Cause:Genetic, sex-linked recessive causing factor VIII deficiency
Pathophys:Intrinsic system defect (Screening Tests of Clotting Function) caused by deficiency of functioning factor VIII, although present in plasma immunologically (defective protein). Factor VIII is synthesized in blood vessel endothelial cells, circulates complexed to von Willebrand protein, which enhances VIII synthesis, protects it from proteolysis, and concentrates it at sites of active hemostasis
80% of all patients with lifelong bleeding diathesis (Ann IM 1966;65:782); 1/7000-10 000 male births, only 1/3 have complete VIII deficiency
Sx: Male; positive family hx in 2/3 (1/3 are due to new mutations). Wide spectrum from postsurgical bleeding to chronic bruising, joint bleeds, and crippling arthritis; gu bleeding (usually insignificant); no bleeding after minor cuts
Si:Bleeding after trauma. Spontaneous hemarthroses only in severe disease
Lifelong, 1995 prognosis nearly comparable to normal population if don't get HIV or hep B (Ann IM 1995;123:823)
Psychiatric conditions related to chronic illness; hepatitis B (Ann IM 1977;86:703) and C; AIDS; flexion contractures of joints; intracranial bleeding, the cause of death in 25%
Lab:
Hem: Prolonged PTT but normal PT and platelet count; r/o factor VIII autoantibody inhibitor, factor XI deficiency, antiphospholipid antibodies, lupus anticoagulants, or factor XII deficiency
Factor VIII levels: None detectable = severe disease, 1-4% of normal = moderate disease, 5-25% of normal = mild disease
Rx:Preventively avoid ASA and other NSAIDs; prenatal dx and abortion (Nejm 1979;300:937), in 1st trimester with DNA probe (Nejm 1985;312:682); detect female carriers by recombinant DNA techniques
Comprehensive outpatient programs save money and lives; try to keep VIII >15% w recombinant DNA VIII, no viral contamination risks (Nejm 1993;328:453; Med Let 1993;35:51), cost $20 000-$100 000/yr
Desmopressin (DDAVP) (Nejm 2004;351:683; 1998;339:245) 0.3 µgm/kg over 30 min iv or sc, or 150 µgm in children, 300 µgm in adults via nasal spray (Ann IM 1991;114:563) increases VIII transiently within 1 h, eg, perisurgically or after trauma (Ann IM 1985;103:228); adequate alone in 80% (Ann IM 1985;103:6); adverse effects: water intoxication, MI/angina
Recombinant activated factor VII (rFVIIa; NovoSeven) (Med Let 2004;46:33) 90 µgm/kg; also being used off-label for traumatic bleeding; cost = $1500/mg so $10K to rx a 70-kg-patient
of VIII antibody formation (IgG) (Nejm 2002;346:662, 702), in 10% and up to 50% of those w severe disease; rx with activated prothrombin concentrates (Konyne); or big doses of VIII; can also use plasmapheresis, steroids, and cyclophosphamide; not yet clear if will be an issue with recombinant VIII (Nejm 1993;328:453)