INHIBITORY EFFECTS OF LYSINE ANALOGS ON T-PA INDUCED WHOLE-BLOOD CLOTLYSIS

The lysine analogues epsilon-aminocaproic acid (EACA) and trans-4-amin omethyl cyclohexane carboxylic acid (AMCA) are used to prevent excessi ve bleeding in patients with coagulopathies, such as hemophilia and th rombocytopenia, or in those who have received tissue plasminogen activ ator (t-PA). However, their relative efficacy in inhibiting lysis of c lots that have been formed in the presence of exogenous t-PA or that h ave been formed and then exposed to exogenous t-PA has not been well c haracterized. The present study utilized blood from normal volunteers and I-125-fibrinogen in a dilute whole blood clot assay to determine t he relative concentrations of lysine analogues required for inhibition of clot lysis induced by exogenous t-PA. AMCA(0.06 mM) and EACA (0.6 mM) were effective in prolonging clot lysis if (1) whole blood clots w ere formed and then exposed to a lysine analogue and exogenous t-PA or if (2) whole blood clots were formed in the presence of exogenous t-P A and a lysine analogue, However, their inhibitory effect was markedly reduced if clots were formed in the presence of t-PA and then exposed to either of the lysine analogues. The analogues did not inhibit the initial binding of t-PA to fibrin. They did inhibit binding of plasmin ogen to fibrin as well as the activation of plasminogen by t-PA in the absence of fibrin. The data suggest that lysine analogues, even at lo w concentrations, reduce the rate of t-PA induced whole blood clot lys is by several mechanisms.