Mild hyperhomocysteinemia is associated with increased TAFI levels and reduced plasma fibrinolytic potential

Background: Mild hyperhomocysteinemia (HHcy) has been shown to be associated with impaired fibrinolysis, but some aspects of this association are unclear. Objective: Using an in vitro model of physiological relevance, we investigated whether and how HHcy influences plasma fibrinolytic potential. Patients/methods: We studied 176 patients with previous venous thromboembolism, 58 with HHcy, 118 with normal total homocysteine (tHcy) levels (NHcy), at least 3months after withdrawal of anticoagulant therapy. Plasma fibrinolytic potential was measured as the fibrinolysis time of tissue factor (TF)-induced clots exposed to 15ngmL -1 t-PA. Results: Fibrinolysis time was longer in HHcy than in NHcy patients, but this difference disappeared when the assay was performed in the presence of the TAFIa inhibitor, PTCI. Plasma levels of thrombin activatable fibrinolysis inhibitor (TAFI) and factor VIII (FVIII) were higher in HHcy than NHcy, whereas PAI-1, fibrinogen and endogenous thrombin potential were similar. Using multivariate analysis, plasma tHcy was identified as an independent predictor of fibrinolysis time. Experiments in which native fibrinogen was replaced by purified fibrinogen suggested that alterations of fibrinogen structure did not contribute appreciably to the hypofibrinolysis of HHcy plasma samples. The acute increase of tHcy either in vivo (after an oral methionine load) or in vitro (after incubation of normal plasma with 0.5m m DL-Hcy) had no effects on fibrinolysis or TAFI levels. Conclusions: We describe an enhanced TAFI-related antifibrinolytic activity in mild HHcy, which might account for the reported heightened thrombosis risk; however, it is unknown whether HHcy is causally related to hypofibrinolysis or an associated bystander.