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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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