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.