title: 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.
authors.affiliation: Center for Cardiovascular Research, Washington University School of Medicine, St Louis, MO 63110, USA.
authors.forename: M P
authors.initials: MP
authors.lastname: Latacha
authors.forename: W T
authors.initials: WT
authors.lastname: Schaiff
authors.forename: P R
authors.initials: PR
authors.lastname: Eisenberg
authors.forename: D R
authors.initials: DR
authors.lastname: Abendschein
mesh_terms: D025901:Carboxypeptidase B2 / Q000378:metabolism; D002268:Carboxypeptidases / Q000378:metabolism*; D005174:Factor XII / Q000378:metabolism*; D015956:Factor XIIa / Q000378:metabolism; D065427:Factor Xa Inhibitors; D005342:Fibrinolysis / Q000187:drug effects; D005343:Fibrinolytic Agents / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D013300:Streptokinase / Q000494:pharmacology; D013917:Thrombin / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010959:Tissue Plasminogen Activator / Q000494:pharmacology
chemical_list: D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents; D005174:Factor XII; D002268:Carboxypeptidases; D013300:Streptokinase; D025901:Carboxypeptidase B2; D015956:Factor XIIa; D013917:Thrombin; D010959:Tissue Plasminogen Activator