Prospective study of circulating factor XI and incident venous thromboembolism: The Longitudinal Investigation of Thromboembolism Etiology (LITE)

Abstract

Elevated plasma concentrations of coagulation factor XI may increase risk of venous thromboembolism (VTE), but prospective data are limited. We studied prospectively the associations of plasma factor XI and a key F11 genetic variant with incident VTE in whites and African Americans. We measured factor XI in 16,299 participants, initially free of VTE, in two prospective population cohorts. We also measured the F11 single nucleotide polymorphism rs4241824, which a genome-wide association study had linked to factor XI concentration. During follow-up, we identified 606 VTEs. The age, race, sex, and study-adjusted hazard ratio of VTE increased across factor XI quintiles (p<0.001 for trend), and the hazard ratio was 1.51 (95% CI 1.16, 1.97) for the highest versus lowest quintile overall, and was 1.42 (95% CI 1.03, 1.95) in whites and 1.72 (95% CI 1.08, 2.73) in African Americans. In whites, the F11 variant was associated with both factor XI concentration and VTE incidence (1.15-fold greater incidence of VTE per risk allele). In African Americans, these associations were absent. In conclusion, this cohort study documented that an elevated plasma factor XI concentration is a risk factor for VTE over extended follow-up, not only in whites but also in African Americans. In whites, the association of the F11 genetic variant with VTE suggests a causal relation, but we did not observe this genetic relation in African Americans.

Plasma contact factors as therapeutic targets

“…For the contact factors, data supporting a role in thrombosis in humans is strongest for FXI. Rates of VTE are lower in FXI-deficient individuals than in the general population [94,95], and higher FXI levels are associated with increased VTE risk in the Leiden Thrombophilia Study (LETS) [96] and the Longitudinal Investigation of Thromboembolism Etiology (LITE) study [97]. FXI deficiency is associated with a reduced incidence of stroke [98], while high FXI levels are linked to increased stroke risk in the Atherosclerosis Risk in Communities (ARIC) study [99] and the Risk of Arterial Thrombosis In relation to Oral contraceptives (RATIO) study [100].…”

Relation of coagulation factor XI with incident coronary heart disease and stroke

“…Our findings suggest that in contrast to VTE [1–3], variation in basal concentrations of FXI may not independently influence the rate of arterial thrombotic events in the elderly.…”

“…Contrasting results for the positive relation of FXI with VTE [1–3] and no relation for CHD [7, 13, 14] or IS [4–7] may reflect the underlying mechanistic differences between arterial and venous thrombosis, despite some shared common risk factors. Venous thrombi are characterized by red blood cells enmeshed in fibrin while arterial thrombi are mainly composed of platelets with little fibrin or red cells [23, 24].…”

“…FXI has been reported to be stable in plasma samples frozen for at least 18 months [26]. It is possible that biological and laboratory variation in a single measure of FXI may have masked a true association between FXI and arterial thrombotic events but this seems unlikely since this was not the case in CHS for VTE [1, 2]. The null findings for CHD, IS and HS may be due to inadequate statistical power to detect small effects.…”

“…While elevated levels of FXI have been consistently positively associated with venous thromboembolism (VTE) [1–3] in epidemiologic studies, the relation of FXI to ischemic stroke (IS) [4–8], hemorrhagic stroke (HS) [7], myocardial infarction [4, 9–12], or coronary heart disease (CHD) [7, 13, 14] remains uncertain.…”