title: Alpha 2-antiplasmin supplementation inhibits tissue plasminogen activator-induced fibrinogenolysis and bleeding with little effect on thrombolysis.
abstract: Tissue plasminogen activator (t-PA) causes fibrinogen proteolysis when alpha 2-antiplasmin levels fall, and this may contribute to t-PA-induced hemorrhage. Because clot-bound plasmin is protected from alpha 2-antiplasmin inhibition, we tested the possibility that alpha 2-antiplasmin supplementation would block t-PA-induced fibrinogenolysis and bleeding without affecting thrombolysis. When added to human or rabbit plasma, alpha 2-antiplasmin inhibits t-PA-induced fibrinogenolysis, but hat 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 alpha 2-antiplasmin, or saline. alpha 2-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 microliter (P < 0.0001). We hypothesize that alpha 2-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 alpha 2-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, alpha 2-antiplasmin supplementation may improve the safety of fibrin-specific plasminogen activators.
authors.affiliation: Department of Medicine, McMaster University, Hamilton, Ontario, Canada.
authors.forename: J I
authors.initials: JI
authors.lastname: Weitz
authors.forename: B
authors.initials: B
authors.lastname: Leslie
authors.forename: J
authors.initials: J
authors.lastname: Hirsh
authors.forename: P
authors.initials: P
authors.lastname: Klement
mesh_terms: D000818:Animals; D007611:Aprotinin / Q000494:pharmacology; D004357:Drug Synergism; D005340:Fibrinogen / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D005342:Fibrinolysis / Q000187:drug effects*; D006470:Hemorrhage / Q000188:drug therapy; D006801:Humans; D011817:Rabbits; D010959:Tissue Plasminogen Activator / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D000979:alpha-2-Antiplasmin / Q000494:pharmacology*
chemical_list: D000979:alpha-2-Antiplasmin; D005340:Fibrinogen; D007611:Aprotinin; D010959:Tissue Plasminogen Activator