Impaired binding of thrombin to thrombomodulin is associated with risk of deep vein thrombosis

The complex of thrombin and thrombomodulin (TM) activates protein C, and impaired binding of thrombin to TM may be a risk factor for thrombosis. In this study, we evaluated the reactivity of thrombin to TM by determining the TM-bound thrombin (TMBTh) to total thrombin generation (t-Th) ratio (TMBT ratio). We also examined whether a decreased TMBT ratio is associated with increased risk of thrombosis. TMBTh was measured on TM-coated plates. Thrombin was generated by addition of prothrombin time reagent to plasma. Levels of t-Th and TMBTh were expressed as percentages of the levels in pooled normal plasma. The study included 124 patients with deep vein thrombosis and 150 age- and sex-matched healthy subjects. The TMBT ratio (TMBTh/t-Th) was significantly lower in patients than in control subjects (p < 0.05). Among the 124 patients, 43 (34.7%) showed TMBT ratios below the 5th percentile value of control subjects, and the odds ratio (OR) for development of deep vein thrombosis was 9.4 (95% confidence interval CI], 4.6-19.1). When patients with a deficiency of natural anticoagulant (antithrombin III, protein C, or protein S) were excluded from analysis, the TMBT ratio in 37 (42.5%) of the remaining 87 patients was below this cutoff point, and the OR (13.1; 95% CI, 6.4-26.9) was increased compared to that in the total patient group. These results suggest that it is possible to evaluate the reactivity of thrombin to TM by determining the TMBT ratio, and this ratio may be a predictor of deep vein thrombosis.