Hemophilia P3D

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    HEMOPHILIA

    Hemophilia A F VIII def.

    B F IX def.

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    Clinical Manifestation

    Hemophilia A + B : X-linked recessive dis.

    Classified :

    Severe < 1% factor activity

    Moderate 1 5%

    Mild > 5%

    White GC : Thromb Hemost 2001; 85:560

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    Male within a family have the same level of def.

    The combined incedence of hemophilia A +hemophilia B is 1 in 5000 live male birth

    Aproximatly 80% have hemophilia A, havesevere disease.

    of individual with hemophilia B have F IXlevel > 1%

    Hemophilia A and hemophilia B of comparableseverety bleed with similar frequency

    Some patients with severe disease have amilder clinical course

    Walker et al. Transfusion 1955; 35:548

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    The Leyden phenotype of hemophilia B :

    severe hemophilia B in childhood that

    became mild after puberty.1

    Mutation at nucleotide-20 in the promoter

    region disrupt the hepatocyte nuclear

    factor-4 (HNF-4) binding site but not the

    overlaping site for an androgen responselement.

    Crassly et al. Science 1992; 257:377Rynen et al. Blood 1993; 82:151

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    Coinheritance of F V Leyden

    mutation and other prothrombotic

    markers occur in a small proportion

    of patient with severe HA counteract the bleeding tendency

    fewer bleeding episode and a later

    onset of first bleeding.

    Shetly et al. Br J Haematol 2007; 138:541

    Escurebla E. Thromb Haemost 2001; 85:218

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    THE MOST COMMON SITE OF BLEEDING

    Joint : 80% ankle children

    elbow, knee, ankle adult

    Muscle GI

    Avena Zukerta Curr Opni Rhematol 1998; 10:86

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    Spontaneous hemarthrosis :characteristic of severe H

    diagnostic

    Mucosal bleeding : epistaxis,ginggival bleeding and bullous

    haemorrhage on the buccal mucosa.

    Manser Burnskaten EP et al. Bleeding Symptom. Thromb Haemost 1988; 59:439Lung R et al. Acla Paediats Scand 1990; 79:196

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    Bleeding : vary with the severity of the disease.

    Occur in respons to injury/trauma/surgery mild

    hemophilia

    Intercurrent injury/surgery : moderate hemophilia Spontaneously, early age : severe

    Female carrier :

    - normal F level

    no bleeding- < 50% F level more often

    Venkateswaran et al. J Pediats Hemat Oncol 1998; 20:32

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    INITIAL PRESENTATION

    The majority of patient : family history.

    25% had bleeding episodes before the

    diagnosis was established.

    The vast majority of newborn with severe

    hemophilia transverse delivery and the

    first few month of live without detection,

    dispite the presense of severe F VIII orF IX def.

    Lyng R et al. Acla Paediats Scand 1990; 79:196

    Rizza CR et al. In : Human Blood Coagulation Blackwell Scientific Publication, Oxford 1976, p.238

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    3 to 5% develop significant sub galeal orintracranial bleeding in the perinatal period.

    Early bleeding also occur in approximatly 50%

    of un-diagnosed hemophilia in association withcircumcission.

    More often, children with severe hemophilia A

    and B became symptomatic after the newbornperiod.

    Koch JA et al. S Afr Med J 1978; 53:721

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    The first symptomatic bleeding having tothe diagnosis of severe hemophillia

    occurred of the median 0.9 years.

    In those carrying prothrombotic risk factor(e.g. F V Leyden, prot. C def.,

    prothrombin G 2010 A gene variant, the

    first bleeding episode occurredsignificantly later, at median time 1.6

    years.

    Pallman, H et al. Eur J Pediat 1999; 158 Suppl : S166

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    However, some children do not bleedbefore age of four.

    The onset of disease occur later in

    patient with moderate and mildhemophilia.

    The mean age at diagnosis of moderate

    and severe hemophilia was 22 and 9 mo.

    Gilbert, MS. Mt Sinai J Med 1977; 44:339

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    SITE OF BLEEDING

    As children begin to ambulate,

    bleeding episode occur more often

    and begin to involve joint and

    muscle, as well as other system.

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    CNS

    ICH : Occur in neonates and older children, as

    well as in adult.

    Spontaneous is more frequently than

    trauma induced bleeding

    Prevalence was 12%

    It present with : headache, vomiting and

    lethargySome ICH are silent.

    Kenge, J et al. Eur J Pediatiar 1999; 158 Suppl 3:S162

    Nelson MD Jr, Hemophilia 1999; 5:306Lyng RC et al. Br J. Haematol 2008; 140:378

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    HEMARTHROSIS

    Hemarthrosis is a painful and physically debilatingmanifestation

    The clinical manifestation vary by age

    In infant : irrilability

    decrease in use

    In older children and adult

    Prodromal stiffness

    Warm sensatian followed by acute pain and

    swelling

    Bleeding episode often affect a variety of joint,

    particularly the knee and ankle.

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    SCELETAL MUSCLE

    Bleeding into muscle most often

    affect the quadriceps, ilio psoas and

    fore arm.

    Fernandez Palazi. Clin Orthop 1996; 378

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    HEAD AND NECK

    Epistaxis Bleeding from oral mucosa and

    teeth.

    Bleeding into the posterior pharynx airway obstruction

    Bagdar, CJ et al. Laryngoscope 1994; 104:789

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    GASTROINTESTINAL

    Blood in the stool

    Bleeding into abdominal wall

    Hematomas of the bowel wall

    Bleeding into the retroporetoneal

    space

    Jones, JJ et al. Arch Intern Med 1984; 144:297

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    POST TRAUMATIC BLEEDING

    Seldom bleed from small cuts or veni

    puncture

    Haemorrhage to occurs after larger

    injuries

    Delayed bleeding in patient with mild

    hemophilia after minor surgical

    procedure

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    LATE COMPLICATIONS

    Joint destruction due to hemarthroses

    Transmission of blood borne infection

    Development of inhibitor antibodies

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    HEMOPHILIC ARTHROPATHY

    Multiple factors : tissue deposition ofiron

    dense fibrosis of the

    joint with contracture

    pain, limitation of

    motion

    Primary prophylactic treatment starting duringearly years of life can markedly reduce therisk of subsequent arthropathy

    Maehak, R et al. Arthritis Rheum 1988; 3:148

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    Physical and x rays examination scores

    increase sequently with age

    All six joints (knee, elbow, ankle) were

    normal in approximatly 10 present, only onehalf remained free of disease at six years.

    The patients had an average of 16.3 bleeds

    affecting the six main joints during the year ofevaluation.

    Molho, P et al. J Intern Med 1994; 236:391

    THE OUTCOME AFTER HEMARTHROSIS

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    All six joints were normal in only 16 presenton physical exam and 4 present on radiologicexam.

    A history of orthopaedic surgery and/or

    rhematologic procedure was in 54%. Thesepatients had undergone a mean of 2.3procedure, primarly synovectomy.

    Limitation in moderate physical activity(walking up a flight of stairs, taking a bath ordressing, were present in 2 to 7%, 18-30%were limited to more sternous activities suchas running, or walking more than one-half amile.

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    THE JOINT OUTCOME STUDY IN THE U.S :

    Prophylaxis with F VIII at 25 35 U/kg b.w.

    every other day is superior to intensive on

    demand factor replacement therapy in

    preventing joint disease.

    Manco Johnson, M. Blood 2005; 106:6a

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    INFECTION

    The concentrate relatedtransmission of infection has been

    reduced markedly by :

    Improvements in donor screening Virucidal technique

    The development of recombinant

    product

    Mamucci, PM et al. Vox Sang 1993; 64:197Traisi, CL et al. Blood 1993; 81:412

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    Patients treated with older F VIII or F IXconcentrated were high risk for infection with

    hepatitis A, B, C and HIV.

    Parvo B19 an exception elimination by dry,

    wet and steam heated method.

    Infections agent for which there are no

    screening test or method to remove inactivate

    the transmitable agent. Creutzfeld Jacobdisease and new variant.

    Kemar A, et al. J Med Viral 1993; 41:205

    Santa Qentino, et al. Transfusion 1997; 37:517Evatt, B et al. World Federation of Hemophilia 199:15

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    DEVELOPTMENT OF INHIBITOR

    25% severe hemophilia A ; 3 5% hemophilia B Less common in mild or moderate hemophilia

    Maturational delay

    PROTECTION AGAINST CHD

    Patients with hemophilia and carrier of

    hemophilia appear to have a reduced risk

    of CHD mortality

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    DIAGNOSIS AND DETECTION OF CARRIERS

    Careful review of family history of the

    maternal site

    Screening test

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    THE FAMILY HISTORY

    In most instances, the mother of a male

    patient can be identified as a carrier

    because of the presence of an

    abnormal bleeding in other member ofher family.

    Approximatly of patient of hemophilia

    have a negative family history

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    A NEGATIVE FAMILY HISTORY

    The patient may have a new mutation

    Neonatal death or passage of the trait

    through a succession of female carrier

    Thompson, AR et al. Lancet 1990; 335:418Lawn, RM. Cell 1985; 42:405

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    SYMPTOMATIC HEMOPHILIA IN FEMALE

    X chromosome inactivation at an

    unusually early stage of embryogenesis.

    Mating between an affected male and

    carrier female

    An abnormal karyotype

    Panarello, C et al. Cytogenet Cell Genet 1992; 59:421

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    DIAGNOSIS : SCREENING TEST

    Bleeding diathesis of unknown etiology1 : Platelet count

    2 : Prothrombin time

    3 : activated partial thromboplastine time

    1 : N

    2 : N hemophilia

    3 : ABN, corrected by normal plasma

    * Specific Assay

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    DESTINCTION FROM VON WILLEBRAND DISEASE

    The restocetin cofactor essay

    Type 2 N von Willebrand mild hemophilia

    CARRIER DETECTION AND PRENATAL

    DIAGNOSIS

    Carrier testing is unnecessary if the individualis an obligated carrier

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    TEST FOR CARRIER DETECTION

    The mean concentration of F VIII in theplasma of heterozygous carrier is

    approximately 50% that of normal woman.

    The subnormal level strongly suggest thepresence of the carrier state, but the

    presence of normal level does not reliably

    exclude is.

    Manser Bumschaten, EP et al. Thromb Haemost 1988; 59:349Klein, HG et al. N Engl J Med 1977; 296:956

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    DNA-based technique are the prefered

    method for carrier detection.

    Derect gene analysis for the intron 22inversion is recommended as first line

    testing for carrier in families with severe

    hemophilia A

    Klein, HG et al. N Engl J Med 1977; 296:956

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    SUMMARY

    Hemophilia A + B : X linked recessive dis.

    Classified as severe, moderate and mild. Male

    within a family have the same level of defisiency

    The combined incidence of hemophilia A + B is 1

    in 5000 male birth. The most common site of bleeding : Joint, muscle

    and GI. Spontaneous hemarthrosis is

    characteristic of severe hemophilia.

    Bleeding vary with the severity of the disease.

    Complications consist of : joint destruction due to

    hemarthrosis. Transmission of blood borne

    infection and development of inhibitor antibodies.

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    SUMMARY

    The concentrate related transmission ofinfection has been reduced markedly by :

    Improvement in donor screening, virucidal

    technique and the development of recombinant

    product. Except : Parvo B19 virus, Creutzfeld

    Jacob disease.

    Diagnosis and detection of carrier : careful

    review of family history of the maternal sitescreening test.

    Carrier detection and prenatal diagnosis : DNA

    base technique.

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