Limited fibrin specificity of tissue-type plasminogen activator and its potential link to bleeding.

Plasminogen activators initiate the fibrinolytic process by converting plasminogen to plasmin. Though plasminogen activators are effective in the treatment of thrombotic disorders, bleeding complications are associated with their use. The development of plasminogen activators with greater fibrin specificity was expected to reduce the incidence of bleeding complications; however, this has not occurred. In our rabbit model (a) bleeding from standardized ear incisions induced by tissue-type plasminogen activator (t-PA) is attenuated when fibrinogenolysis is reduced by the coadministration of alpha 2-antiplasmin and (b) when used in doses that produce equivalent thrombolysis, vampire bat plasminogen activator (b-PA), an agent that is more fibrin specific than t-PA, causes less bleeding than t-PA. In addition, we have found that the (DD)E complex formed as a result of degradation of crosslinked fibrin is a potent stimulator of t-PA-induced plasminogen activation but has no effect on b-PA. Fragment X, a high-molecular-weight clottable fibrinogen degradation product, accumulates after treatment with t-PA but not with t-PA given with alpha 2-antiplasmin or with b-PA. These findings suggest that there is a link between plasminogen activator-induced fibrinogenolysis and bleeding, and that the composition of fibrin within hemostatic plugs may influence susceptibility to lysis. Whether these results mean that fibrin-specific plasminogen activators like b-PA will have a better risk-to-benefit profile in humans requires rigorous testing in well-designed clinical trials. However, at the very least, our findings suggest that the development of plasminogen activators that are more fibrin specific than t-PA is a worth-while exercise.