Low Molecular Weight Heparin Modulates Thrombin Generation in Cancer Patients Undergoing Antithrombotic Therapy for Overt Venous Thromboembolism

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.