Factor XII-dependent increases in thrombin activity induce carboxypeptidase-mediated attenuation of pharmacological fibrinolysis

Abstract

Activation of the contact system in patients treated with fibrinolytic agents may be an important source of thrombin that activates thrombin-activated fibrinolysis inhibitor (TAFI) and attenuates fibrinolysis. Factor (F)XIIa in plasma increased 2-fold over 60 min in patients given either tissue plasminogen activator (t-PA) or streptokinase (SK). To determine whether FXIIa-mediated generation of thrombin and activated TAFI (TAFIa) attenuates fibrinolysis in vitro, plasma clots were incubated with SK (250 U mL-1) or t-PA (2.5 g mL-1) and the rate of lysis was measured. Plasma FXIIa impaired lysis judging from marked acceleration when 2.5 micro m corn trypsin inhibitor were added (lysis increased by 172 +/- 144% for SK and 40 +/- 31% for t-PA vs. no inhibitor, n = 16, P < 0.01). Moreover, inhibition of thrombin with hirudin and TAFIa with carboxypeptidase inhibitor accelerated lysis. We conclude that activation of FXII increases thrombin generation, which promotes TAFIa-mediated attenuation of fibrinolysis.