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 beta-thromboglobulin [beta-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.(ABSTRACT TRUNCATED AT 250 WORDS)