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(Arteriosclerosis, Thrombosis, and Vascular Biology. 1995;15:886-892.)
© 1995 American Heart Association, Inc.

Articles

Effects of Recombinant Hirudin (r-Hirudin, HBW 023) on Coagulation and Platelet Activation In Vivo

Comparison With Unfractionated Heparin and a Low-Molecular-Weight Heparin Preparation (Fragmin)

Sabine Eichinger; Michael Wolzt; Barbara Schneider; Malgorzata Nieszpaur-Los; Hubert Heinrichs; Klaus Lechner; Hans-Georg Eichler; Paul A. Kyrle

From the Department of Medicine I, Division of Hematology and Hemostaseology (S.E., M.N.-L., K.L., P.A.K.), and the Department of Clinical Pharmacology (M.W., H.-G.E.), Institute of Medical Statistics and Documentation (B.S.), Vienna University Hospital, Vienna, Austria, and Behringwerke AG, Marburg (H.H.), Germany.

Correspondence to P.A. Kyrle, MD, Allgemeines Krankenhaus, Klinik für Innere Medizin I, Abteilung für Hämatologie/Hämostaseologie, Währinger Gürtel 18-20, A-1090 Wien, Austria.

Abstract In a double-blind, randomized, crossover study, we investigated in 15 healthy male volunteers the effects of recombinant (r-) hirudin (HBW 023, 0.35 mg/kg body wt SC), unfractionated heparin (UFH, HeparinNovo; 150 IU/kg body wt SC), and a low-molecular-weight heparin preparation (LMWH, Fragmin; 75 IU/kg body wt SC) on coagulation and platelet activation in vivo by measuring specific coagulation-activation peptides (prothrombin fragment 1+2 [F1+2], thrombin–antithrombin-III complex [TAT], and ß-thromboglobulin [ß-TG]) in bleeding-time blood (activated state) and venous blood (basal state). In bleeding-time blood, r-hirudin and the heparin preparations significantly inhibited formation of both TAT and F1+2. However, the inhibitory effect of r-hirudin on F1+2 generation was short-lived and weaker compared with that of UFH and LMWH, and the TAT-to-F1+2 ratio was significantly lower after r-hirudin than after UFH or LMWH. Thus, in vivo, when the coagulation system is in an activated state, r-hirudin exerts its anticoagulant effects predominantly by inhibiting thrombin (factor IIa), whereas UFH and LMWH are directed against both factors Xa and IIa. A different mode of action for UFH and LMWH was not detectable. In venous blood, r-hirudin caused a moderate reduction in TAT formation and an increase (at 1 hour) rather than a decrease in F1+2 generation. Formation of TAT and F1+2 was suppressed at various time points following both UFH and LMWH. There was no difference in the TAT-to-F1+2 ratio after r-hirudin and heparin. Thus, a predominant effect of r-hirudin on factor IIa (as found in bleeding-time blood) was not detectable in venous blood. In bleeding-time blood, r-hirudin (but neither UFH nor LMWH) significantly inhibited ß-TG release. In contrast, both UFH and LMWH caused an increase in ß-TG 10 hours after heparin administration. Our observation of reduced platelet function after r-hirudin compared with delayed platelet activation following UFH and LMWH suggests an advantage of r-hirudin over heparin, especially in those clinical situations (such as arterial thromboembolism) where enhanced platelet activity has been shown to be of particular importance.

Key Words: hirudin • heparin • hemostatic system activation • bleeding time

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