EFFECTS OF RECOMBINANT HIRUDIN (R-HIRUDIN, HBW-023) ON COAGULATION AND PLATELET ACTIVATION IN-VIVO - COMPARISON WITH UNFRACTIONATED HEPARINAND A LOW-MOLECULAR-WEIGHT HEPARIN PREPARATION (FRAGMIN)

In a double-blind, randomized, crossover study, we investigated in 15 healthy male volunteers the effects of recombinant (r-) hirudin (HEW 0 23, 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 activ ation in vivo by measuring specific coagulation activation peptides (p rothrombin fragment 1+2 [F1+2], thrombin-antithrombin-III complex [TAT ], and beta-thrombo-globulin [beta-TG]) in bleeding-time blood (activa ted state) and venous blood (basal state). In bleeding-time blood, r-h irudin and the heparin preparations significantly inhibited formation of both TAT and F1+2. However, the inhibitory effect of r-hirudin on F 1+2 generation was short-lived and weaker compared with that of UFH an d LMWH, and the TAT-to-F1+2 ratio was significantly lower after r-hiru din 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 LMW H are directed against both factors Xa and IIa. A different mode of ac tion for UFH and LMWH was not detectable. In venous blood, r-hirudin c aused 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. Th ere was no difference in the TAT-to-F1+2 ratio after r-hirudin and hep arin. Thus, a predominant effect of r-hirudin on factor IIa (as found in bleeding-time blood) was not detectable in venous blood. In bleedin g-time blood, r-hirudin (but neither UFH nor LMWH) significantly inhib ited beta-TG release. In contrast, both UFH and LMWH caused an increas e in beta-TG 10 hours after heparin administration. Our observation of reduced platelet function after r-hirudin compared with delayed plate let activation following UFH and LMWH suggests an advantage of r-hirud in over heparin, especially in those clinical situations (such as arte rial thromboembolism) where enhanced platelet activity has been shown to be of particular importance.