Healthcare - West Virginia State Medical Association

Special Article |population per year of acquiredhemophilia A. 7-8 In another survey,it was found that most of thepatients were over age of 50, exceptfor women who were pregnant orpostpartum. The major identifiablecauses were pregnancy or thepostpartum period, rheumatoidarthritis, malignancy, drug reactions,systemic lupus erythematosusand other autoimmune disorders.However, in almost half of thecases no underlying disorder waspresent. Our first patient waspostpartum with no other obviousunderlying cause. In the secondpatient, no underlying cause wasfound. On multivariate analyses,factors predicting improved overallsurvival were attainment of completeremission, age less than 65 andpostpartum status. 9 Our first patientmeets all three criteria and thesecond meets two of the three criteriafor improved survival. The risk ofdeveloping an inhibitor is greatestafter first delivery. 10 The median timeto acquire an inhibitor after deliverywas two months in this study witha range of less than 1 month to 12months. Our first patient, with noother obvious underlying cause,developed acquired hemophilia A 3months after her second delivery.The hallmark of Factor VIIIinhibitor is bleeding. Symptomaticpatients often present with largehematomas, extensive ecchymoses orsevere mucosal bleeding includingepistaxis, gastrointestinal bleeding,and gross hematuria. In womenwho were postpartum, soft tissuebleeding was the most commonpresenting symptom followed byintramuscular, vaginal, intraarticularbleed and hematuria. 2 Our patientshad soft tissue and intramuscularbleeding at the time of presentation.The treatment of this conditionconsists of two steps, control ofbleeding and elimination of theinhibitor. 11,12 Treatment strategiesto control active bleeding includethe use of desmopressin (DDAVP),Factor VIII concentrate, activatedprothrombin complex or APC(FEIBA – Anti-inhibitor coagulantfactor), and Recombinant VIIa(NovoSeven). 3,11‐15 Patient with nonlife threatening bleeding and lowinhibitor titers (less than 5 Bethesdaunits) may respond to DDAVP (0.3mcg/kg/d x 3-5 days) or intravenousFactor VIII concentrate in highdoses. For patients with high titerinhibitor, APC or Recombinant FactorVIIa should be employed. Our firstpatient had a moderately high titerinhibitor that did not respond toFactor VIII concentrate and requiredFactor VIIa infusions. Eliminatingthe inhibitor most often requiresimmunosuppressive therapy.Prednisone and cyclophosphamideare the first line agents followed byIVIG, 16 Rituximab, Cladarabine andCyclosporine. 17-18 In a randomizedtrial of 14 patients, variousimmunosuppressive regimens withprednisolone, cyclophosphamide,or both reduced the inhibitor titersto undetectable levels in 68% ofpatients with low-titer inhibitors (lessthan 5 BU/mL). 19,20 The responseto chemotherapy, especially inhigh-titer patients, may requireseveral months. A meta-analysisby Delgado et al of 245 inhibitorpatients focused on the response tovarious treatments and prognosticfactors. 21 Patients in whom theinhibitor could not be eliminated hada mortality rate of 42%, providinga strong argument for rapid andlong-term inhibitor eliminationas part of treatment. The metaanalysisshowed an overall mortalityrate of up to 16% for varioustreatment regimens and a highrate of complications, which weremainly associated with infectionsrelated to chemotherapy-inducedneutropenia. The leading causeof death in patients with acquiredhemophilia is not the bleeding itselfbut the complications that occur asa result of extended bleeding andits treatment, such as surgery forcompartment syndrome, transfusionrelatedreactions, and infectionscaused by prolonged chemotherapy,particularly in elderly patients. 22Despite the low estimatedincidence of the disease, it is adevastating disorder, and the costsof treatment can be immense.Therefore, there is considerableinterest in improving and optimizingexisting treatment regimens. Longtermimmune tolerance induction(ITI) may be effective in acquiredhemophilia. The modified Bonn-Malmo¨ Protocol (MBMP) for thetreatment of acquired hemophilia,published in 2004, involves thecombination of 4 therapeutic steps:(1) immunoadsorptive inhibitorremoval, (2) high-dose Factor VIIIadministration, (3) Intravenousimmunoglobulin (IVIG), and (4)immunosuppressive medication.MBMP protocol incorporatesimmunoadsorption in additionto conventional treatment. In all35 patients in their study, theacute bleeding episodes wererapidly controlled within the first2 to 3 apheresis procedures, andno subsequent episodes wereencountered and the completeremission (CR) was 97%. Theyattribute the high efficacy of theMBMP to the immunoadsorption.The primary objectives for treatingpatients with acquired hemophiliashould be control of the bleeding andrapid elimination of the inhibitor. Theinhibitor in our patients responded toIVIG and corticosteroids initially butrelapsed when steroids were tapered.The first (postpartum) patient thenresponded to a second course ofhigh dose steroids and simultaneoustreatments with Rituximab (amonoclonal antibody directed againstthe CD20 antigen on B-lymphocytes).The second patient required theaddition of oral cyclophosphamideto eliminate the inhibitor.In conclusion the sudden presenceof large hematoma or extensiveecchymoses especially in the elderlyor in postpartum women withoutsignificant trauma or known bleedingdisorder should raise suspicion ofan acquired Factor VIII inhibitor.Since the lupus anticoagulant mayoccasionally be associated with thepresence of a Factor VIII inhibitor,it is important to exclude the coexistenceof these entities in any34 West Virginia Medical Journal