ALPHA-2-ANTIPLASMIN SUPPLEMENTATION INHIBITS TISSUE PLASMINOGEN-ACTIVATOR INDUCED FIBRINOGENOLYSIS AND BLEEDING WITH LITTLE EFFECT ON THROMBOLYSIS

Tissue plasminogen activator (t-PA) causes fibrinogen proteolysis when alpha2-antiplasmin levels fall, and this may contribute to t-PA-induc ed hemorrhage. Because clot-bound plasmin is protected from alpha2-ant iplasmin inhibition, we tested the possibility that alpha2-antiplasmin supplementation would block t-PA-induced fibrinogenolysis and bleedin g without affecting thrombolysis. When added to human or rabbit plasma , alpha2-antiplasmin inhibits t-PA-induced fibrinogenolysis, but has l ittle effect on the lysis of I-125-fibrin clots. To examine its effect in vivo, rabbits with preformed I-125-labeled-jugular vein thrombi we re randomized to receive t-PA, t-PA and alpha2-antiplasmin, or saline. alpha2-Antiplasmin infusion produced a modest decrease in t-PA-induce d 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 fr om standardized ear incisions from 5,594 to 656 mul (P < 0.0001). We h ypothesize that alpha2-antiplasmin limits t-PA-induced hemorrhage by i nhibiting fibrinogenolysis and subsequent fragment X formation because (a) SDS-PAGE and immunoblot analysis indicate less fragment X formati on in alpha2-antiplasmin treated animals, and (b) when added to a solu tion of fibrinogen and plasminogen clotted with thrombin in the presen ce of t-PA, fragment X shortens the lysis time in a concentration-depe ndent fashion. These findings suggest that fragment X incorporation in to hemostatic plugs contributes to t-PA-induced bleeding. By blocking t-PA-mediated fibrinogenolysis, alpha2-antiplasmin supplementation may improve the safety of fibrin-specific plasminogen activators.