2003; baxter - Supplements - Haematologica

80L. Hess et al.the chromogenic assay yielded a factor VIII activitywhich did not reflect in particular the clinicalaspect, i.e. the degree of bleeding diathesis. Thetwo measuring methods will only converge uponreaching a normal range of FVIII plasma activityin the one-stage clotting assay.The only treatment objective accepted was successfulinhibitor elimination. Successful inhibitorelimination was defined, for the above reasons, asthe normalization of factor VIII plasma levelsboth in the one-stage clotting assay and in thechromogenic assay. Factor activity had to bedemonstrated permanently over 100% for bothmethods without requiring any supportive factorVIII substitution or other drug therapy (immunosuppression,IgG administration).A single negative inhibitor test alone was notincluded in the definition as negative inhibitorresults were usually measured even at pathologicalfactor VIII activity.As soon as the patient’s clinical conditionallowed, diagnosis was performed with regard toinhibitor-associated disease, the main focusbeing on causal tumor disease.Total patient populationBetween 1986 and July 2001, we treated 24patients suffering from acutely life-threateninghigh-titer inhibitor against factor VIII (age: median69; mean 64.9; maximum 89; minimum 30years). Inhibitor titer at the beginning of treatment:median 61; mean 273.3; max. 3556; min.5 Bethesda units; women: 13, men: 11).All patients had a life-threatening bleedingwhich in most cases consisted in extensive truncalor soft-tissue bleedings. These caused problemsdue to displacement symptoms, e.g. compartmentsyndrome, obstruction of the airways,nerve lesions and secondary infection of hematomas.All 24 patients were examined forinhibitor-associated diseases. We diagnosed fourcollagenoses, three postpartal courses, three carcinomas(two prostate and one pulmonary carcinoma)as well as one Hashimoto’s autoimmunethyreoiditis as inhibitor-associated diseases.In 13 patients there was no indication oftypical inhibitor-associated disease.Patients treated using conventional strategiesFive patients with high-titer inhibitor againstfactor VIII (age: median 79, mean 76.7, maximum87, minimum 62) (inhibitors at initiationof treatment: median 51.5, mean 104, maximum308, minimum 5) (women: 3, men: 2) initiallyreceived immunosuppressive or immunomodulatorytreatment only. Two of those patients wereadditionally treated according to the Bonn Protocol.At the beginning of treatment, all patientsexhibited life-threatening bleeding. Threepatients who were refractory or suffered a relapsewere started on a therapy according to the MBMProtocol (Figure 1).Patients treated according to the MBMProtocolSince 1996 we have treated 22 patients accordingto the MBM Protocol, all of whom had hightiterinhibitor against factor VIII and sufferedfrom life-threatening bleeding at the beginningof treatment (Figure 1). The patient populationconsisted of ten men and twelve women with amean age of 64.7 years (median 69, maximum89, minimum 30 years). The highest inhibitortiter measured during inhibitor treatment was8,400 BU (median 63; maximum 8,400; minimum15).Results of the MBM ProtocolOf the 22 patients who suffered from high-titerfactor VIII inhibitor, 17 were able to completethe entire treatment protocol and were treateduntil total inhibitor elimination. Four patientshad to be excluded due to secondary underlyingdiseases even though they were responding wellto the therapy, with negative inhibitor test orreduction of inhibitor activity to below 10 BU.Despite all efforts, one patient could not be treatedsuccessfully under this treatment protocol.The following is the exemplary course of treatmentof 53-year-old female patient M.E., whosuffered from high-titer inhibitor (110 BU). Thepatient exhibited extensive soft-tissue hematomasof the trunk, the extremities and the face.In addition, she developed a compartment syndromeat the right lower leg during her stay at thereferring hospital. Rapid diagnosis and immediateinitiation of treatment using the MBM Protocolrendered the use of APCC or recombinantfactor VIIa unnecessary. The curve in Figure 2illustrates factor VIII increase, which had initiallybeen below 1% plasma activity, during thecourse of the MBM Protocol. The trianglesdepicted symbolize the days on which immunoadsorptionwas performed. The squares depictedsymbolize the days on which immunoglobulinswere applied. During the entire treatment cyclethe patient received oral prednisolone and cyclophosphamide.During the MBM Protocol wewere able to measure inhibitor titer reductionfrom 110 BU in parallel to the increase of factorVIII plasma activity. Factor VIII inhibitor was nolonger detectable on day 7 of treatment. Thedosages of factor VIII are illustrated in Figure 3.Application was performed depending on thepatient’s clinical condition as well as on the factorVIII plasma activity detected. The markeddecrease of factor VIII plasma activity upon stoppingthe application of exogenous factor VIII wascompensated for by repeating immunoadsorptionon days 19 and 21. The outcome of treatment,which is illustrated here, is representativefor all 17 patients who were able to complete theentire treatment protocol.In patients with life-threatening bleeding eventswe have to differentiate four stages until inhibitorelimination within the framework of the MBMhaematologica vol. 88(supplement n. 12):september 2003