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

Abstract

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 (Ks) 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% Ks), 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 Ks and CLT correlated with H3Cit (r = −.58 and r = .31, P < .05, respectively). The Kaplan–Meier survival analysis showed that reduced Ks (the first quartile, ≤6.2 × 10−9 cm2), prolonged CLT (the top quartile, >106 min), and higher ETP (the top quartile, >1657 nM × min) were predictors of cancer diagnosed during follow‐up. The multivariable Cox proportional hazards model showed that patients with the prothrombotic clot phenotype (low Ks 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.

Quantification of citrullinated histones: Development of an improved assay to reliably quantify nucleosomal H3Cit in human plasma

“…Hypercitrullination weakens the histone interaction with DNA, thus unfolding the tightly packed chromatin 10 (Figure 1B) and contributing to NET formation (Figure 1C). H3Cit is therefore considered a useful marker of NET formation 23‐34 …”

Fibrinolysis in Venous Thromboembolism

“…During a long-term follow-up, malignancy was diagnosed in 6% of VTE patients, who had several fibrin-related abnormalities, including impaired fibrinolysis (þ25.5% CLT) measured after a mean 4month anticoagulation had been stopped. 68 Interestingly, there was a weak positive association of CLT with NETs formation as evidenced by circulating H3Cit levels. 68 These recent findings suggest that prothrombotic clot properties might be a sensitive marker of various pathologies increasing the risk of recurrent VTE, as shown for occult cancer.…”

“…68 Interestingly, there was a weak positive association of CLT with NETs formation as evidenced by circulating H3Cit levels. 68 These recent findings suggest that prothrombotic clot properties might be a sensitive marker of various pathologies increasing the risk of recurrent VTE, as shown for occult cancer.…”

Inflammatory Biomarkers in the Short-Term Prognosis of Venous Thromboembolism: A Narrative Review

“…Nevertheless, elevated levels of P-selectin at diagnosis of unprovoked VTE increase the risk of cancer diagnosis afterwards, with a high predictive capacity (C-statistic: 0.9 [0.83-0.97] for a threshold level of 45 ng/mL) [65]. Another study evaluated 43 potential biomarkers in patients with DVT.…”