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  Review Article  Introduction: The hemophilias are the commonest inherited bleedingdisorder which can lead to chronic disorder and lifelong disabilities if not properly managed 1 . Althoughmedical literature supports the existence of life longbleeding disorders along with their familial occurrencesince tenth century, physicians were the helplesswitness of the exsanguinating bleeders of thehemophiliacs 2 . Understanding of the patho-physiologyhas long been delayed due to complexity of clottingmechanism. Due to advancement in protein chemistryand recombinant DNA technology a comprehensiveaccount of normal coagulation and molecular geneticsof hemophilia have been explored. Application of restriction fragment length polymorphism (RFLP) for carrier detection has revolutionized lab process  3 . Inthe past decades, hemophilia has moved from thestatus and fatal heredity disorder to that of a definedgroup of disorder in a molecular basis for which safeand effective treatment is available 4 . And hemophiliais likely to be first common severe genetic disorder tobe cured by gene therapy until then main challengeremains to overcome the development of inhibitor andmanaging patient with inhibitors and in fact it is also agreat challenge for the society to provide proper management to four fifth of hemophilia, who are livingin developing countries  4 . Definition and Types: Hemophilias are the hereditarybleeding disorder due to absence or deficiency of plasma clotting factors, resulting in prolong anduncontrolled bleeding either spontaneously or followingtrauma 4 . Two most common forms of hemophilia areHemophilia A (HA) and Hemophilia B (HB) and arecaused by deficiency of factors VIII and IX respectively.HA accounts for 80-85% of cases and HB in 15-20%of cases 5, 6 . Both types are inherited as X linkedrecessive pattern characterized by prolonged bleedingand hemorrhages typically in joints and soft tissues 5 . A Review on Hemophilia in Children MD. ANWARUL KARIM, CHOWDHURY YAKUB JAMAL Department of Pediatric Hematology and Oncology,Bangabanadhu Sheikh Mujib Medical University Correspondence: Dr. Md. Anwarul Karim, AssociateProfessor, Department of Pediatric Hematology and Oncology,Bangabanadhu Sheikh Mujib Medical University  An uncommon type, Hemophilia C is an autosomalrecessive defect that results in deficiency of factorsXI and is characterized by bleeding in mucousmembrane, the pattern of bleeding similar to VonWillebrand disease rather that hemophilia A and B 6,7 . This review will focus on Hemophilia A andHemophilia B. Epidemiology: Hemophilia is prevalent worldwide andoccurs in all racial and socioeconomic groups  5 . Theincidence of HA and HB is about 15-20 per 100 000male born world wide. HA is also known as ‘Classicalhemophilia’ and account about 80% of cases of hemophilia and occurs 1 in 10,000 male births 8 . HBalso known as ‘Christmas disease’ occurs in about 1in 25,000 male births. According to the Report of theannual global survey 2009, the 11th survey by Worldfederation of Hemophilia (WFH) with a participating105 countries, total number of hemophiliac is 153,253of which 115,209 is HA and 24,038 is HB 9 . Number of HA and HB patients with clinically identified inhibitorswas 5013 & 363, Reported number of Hemophiliacsinfected with HIV and HCV was 5,665 & 24,340 9 .However, these figures are an underestimate thanactual ones. Because as per estimation of WFH, witha prevalence of HA and HB of 135 per million malechild (world population being 6 billion), there wouldhave been 399,000 hemophilia worldwide. So majorityof the patients remains under diagnosed and it is truethat most of them are living in the developingcountries 10 . Genetics: HA and HB are transmitted by X linkedrecessive fashion. Genes for HA and HB are locatedon tip of the long arm of X chromosomes in band Xq28& Xq27 respectively 1 . So there is 50% chance thatson of a female carrier will inherit the disorder. Malewith hemophilia will not transmit this disease to hisson but all his daughters will be carrier. Female carriersusually don’t have symptoms of hemophilia but heymay have lower than usual level of clotting factors  8 .Genes encoding factor VIII is large and complex (186kb). HA can result from many genetic errors like- alarge variety of point mutation, gene deletion, stop BANGLADESH J CHILD HEALTH 2013; VOL 37 (1) : 27-40.  codon abnormality, frame shift mutation and inversionmutation.These knowledge help in carrier identificationby DNA analysis and correction of gene defect toprevent inhibitor development 1 .Early studies identified genetic defect in nearly allpatients who had mild to moderate hemophilia butonly 50% of cases of severe hemophilia. Recent worksshowed that a novel “FLIP TIP” inversion at the end of X chromosome is responsible for the 50% cases of hemophilia. Here, a small gene of unknown mutationtermed F8A is inserted within a non coding region of large FVIII resulting division and inactivation of FVIIIgene. This mutation facilitates testing DNA for carrier identification.The gene for FIX is 34 KB long and the nature of theprotein is vitamin K dependent serine proteasecomposed of 415 amino acids synthesized in the liver  1 . Gene deletion and point mutation are seen in HBgene. FIX is synthesized in liver and requires vitaminK for gamma carboxylation. Plasma concentration is50 times more than FVIII and it has a half life of 24hours which accounts for a milder phenotype of HB 11 . Hemostasis and the role of factor VIII and IX: Bleeding occurs in hemophilia due to failure of secondary hemostasis. Primary hemostasis is theformation of the platelet plug that occurs normally butthe stabilization of the fibrin is defective becauseinadequate amount of fibrin are generated. Factor VIIIand IX are known to be central to the process of bloodcoagulation and for the adequate generation of thrombin  5 . Following an injury cryptic tissue factors(TF) on the TF bearing cells activates FVII to factor VIIa in order to from a TF-VIIa complex  , which in turnactivates FX to FXa and some FIX to FIXa. Thisactvated FXa form complex with plasma derived FVto form FXa /FVa (prothrombinase) complex   on theTF bearing cells which converts a small amount of prothrombin to thrombin. This priming dose of thrombin, formed in the initiation phase, is not  (derived from FVIIa as well as FXIa activation) forms atenase complex with FVIIIa and results in activationof large amounts of FXa–FVa complex (prothrombinase)  that leads to generation of largeamounts of thrombin (or   thrombin burst ) that convertslarge amounts of fibrinogen to fibrin resulting in a clot.In hemophilia, thrombin is not generated on the plateletsurface due to lack of FVIII or IX (lack of tenaseformation). Thus there is no thrombin burst or generation of large amounts of thrombin 5 . Clinical manifestation: The Clinical manifestationof HA and HB are identical, however HB is relativelymilder disease so often diagnosed relatively in later life 6 . Hemophiliacs have the heterogenous phenotypicpresentation depending upon its severity described inthe table   12, 13 . sufficient to generate large amounts of fibrin . It bindsto platelets and initiates several reactions on theplatelet surface. It releases FVIII from VWF andactivates it to FVIIIa, activates platelet FV to FVa,and FXI to XIa that converts plasma FIX to IXa andreactivates the platelet. This is called the amplification phase . In the final or propagation phase, the FIXa Figure: Schematic model of coagulation in vivo  Abbreviations: TFPI-Tissue factor pathway inhibitor. Table I Relationship of factor level to the severity of clinical presentation in hemophilia Types% of FVIII & FIXType of hemorrhageSevere<1Spontaneous; hemarthroses and deep tissue hemorrhagesModerate1-5Gross bleeding following mild to moderate trauma,; some hemarthroses;seldom spontaneous hemorrhagesMild>5-<40Severe hemorrhages only following moderate to severe trauma, spontaneousbleeding is rare BANGLADESH J CHILD HEALTH 2013; VOL 37 (1) : 28A Review on Hemophilia in Children  Severe hemophilia usually present in neonatal periodand early infancy, while moderate hemophilia in toddlersand mild hemophilia in late childhood or adolescentand adult often incidental or following major trauma 13 .Bleeding is the hallmark of hemophilia, sites and patternof bleeding varies over life time 8 . Table shows thecommon site of hemorrhage in hemophilia   13 . In neonatal period and infancy: Newborns withhemophilia have distinctive different pattern of ascompared with older children and adult 11 . And it couldbe misdiagnosed especially in the setting of negativefamily history 14 . Though hemarthrosis is rare,iatrogenic and cranial bleeding is common 15 . According to US HTC surveillence study on a largesample of 864 hemophiliacs of 0-2 years of age, 73%of the severe hemophilia was diagnosed within firstmonth of life, however among these cases only 28.8%cases were diagnosed due to bleeding. Among therest 47.2% cases of carrier mother, 23.2% due tofamily history. Bleeding from circumcision was themost common hemorrhagic complication in 45% casesfollowed by head bleeds in 17.7% cases. Mostcommon first bleeding sites are shown table  15. Table-III Sites of bleeding episodes in 278 newborn with hemophilia 15  Sites of bleedingFrequencyPercentageCircumcission12645.49Head (ICH)49(16)17.69 (32.6)Heal stick4114.8Venepuncture103.6Intramuscular injection93.25Soft tissue72.53Oral mucosa31.08Joint10.36others227.94Unknown93.25Similar pattern of bleeding is also reported by another large hospital based retrospective study in 399newborn 16, 17 .Intracranial hemorrhage (ICH), thoughrare, is the serious complication often misdiagnosedin neonatal period because of vague presentationespecially with negative family history. High index of suspicions are necessary to pick these cases. Thereported incidence of ICH (3.5-4%), though higher thangeneral population is misleading and may be higher if one consider asymptomatic ICH 15 . The HemophiliaGrowth and Development study found abnormal MRIin 20% of children with hemophilia and 50% of themhad silent ICH 18 . In the UDC data, 3.47% newbornhad an ICH associated with delivery and the incidencewas more with vaginal delivery. The most commonsites for ICH were subdural (68.2%), intracere34al(13.6%), cerebellar (9%), and 4.6% each of subarachnoid and ventrcular 18 .Beyond neonatal period most hemophilic seldom havebleeding episode requiring treatment unless accidentalinjury occurs. Beginning around 1 year of age whenthe child learns to walk has frequent fall or bumpsinto the furniture, acute hemarthrosis may occur. Softtissue bruising and laceration is common in this agegroup and in a family with unaware of the diseasestatus, he or she might have been suspected as childabuse. Tongue and mouth laceration may occur aroundthis time 1 . Older children and adolescent: Hemarthrosis  isthe leading bleeding symptoms in older children andadolescent. Recurrent bleedings causes pathologicalchanges leading to ‘target joint’ and eventually further bleeding into the joint occur without trauma, overtimethis cycle of bleeding causes erosion of joint cartilageresulting in arthritis and the crippling deformities of hemophilic arthropathy 1,8 . Radiological joint damage Table-II Common sites of hemorrhage in hemophilia. HemarthrosisRetropharyngelIntrmuscular hematoma hematuriaRetroperitonealMucous membrane hemorrhage:Hemorrhage causing compartmentalMouthsyndrome/nerve compressionDentalFemoral (ilispoas),EpistaxisSciatic (buttock), High risk hemorrhage Tibial (calf muscle),Central nervous systemPerineal (anterior compartment of leg),Intracranial extracranialMedian and Ulnar nerve (flexor muscles of fore arm) BANGLADESH J CHILD HEALTH 2013; VOL 37 (1) : 29  might appear by 6 years in subjects with no or minimalepisode of hemarthrosis 19 . Eighty percent of bleedingoccurs in knee, ankles, and elbow; however involvement of other joints is not unusual. Karim et alin their study in Bangladeshi children shows 82%children present with joint symptoms and knee jointinvolvement was the most common (68%) followedby ankle joint (44%) and elbow joint in 14% cases 20 .Hemarthrosis as the predominant presentation withmost affected joint being knee joints were also foundin Korean study 21 . However many other studiesconducted in Netherlands, France and Spain showedankle joint as mostly affected joints 22, 23, 24 . Muscular hemorrhage: Muscular bleeding occursin 10-25% of all bleeds in severe hemophilia andbleeding may become limb threatening, recovery andrehabilitation may be protracted 25 . In contrast tohemarthrosis, muscle bleeds are mostly associatedwith trauma 25.  Affected muscles become swollen,painful and stiff. There may be bruising on overlyingskin if the bleeding occurs in superficial muscle.Deeper muscle bleeding causes pressure on nervesleading to numbness and tingling sensation and if notproperly treated by factor replacement leads tocompartmental syndrome 4  and insufficiently treatedmuscle bleed may also result in several other complications like irreversible damage to muscle,reduce range of movement, loss of function, myositisossificans and damage to tendon (Volksmann’sischemic contractures). Iliopsoas bleeding might belife threatening as large volume of blood is accumulatedcausing shock. Signs of iliopsoas bleeding includeupward flexion and discomfort on passive extension of thigh, tendeness on palpation on the lower quadrantand paresthesias just below the inguinal ligament fromfemoral nerve compression 1, 25 .Intracranial hemorrhage: Intracranial hemorrhageis the serious complication of hemophilia with asignificant cause of disability and long termneurological sequelae as many as 60-75% cases 16,17 . Prevalence of symptomatic ICH in all ages variesfrom 3-12% with a substantial proportion occurring inchildren  26 . Severity of the disease, trauma to head,mode delivery and presence of inhibitor are the riskfactors for developing ICH 27 . Beyond neonatal period,ICH is 20-50 times more frequent in hemophiliac thangeneral population and trauma appears the risk factorsin 22-53% cases 16, 26.  In children <2 years of agemost frequent first documented symptom were apathyand or unusual tears (20.7%), Vomiting (17.2%) andcoma (13.8%). In those e”2 years most frequentsymptoms were headache (46.9%), coma (21%) andvomiting (12.3%) and Irrespective of age coma wasobserved during the course of ICH in 2/3 rd  of thecases 5 . Hematuria: Hematuria usually results from blow tothe flank, renal calculi and rarely, it may bespontaneous and asymptomatic. It is an infrequentoccurrence before 12 years of age. Every patient withhaemophilia will present at least one episode of haematuria in his lifetime. There is a greater incidencein spring and autumn. In general, haematuria episodeshave a short duration and do not cause any severesequelae, except in patients with high titer inhibitorsand in HIV patients with bone marrow hypoplasia 28 . Diagnosis of hemophilia 29 : At birth: Hemophiliais diagnosed either due to known family history or after presentation with bleeding. Collection of bloodsample:  Arrangement of collection of blood samplefrom fetal side of placenta should be done if there ispossible family history or mother of a male fetus isknown or possible carrier. If any newborn /childpresents with unusual / prolonged bleeding is subjectedfor basic screening test. Screening tests: Completeblood count- remains normal other than anemia.Bleeding time: remains normal. Prothrombin time(PT) :  also normal in hemophilia.  Activated partial thromboplastin time (APTT) :  usually increased byone and half fold to more than 2 fold. Normalhemogram, bleeding time and PT with prolonged APTTleads to the suspicion of hemophilia which warrantsspecific factor analysis. Specific study: Correction study with deficient plasmamight identify the types of hemophilia and with normalplasma might suggest presence of inhibitors.Quantitative assay of FVIII, FIX helps in identify thetypes of hemophilia and its severity. Molecular genetic testing: a. Sequence analysis, b. Targeted sequenceanalysis, c. Deletion and duplication analysis andLinkage analysis for a) Tracking an unidentifiedmutation, b) Identifying the srcin of de novo mutation Carrier detection : a) Factor assay- usually lower thannormal b) DNA analysis- identifies the geneticabnormality.  Antenatal diagnosis : by collecting sample of chorionicvillous (CVS) in10-12 weeks of pregnancy and amnioticfluid (amniocentesis) in 16-20 weeks of pregnancy for molecular genetic testing. BANGLADESH J CHILD HEALTH 2013; VOL 37 (1) : 30A Review on Hemophilia in Children
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