Consequences of inhibition of plasma carboxypeptidase B on in vivo thrombolysis, thrombosis and hemostasis

To further evaluate the role of plasma carboxypeptidase B (pCPB) in modulating fibrinolysis, we investigated the effects of inhibiting pCPB on tissue plasminogen activator (tPA) induced lysis of preformed whole blood clots and on thrombus formation in vivo, in a rabbit arterio-venous shunt model we observed that a systemic administration of potato carboxypeptidase inhibitor (PCI), an inhibitor of pCPB, accelerated the rate of clot lysis induced by therapeutic concentrations of tPA, This effect was equivalent to increasing the relative potency of tPA by more than a factor of two and was achieved even when PCI was administered systemically in the presence of heparin. The effect of pCPB inhibition on thrombus formation was evaluated in a novel rabbit model of venous thrombosis. In this model, systemic administration of PCI reduced thrombus weight to 33% of saline treated controls. However, this regimen resulted in a modest bleeding tendency, comparable to that seen in rabbits treated with an antithrombotic regimen of heparin, Taken together, these data further support the hypothesis that pCPB's function is to attenuate fibrinolysis and may thereby play a role in hemostasis following vascular injury. (C) 2000 Harcourt Publishers Ltd.