Prothrombotic fibrin clot properties associated with increased endogenous thrombin potential and soluble P-selectin predict occult cancer after unprovoked venous thromboembolism

Background Compact fibrin clots relatively resistant to lysis are observed in patients at increased risk of venous thromboembolism (VTE) including malignancy. The citrullinated histone H3 (H3Cit) predicts VTE in cancer patients. Objectives We performed a cohort study to investigate whether abnormal clot properties predict cancer diagnosis following unprovoked VTE. Methods In 369 consecutive patients aged <70 years without malignancy detected during routine screening, we determined plasma clot permeability (K-s) and clot lysis time (CLT), along with several prothrombotic markers and H3Cit after 2 to 8 months since VTE. Results During follow-up (median, 37; interquartile range, 33-39 months), malignancy was diagnosed in 22 patients (6%), who were older. This group had denser fibrin networks (-13% K-s), impaired fibrinolysis (+25.5% CLT), increased endogenous thrombin potential (ETP,+7%), soluble P-selectin (+40.3%), and H3Cit (+169.2%) measured off anticoagulation after median 4 months since VTE. The K-s and CLT correlated with H3Cit (r = -.58 and r = .31, P < .05, respectively). The Kaplan-Meier survival analysis showed that reduced K-s (the first quartile, <= 6.2 x 10(-9 )cm(2)), prolonged CLT (the top quartile, >106 min), and higher ETP (the top quartile, >1657 nM x min) were predictors of cancer diagnosed during follow-up. The multivariable Cox proportional hazards model showed that patients with the prothrombotic clot phenotype (low K-s and long CLT) had the highest risk of cancer diagnosis [hazard ratio(HR), 23.4; 95% confidence interval (CI), 6.67-82.15]. Conclusions Prothrombotic clot properties following unprovoked VTE might help identify patients at risk of a diagnosis of cancer within the first 3 years of follow-up.