Plasminogen activation without changes in tPA and PAI-1 in response to subcutaneous administration of ancrod

Ancrod is a purified fraction of venom from the Malayan pit viper, Calloselasma rhodostoma, currently under investigation for treatment of ischemic stroke. The therapeutic effect is ascribed to a lowering of plasma fibrinogen. Thirty-two healthy volunteers received subcutaneous ancrod at doses of 1.0, 1.5 and 2.0 IU/kg body weight or placebo. Blood samples were drawn before the injection and at various time points until 96 h after the injection. Ancrod leads to the formation of desAA-fibrin, which serves as cofactor in tissue plasminogen activator activity (tPA)-induced plasminogen activation. Unchanged concentrations of prothrombin fragment F1.2 and thrombin-antithrombin complex (TAT) indicate that fibrin formation occurs independent of thrombin. Plasmin generation is independent of an increase in tPA activity or changes in plasminogen activator inhibitor-1 (PAI-1) concentration in plasma. Subcutaneous injection of ancrod leads to a generalized fibrino(geno)lytic response caused solely by providing tPA with soluble fibrin as its cofactor in plasminogen activation. Maximal plasmin activity is present 12 h after subcutaneous injection.