Plasmin-mediated activation of contact system in response to pharmacological thrombolysis.

BACKGROUND

Thrombin activity increases in patients treated with coronary thrombolysis for acute myocardial infarction, but the mechanisms are not well defined. We have shown that thrombin activity increases in plasma and whole blood incubated with plasminogen activators and appears to be plasmin mediated and dependent on activity of the factor VIIIa/IXa complex.

METHODS AND RESULTS

In the present study, increases in thrombin activity induced by incubation of recalcified citrated plasma with 0.16 to 0.5 mumol/L plasmin at 37 degrees C were markedly attenuated in recalcified citrated plasma deficient in factors XI or XII, prekallikrein, or high molecular weight kininogen, as well as in plasma incubated with plasmin in the presence of 3.5 mumol/L corn trypsin inhibitor, a specific factor XIIa inhibitor. Increases in thrombin activity also occurred in nonanticoagulated whole blood incubated with pharmacological concentrations of plasminogen activators and were markedly attenuated in the presence of corn trypsin inhibitor. Plasmin-mediated (0.25 mumol/L) activation of purified factor XII occurred in 0.05 mol/L Tris-HCl and 0.012 mol/L NaCl (pH 7.8) at 37 degrees C, resulting in equimolar quantities of two fragments that corresponded to cleavage of factor XII at Arg353-Val354, the site involved in kallikrein-mediated activation of factor XII, and cleavage at Lys346-Ser347, an apparently novel site of plasmin-mediated hydrolysis of factor XII. Contact activation was also demonstrated in plasma samples from patients after treatment with fibrinolytic agents for myocardial infarction, by demonstrating cleavage of high molecular weight kininogen from its one-chain to its two-chain form by ligand blotting with 125I-prekallikrein.

CONCLUSIONS

Plasmin-mediated activation of the contact system of coagulation appears to account, at least in part, for increases in procoagulant activity in patients treated with fibrinolytic agents. It may also explain hypotension, by release of bradykinin from high molecular weight kininogen, and complement activation, by activated factor XII, that has been demonstrated in these patients.