Plasma Homocysteine Affects Fibrin Clot Permeability and Resistance to Lysis in Human Subjects

Abstract

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 (nϭ76), male patients with advanced coronary artery disease (CAD) taking low-dose aspirin (nϭ33), men with diabetes mellitus diagnosed recently (median hemoglobin A 1c 7.65%; nϭ16), and patients with isolated hypercholesterolemia (Ͼ7.0 mmol/L; nϭ15). 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 ϭ0.88, PϽ0.0001 and R 2 ϭ0.54, PϽ0.0001, respectively). In CAD patients, tHcy and fibrinogen were stronger predictors of the permeation coefficient (R 2 ϭ0.84; PϽ0.0001) than was fibrinogen alone (R 2 ϭ0.66; PϽ0.0001), whereas tHcy was the only predictor of lysis time (R 2 ϭ0.69; PϽ0.0001). 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 (Pϭ0.0002) and shorter lysis time (PϽ0.0001). 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.

May modifications of human plasma proteins stimulated by homocysteine and its thiolactone induce changes of hemostatic function of plasma in vitro?

“…2A and B). Mass spectrometric analysis of plasma fibrinogen, which is the main substrate for coagulation cascade and form a polymerized fibrin clot, treated with Hcys revealed twelve lysines that were homocysteinylated (Sauls et al 2003(Sauls et al , 2007Undas et al 2006;Sauls et al 2007). Sauls et al (2007) suggest that homocysteinylation of lysine residues in fibrinogen may be linked to three important functional consequences.…”

Bound Homocysteine, Cysteine, and Cysteinylglycine Distribution between Albumin and Globulins

“…Fibronectin and coagulation factor V have been suggested as targets of Hcy binding that may result in altered function (8 ). High circulating concentrations of Hcy appear to influence the permeability and resistance to lysis of fibrin clots (31,32 ), possibly through disulfide-linkage to various plasma proteins. The molecular variant apolipoprotein A-I Milano, which introduces a single Cys residue into the protein, has a strong protective effect against atherosclerosis (23,24 ).…”

Relation of homocysteine levels with patency and flow rate of infarct related artery in patients receiving fibrinolytic therapy

“…These changes would make the clot more resistant to fibrinolysis. In a study, plasma homocysteine levels significantly correlated with plasma fibrin clot permeation and clot susceptibility to fibrinolysis both in apparently healthy subjects and in patients with advanced CAD (17). These associations were observed regardless of whether the subjects studied took low-dose aspirin or not.…”