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HEMOPHILIA

HEMOPHILIA. Inherited deficiency of factor VIII (hemophilia A) or factor IX (hemophilia B) Sex-linked inheritance; almost all patients male Female carriers may have mild symptoms Most bleeding into joints, muscles; mucosal and CNS bleeding uncommon

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HEMOPHILIA

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  1. HEMOPHILIA • Inherited deficiency of factor VIII (hemophilia A) or factor IX (hemophilia B) • Sex-linked inheritance; almost all patients male • Female carriers may have mild symptoms • Most bleeding into joints, muscles; mucosal and CNS bleeding uncommon • Severity inversely proportional to factor level < 1%: severe, bleeding after minimal injury 1-5%: moderate, bleeding after mild injury > 5%: mild, bleeding after significant trauma or surgery

  2. GENETICS OF HEMOPHILIA • About half of cases of hemophilia A due to an inversion mutation in intron 1 or 22 • Remainder genetically heterogeneous • Nonsense/stop mutations prevent factor production • Missense mutations may affect factor activity rather than production • 15-20% of cases due to new mutations

  3. Deficiency of factor VIII or IX affects the propagation phase of coagulation • Most likely to cause bleeding in situations where tissue factor exposure is relatively low

  4. ACUTE COMPLICATIONS OF HEMOPHILIA Hemarthrosis (joint bleeding) Muscle hematoma (pseudotumor)

  5. Joint destruction Nerve damage LONG-TERM COMPLICATIONS OF HEMOPHILIA

  6. Hemophilic arthropathy “Target joint” = irreversibly damaged joint with vicious cycle of injury and repeated bleeding

  7. Hemophilic arthropathy J Thromb Hemost 2010;8:1895

  8. Hemophilic arthropathyVariable relationship between # of joint bleeds and severity Green line: Evidence of early joint damage with relatively few bleeds Yellow line: Linear relationship between # of bleeds and joint damage Red line: Joint damage occurs after threshold # bleeds Blue line: Little joint damage despite many bleeds J Thromb Hemost 2010;8:1895

  9. Management of hemophilic arthropathy • Physical therapy • Weight control • COX-2 inhibitors safe and effective • Judicious use of opioids • Surgical or radionuclide synovectomy • Joint replacement

  10. OTHER COMPLICATIONS OF HEMOPHILIA • Pseudotumor: gradually enlarging cyst in soft tissue or bone (requires surgery) • Retroperitoneal hemorrhage • Bowel wall hematoma • Hematuria → renal colic (rule out structural lesion) • Intracranial or intraspinal bleeding (rare but deadly) – usually after trauma

  11. HEMOPHILIATreatment of bleeding episodes • Unexplained pain in a hemophilia should be considered due to bleeding unless proven otherwise • External signs of bleeding may be absent • Treatment: factor replacement, pain control, rest or immobilize joint • Test for inhibitor if unexpectedly low response to factor replacement

  12. Dosing clotting factor concentrate • 1 U/kg of factor VIII should increase plasma level by about 2% (vs 1% for factor IX) • Half-life of factor VIII 8-12 hours, factor IX 18-24 hours • Volume of distribution of factor IX about twice as high as for factor VIII • Steady state dosing about the same for both factors – initial dose of factor IX should be higher

  13. Give factor q 12 hours for 2-3 days after major surgery, continue with daily infusions for 7-10 days • Trough factor levels with q 12 h dosing after major surgery should be at least 50-75% • Most joint and muscle bleeds can be treated with “minor” (50%) doses for 1-3 days without monitoring

  14. FACTOR VIII CONCENTRATE • Recombinant • Virus-free, most expensive replacement • Treatment of choice for younger/newly diagnosed hemophiliacs • Somewhat lower plasma recovery than with plasma-derived concentrate • Highly purified • Solvent/detergent treated, no reports of HIV or hepatitis transmission • Intermediate purity (Humate-P™) • Contains both factor VIII and von Willebrand factor • Solvent/detergent treated, no reports of HIV or hepatitis transmission • Mainly used to treat von Willebrand disease

  15. FACTOR IX CONCENTRATE • Recombinant (slightly lower plasma recovery) • Highly purified (solvent/detergent treated, no reports of virus transmission) • Prothrombin complex concentrate • Mixture of IX, X, II, VII • Low risk of virus transmission • Some risk of thrombosis

  16. DDAVP • Releases vWF/fVIII from endothelial cells • Factor VIII levels typically rise 2-4 fold after 30-60 min (IV form) or 60-90 min (intranasal) • Enhanced platelet adhesion due to ↑ vWF • Useful for mild hemophilia (VIII activity > 5%) prior to dental work, minor surgery etc • Trial dose needed to ensure adequate response • Cardiovascular complications possible in older patients

  17. Bethesda Assay for Inhibitors • Serial dilutions of patient plasma in normal plasma • Incubate 2 hours • Assay residual factor activity • 1 Bethesda Unit neutralizes 50% of factor in an equivalent volume of normal plasma • Example: 1:100 dilution of patient plasma + normal plasma → 50% residual factor activity, so inhibitor titer is 100 BU

  18. Bethesda Assay 50% Residual factor activity 100 BU 1:1 1:10 1:100 1:1000 dilution pt plasma

  19. TREATMENT OF HEMOPHILIACS WITH INHIBITORS • Recombinant factor VIIa • FEIBA (Factor Eight Inhibitor Bypassing Activity) • Mixture of partially activated vitamin K-dependent clotting proteases including VIIa • High dose factor VIII (if low titer inhibitor) • Induction of tolerance with daily factor VIII infusions • Optimal dose not established • Role for concomitant immunosuppression?

  20. Liver disease in hemophilia • Hepatitis C still a problem, though incidence falling with safer factor concentrates • Treatment for hepatitis C with interferon often causes thrombocytopenia • Liver transplantation done occasionally (cures hemophilia) • All newly diagnosed hemophiliacs should be vaccinated against hepatitis A and B

  21. ACQUIRED FACTOR VIII DEFICIENCY • Due to antibody to factor VIII (most common autoimmune factor deficiency) • Most patients elderly • Often presents with severe soft tissue or mucosal bleeding (different bleeding pattern than inherited hemophilia) • Laboratory: prolonged aPTT not corrected by mixing, very low factor VIII activity • Normal INR, thrombin time and platelet count • Treatment: rVIIa, FEIBA, immunosuppression

  22. VON WILLEBRAND DISEASE • Common (most common?) inherited bleeding disorder • Partial lack of VWF causes mild or moderate bleeding tendency • Menorrhagia, bleeding after surgery, bruising • Typically autosomal dominant with variable penetrance • Laboratory: • Defective platelet adherence (PFA-100) or long bleeding time • Subnormal levels of von Willebrand antigen and factor VIII in plasma • Low Ristocetin cofactor activity or VWF activity

  23. VON WILLEBRAND DISEASE • Type 1 – decreased production of vWF • Levels 20-50%, antigen ≈ activity • Type 2 – qualitative defect (missense mutation) • Several different types • Usually a disproportionate decrease in vWF activity vs antigen • Type 3 – severe deficiency • Antigen, activity and factor VIII levels < 10% • Hemophilia-like phenotype • Recessively inherited

  24. Type 2 vWD • 2A: Selective deficiency of large multimers • Defective assembly • Increased susceptibility to proteolysis • 2B: Increased affinity for platelet Gp Ib • Large multimers bind spontaneously to platelets and cleared from blood • Rarely, a mutation in Gp Ib may have the same effect (“platelet-type” vWD) • 2M: Decreased vWF function but no loss of large multimers • 2N: Decreased binding of factor VIII to vWF (recessive)

  25. Weibel-Palade body (arrows) in the cytoplasm of endothelial cell. N - nucleus. Scale = 100 nm. (Human, skin.)

  26. Desmopressin (DDAVP) in vWD • DDAVP releases vWF from endothelial cells • Can be given IV or intranasally • 0.3 mcg/kg IV, or 150 mcg per nostril • Typically causes 2-4 fold increase in blood levels of vWF (in type 1 vWD), with half-life of 8+ hours • Response to DDAVP varies considerably • Administration of a trial dose necessary to ensure a given patient responds adequately • Peak response • Duration of response

  27. Indications for clotting factor concentrate administration in vWD • Type 2 or 3 vWD • Active bleeding • Surgery or other invasive procedure • Type 1 vWD with inadequate response to DDAVP

  28. Acquired von Willebrand disease • Monoclonal gammopathy: vWF neutralized by paraprotein (?) • Autoimmune disorders: Autoantibody to vWF • Myeloproliferative disorder: large multimers absorbed onto neoplastic cells (platelets?) • Cardiovascular diseases (AS, VSD, etc): High shear stress causes unfolding/proteolysis of large multimers • Hypothyroidism: Decreased release of vWF from endothelial cells • Treatment varies depending on cause/mechanism

  29. ACQUIRED VON WILLEBRAND DISEASE NEJM 2009;361:1887

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