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_1c7.65%; 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 (R²=0.88,P<0.0001 andR²=0.54,P<0.0001, respectively). In CAD patients, tHcy and fibrinogen were stronger predictors of the permeation coefficient (R²=0.84;P<0.0001) than was fibrinogen alone (R²=0.66;P<0.0001), whereas tHcy was the only predictor of lysis time (R²=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.

Objectives— We sought to investigate whether patients with in-stent thrombosis (IST) display altered plasma fibrin clot properties. Methods and Results— We studied 47 definite IST patients, including 15 with acute, 26 subacute and 6 late IST, and 48 controls matched for demographics, cardiovascular risk factors, concomitant treatment and angiographic/stent parameters. Plasma clot permeability (K_s), which indicates a pore size, turbidity (lag phase, indicating the rate of fibrin clot formation, ΔAbs_max, maximum absorbance of a fibrin gel, reflecting the fiber thickness), lysis time (t_50%) and maximum rate of d-dimer release from clots (D-D_rate) were determined 2 to 73 (median 14.7) months after IST. Patients with IST had 21% lower K_s, 14% higher ΔAbs_max, 11% lower D-D_rate, 30% longer t_50% (all P<0.0001) and 5% shorter lag phase compared to controls (P=0.042). There were no correlations between clot variables and the time of IST or that from IST to blood sampling. Multiple regression analysis showed that K_s (odds ratio=0.36 per 0.1 μm², P<0.001), D-D_rate (odds ratio=0.16 per 0.01 mg/L/min, P<0.001) and stent length (odds ratio=1.1 per 1 mm, P=0.043) were independent predictors of IST (R²=0.58, P<0.001). Conclusions— IST patients tend to form dense fibrin clots resistant to lysis, and altered plasma fibrin clot features might contribute to the occurrence of IST. Plasma fibrin clot properties were assessed in patients after in-stent thrombosis (IST). Our findings suggest that altered fibrin clot features associated with attenuated fibrinolysis can be detected in patients with IST. Reduced clot permeability and susceptibility to lysis represent a novel prothrombotic mechanism, which might contribute to the IST.