Tissue plasminogen activator (t-PA) causes fibrinogen proteolysis when α2-antiplasmin levels fall, and this may contribute to t-PA-induced hemorrhage. Because clot-bound plasmin is protected from α2-antiplasmin inhibition, we tested the possibility that α2-antiplasmin supplementation would block t-PA-induced fibrinogenolysis and bleeding without affecting thrombolysis. When added to human or rabbit plasma, α2-antiplasmin inhibits t-PA-induced fibrinogenolysis, but has little effect on the lysis of 125I-fibrin clots. To examine its effect in vivo, rabbits with preformed 125I-labeled-jugular vein thrombi were randomized to receive t-PA, t-PA and α2-antiplasmin, or saline. α2-Antiplasmin infusion produced a modest decrease in t-PA-induced thrombolysis (from 40.2% to 30.1%, P = 0.12), but reduced fibrinogen consumption from 87% to 27% (P = 0.0001), and decreased blood loss from standardized ear incisions from 5,594 to 656 μl (P < 0.0001). We hypothesize that α2-antiplasmin limits t-PA-induced hemorrhage by inhibiting fibrinogenolysis and subsequent fragment X formation because (a) SDS-PAGE and immunoblot analysis indicate less fragment X formation in α2-antiplasmin treated animals, and (b) when added to a solution of fibrinogen and plasminogen clotted with thrombin in the presence of t-PA, fragment X shortens the lysis time in a concentration-dependent fashion. These findings suggest that fragment X incorporation into hemostatic plugs contributes to t-PA-induced bleeding. By blocking t-PA-mediated fibrinogenolysis, α2-antiplasmin supplementation may improve the safety of fibrin-specific plasminogen activators.
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CITATION STYLE
Weitz, J. I., Leslie, B., Hirsh, J., & Klement, P. (1993). α2-antiplasmin supplementation inhibits tissue plasminogen activator-induced fibrinogenolysis and bleeding with little effect on thrombolysis. Journal of Clinical Investigation, 91(4), 1343–1350. https://doi.org/10.1172/jci116335