Plasma homocysteine affects fibrin clot permeability and resistance to lysis in human subjects

Objective - Homocysteine (Hcy) is a risk factor for thrombosis. We investigated a hypothesis that the clot permeability and its resistance to fibrinolysis is associated with plasma total Hcy (tHcy) in human subjects. Methods and Results - We studied healthy men not taking any medication (n = 76), male patients with advanced coronary artery disease (CAD) taking low-dose aspirin (n = 33), men with diabetes mellitus diagnosed recently ( median hemoglobin A(1)c 7.65%; n = 16), and patients with isolated hypercholesterolemia (> 7.0 mmol/L; n = 15). We assessed clot permeability and turbidimetric lysis time as the determinants of fibrin clot structure. In a regression model, including age and fibrinogen, plasma tHcy was an independent predictor of clot permeation and fibrinolysis time in healthy subjects (R-2 = 0.88, P < 0.0001 and R-2= 0.54, P < 0.0001, respectively). In CAD patients, tHcy and fibrinogen were stronger predictors of the permeation coefficient (R-2 = 0.84; P < 0.0001) than was fibrinogen alone (R-2 = 0.66; P < 0.0001), whereas tHcy was the only predictor of lysis time (R-2 = 0.69; P < 0.0001). Elevated tHcy levels observed after methionine load were not associated with any of the fibrin clot properties. In patients with diabetes or hypercholesterolemia, the influence of Hcy on permeation and, to a lesser extent, on the lysis time was obscured by dominant effects of glucose and cholesterol. In 20 asymptomatic men with hyperhomocysteinemia treated with folic acid, reduction in tHcy levels resulted in increased clot permeability (P = 0.0002) and shorter lysis time (P < 0.0001). Conclusions - Our results indicate that plasma tHcy predicts clot permeation and susceptibility to fibrinolysis in healthy men and CAD patients. Our data are consistent with a mechanism of thrombosis in hyperhomocysteinemia, which involves modification of fibrinogen by Hcy-thiolactone.