Low Molecular Weight Heparin Modulates Thrombin Generation in Cancer Patients Undergoing Antithrombotic Therapy for Overt Venous Thromboembolism
Authors: Falanga Anna , Tartari Carmen J , Marchetti Marina R , Russo Laura , Lambregts Kim WFM , Resta Davide , D'Alessio Andrea 
Published: October 2019

Abstract
Introduction The incidence and recurrence rate of venous thromboembolism (VTE) are increased in the cancer compared to the non-cancer population. Low molecular weight heparin (LMWH) is recommended for both initial and long-term anticoagulant therapy for cancer-associated thrombosis, being more effective and safer than vitamin K antagonist therapy. However, failure of anticoagulation with LMWH in cancer-associated thrombosis still remains significantly elevated (VTE recurrence = 9-15%). In this study we tested whether thrombin generation (TG), a global hemostatic assay, may represent a modality to evaluate the LMWH anticoagulant level in vivo and help identifying patients at high risk for VTE recurrences. In a prospective cohort of cancer patients with VTE receiving LMWH nadroparin 200 U.I./Kg once a day, we evaluated whether LMWH treatment modulated the plasma TG capacity, together with other hemostatic parameters, i.e. microparticle (MP)-associated procoagulant activity (PCA) and D-dimer levels. Second we wished to explore whether these parameters may predict for VTE recurrence and/or bleeding.
Methods Fifty eight consecutive cancer patients with acute VTE were enrolled into the study. Plasma samples were obtained at the following time intervals: at the thrombotic event (T0), at 1 month LMWH therapy (T1), and at discontinuation (T2), i.e. 6 months after VTE. Patients were followed up clinically for a total 9 months to detect overt thrombotic or bleeding events. TG was measured by the CAT assay, MP-associated procoagulant activity (PCA) by the STA Procoag PPL assay, and D-dimer by HemosIL D-dimer test.
Results In this study cohort, the most represented malignancies were colon (25.9%), breast (15.5%), lung (15.5%), and gastric cancer (13.8%). Thirty six patients had metastatic disease, 22 had a limited disease. The VTE sites were: subclavian (36.2%), femoro-popliteal (20.7%), pulmonary (13.8%), jugular (8.6%), and brachial (6.9%) veins. Six patients had simultaneous femoro-popliteal venous thrombosis and pulmonary embolism. At T0 patients were characterized by a procoagulant phenotype as reflected by increased TG potential, and elevated MP-associated PCA and D-dimer compared to controls. In particular, cancer patients displayed a higher levels (p<0.01) of endogenous thrombin potential (ETP) and peak of thrombin vs controls (ETP: 1612±538 vs 1210±344 nMol*min and peak: 305±123 vs 182±84 mMol). These data were accompanied by a significant increase in MP-associated PCA (i.e. shorter clotting time 58±18 vs controls 89±12 sec; p<0.01), and D-dimer plasma levels (1430±1615 vs controls 90±96 ng/ml; p<0.01). During LMWH nadroparin therapy, a significant reduction in both TG potential (ETP-T1: 1254±810 nMol*min) and D-dimer levels (397±697 ng/ml) occurred, and after LMWH discontinuation (T2), TG potential as well as D-Dimer levels rose back, becoming similar to the control values. Differently, no reduction in MP-associated PCA was observed during LMWH therapy. Twenty-seven patients (46.6%) died during follow-up because of cancer disease. No patients had VTE recurrence. The analysis according to the stage of disease showed a significant difference with a higher mortality rate among those with a metastatic stage (p < 0.01). No correlations were observed according to chemotherapy.
Conclusion Our results show that LMWH therapy modulates the global thrombin generation capacity and affects the hypercoagulable state of cancer patients, whereas MP-PCA is insensitive to it. In this cohort LMWH treatment was effective (0% VTE recurrences) and safe (1 major bleeding episode). As no recurrences were observed, it was not possible to identify a predictive value for the biological parameters. It is worth to define in a large trial the clinical utility of the TG global coagulation assay to monitor LMWH anticoagulation levels in this high risk population.

Disclosures
No relevant conflicts of interest to declare.