Elevated Plasma MBL Levels Are Associated With Risk of Future Venous Thromboembolism: The HUNT Study.

Abstract

Background: MBL (mannose-binding lectin), a pattern recognition molecule circulating in complex with MASPs (MBL-associated serine proteases), activates the lectin complement pathway and facilitates thrombin generation upon binding to specific moieties on pathogens or altered host cells. We aimed to investigate the association between plasma MBL levels and risk of future venous thromboembolism (VTE) and to explore the effect of MBL-MASP-1/2 complexes on thrombin generation.

Methods: We conducted a population-based case-cohort (294 VTE patients, 1066 sex- and age-weighted subcohorts) derived from HUNT (The Trøndelag Health Study). Plasma MBL levels were measured using the SomaScan 7k aptamer-based platform. Cox proportional hazards regression models were used to estimate hazard ratios for VTE across quartiles of MBL levels. Thrombin generation in plasma induced by MBL-MASPs complexes was assessed in vitro.

Results: Subjects with MBL levels in the highest quartile had a 79% higher risk of overall VTE (hazard ratio, 1.79 [95% CI, 1.23-2.61]) than those with MBL levels in the lowest quartile after multivariable adjustments. The risk estimates by high plasma MBL were particularly strong for deep vein thrombosis (hazard ratio, 2.50 [95% CI, 1.42-4.37]) and unprovoked VTE (hazard ratio, 2.81 [95% CI, 1.53-5.16]). MBL-MASP-1/2 complexes promoted complement activation and thrombin generation, and monospecific inhibitors abolished their enzymatic activity.

Conclusions: Our findings support the notion that high plasma MBL levels are associated with an increased risk of future VTE and suggest that the risk increase is partially mediated through the initiation of thrombin generation by MBL-MASP-1/2 complexes at the site of venous thrombosis formation.