Zinc delays clot lysis by attenuating plasminogen activation and plasmin-mediated fibrin degradation

Zinc circulates free in plasma at a concentration of 0.1-2 µM, but its levels increase locally when it is released from activated platelets. Although zinc influences many processes in haemostasis, its effect on fibrinolysis has not been thoroughly investigated. Using a fluorescent zinc-binding probe, we demonstrated that zinc binds tissue-type plasminogen activator (tPA) and plasmin with high affinity (Kd values of 0.2 µM), and surface plasmon resonance studies revealed that zinc binds fibrin with a Kd of 12.8 µM. Zinc had no effect on the affinity of plasminogen or plasmin for fibrin, but increased the affinity of tPA by two-fold. In the presence of 5 µM zinc, the catalytic efficiency of plasminogen activation by tPA was reduced by approximately two-fold, both in the absence or presence of fibrin. Zinc attenuated plasmin-mediated degradation of the fibrinogen alpha-chain by 43 %, but had no effect on trypsin degradation. tPA-mediated fibrin clot lysis was prolonged 2.5-fold by zinc in a concentration-dependent fashion, and tPA-mediated plasma clot lysis was attenuated by 1.5-fold. Therefore, our data indicate that zinc modulates fibrinolysis by attenuating tPA-mediated plasminogen activation and plasmin-induced fibrin degradation. These findings suggest that local release of zinc by platelets attenuates fibrinolysis.