomyomata) may com-pound menorrhagia in women withRBDs and may even lead to life-threatening bleeding.54 Women withRBDs are also at increased risk of de-veloping hemorrhagic ovarian cysts,which are a less common but per-haps more specific manifestationof an underlying bleeding disorderthan menorrhagia.53,55 A rupturedfollicle may lead to hemoperitoneumin women with RBDs, as previouslydescribed.37 Women with RBDs mayexperience obstetric complicationsas well, including postpartum hemor-rhage56 and recurrent miscarriagesdue to the roles that deficient factors(namely FXIII and FI) play in placentalimplantation and pregnancy mainte-nance.43,57–59

Combined Factor Deficiencies

Even rarer than isolated deficiencies arecombined factor deficiencies. CombinedFV/FVIII deficiency exists due to a com-mon molecular defect affecting intra-cellular processing of both proteins,rather than coincident defects in thegenes for both factors.60 This condition isassociated with a mild bleeding pheno-type, without any apparent cumulativeeffect of the combined deficiencies.60

In contrast, VKCFD is often associatedwith significant bleeding.31 VKCFD re-sults from inherited defects in activa-tion (g-carboxylation) of the vitaminK–dependent factors (FII, FVII, FIX, andFX).31 Affected children often present ininfancy or in early childhood with se-rious bleeding events, including ICH.Skeletal abnormalities have also beenreported, possibly due to defective g-carboxylation of bone matrix proteins.31

DIAGNOSTIC EVALUATION ANDCONSIDERATIONS

After obtaining thorough personal andfamily histories, the initial laboratoryevaluation of a child with suspectedpathologic bleeding should consist ofa complete blood count and routinecoagulation studies (prothrombin time[PT], activated partial thromboplastintime [APTT], FI, and thrombin time). Theresults of routine coagulation studiescan be used to narrow down the pos-sible disorders (Fig 1, Table 3).61–65 Inisolation, the PT and APTT, respectively,assess the integrity of the extrinsic andintrinsic pathways of the coagulationcascade.63 Together, PTand APTTassessthe integrity of the final common path-way of the coagulation cascade.63 Like-wise, PT and APTT are simultaneouslyprolonged in conditions that involvedeficiencies spanning all 3 pathways,such as VKCFD.31,64 Because fibrin gen-eration is not affected in FXIII deficiency,PT and APTT are normal in this RBD.61

Consultation with a hematologist is rec-ommended to assist with interpretation

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of laboratory results, facilitate furth-er definitive testing, and ensure thatconfirmatory laboratory assays areperformed properly. If readily avail-able, a mixing study combining normalpooled plasma and patient plasma ina 1:1 ratio may be performed to de-termine the cause of an abnormal PT orAPTT (Fig 1). In quantitative factor defi-ciencies such as RBDs, the addition ofnormal plasma replaces the deficientfactor(s), thereby correcting the ab-normal PT or APTT. Conversely, a lack ofor partial correction in a mixing studysuggests the presence of a specific ornonspecific coagulation factor antibody(inhibitor). Nonspecific inhibitors in-clude lupus anticoagulants, which mayoccur transiently in children (eg, afterviral illness),66 are typically asymptom-atic,66 and tend to be the most commoncause of a prolonged APTT in non-bleeding children. Specific coagulationfactor inhibitors are far less commonin children, even less common thanmost RBDs. Therefore, when a prolongedAPTT or simultaneously prolonged APTTand PT fail to correct in a mixingstudy, consideration should first begiven to further investigation for a lu-pus anticoagulant. This investigation is

FIGURE 1Basic process for evaluating coagulation profile abnormalities. If available, amixing study should be performed to differentiate a coagulation factor deficiencyfroman inhibitor. The possible factors involvedmay then be narroweddown on the basis of which coagulation study or studies are abnormal. Note: PTand APTTare normal in FXIII deficiency.61 H/LMWK, high-/low-molecular-weight kininogen.

TABLE 2 Distinguishing Epidemiologic, Genetic, Clinical, and Laboratory Features of theHemophilias and RBDs

HA and HB RBDs

Together with VWD, account for .90% of allinherited bleeding disorders17

Account for 3% to 5% of all inherited coagulationdisorders19,20,25

XR inheritance; therefore, majority ofaffected individuals are male

Autosomal inheritance, so both boys and girlsaffected; most are AR (except for FXIdeficiency [AV] and dysfibrinogenemia [AD]);however, heterozygotes variably symptomatic,especially in FVII and FXI deficiencies

Family history of disease in brothers or inmaternal male relatives; may be absent inup to one-third of patients16

Family history often lacking; most RBDs moreprevalent where consanguinity is commonplace21,22,27

Clinical course predominated by soft tissueand musculoskeletal bleeding, especially inolder children16; postcircumcision/post-heel stick and CNS bleeding most commonbleeding events in newborns16

Clinical presentation variable within and amongindividual RBDs; mucocutaneous bleeding ismost common symptom overall20,22,25–27;serious bleeding (eg, ICH) characteristic ofFX and FXIII deficiencies in particular22 butcan occur in virtually any of the RBDs

Initial laboratory evaluation remarkable forisolated prolonged APTT that correctsin a mixing study

Both PT and APTT prolonged in most RBDs (seeFig 1); PT/APTT abnormalities correct in amixing study; quantitative functional FXIIIactivity assay should be used to screen forFXIII deficiency, in which PT/APTT are normal23

Clinical severity correlates with coagulantactivity16

Poor association between clinical severity andcoagulant activity in FV and FVII deficiencies;no association between clinical severity andcoagulant activity, both when undetectable ormoderately reduced (,20%), in FXI deficiency24

AD, autosomal dominant; AV, autosomal variable penetrance; CNS, central nervous system; VWD, von Willebrand disease;XR, X-linked recessive.

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first accomplished by demonstratingphospholipid-dependence of the inhib-itor, given that lupus anticoagulants fallinto this category.66 Correction of APTTorof another phospholipid-based screen-ing test, the dilute Russell viper-venomtime, after the addition of a phospholipid-rich source (eg, platelets in the plateletneutralization procedure) confirms thepresence of a lupus anticoagulant.63,66 Iftesting for a coagulation factor inhibitoris indicated based on clinical groundsor negative lupus anticoagulant testing,the coagulation factors of interest canbe narrowed down on the basis of theuncorrected coagulation study (Fig 1).

RBDs are generally confirmed by re-duced activity of the respective factor(s)in a functional activity assay, which isthe assay commonly usedwhena factorlevel is ordered. Because routine co-agulation studies are normal in FXIIIdeficiency, alternative “screening”tests must be used when there is sus-picion of (or to rule out) this deficiency.Currently, a quantitative functional FXIIIactivity assay (ammonia-release oramine-incorporation) is recommendedfor screening instead of the tradition-ally used clot solubility test, which issensitive at only low FXIII levels (,0.5%

to 5%) and may thus miss more mod-erate deficiencies.23,67,68 FXIII deficiencyis then confirmed by quantification ofFXIII-A2B2 antigen by enzyme-linked im-munosorbent assay, followed by quanti-fication of the A- and B-subunit antigensif FXIII-A2B2 antigen is reduced.23,67,69

There are several important consid-erations in the laboratoryevaluation forRBDs in children. First, reference valuesfor full-term and preterm infants in thefirst 6 months of life (and beyond, insome cases) differ from those in adults,particularly forAPTTandall coagulationfactor levels except for FVIII.70–72 Be-cause the levels of many factors in-crease over the first month of life,milder or equivocal deficiencies mayneed to be confirmed once a child isolder or by screening both parents.35

As always, several things may artifac-tually affect coagulation study results,including heparin contamination of thesample35,73 and failure to collect thespecified amount of blood within thecollection tube (for an optimal plasma-to-citrate ratio).63 Immediate gentlemixing of the sample with anticoagu-lant is recommended to avoid activa-tion of coagulation.35 Samples shouldideally be analyzed within 4 hours of

collection or, alternatively, frozen im-mediately for future use.35 If originallydrawn after empirical administrationof fresh frozen plasma (FFP) to treatactive bleeding, coagulation testsshould be repeated before interpretingthe results and concluding whethera patient has an RBD. The timing forrechecking coagulation studies to ruleout RBDs (or other bleeding disorders)will depend on the half-lives74 of thepotentially affected coagulation factors(ie, FXI in an isolated APTT abnormality;FVII when only the PT is abnormal; FI, FII,FV, or FX when both APTT and PT areabnormal; and FXIII when both APTTandPTare normal; Fig 1, Table 4). Individualfactor levels may likewise be affectedby previous administration of FFP andmay thus need to be rechecked after anappropriate amount of time has elapsed(again, based on half-life; Table 4). Ingeneral, relevant coagulation studies orfactor levels should be rechecked after5 elimination half-lives of the suspecteddeficient factor(s) have elapsed if aim-ing to make a diagnosis of an RBD afteradministration of FFP to treat an initialbleeding episode. Ideally, samples forhematologic testing should be collectedinto $2 blue-top tubes (which containsodium citrate as the anticoagulant)before administering FFP or any otherfactor replacement products when thepresence of a bleeding disorder is pos-sible or suspected.

In situations in which nonaccidentaltrauma is suspected, clinicians are of-ten rightly concerned about missing an

TABLE 3 Findings of Initial Laboratory Studies in RBDs

RBD PT APTT FIa TT

FII deficiency64 Prolongedb Prolongedb Normal NormalFV deficiency35,45 Prolonged Prolonged Normal NormalFVII deficiency28,35 Prolonged Normal Normal NormalFX deficiency35,47 Prolongedc Prolongedc Normal NormalFXI deficiency62,64 Normal Prolongedd Normal NormalFXIII deficiency23 Normal Normal Normal NormalFI deficiencyAfibrinogenemia43 Prolonged Prolonged ,1 g/L ProlongedHypofibrinogenemia43 Normal/prolongede Normal/prolongede 1–1.5 g/L Mildly prolongedDysfibrinogenemia35,43 Normal/prolonged Normal/prolonged Normal/slightly

reducedProlonged

Combined FV/FVIIIdeficiency64,65

Prolonged Prolonged Normal Normal

VKCFD31,64 Prolonged Prolonged Normal Normal

Findings exclude complete blood count results. (Platelet count will presumably be normal in all cases.) TT, thrombin time.a Normal range = 1.5–3.5 g/L.b May be only minimally prolonged depending on reagents used; results may also be within normal range.c Congenital variants with normal PT and APTT have been reported.d Normal APTT does not exclude a diagnosis of mild FXI deficiency, particularly if FVIII levels are elevated.35e PTor APTTmay be normal or prolonged in hypofibrinogenemia, depending on how low the FI level is; PTand APTTare typicallynormal when FI level exceeds 1 g/L.41

TABLE 4 Half-lives of Coagulation Factors

Coagulation Factor Plasma Half-life, h

FI (fibrinogen) 90FII 65FV 15FVII 5FVIII 10FIX 25FX 40FXI 45FXIII 200

Hoffbrand and Moss (74).

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underlying bleeding diathesis. Althoughsubduralhematomasinchildren,2yearsof age are most often caused by non-accidental trauma,75 particularly if as-sociated with retinal hemorrhages,76

there are anecdotal reports of patientsin whom this combination of findingswas attributed to a bleeding diathesis,including vitamin K–deficiency bleed-ing in the newborn (also known as latehemorrhagic disease of the new-born),77,78 HA,77 von Willebrand diseasetype 1,79 and Hermansky-Pudlak syn-drome.76 Bleeding disorders have onlyrarely been reported to be the cause ofisolated retinal hemorrhages in neo-nates.80 Multiple fractures of differingages (especially posterior rib fracturesin infants with subdural hematoma) orinconsistencies between the reportedmechanism and the pattern or ex-tent of injuries suggest nonaccidentaltrauma, especially when there is a de-lay in seeking medical attention.81 Con-versely, consideration should be given toRBDs in children from consanguineousparents or with a personal or familyhistory of bleeding, particularly in theabsence of other features suggestingnonaccidental trauma. Recommenda-tions for consideration of various bl-eeding disorders, including RBDs, in thesetting of possible nonaccidental traumawere recently summarized in a tech-nical report from the American Acad-emy of Pediatrics.82 The presence ofa bleeding disorder and nonaccidentaltrauma are not mutually exclusive, sothe possibility of the latter must alwaysbe kept in mind, especially if any of theaforementioned features suggestive ofnonaccidental trauma apply.

MANAGEMENT

Overall, there is relatively little infor-mation regarding the managementof individuals with RBDs,25 althoughguidelines for the management ofbleeding episodes, surgery, and preg-nancy (including care of the potentially

affected newborn)35 have been pro-posed on the basis of existing literatureand clinical experience. Nevertheless,given the rarity of RBDs and the com-plex, often costly nature of treatment,affected children should be followed ata hemophilia treatment center at leastbiannually to guarantee not only ap-propriate care but also ready access totherapies that may not be immediatelyavailable elsewhere.29,83 The hemophiliatreatment center should be consultedregarding management of any bleedingas well as hemostatic coverage andprecautions for invasive procedures. Notall bleeding events require treatment. Ingeneral, the need for hemostatic cover-age for surgery or other invasive proce-dures is based on the general risk ofbleeding attributable to the respectivefactor deficiency and procedure itselfand on personal and family history ofbleeding with previous hemostatic chal-lenges, including surgery.

Replacement Products

Replacement products available in theUnitedStates for treatmentorpreventionof bleeding in RBDs, when indicated,are summarized in Table 5.31,35,84–86

When available, specific, single-factorconcentrates are the treatment ofchoice. In the United States, single-factor concentrates are available forall deficient factors encompassed by theRBDs except for FII, FV, FX (concentratein clinical development), and FXI (con-centrate available only in Europe). Fordeficiencies of FII and FX, prothrombincomplex concentrates (PCCs) are rec-ommended. PCCs are highly purifiedconcentrates of specific coagulationfactors obtained from pooled normalplasma,87 namely FII, FIX, FX, and FVIIin varying amounts depending on theproduct.84 PCCs contain known amountsof the factors therein and are submittedto a process of viral inactivation,makingthem preferable to FFP and cryo-precipitatewhen aiming to replace FII orFX.

FFP is often used as an alternativesource of factor replacement in RBDsand is a mainstay of treatment for FVdeficiency, absent any other productscontaining this factor. FFP may also beused when hemostatic treatment orcoverage is indicated in FXI deficiency inthe United States.62 Cryoprecipitate,a byproduct of FFP obtained afterthawing a single-donor volume of FFPat 4°C, is rich in von Willebrand factor,FVIII, FXIII, and FI and is most often usedfor replacement of FI and FXIII, althoughmore recently, purified plasma-derivedproducts have become available totreat these latter 2 deficiencies.49,84,88

Althoughwidely available and relativelyinexpensive,25 FFP and cryoprecipitatehave potential disadvantages com-pared with single-factor concentratesand PCCs in that they are not subjectedto a viral inactivation process in theUnited States (although donors andplasma are comprehensively screened)and, given the relatively small amountsof individual factors therein, are oftenrequired in large volumes to replacea single factor, potentially puttingrecipients at risk for fluid overload.35

Hemostatic treatment or coverage incombined FV/FVIII deficiency consists ofreplacement of both factors using FFP toreplace FV and plasma-derived orrecombinant FVIII concentrates to re-place FVIII (Table 5). Based primarily onexperience with reversing warfarinanticoagulation, FFP or PCCs are rec-ommended for treatment of bleeding orfor surgical coverage in VKCFD, in ad-dition to maintenance oral vitamin K.31

Ancillary Therapies

Ancillary therapies that may be usedas alternatives or adjuncts to factorreplacement include systemic antifibr-inolytics (ie, tranexamic acid and ε-aminocaproic acid), topical hemostaticagents (eg, fibrin glue), and, in the set-ting of combined FV/FVIII deficiency,65

desmopressin to boost FVIII levels. In

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some cases, antifibrinolytics may beexclusively used for mucosal bleedingor minor (eg, dental) procedures toavoid using pooled blood products. ForRBD-related menorrhagia, hormonaltherapies and antifibrinolytics are ofteneffective and considered first-line ther-apies, as they are in women withoutbleeding disorders.7,89

Prophylactic Replacement Therapy

In some cases, ongoing prophylactichemostatic therapy may be warranted,either primarily (initiated before anybleeding occurs) or secondarily (initi-ated after a bleeding event, to preventrecurrence). Primary prophylaxis hasbeen effectively used in boys with se-vere HA to reduce joint damage fromrecurrent hemarthroses.90 However,data regarding any benefit of primaryprophylaxis in RBDs are sparse. Theonly RBD for which prophylaxis isroutinely recommended is severe FXIII

deficiency, in which prophylaxis is rec-ommended from the time of diagnosisbecause of the risk for serious, evenlife-threatening, bleeding events suchas ICH.91 Secondary prophylaxis maybe considered after musculoskeletalbleeding or life-threatening hemor-rhage to prevent recurrent bleeding,particularly in deficiencies of FXIII, FX,and FVII and in severe cases of FI and FVdeficiencies.25

Perinatal Recommendations

Delivery of a potentially affected neo-nate should ideally take place in a spe-cialized center with advance planningto limit the risk of bleeding in bothmother and infant.35 Fetal scalp moni-toring and forceps- or vacuum-assisteddelivery should be discouraged. Com-munication among the hemophiliatreatment center, obstetrician, andpediatrician or neonatologist is key toprevent serious consequences such as

ICH in the potentially affected newbornand for ongoing management there-after. After delivery, a thorough diag-nostic evaluation of the neonate isindicated; cord blood may be sent ifthere is a known family history of anRBD, given ease of collection and toavoid venipuncture-related soft tissuebleeding. Hemostatic challenges (eg,circumcision, arterial sticks) should beavoided until the results are obtained.A cranial ultrasound is recommendedduring the first week of life in neonateswith known severe RBDs to exclude thepresence of ICH.35

Additional PediatricRecommendations

In the neonatal period and beyond,consideration should be given to sub-cutaneous (rather than intramuscular)administrationofmedications (includingvitamin K in the newborn) and imm-unizations, when possible. In particular,

TABLE 5 Factor Replacement Products Currently Available in the United States for Treatment or Prevention of Bleeding in RBDs

Product Content Virally inactivated? Therapeutic Option for

First-Line Second-Line

Single-factor concentrates84

NovoSevena rFVIIa N/Ab FVII deficiencyc

Corifactd pd-FXIIIe Yes FXIII deficiencyRiaSTAPf pd-FI Yes FI deficiencyFVIII (numerous options)g rFVIII or pd-FVIII N/A (rFVIII), yes (pd-FVIII) FV/FVIII deficiencyh

PCCs35,84

Profilninei FII, FIX, FX, and FVIIj Yes FII deficiency FX deficiency, VKCFDBebulink FII, FIX, FX, and FVIIj Yes FX deficiency FII deficiency, VKCFD

FFP31,35 All coagulation factors No FV deficiency, FXIdeficiency, VKCFD

All RBDs

Cryoprecipitate35,84 Rich in FVIII, FI, VWF, and FXIII No FI deficiencyl, FXIII deficiency

N/A, not applicable; pd-, plasma-derived; rFVIIa, recombinant activated FVII; rFVIII, recombinant FVIII; VWF, von Willebrand factor.a NovoSeven� RT (Novo Nordisk A/S, Bagsvaerd, Denmark).b No human-derived proteins are used in the production or formulation of NovoSeven RT.85c rFVIIa should be used at lower doses less frequently for FVII deficiency than for other indications.85d Corifact�; CSL Behring GmbH, Marburg, Germany.e A recombinant FXIII concentrate86 is approved for treatment of FXIII deficiency in the European Union and Switzerland and is pending regulatory review in the United States.f RiaSTAP�; CSL Behring GmbH, Marburg, Germany.g Numerous options are available for replacement of FVIII in the United States, but rFVIII products are generally preferred as first-line therapy. (See recommendations from the Medical andScientific Advisory Council of the National Hemophilia Foundation.84)h Refers to treatment of the FVIII component of a combined FV/FVIII deficiency.i Profilnine� SD (Grifols Biologicals, Los Angeles, CA).j FVII is present in low amounts.k Bebulin�; Baxter Healthcare Corporation, Westlake Village, CA.l Cryoprecipitate is generally preferred over FFP as a second-line option for FI replacement.

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hepatitis A and B vaccines should begivenasrecommended forall childrenbythe US Centers for Disease Control andPrevention.92 Routine preventive dentalcare should be encouraged and facili-tated via consultation with the hemo-philia treatment center regarding thenecessity of prophylaxis and other he-mostatic measures. Parents shouldavoid giving children with RBDs analge-sics/antipyretics that may affect plateletfunction (ie, nonsteroidal antiinflam-matory drugs).35 Providers and parentsmay consult existing resources (eg, fromthe National Hemophilia Foundation93

and the World Federation of HemophiliaWeb site at www.wfh.org) and the he-mophilia treatment center for guidancepertaining to physical activity and otheraspects of care in children and adoles-cents with RBDs. Finally, genetic coun-seling and screening should be offered

to the entire family to identify potentialcarriers at risk for affected progeny,especially in countries where the in-cidence of consanguinity is high orwhena specific genetic mutation has beenidentified in the family.

CONCLUSIONS

Early identification of RBDs in childrenis critical to ensure optimal treatmentof any bleeding events and to mitigateany risk for future bleeding. Bleedingmay be severe, even life-threatening,and given the congenital nature ofthese disorders, symptoms may beginduring the neonatal period or earlychildhood. Serious bleeding episodes,including ICH, may be preceded byrelatively minor bleeding events, pro-viding an opportunity for diagnosisbefore the former occur. Primary care

and other nonhematologist pediatricproviders must be familiar with thevariableclinicalpresentationand initialdiagnostic evaluation of these raredisorders. RBDs should be considered,in particular, when there is consan-guinity. Consultation with a hematolo-gist who is ideally affiliated witha hemophilia treatment center will fa-cilitate efficient diagnosis and appro-priate ongoing management.

ACKNOWLEDGMENTSWriting assistance was provided byLara Primak, MD, of ETHOS Health Com-munications in Newtown, PA, with fi-nancial support from Novo Nordisk,Inc, in compliance with internationalGood Publication Practice guidelines.Dr Acharya received no remunerationof any kind for the development of thismanuscript.

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