Relationships Between Homocysteine, Factor VIIa, and Thrombin Generation in Acute Coronary Syndromes

Abstract

Background-It has been suggested by clinical, epidemiological, and experimental in vitro studies that homocysteine potentiates thrombin generation. This prothrombotic effect however has not previously been demonstrated in patients presenting with acute coronary syndromes (ACS). Methods and Results-Patients with ACS (n ϭ117) presenting with confirmed acute myocardial infarction (MI) (n ϭ57) or unstable angina pectoris (UAP) (n ϭ60) were consecutively recruited together with patients (n ϭ18) in whom the presenting chest pain was not of cardiac origin (NCP), included as controls. Plasma samples were collected on admission and before clinical intervention. Homocysteine was assayed by high performance liquid chromatography, and both Factor VIIa and prothrombin fragment F1ϩ2 were analyzed by ELISA. There were significant elevations in F1ϩ2 in MI (PϽ0.001) and UAP (Pϭ0.003), and modest elevations in Factor VIIa in UAP (PϽ0.05) compared with NCP but no differences in homocysteine levels among those groups. On dividing patients with ACS into quartiles of homocysteine, there was a stepwise increase in F1ϩ2 (PϽ0.0001) and of Factor VIIa (PϽ0.05). There were significant correlations in ACS between homocysteine and F1ϩ2 (rϭ0.46, PϽ0.0001), homocysteine and Factor VIIa (rϭ0.24, PϽ0.01), and F1ϩ2 and Factor VIIa (rϭ0.41, PϽ0.0001). There was no correlation between homocysteine and either F1ϩ2 (rϭϪ0.15, Pϭ0.57) or Factor VIIa (rϭ0.22, Pϭ0.37) in the NCP patients. Conclusions-Elevated plasma homocysteine is associated with and may cause elevated Factor VIIa and thrombin generation in patients presenting with ACS. These findings suggest an explanation for the prothrombotic effect of homocysteine in ACS.

A subtle sign of aortic outflow obstruction in an infected 29 year old Starr-Edward's valve

“…In a previous study, 6 we found that high admission plasma homocysteine concentrations were associated with increased thrombin formation, as judged by prothrombin fragments F1+2. Evidence that hyperhomocysteinaemia was triggering the thrombosis cascade was obtained from raised concentrations of activated factor VII (factor VIIa), the product of the reaction of factor VII with tissue factor.…”

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

“…In in vitro models, elevated homocysteine levels induced a hypercoagulable state by reducing thrombomodulin level, protein C activity and heparin sulfate level, as well as inhibiting the binding of tissue plasminogen activators to endothelial cells (10)(11)(12)(13). Hyperhomocysteinemia was associated with activation of coagulation systems in patients with premature atherosclerotic arterial disease and with thrombin generation in patients with acute coronary syndrome (3,4). In hyperhomocysteinemic rabbits, fibrin clots are composed of thinner and more tightly packed fibers compared with normal animals (14).…”

“…Several clinical studies have associated elevated plasma homocysteine levels to increased risk of cardiovascular diseases such as coronary artery disease (CAD), peripheral artery disease and venous thrombosis (1,2). In patients with acute coronary syndrome, elevated plasma homocysteine levels were associated with hypercoagulability and increased platelet aggregation (3,4). Recent studies have investigated the association of increased homocysteine levels with markers of thrombosis and fibrinolysis in individuals without evidence of CAD and have shown that an increase in homocysteine levels was associated with elevated plasma levels of D-Dimer as well as tissue-type plasminogen activator (t-PA) and plasminogen activator inhibitor (PAI-1) antigen (5-7).…”

Commentary: On the Pathophysiology of Coronary Heart Disease

“…The factors in non-diabetic patients that subsequent events did correlate with were: infarct size (as assessed by troponin [15], previous ACS, insulin resistance [16], plasma homocysteine rose above normal [17] and raised lipoprotein(a) [18]. Of particular interest was the link between raised homocysteins and pro-thrombosis [19].…”