Summary
Plasmin generation is localized to the fibrin surface because tissue-type plasminogen
activator (t-PA) and plasminogen bind to fibrin, an interaction that stimulates plasminogen
activation over a hundred-fold. To ensure efficient fibrinolysis, plasmin bound to
fibrin is protected from inhibition by α2-antiplasmin. (DD)E, a major soluble degradation product of cross-linked fibrin that
is a potent stimulator of t-PA, compromises the fibrin-specificity of t-PA by promoting
systemic activation of plasminogen. In this study we investigated whether (DD)E also
protects plasmin from inhibition by α2-antiplasmin, facilitating degradation of this soluble t-PA effector. (DD)E and fibrin
reduce the rate of plasmin inhibition by α2-antiplasmin by 5- and 10-fold, respectively. Kringle-dependent binding of plasmin
to (DD)E and fibrin, with Kd values of 52 and 410 nM, respectively, contributes to the protective effect. When
(DD)E is extensively degraded by plasmin, yielding uncomplexed fragment E and (DD),
protection of plasmin from inhibition by α2-antiplasmin is attenuated. These studies indicate that (DD)E-bound plasmin, whose
generation reflects the ability of (DD)E to stimulate plasminogen activation by t-PA,
has the capacity to degrade (DD)E by virtue of its resistance to inhibition. This
provides a mechanism to limit the concentration of (DD)E and maintain the fibrin-specificity
of t-PA.
Keywords
Plasmin - α
2-antiplasmin - fibrin - tissue-type plasminogen activator - (DD)E
