Reactive coagulation induced by plasmin in patients treated with recombinant tissue-type plasminogen activator

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Abstract
We and others have demonstrated that administration of thrombolytic agents causes the generation of thrombosis-promoting agents. At present, we have studied whether formation in vivo of excessive amounts of plasmin is responsible for the activation of coagulation in patients treated with recombinant tissue-type plasminogen activator. Modified crossed immunoelectrophoresis was used for determination of the plasminogen-binding form of alpha 2-antiplasmin. Enzyme-linked immunosorbent assay methods were used for determination of hemostatic reaction products. The association between the generation of hemostatic reaction products and the exhaustion of the plasminogen-binding form of alpha 2-antiplasmin (PB alpha 2AP) was studied in 21 patients with acute myocardial infarction and 11 patients with unstable angina pectoris who were given a 3-hour, 100-mg intravenous infusion of recombinant tissue-type plasminogen activator (rt-PA). We observed in all patients a fall in blood concentrations of PB alpha 2AP (P < 0.01) after 2.25 hours of treatment and, simultaneously, a significant increase in fibrin degradation products (P < 0.01), D-dimer (P < 0.01), fibrinogen degradation products (P < 0.01), prothrombin fragment 1 + 2 (P < 0.01), and thrombin-antithrombin III complexes (P < 0.01). When we evaluated individual data, we observed high concentrations of the reaction products when the PB alpha 2AP concentration after 2.25 hours of treatment was lower than 25% of the pretreatment values. Also, we observed highly significant associations between the increase in the plasma concentrations of fibrin degradation products and thrombin-antithrombin III complexes (rs = 0.72; P < 0.01), the increase in plasma concentrations of fibrin degradation products and prothrombin fragment 1 + 2 (rs = 0.63; P < 0.01), the increase in plasma concentrations of D-dimer and thrombin-antithrombin III complexes (rs = 0.78; P < 0.01), and the increase in plasma concentrations of D-dimer and prothrombin fragment 1 + 2 (rs = 0.79; P < 0.01). Generation of excessive amounts of plasmin is the main factor in producing the procoagulant response in patients who receive thrombolytic therapy with rt-PA, and intravenous heparin does not abolish this response. Plasmin inhibitors might be used in relation to thrombolytic therapy as indirect "antithrombotics."

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