Prothrombotic clot properties can predict venous ulcers in patients following deep vein thrombosis: a cohort study

Abstract

Venous ulcers are the most severe manifestation of post-thrombotic syndrome (PTS). We have previously demonstrated that formation of compact fibrin clots resistant to lysis is observed in patients following deep-vein thrombosis (DVT) who developed PTS. The current study investigated whether unfavourable fibrin clot properties can predict post-thrombotic venous ulcers. In a cohort study on 186 consecutive patients following DVT, we determined plasma fibrin clot characteristics, including clot permeability and lysability, inflammatory markers, thrombin generation, fibrinolysis proteins at 3 months since the index event. Occurrence of PTS and venous ulcers was recorded during follow-up (median, 53; range 24 to 76 months). Fifty-seven DVT patients (30.6%) developed PTS, including 12 subjects (6.45%) with a venous ulcer (4 individuals with recurrent ulcers). Patients who developed ulcers compared with the remainder had at enrolment 13.0% lower clot permeability (Ks), 17.4% longer clot lysis time (CLT), 13.1% longer lag phase of clot formation, and 5.0% higher maximum absorbance, with no difference in fibrinogen, C-reactive protein, and thrombin generation. The baseline prothrombotic fibrin clot phenotype (Ks ≤ 6.5 × 10−9 cm2 and CLT > 100 min) was associated with a higher risk of ulcers [hazard ratio (HR), 5.37; 95% confidence interval (CI), 1.3–21.5]. A multivariate model adjusted for age, sex, and fibrinogen showed that independent predictors of the ulcer occurrence were body mass index (HR 1.53; 95% CI 1.30–1.86), CLT (HR 1.43; 95% CI 1.04–2.05), and α2-antiplasmin (HR 0.95; 95% CI 0.90–0.99). This study suggests that formation of denser fibrin clots with impaired fibrinolysis predisposes to post-thrombotic venous ulcers.