Risk of Coronary Heart Disease and Activation of Factor XII in Middle-Aged Men

Abstract

Increased activity is known to be present in the extrinsic, intrinsic, and final common pathways of the hemostatic system in men at high risk of coronary heart disease (CHD), but the status of the contact system of coagulation in this condition is uncertain. Plasma levels of activated factor XII (XIIa), the initial product of contact activation, have therefore been measured by ELISA in 2464 men aged 51 to 62 years, clinically free of CHD, who were taking part in a prospective cardiovascular survey based in general medical practices. Statistically significant, independent, and positive associations of XIIa were found with serum cholesterol and triglyceride concentrations, blood pressure, body mass index, factor VII activity, plasma fibrinogen concentration, and tobacco smoking, all associated with CHD. Plasma XIIa also increased with recent alcohol intake. Men in the highest quintile of risk according to their conventional risk factors had a mean XIIa of 2.07 ng/mL (95% confidence interval 1.99-2.16), 31% higher than that of men in the lowest quintile (1.58; 95% confidence interval 1.51-1.65). Thus, the contact system of coagulation appears to be activated when CHD risk is increased. Furthermore, the independent associations of XIIa with the major conventional CHD risk factors and its broad range of values in the general population (0.1 to 12.5 ng/mL), combined with a relatively low day-to-day variability in individuals (the within-person component of its total variation being 14.7%), suggest its potential usefulness as a marker of atherosclerotic vascular damage.

Levels of intrinsic coagulation factors and the risk of myocardial infarction among men: opposite and synergistic effects of factors XI and XII

“…This would suggest that the effect of factor XII on risk is not by activation of factor XI, but by an alternative mechanism. Previous studies have suggested that plasma levels of factor XIIa are related to plasma levels of cholesterol and triglyceride, 23,27,28 but not HDL cholesterol. 22 The present study corroborates these findings.…”

Factor XII Regulates the Pathological Process of Thrombus Formation on Ruptured Plaques

“…This is in accordance with clinical evidence that elevated levels of FXII(a) positively associate with arterial thrombosis, ischemic stroke, and coronary heart disease. [29][30][31] On the contrary, conflicting evidence exists on whether individuals with partly reduced FXII levels have an increased risk of cardiovascular disease (reviewed in Renné et al 15 and Woodruff et al 16 ). In this regard, the thrombus-destabilizing effect observed under conditions of reduced FXII activity needs more attention.…”

Homozygosity of the T Allele of the 46 C→T Polymorphism in the F12 Gene Is a Risk Factor for Ischemic Stroke in the Spanish Population

“…9 -11 Factor XII is a plasma protein and a member of the serin-protease family. [12][13][14] Once activated, it initiates the contact activation system; it also has fibrinolytic properties. 15 Severe congenital Factor XII deficiencies have been described, but its association with thromboembolic complications is controversial.…”

“…10 Some studies have reported that variability of plasma Factor XII levels are associated with the predisposition to arterial thrombosis. 13,14 A common genetic polymorphism (46 C to T substitution) in the 5Ј-untranslated region of the coagulation Factor XII gene has been associated with low translation efficiency and variability of Factor XII levels in the general population. 12 Association studies have shown the relationship of Factor XII levels and the 46 C3 T polymorphism in the development of arterial disease, but the results are controversial.…”