Haemophilia A

Haemophilia AHEMOPHILIAInherited deficiency of factor VIII (hemophilia A) or factor IX (hemophilia B)Sex-linked inheritance; almost all patients maleFemale carriers may have mild symptomsMost bleeding into joints, muscles; mucosal and CNS bleeding uncommonSeverity inversely proportional to factor level< 1%: severe, bleeding after minimal injury1-5%: moderate, bleeding after mild injury> 5%: mild, bleeding after significant trauma or surgery

HEMOPHILIATreatment of bleeding episodesUnexplained pain in a hemophilia should be considered due to bleeding unless proven otherwiseExternal signs of bleeding may be absentTreatment: factor replacement, pain control, rest or immobilize jointTest for inhibitor if unexpectedly low response to factor replacementDosing clotting factor concentrate1 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 hoursVolume of distribution of factor IX about twice as high as for factor VIIISteady state dosing about the same for both factors initial dose of factor IX should be higher

Give factor q 12 hours for 2-3 days after major surgery, continue with daily infusions for 7-10 daysTrough factor levels with q 12 h dosing after major surgery should be at least 50%Most joint and muscle bleeds can be treated with minor (50%) doses for 1-3 days without monitoringHEMOPHILIAHEMOPHILIAFactor replacement in severe hemophilia ASite of bleedDesired factor levelDoseOtherJoint40-50%20-40 U/kg/day Rest, immobilization, PTMuscle40-50%20-40 U/kg/dayRisk of compartment syndrome or neuro compromiseOral mucosa50% initially25 U/kg x 1Follow with antifibrinolytic therapyEpistaxisInitially 80-100%, then 30% until healed40-50 U/kg then 30-40 U/kg dailyPressure, packing, cauteryGIInitially 100%, then 30% until healed40-50 U/kg then 30-40 U/kg dailyEndoscopy to find lesionGUInitially100%, then 30% until healed40-50 U/kg then 30-40 U/kg dailyR/O stones, UTICNSInitially100%, then 50% until healed50 U/kg then 25 U/kg q 12h infusionTrauma or surgeryInitially100%, then 50% until healed50 U/kg then 25 U/kg q 12h infusionTest for inhibitor before surgery!FACTOR VIII CONCENTRATERecombinantVirus-free, most expensive replacementTreatment of choice for younger/newly diagnosed hemophiliacsSomewhat lower plasma recovery than with plasma-derived concentrateHighly purifiedSolvent/detergent treated, no reports of HIV or hepatitis transmissionIntermediate purity (Humate-P)Contains both factor VIII and von Willebrand factorSolvent/detergent treated, no reports of HIV or hepatitis transmissionMainly used to treat von Willebrand diseaseFACTOR IX CONCENTRATERecombinant (slightly lower plasma recovery)Highly purified (solvent/detergent treated, no reports of virus transmission)Prothrombin complex concentrateMixture of IX, X, II, VIILow risk of virus transmissionSome risk of thrombosis Mostly used to reverse warfarin effect DDAVPReleases vWF/fVIII from endothelial cellsFactor VIII levels typically rise 2-4 fold after 30-60 min (IV form) or 60-90 min (intranasal)Enhanced platelet adhesion due to vWFUseful for mild hemophilia (VIII activity > 5%) prior to dental work, minor surgery etcTrial dose needed to ensure adequate responseCardiovascular complications possible in older patientsInhibitor formation in hemophiliaMore common in hemophilia A< 1% of hemophilia B patients develop inhibitors7-10 x more common in severe hemophiliaAbout 30% of patients with intron 22 inversion develop inhibitorsOther genetic factors also involvedBethesda Assay for InhibitorsSerial dilutions of patient plasma in normal plasmaIncubate 2 hoursAssay residual factor activity1 Bethesda Unit neutralizes 50% of factor in an equivalent volume of normal plasmaExample: 1:100 dilution of patient plasma + normal plasma 50% residual factor activity, so inhibitor titer is 100 BUBethesda AssayResidual factor activitydilution pt plasma50%1:11:101:1001:1000100 BUTREATMENT OF HEMOPHILIACS WITH INHIBITORSRecombinant factor VIIaEnhances TF-driven thrombin formationFEIBA (Factor Eight Inhibitor Bypassing Activity)Mixture of partially activated vitamin K-dependent clotting proteases including VIIaHigh dose factor VIII (if low titer inhibitor)Induction of tolerance with daily factor VIII infusionsOptimal dose not establishedRole for concomitant immunosuppression?Liver disease in hemophiliaHepatitis C still a problem, though incidence falling with safer factor concentratesTreatment for hepatitis C with interferon often causes thrombocytopeniaLiver transplantation done occasionally (cures hemophilia)All newly diagnosed hemophiliacs should be vaccinated against hepatitis A and B

Hemophilia: carrier testingFactor level alone should not be usedVIII:VWF ratio may be helpfulDNA testing should be done if possibleIdentification of causative mutation in an affected relative helpful, particularly for families with missense mutationsACQUIRED FACTOR VIII DEFICIENCYDue to antibody to factor VIII (most common autoimmune factor deficiency)Most patients elderlyOften 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 activityNormal INR, thrombin time and platelet countTreatment: rVIIa, FEIBA, immunosuppression