2003; baxter - Supplements - Haematologica

[Acquired Inhibitors in Non-Hemophiliacs]review paperManagement of severehemorrhage and inhibitor-eliminationin acquired hemophilia:the modified Heidelberg-Malmöprotocolhaematologica 2003; 88(suppl. n. 12):86-92http://www.haematologica.org/free/immunotolerance2001.pdfA. HUTH-KÜHNE, P. LAGES, H. HAMPEL, R. ZIMMERMANNKurpfalzkrankenhaus and Haemophilia Center, Heidelberg,GermanyThe overall goals in the treatment of patients withacquired hemophilia are the management of acutebleeds and permanent inhibitor elimination. A newtreatment option, represented by the modified Heidelberg-Malmöprotocol (MHMP), has been successfullyapplied to 8 patients with acquired hemophiliaand severe bleeding complications. It consistsof long-term immunoadsorption (IA) by Ig-apheresisin combination with high-dose factor VIII (FVIII),intravenous immunoglobulin (IVIG) between adsorptioncycles, and immunosuppressive therapy withcyclophosphamide and prednisolone to avoidautoantibody rebound. This treatment was continueduntil patients maintained normal FVIII:C levelswithout replacement therapy. Acute bleeding wascontrolled in all patients following the application ofrecombinant factor VIIa (rFVIIa). With this new protocol,which combines 4 immuno-modulatory strategies,inhibitors were eliminated in all cases and allpatients continue to be in remission.Correspondence: Dr A. Huth-Kühne, Kurpfalzkrankenhaus andHaemophilia Center, Bonhoefferstraße 5 D 69123 Heidelberg,Germany. Phone: international +49.06221.884088.Fax: international +49.06221.88401.E-mail: angela.huth-kuehne@kkh.srh.deAcquired hemophilia is a rare but sometimeslife-threatening bleeding condition causedby autoantibodies depleting circulatingFVIII. Autoantibodies to FVIII:C constitute themost common spontaneous inhibitor to anycoagulation factor and arise in patients with previouslynormal FVIII:C activity in association witha diverse variety of clinical settings. Inhibitor formationis rare with an incidence of 0.2-1 per onemillion persons per year, 1 although clinical experiencesuggests, that this condition was either previouslyunderdiagnosed or is increasing in incidence.These autoantibodies often occur as anepiphenomenon of autoimmune disorders andmay represent a component of immune dysfunction.Conditions associated with spontaneousinhibitor formation include rheumatoid arthritis,bronchial asthma, myasthenia gravis, systemiclupus erythematosus, as well as postpartum periodand malignancies. 2-5 However, in approximately50% of cases no underlying disease isfound. 1,6Concerning pharmacokinetics, there is a significantdifference between allo- and autoantibodies.Alloantibodies to FVIII:C (type I), whichcan develop in response to replacement therapy inpatients with congenital hemophilia, display atype I reaction kinetic with a linear and completeinactivation of FVIII. In contrast FVIII autoantibodies(type II) inactivate endogenous FVIII in anon linear and incomplete fashion and display acomplex type II inhibition kinetic. 7,8 As a resultthere may be no correlation between inhibitortiter, FVIII activity and the severity of bleeding.Inhibitors are quantified using the Bethesdaassay,which depends on the measurement ofresidual FVIII activity and a linear inhibitionkinetic. Therefore quantitation of type IIinhibitors is very arbitrary, because the inhibitorneither inactivates FVIII completely nor becomessaturated with FVIII and the in vivo inhibitorpotency may be underestimated. 7,8 These propertiescorrespond to the clinical situation, that lowlevels of FVIII may still be detectable despite theconcomittant presence of a high titer inhibitorand extensive bleeding. Recovery and half-life ofinfused FVIII may be significantly reduced evenhaematologica vol. 88(supplement n. 12):september 2003