Effects of recombinant human soluble thrombomodulin (rhs-TM) on clot-induced coagulation in human plasma

Recent studies have suggested that clot-bound thrombin plays an important r ole in thrombus growth. In this study, we examined the effects of recombina nt human soluble thrombomodulin (rhsTM) on clot-induced coagulation, rhsTM enhanced the activation of protein C by clots, and attenuated clot-induced thrombin generation and fibrinopeptide A (FPA) production in a dose-depende nt manner. The inhibitory effect of rhsTM was abolished by anti-protein C a ntibody. The inhibitory effect of rhsTM on clot-induced thrombin generation continued for over 60 min after the addition of the clot, while an active site-directed thrombin inhibitor, argatroban, produced a more transient inh ibition. rhsTM also inhibited the regrowth of the clot in I-125-fibrinogen- supplemented plasma. We also examined the effect of rhsTM by thromboelastog raphy; rhsTM reduced the growth of the clot but had little effect on the ri me to begin clotting, while heparin and Fragmin (low molecular weight hepar in) had effects opposite to those of rhsTM. These findings suggest that rhs-TM attenuates the growth of the clot by act ivating protein C and inhibiting further thrombin generation in the clot.