Development of Venous Thromboembolic Events in Cancer Patients with Elevated Levels of Tissue Factor-Bearing Microparticles

Abstract Cancer cells shed procoagulant vesicles containing tissue factor, and these tissue factor-bearing microparticles (TFMP) may play a role in thrombus formation in vivo. Using impedance-based flow cytometry to quantify microparticles and a high affinity monoclonal antibody specific for tissue factor, we previously demonstrated the presence of tissue factor-bearing microparticles in platelet-poor plasma in cancer patients. In this case control study, tissue factor-bearing microparticles represented a 4-fold risk factor for venous thromboembolic events (VTE) in cancer patients with acute VTE compared to age, stage, sex, diagnosis-matched controls with cancer but without acute VTE. To further assess the relationship between tissue factor-bearing microparticles and VTE, we performed a retrospective analysis of deep venous thrombosis or pulmonary emboli diagnosed in cancer patients initially enrolled without evidence of VTE. All radiographic reports for the cancer-no VTE group in the 2 years following enrollment were analyzed by a reviewer blinded to microparticle status. Only documented evidence of a new proximal extremity deep vein thrombosis or pulmonary embolism was included in the analysis. The TFMP and no-TFMP groups did not differ significantly for age, sex, active cancer treatment, smoking status, diabetes, or the presence of metastatic disease at time of enrollment. Sixteen of the 60 patients in this group had measurable tissue factor-bearing microparticles, 4 (4/16; 25%) of which subsequently developed radiographic evidence of VTE within 12 months of enrollment. No thrombotic events were recorded among the 44 patients without detectable tissue factor-bearing microparticles within the initial 12 months; however, one patient developed a pulmonary embolism 17 months following enrollment. Identifying death without VTE as a competing risk, the one-year estimate of the rate of VTE in cancer patients with detectable tissue factor-bearing microparticles was 34.8%; among the same group without detectable tissue factor-bearing microparticles, the 1-year rate was 0% (Log Rank p-value=0.002). The presence of tissue factor-bearing microparticles in cancer patients initially thrombosis-free predicted a 7-fold increased risk of thrombosis over cancer patients who were negative for tissue factor-bearing microparticles (OR 7.00, 95% CI 0.85–82.74, P=0.02). These tissue factor-bearing microparticles appear to be derived from the underlying malignancy since samples analyzed from patients with pancreatic cancer demonstrated co-expression of both tissue factor and MUC-1, a transmembrane glycoprotein overexpressed in epithelial malignancies. These data further support the role of tissue factor-bearing microparticles in the pathogenesis of cancer-associated thrombosis and as a biomarker for the prediction of cancer patients at risk of thrombosis. A prospective clinical study, currently being initiated, is required to evaluate this biomarker for the prediction of VTE risk in cancer patients and the utility of thromboprophylaxis in patients with elevated numbers of tissue factor-bearing microparticles.