2003; baxter - Supplements - Haematologica

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28E. Berntorp et al.and the scheduled 60 patients is still a substantialsized cohort for this kind of disease. Anotherapproach to gain more study material wouldbe to study more than two bleeds in each patient.This approach, however, would introduce anotherbias as the patient then would have previousexperience of both drugs provided that each bleedis randomized and, depending on the response tothe treatment, the patients may prefer one of theproducts when the third and forth bleeds occur.The FENOC study should be considered as abasic study in order to gain more knowledgeabout bypassing agents, their effects and the possibilityof predicting efficacy based on in vitroassays. The FENOC study, which is in progress ina number of sites in Europe and the US, has thepotential to provide a platform for future studieson the treatment of acute bleeds in patients withinhibitors.AcknowledgmentsThis study was supported by grants from BaxterBioScience, Malmö University Hospital andthe county of Scania.References1. Gruppo R, Bray GL, Schroth P, Perry M, Gompers ED.The Recombinant factor VIII (Recombinate) in previouslyuntreated patients (PUPs): a 6.5 year update.Thromb Haemost 1997; 162 Suppl:a[abstract PD-663].2. Rothschild C, Laurian Y, Satre EP, Borel Derlon A, ChambostH, Moreau P, et al. French previously untreatedpatients with severe hemophilia A after exposure torecombinant factor VIII : incidence of inhibitor and evaluationof immune tolerance. Thromb Haemost1998;80:779-83.3. Lusher JM, Shapiro A, Gruppo R, Bedrosian CL, NguyenK. Safety and efficacy in previously untreated patients(PUPs) treated exclusively with B-domain deleted factorVIII (BDD rFVIII). The ReFacto PUP Study Group.Thromb Haemost 2001; Suppl:a[abstract 2558].4. Ehrenforth S, Kreuz W, Scharrer I, Linde R, Funk M,Gungor T, et al. Incidence of development of factor VIIIand factor IX inhibitors in haemophilias. 1992;339:594-8.5. Yee TT, Williams MD, Hill FGH, Lee CA, Pasi JK.Absence of inhibitors in previously untreated patientswith severe haemophilia A after exposure to a singleintermediated purity factor VIII product. ThrombHaemost 1997;78:1027-9.6. Hilgartner M, Aledort L, Gill AJ, and the members of theFEIBA Study Group. Efficacy and safety of vapor-heatedanti-inhibitor coagulant complex in hemophiliapatients. Transfusion 1990;30:626-30.7. Negrier C, Goudemand J, Sultan Y, Bertrand M, RothschildC, Lauroua P. Multicenter retrospective study onthe utilization of the FEIBA in France in patients withfactor VIII and factor IX inhibitors. The members of theFrench Feiba study group. Thromb Haemost 1997;77:1113-9.8. Ingerslev J, Thykjaer H, Kudsk Jensen OK, Fredberg U.Home treatment with recombinant factor VIIa: resultsfrom one centre. Blood Coagul Fibrinolysis 1998; Suppl1:S107-10.9. Lusher J, Ingerslev J, Roberts H, Hedner U. Clinical experiencewith recombinant factor VIIa. Blood Coagul Fibrinolysis1998;9:119-28.10. Hemker HC, Beguin S. Thrombin generation in plasma:its assessment via the endogenous thrombin potential.Thromb Haemost 1995;74:1388.11. Hedner U. Recombinant factor VIIa (NovoSeven) as ahemostatic agent. Dis Mon 2003;49:39-48.12. Abshire TC, Brackmann HH, Scharrer I, Hoots K,Gazengel C, Powell JS, et al. Sucrose formulated recombinanthuman antihemophilic Factor VIII is safe andefficacious for treatment of hemophilia A in home therapy(results of a multinational, international, clinicalinvestigation). Thromb Haemost 2000; 83:811-6.13. Bray GL, Gomperts ED, Courter S, Gruppo R, GordonEM, Manco-Johnson M, et al. A multicenter study ofrecombinant factor VIII (recombinate): safety, efficacy,and inhibitor risk in previously untreated patients withhemophilia A. The Recombinate Study Group. Blood1994;83:2428-35.14. Berntorp E. Second generation, B-domain deletedrecombinant factor VIII. Thromb Haemost 1997; 78:256-60.haematologica vol. 88(supplement n. 12):september 2003
[Round Table on Immune Tolerance Treatment]review paperAntibody reactivity to factorVIIa may impede the effect ofby-passing agents in patientswith hemophilia Bhaematologica 2003; 88(suppl. n. 12):29-33http://www.haematologica.org/free/immunotolerance2001.pdfJAN ASTERMARK, ERIK BERNTORPDepartment for Coagulation Disorders, University of Lund,Malmö, SwedenWe studied patients with hemophilia B and highrespondingfactor IX inhibitors to detect possiblecross-reactivity with other vitamin K-dependent procoagulantfactors due to the structural similarity ofthe proteins. The aim was to explain why the hemostaticeffect of by-passing agents such as activatedprothrombin complex concentrates (aPCC) andrecombinant factor VIIa is inadequate in somepatients. Immunoglobulins (Igs) from three patientswere separately purified on protein A sepharose andthen subjected to immunoaffinity chromatographyon factor IX- and factor VIIa sepharose. All three Igfractions, but not commercially available Ig, containedantibodies that bound to both gels. The Igfractions and the immunoaffinity purified anti-factorIX and VIIa antibodies inhibited thrombin formationin a plasma system using Feiba‚ (12 mU/mL) asactive enzyme, but had little effect in the presenceof NovoSeven‚ (18 U/mL). Minor inhibition of factorXa formation also occurred in a system containingpurified proteins. The divergent effect of the twoproducts may be due to the availability of varyingamounts of factor VIIa for neutralization by the antibodies.Our findings are of unknown clinical significancebut may suggest characterization of the antibodyprofile of individual inhibitor patients to optimizethe type and dose of the agent used to treatsevere bleeds.©2003, Ferrata Storti FoundationKey words: hemophilia B, inhibitors, antibodies,by-passing agents, factor VIIa.Correspondence: Jan Astermark, M.D. Ph.D., Department forCoagulation Disorders, University Hospital, SE-205 02 Malmö,Sweden. Phone: international +46.40.332392. Fax: international+46.40.336255. E-mail:jan.astermark@medforsk.mas.lu.seDevelopment of inhibitory antibodies inpatients with hemophilia still representsa major challenge in regard to both eradicationof the inhibitor and treatment of bleedingepisodes. 1,2 In the case of major bleeds, bypassingagents such as activated prothrombincomplex concentrates (e.g. Feiba ® ‚ and Autoplex® , Baxter) or recombinant factor VIIa(NovoSeven‚ ® Novo-Nordisk) are needed andboth agents seem to be effective in 80-90% of allhemorrhages in inhibitor patients. However,some patients still do not achieve an adequatehemostatic response. 3-7 The reason for this is notyet known.Factor IX is structurally very similar to the othervitamin K-dependent procoagulant factors i.e.factor VII, factor X and prothrombin. 8 In addition,inhibitory antibodies that may develop inpatients with hemophilia in response to giventreatment are known to be synthesized by differentclones. Thus, from a structural point ofview, it would not be surprising if antibodiesagainst factor IX in patients with hemophilia Bwere to cross-react with one or more of the othervitamin K-dependent coagulation factors andthereby to some extent possess the capacity toreduce the hemostatic effect of factor VIIaand/or activated prothrombin complex concentrates(aPCCs). We conducted an investigationto ascertain whether Ig fractions from hemophiliaB patients with high-responding factor IXinhibitors exhibit antibody reactivity to other vitaminK-dependent proteins including factorVIIa. We also evaluated the effect of these antibodieson the formation of factor Xa and thrombinin vitro before and after immunoaffinitychromatography.Materials and MethodsMaterialsRecombinant factor VIIa (NovoSeven ® ) wasfrom Novo Nordisk A/S. Recombinant albuminfreefactor VIII was kindly provided by Dr. V. Foster,Baxter, and BeneFIX ® and Feiba ® were purchasedfrom the same company. Purified recombinantfactor VIIa was a generous gift from Dr.Persson, Novo Nordisk A/S. Intravenous immu-haematologica vol. 88(supplement n. 12):september 2003
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