High incidence of thrombin generation resistance to thrombomodulin in patients with unprovoked venous thromboembolism

Poorly controlled thrombin generation (TG) can induce venous thromboembolism (VTE). Assessing the global coagulation potential may help to characterize the risk of VTE. TG assay (TGA) quantifying the endogenous thrombin potential (ETP) and its inhibition after adding purified thrombomodulin (TM) allows certain thrombotic phenotypes to be recognized. We tested the TM-induced ETP variation in 989 uncoagulated patients with their first unprovoked VTE and 200 controls using an automated TGA and commercially available reagents. We found evidence of ETP resistance to TM, defined at the fifth percentile value found in controls, in 406 patients (41.1%, <i>P</i> < .0001), mixing tests in patients who were antiphospholipid antibody-negative showing no inhibitory activity. We investigated the 422 patients with full clinical and laboratory information for predictors of ETP resistance to TM (R-ETP/TM), found positive in 163 of them (38.6%). Multivariate analysis showed that D-dimers were positive, protein S and Rosner index were negative risk factors for R-ETP/TM (quantitative model), high D-dimers and factor VIII, protein C <65 IU, and protein S <50 IU were risk factors (qualitative model). The scores derived had insufficient predictive performances to diagnose R-ETP/TM, which is a frequent plasma phenotype in patients with unprovoked VTE. The complete identification of its determinants deserves further investigation.