2003; baxter - Supplements - Haematologica

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84L. Hess et al.Table 3.ular intervals as specified in the MBM Protocol incombination with immunoadsorption and thecontinued endogenous FVIII synthesis resultedin detectable factor VIII plasma levels within thefirst 1-2 apheresis treatments.In addition, application of exogenous factorVIII creates an antigen stimulus, which ininhibitor patients both of acquired as well as congenitalgenesis results in a booster effect due toincreased lymphocyte proliferation. 27,28 Thisshould also be discussed with regard to an elevatedsensitivity of inhibitor clones towardsimmunosuppressants.A minor booster effect is also observed duringthe first treatment cycle of the MBM Protocol.This is of no clinical relevance in the presence ofdetectable FVIII recovery values. This short-termquantitative increase in inhibitor activity is neutralizedby the patient’s exogenous and endogenousFVIII levels as FVIII plasma activity remainsdetectable and there is clinical proof of a hemostaticeffect. In the end, booster effect is of lowclinical relevance as the inhibitor titers are nolonger detectable after a median of five apheresisdays. Whether or not booster effect is of any elementarysignificance for inhibitor eliminationcannot be decided at present. There is empiricalproof at least of limited effectiveness of prednisoloneand cyclophosphamide in the treatmentof hemophilia patients with alloantibodies asopposed to the treatment of patients withacquired autoantibodies. 25 In the combination ofmeasures (FVIII, immunoadsorption, IgG application)the additional immunosuppressive effectleads to permanent inhibitor elimination. TheFVIII levels measured, as in the case reported, are6-8-12-hour recovery values. We can assumethat after application of FVIII plasma levels arereached which sufficiently explain the earlyhemostatic effect we have observed, even at lowrecovery values. 24 Therapeutic response cantherefore be monitored by determination of FVIIIactivity, apart from the clinical parameters. Ourexperience suggests that the factor VIII activitiesmeasured by one-stage clotting assay are closelyrelated to bleeding tendency and its decrease duringthe MBM Protocol.This type of factor VIII determination allowsmonitoring the treatment of bleedings as well asthe success of therapy, so that treatment can beadjusted as appropriate. Comparable laboratorymonitoring is currently not available for APCC orrFVIIa therapy, or only at an unsatisfactory level.8,29The MBM Protocol consists of two components:the modified Bonn Protocol and the modifiedMalmö Protocol. In the Bonn Protocol, which wasdeveloped in 1974/75, 100-150 factor VIIIunits/kg BW are applied daily until permanentinhibitor elimination. For the Malmö Protocol,the Bonn Protocol was modified, and infusion ofcomparable amounts of factor VIII is preceded byimmunoadsorption if the inhibitor titer exceeds10 BU. As opposed to the Malmö Protocol theMBM Protocol involves long-term immunoadsorptionover several weeks. The target volume tobe absorbed within one apheresis day (2.5 timesthe plasma volume) is reached after 4-5 hours.This permits quick inhibitor reduction and, withthe Therasorb columns used, the binding of allIgG subclasses.In addition, immunosuppressive therapy waschanged from short-term bolus therapy usingcyclophosphamide within the Malmö Protocol tocontinuous oral administration in combinationwith oral prednisolone for up to 6 weeks afterinhibitor eradication.IgG is applied in a changed mode on a regularand standardized basis after several days ofimmunoadsorption.Conclusive assessment is problematic due tothe difficult data situation in current literature.haematologica vol. 88(supplement n. 12):september 2003
IV International Workshop on Immune Tolerance in Hemophilia 85This is due to the low incidence of inhibitor formation.Suggested models for explaining themodes of action of the MBM Protocol presentedhere are of a rather speculative nature. The focusremains on empirical experience and the statedadvantages of the MBM Protocol over conventionaltherapies in the treatment of inhibitorpatients.The working group of Prof. R. Zimmermannand Dr. A. Huthe-Kühne in Heidelberg (Germany)came up with similar results for the treatmentof patients with acquired inhibitors. Theonly difference to the MBM Protocol, whichinvolves bolus injections, is continuous i.v. applicationof factor during the treatment cycle,which proved to be efficient.The life-threatening nature of acquired factorVIII inhibitors necessitates the use of highly efficienttreatment options. We think that if at all,reviewing individual treatment components of theMBM Protocol should be done with great cautionso as not to jeopardize the chances of recovery andthe treatment outcome. In addition, in view ofthe low incidence and the resulting low case numberswe advise against further modification of theprotocol for the time being, in favor of a growingpatient population. Testing the MBM Protocolpresented here at other centers would be appreciated.References1. Lusher JM. Factor VIII inhibitors. Etiology, characterization,natural history, and management. Ann NY AcadSci 1987;509:89-102.2. Cohen AJ, Kessler CM. Acquired inhibitors. BaillièresClin Haematol 1996;9:331-54.3. Lavergne JM, Meyer D, Reisner H. Characterization ofhuman antifactor VIII antibodies purified by immunecomplex formation. Blood 1976;48:931-6.4. Glueck HI and Hong R. A circulating anticoagulant inIgA-multiple myeloma: its modification by penicillin. JClin Invest 1965;44:1866-81.5. Hoyer LW, Gawryl MS and de la Fuente B. Immunochemicalcharacterization of factor VIII inhibitors. ProgClin Biol Res 1984;150:73-85.6. Kessler CM. An introduction to factor VIII inhibitors:the detection and quantitation. Am J Med 1991;91:1S-5S.7. Green D, Lechner K. A survey of 215 non-hemophilicpatients with inhibitors to Factor VIII. Thromb Haemost1981;45:200-3.8. Hay CR, Negrier C and Ludlam CA. The treatment ofbleeding in acquired haemophilia with recombinant factorVIIa: a multicentre study. Thromb Haemost 1997;78:1463-7.9. Sultan Y, Kazatchkine MD, Nydegger U, Rossi F, DietrichG, Algiman M. Intravenous immunoglobulin inthe treatment of spontaneously acquired factor VIII:Cinhibitors. Am J Med 1991;91:35S-9S.10. Green D. Suppression of an antibody to factor VIII by acombination of factor VIII and cyclophosphamide.Blood 1971;37:381-7.11. Green D, Rademaker AW, Briet E. A prospective, randomizedtrial of prednisone and cyclophosphamide inthe treatment of patients with factor VIII autoantibodies.Thromb Haemost 1993;70:753-7.12. Spero JA, Lewis JH, Hasiba U. Corticosteroid therapy foracquired F VIII:C inhibitors. Br J Haematol 1981;48:635-42.13. Lian EC, Larcada AF, Chiu AY. Combination immunosuppressivetherapy after factor VIII infusion foracquired factor VIII inhibitor. Ann Intern Med 1989;110:774-8.14. Shaffer LG, Phillips MD. Successful treatment ofacquired hemophilia with oral immunosuppressivetherapy. Ann Intern Med 1997;127:206-9.15. Nilsson IM, Berntorp E, Zettervall O. Induction ofimmune tolerance in patients with hemophilia andantibodies to factor VIII by combined treatment withintravenous IgG, cyclophosphamide, and factor VIII. NEngl J Med 1988;318:947-50.16. Knöbl P, Derfler K, Korninger L, et al. Elimination ofacquired factor VIII antibodies by extracorporal antibody-basedimmunoadsorption (Ig-Therasorb). ThrombHaemost 1995;74:1035-8.17. Brackmann HH. Induced immunotolerance in factorVIII inhibitor patients. Prog Clin Biol Res 1984;150:181-95.18. Brackmann HH, Oldenburg J, Schwaab R. Immune tolerancefor the treatment of factor VIII inhibitors—twentyyears’ ‘Bonn Protocol’. Vox Sang 1996;70 Suppl 1:30-5.19. Oldenburg J, Schwaab R, Brackmann HH. Induction ofimmune tolerance in haemophilia A inhibitor patientsby the ‘Bonn Protocol’: predictive parameter for therapyduration and outcome. Vox Sang 1999;77:49-54.20. Nilsson IM, Freiburghaus C. Apheresis. Adv Exp MedBiol 1995;386:175-84.21. Freiburghaus C, Berntorp E, Ekman M, Gunnarsson M,Kjellberg BM, Nilsson IM. Immunoadsorption forremoval of inhibitors: update on treatments in Malmö-Lund between 1980 and 1995. Haemophilia 1998;4:16-20.22. Brackmann HH, Gormsen J. Massive factor-VIII infusionin haemophiliac with factor-VIII inhibitor, highresponder. Lancet 1977;2:933.23. Gilles JG, Desqueper B, Lenk H, Vermylen J, Saint-RemyJM. Neutralizing antiidiotypic antibodies to factor VIIIinhibitors after desensitization in patients with hemophiliaA. J Clin Invest 1996;97:1382-8.24. Francesconi M, Korninger C, Thaler E, Niessner H,Hocker P, Lechner K. Plasmapheresis: its value in themanagement of patients with antibodies to factor VIII.Haemostasis. 1982;11:79-86.25. Kessler CM. Acquired factor VIII autoantibodyinhibitors: current concepts and potential therapeuticstrategies for the future. Haematologica 2000;85 Suppl10: 57-63.26. Inhibitor Subcommittee of the association of hemophiliaclinic directors of Canada. Suggestions for themanagement of factor VIII inhibitors. Haemophilia2000;6 Suppl 1:52-9.27. Schroeder JO, Euler HH, Löffler H. Synchronization ofplasmapheresis and pulse cyclophosphamide in severesystemic lupus erythematosus. Ann Intern Med 1995;107:344-6.28. Jarreuse B, Blinchet P, Gayrand M et al. Synchronizationof plasma exchanges and cyclophosphamide in severesystemic diseases. Press Med 1993;22:293-8.29. Hedner U, Glazer S, Falch J. Recombinant activated factorVII in the treatment of bleeding episodes in patientswith inherited and acquired bleeding disorders. TransfusMed Rev 1993;7:78-83.haematologica vol. 88(supplement n. 12):september 2003
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