Inhibition of clot-bound alpha 2-antiplasmin enhances in vivo thrombolysis.
Recent experiments in vitro have shown that inhibition of human alpha 2-antiplasmin by a monoclonal antibody (MAb RWR) markedly enhances clot lysis by plasminogen activators. To extend these studies in vivo, we tested whether inhibition of clot or fibrin-bound alpha 2-antiplasmin by MAb RWR could enhance the lysis of a human clot by tissue-type plasminogen activator (t-PA) in a rabbit jugular vein thrombosis model. Compared with a saline placebo or a control antibody, MAb RWR significantly increased thrombolysis by endogenous plasminogen activator in rabbits to which no t-PA was administered (p less than 0.05). In rabbits that received t-PA, the combination of MAb RWR and t-PA caused significantly greater thrombolysis than equivalent doses of t-PA alone (p less than 0.05). However, compared with equipotent doses of t-PA alone, the combination of MAb RWR and t-PA did not increase the nonspecific consumption of fibrinogen. These experiments suggest that the combination of an alpha 2-antiplasmin inhibitor and a plasminogen activator could be a more potent thrombolytic strategy.
Massachusetts General Hospital, Cardiac unit, Boston 02114.
G L
GL
Reed
G R
GR
Matsueda
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E
Haber
D000818:Animals; D000911:Antibodies, Monoclonal; D001777:Blood Coagulation; D005340:Fibrinogen / Q000378:metabolism; D005341:Fibrinolysin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005343:Fibrinolytic Agents / Q000494:pharmacology*; D006801:Humans; D011817:Rabbits; D010959:Tissue Plasminogen Activator / Q000494:pharmacology; D000979:alpha-2-Antiplasmin / Q000378:metabolism; D000511:alpha-Macroglobulins / Q000037:antagonists & inhibitors* / Q000378:metabolism
D000911:Antibodies, Monoclonal; D005343:Fibrinolytic Agents; D000979:alpha-2-Antiplasmin; D000511:alpha-Macroglobulins; C024668:plasmin-alpha(2)-macroglobulin complex; D005340:Fibrinogen; D010959:Tissue Plasminogen Activator; D005341:Fibrinolysin