hemophilia


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1 : Hemophilia Dr Chitra james
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4 : Inherited bleeding disorder caused by deficiency of factor viiii or factor ix X linked recessive inheritance hence affect males exclusively. Incidence in Hemophilia A 1 in 5000 male live births Incidence in Hemophilia B 1 in 30,000 male live births
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6 : Genetics in Hemophilia Familial or sporadic mutation Inversion in the intron 22 of factor viii gene – most common mutation Diagnosis can be made by CVS, cordocentesis at 18-20 weeks by molecular biological techniques like RFLP, gel electrophoresis etc. Cord blood factor viii or factor ix assay can be done. Leyden phenotype of Hemophilia B severe hemophilia in childhood that becomes mild after puberty
7 : Clinical Features Clinically indistinguishable. Perinatally presents as sub galeal or intracranial hemorrhage. Median age of presentation 9 months in severe hemophilia. Moderate 22 months & mild 14-62 yrs. Spontaneous hemarthrosis most common presentation almost diagnostic.
8 : Recurrent hemarthrosis then progresses to painful & debilitating arthropathy. One joint affected at a time, target joint-Fibrosis,contracture,pain & limitation of movts Bleeding into muscles next common presentation. Epistaxis,Oral mucosal bleed, GI tract bleed, hematuria.
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12 : CLASSIFICATION
13 : LAB FINDINGS aPTT prolonged Bleeding time ,platelet count, thrombin time and prothrombin time are normal. Factor viii & ix assays are diagnostic. Plasma mixing studies are useful unless inhibitors have developed. Inhibitor titre is quantitatively measured – BETHESDA assay.
14 : MANAGEMENT Optimal management complex Preventive care Replacement therapy Treatment of complications of disease and therapy.
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16 : Evolution of Treatment Fresh frozen plasma Cryo precipitate – f viiii,fibrinogen,vwf,factor xiii increased risk of blood borne infections storage temperature -20 to -30 needed marked variation in content of factorviii & vwf Virus attenuation & reduction done
17 : Plasma derived Factor viii concentrates Plasma derived factor viiii products of intermediate , high & ultra high purity were developed depending on the IU of clotting factor activity per mg of product.Albumin was the stabilizer in earlier generations. Humate P, Alphanate , Monoclate P Still risk of transfusion transmitted infections could not be ruled out.
18 : Recombinant factor VIII Developed by molecular cloning of c DNA encoding human factor VIII scale up , purification & standardisation done First generation – Bioclate, Kogenate Same pharmacokinetics & effectiveness as plasma derived products Albumin present as stabilizer-could transmit disease
19 : SECOND GENERATION Kogenate F S , refacto B Domain Depleted factor viii no serum albumin in final product sucrose instead of albumin Dis adv- one stage aPTT based assays gave 50% of expected values in recepients plasma Chromogenic substrate assays gave correct results THIRD GENERATION- advate no human or animal proteins either in initial stages of preparation & final formulation.
20 : Indications of factor VIII Acute hemarthrosis Intramuscular bleed Prevent and reduce complications Prophylaxis Immune Tolerance Induction in patients with inhibitors
21 : DOSAGE & ADMINISTRATION 1 IU of factor VIII/kg body weight will raise patients factor VIII levels by 2% Reqd units= body wt(kg) x desired factor viii rise %x 0.5 IU/kg Major bleeding episode : continous infusion of F VIII after initial bolus of 40-50 IU/g -80-100% continous infusion of 2 IU/kg/hr 25% target level
22 : PROPHYLAXIS Primary : prevent spontaneous hemorrhage first began at MALMO centre. Usually given for those with levels < .01 IU/ml Target conc >1% factor viiii two infusions / week Factor ix three times/week 48 hrs half life Secondary : prevent joint damage in youg boys with hemophilia.
23 : Hemophilia B PCC containing vit K dependent clotting 2,7,9,10,protein C ,protein S Activated factors may precipitate DIC So high purity F ix concentrates prepared less thrombogenic Recombinant Factor IX no albumin & human products were used. Benefix,wyeth,collegeville No evidence of inhibitor development , allergic reaction, thrombosis.
24 : Dosage & administration Factor IX smaller molecule diffuses from intravascular to extra vascular site- larger dose required 1 IU/kg of Factor IX will raise circulating level by 1 % Reqd Factor IX = body wt (kg) x desired factor IX rise % Recombinant factor IX decreased recovery with respect to plasma derived factor IX
25 : TREATMENT OPTIONS DDAVP( desmopressin) Treatment of choice in mild hemophilia A Increase 3-5 fold 30-60 mins after administration Required dose 0.3microgram/kg given IV 8-12 hrs Repeated doses – Tachyphylaxis ( diminishing response) Undesired side effects : Facial flushing,facial warmth,w/f hyponatremia & water intoxication Intranasal spray 150 micro gram desmopressin in metered pump.
26 : Antifibrinolytic agents EACA & Tranexamic acid inhibit plasminogen activation EACA 75 mg/kg every 4-6 hrly orally. Tranexamic acid after loading dose of 100 mg/kg 25 mg/kg Q6H Other options Hep B & Hep A vaccinations Avoid drugs causing platelet dysfunction-aspirin,antihistamines,indometthacin
27 : Inhibitors 25-35% with hemophilia A develop inhibitors 2-5% with Hemophilia B Anaphylaxis can occur in 5% patients with F IX inhibitors, nephrotic syndrome can occur. Less common in mild or moderate disease. Typically develop in early childhood within first 10-20 exposure to exogenous factor viii Bleeding difficult to control.
28 : Inhibitor titre in Bethesda units. High response inhibitor > 5 BU/ml (50%) Low response inhibitor < 5 BU /ml Occurs within first 20 days of exposure to factor viii.
29 : Management Treat bleeding Eliminate inhibitor Monitoring and management of anaphylaxis to factor ix concentrates Low responders- Factor viiii concentrtes in usual or increased dosages coz anamnestic response minimal.
30 : TREATMENT OF INHIBITORS PROTHROMBIN COMPLEX CONCENTRATES standard PCCs largely replaced by activated products Recommended dose of FEIBA is 50-75 IU/kg every 12-24 hrs for 3-5 days Used in treating acute bleeding,perioperative control of bleeding,prophylaxis for patients with inhibitors.
31 : Porcine Factor viii concentrates Polyelectrolyte porcine factor viii Allergic reactions can happen generally mild. Viral contamination with parvovirus B 19 Permits the measurement of Factor viii levels in recepients.
32 : Recombinant factor viia Inhibitors with life threatening bleeding episodes Prophylaxis for joint bleeding Hemophilia b with allergy to Factor ix concentrates. Concentrations of factor viiia mediate tissue factor independent conversion of factor x to factor xa rFactor viia induces hemostasis by enhancing thrombin generation on thrombin activated platelet surface Recommended dose 90 microgram/kg/dose IV with repeat dosing 2-3 hrs Risk of thromboembolism less.
33 : Staphylococcal protein A immunoabsorption of inhibitors To rapidly reduce a very high titre Decrease inhibitor titre in preparation of immunotolerance regimens.
34 : Immune tolerance regimens Bonn regimen – large & frequent doses of factor viiii Optimal time when inhibitor titre is < 10 BU best accomplished by avoiding exposure to factorviii Good risk & poor risk cases Gene therapy – transfect targetted tissues with nucleic acid to replace mutated area of genome.
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