2003; baxter - Supplements - Haematologica

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32J. Astermark et al.Figure 3. Factor Xa (A and B) and thrombin (C and D) formationin the absence () and presence of anti-factor VIIaantibodies isolated from Ig fractions from patients P1 (),P2 () and P3 (), respectively. In the factor X assays, thefinal concentration of Feiba‚ was 0.5 U/mL (A), NovoSeven ®0.25 U/mL (B) and tissue factor 0.5 ng/mL, whereas theconcentrations used in the thrombin assay were as indicatedin Figure 2. Each reaction was initiated by adding 5mM CaCl2. The amount of factor Xa and thrombin formed ateach time point was measured and expressed as described.The final concentration of the antibodies in Hepes bufferwas approximately 0.1 mg/mL.larity between the two factors. We do not knowwhether the antibodies may have developed secondaryto treatment with factor VII(a) or factorIX concentrates, since all three subjects had beenextensively treated with blood products beforestarting ITI.The antibodies exerted only minor inhibitoryeffects in the system that used purified proteinsto measure the amount of factor Xa formed. Onthe other hand, pronounced inhibition was seenwith both the immunoaffinity-purified anti-factorIX and the anti-factor VIIa antibodies in theplasma-based thrombin assay when using Feiba ®as the active enzyme. Minor or no effects wereseen in the presence of factor VIIa. Consideringthat the reaction was dependent on the additionof tissue factor and that Feiba ® contains muchless factor VIIa than NovoSeven ® it is possiblethat the amount of antibodies in the assays withNovoSeven ® were saturated with an excess of factorVIIa, whereas the smaller amount of factorVIIa in Feiba ® was not enough to saturate and toovercome the neutralizing effect of the antibodies.This would also explain the lower degree ofinhibition seen in the factor Xa assay, since theamount of Feiba ® used was approximately 40-fold higher than in the thrombin assay. Moreover,the 70-fold lower concentration of Novo-Seven ® used in the factor Xa assay may have beenresponsible for the inhibitory effects that weobserved in this system but not in the correspondingthrombin assay.Little is known about the hemostatic mechanism(s)of Feiba ® and the amount of thrombingenerated in our in vitro assay may be dependentnot only on the amount of factor VIIa present,but also on the activity of factor IX in the concentrate.Therefore, the inhibition of thrombinformation that occurred in the presence of thefactor IX antibodies may have been due to directinhibition of factor IX.Taken together, our data support the conceptthat antibody reactivity to factor VIIa might occurin the plasma of hemophilia B patients withhigh-responding inhibitors. These antibodiescould be developed in response to treatment withfactor VII(a) containing products and/or identifieddue to cross-reactivity. Theoretically, theextent to which such antibody reactivity to factorVIIa might influence the hemostatic effect ofboth Feiba ® and NovoSeven ® could depend onthe epitope profile of the patient being treated. Itis difficult to estimate the exact concentration ofthe activated factor(s) at the site of bleeding.Therefore, it is possible that the amount of antibodiesactually present in vivo at a site of injuryis sufficient to exert an inhibitory effect that renderssome patients less responsive to therapy orthat the pharmacokinetic profile of the infusedfactor VIIa could be affected. Our findings suggestthat screening for antibody reactivity to vitaminK-dependent coagulation factors otherthan factor IX might be informative in hemophiliaB patients with high-responding inhibitorsin order to optimize and individualize the typeand dosage of the therapeutic agent used.References1. White GC, Roberts HR. The treatment of factor VIIIinhibitors: a general overview. Vox Sang 1996; 70 Suppl1:19-23.2. Ingerslev J. Hemophilia. Strategies for the treatment ofinhibtor patients. Haematologica 2000; 85 Suppl 10:15-20.3. Hilgartner,M, Aledort L, Gill A. Efficacy and safety ofvapor-heated anti-inhibitor coagulant complex inhemophilia patients. The FEIBA Study Group. Transfusion1990; 30:626-30.4. Negrier C, Goudemand J, Sultan Y, Bertrand M, RothschildC, Lauroua P. Multicenter retrospective study onthe utilization of FEIBA in France in patients with factorVIII and factor IX inhibitors. The French Feiba studygroup. Thromb Haemost 1997; 77:1113-9.5. Ingerslev J, Thykjaer H, Kudsk JOK, Fredberg U. Hometreatment with recombinant factor VIIa: results fromone centre. Blood Coagul Fibrinolysis 1998; Suppl 1:S107-10.6. Lusher J, Ingerslev J, Roberts H, Hedner U. Clinical experiencewith recombinant factor VIIa. Blood Coagul Fibrinolysis1998; 9:119-28.haematologica vol. 88(supplement n. 12):september 2003
IV International Workshop on Immune Tolerance in Hemophilia337. Key NS, Aledort LM, Beardsley D, Cooper GD, EwensteinBM, Gilchrist GS, et al. Home treatment of mildand moderate bleeding episodes using recombinant factorVIIa (Novoseven) in haemophiliacs with inhibitors.Thromb Haemost 1998; 80:912-8.8. Furie B, Furie BC. The molecular basis of blood coagulation.Cell 1988; 53:505-18.9. 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; 4:16-20.10. Nilsson IM, Hedner U. Immunosuppressive treatmentin haemophiliacs with inhibitors to factor VIII and factorIX, Scand J Haematol 1976; 16:369-82.11. Astermark J, Sottile J, Mosher DF, Stenflo J. Baculovirusmediated expression of the EGF-like modules of humanfactor IX fused to the factor XIIIa transamidation site infibronectin. Evidence for a direct interaction betweenthe N-terminal EGF-like module of factor IXab and factorX. J Biol Chem 1994; 269:3690-7.12. Nilsson IM, Freiburghaus C, Sundqvist SB, Sandberg H.Removal of specific antibodies from whole blood in acontinuous extracorporeal system. Plasma Ther TransplTechnol 1984; 5:127-34.13. Gallistl S, Cvirn G, Muntean W. Recombinant factorVIIa does not induce hypercoagulability in vitro. ThrombHaemost 1999; 81:245-9.14. Lindley CM, Sawyer WT, Macik BG, Lusher J, HarrisonJF, Baird-Cox K, et al. Pharmacokinetics and pharmacodynamicsof recombinant factor VIIa. Clin PharmacolTher 1994; 55:638-48.15. Erhardtsen E. Pharmacokinetics of recombinant activatedfactor VII (rFVIIa). Semin Thromb Hemost 2000;26:385-91.haematologica vol. 88(supplement n. 12):september 2003
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