HEMOPHILIA Hemophilia A F VIII def. B F IX def.

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

 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, have severe disease. of individual with hemophilia B have F IX level > 1% Hemophilia A and hemophilia B of comparable severety bleed with similar frequency Some patients with severe disease have a milder clinical course

Walker et al. Transfusion 1955; 35:548

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

 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

THE MOST COMMON SITE OF BLEEDING

Joint : 80% ankle children

elbow, knee, ankle adult

Muscle GI

Avena Zukerta Curr Opni Rhematol 1998; 10:86

 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; 59:439 Lung R et al. Acla Paediats Scand 1990; 79:196

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

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 or F 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

 3 to 5% develop significant sub galeal or

intracranial bleeding in the perinatal period. Early bleeding also occur in approximatly 50% of un-diagnosed hemophilia in association with circumcission. More often, children with severe hemophilia A and B became symptomatic after the newborn period.

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

 The first symptomatic bleeding having to

the 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 occurred significantly later, at median time 1.6 years.
Pallman, H et al. Eur J Pediat 1999; 158 Suppl : S166

 However, some children do not bleed

before age of four. The onset of disease occur later in patient with moderate and mild hemophilia. The mean age at diagnosis of moderate and severe hemophilia was 22 and 9 mo.

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

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.

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 lethargy Some ICH are silent.
Kenge, J et al. Eur J Pediatiar 1999; 158 Suppl 3:S162 Nelson MD Jr, Hemophilia 1999; 5:306 Lyng RC et al. Br J. Haematol 2008; 140:378

HEMARTHROSIS
Hemarthrosis is a painful and physically debilating

manifestation 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.

SCELETAL MUSCLE

Bleeding into muscle most often

affect the quadriceps, ilio psoas and fore arm.

Fernandez Palazi. Clin Orthop 1996; 378

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

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

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

LATE COMPLICATIONS

Joint destruction due to hemarthroses Transmission of blood borne infection Development of inhibitor antibodies

HEMOPHILIC ARTHROPATHY

Multiple factors :

tissue deposition of iron dense fibrosis of the joint with contracture pain, limitation of motion

Primary prophylactic treatment starting during early years of life can markedly reduce the risk of subsequent arthropathy
Maehak, R et al. Arthritis Rheum 1988; 3:148

THE OUTCOME AFTER HEMARTHROSIS

Physical and x rays examination scores

increase sequently with age All six joints (knee, elbow, ankle) were normal in approximatly 10 present, only one half remained free of disease at six years. The patients had an average of 16.3 bleeds affecting the six main joints during the year of evaluation.

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

 All six joints were normal in only 16 present

on physical exam and 4 present on radiologic exam. A history of orthopaedic surgery and/or rhematologic procedure was in 54%. These patients had undergone a mean of 2.3 procedure, primarly synovectomy. Limitation in moderate physical activity (walking up a flight of stairs, taking a bath or dressing, were present in 2 to 7%, 18-30% were limited to more sternous activities such as running, or walking more than one-half a mile.

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

INFECTION

The concentrate related

transmission 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; 64:197 Traisi, CL et al. Blood 1993; 81:412

 Patients treated with older F VIII or F IX

concentrated 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 Jacob disease and new variant.
Kemar A, et al. J Med Viral 1993; 41:205 Santa Qentino, et al. Transfusion 1997; 37:517 Evatt, B et al. World Federation of Hemophilia 199:15

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

DIAGNOSIS AND DETECTION OF CARRIERS

Careful review of family history of the

maternal site Screening test

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 of her family. Approximatly of patient of hemophilia have a negative family history

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; 335:418 Lawn, RM. Cell 1985; 42:405

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

DIAGNOSIS : SCREENING TEST

Bleeding diathesis of unknown etiology 1 : Platelet count 2 : Prothrombin time 3 : activated partial thromboplastine time
1:N 2:N 3 : ABN, corrected by normal plasma * Specific Assay

hemophilia

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 individual

is an obligated carrier

TEST FOR CARRIER DETECTION

The mean concentration of F VIII in the

plasma of heterozygous carrier is approximately 50% that of normal woman. The subnormal level strongly suggest the presence of the carrier state, but the presence of normal level does not reliably exclude is.

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

 DNA-based technique are the prefered

method for carrier detection. Derect gene analysis for the intron 22 inversion 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

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.

SUMMARY

The concentrate related transmission of

infection 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 site screening test. Carrier detection and prenatal diagnosis : DNA base technique.

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