The association between malignancy and thrombosis dates back to the mid 1800's when Armand Trousseau first observed the thrombotic predilection of patients suffering from cancer, and yet the pathogenic substance leading to thrombosis in cancer patients remains speculative. Over 25 years ago, researchers observed tumor cells that shed microparticles containing procoagulant activity but only recently have microparticles been identified as instrumental in the propagation of a thrombus in vivo. We have developed an impedance- based flow cytometer to assist in the characterization of microparticles in cancer patients. Our preliminary data suggests that tissue factor bearing microparticles are elevated in pancreatic cancer patients which is a malignancy commonly associated with thromboembolic events. Elevated tissue factor bearing microparticles were also identified in all six pancreatic cancer patients who recently suffered a thrombotic event. In this grant application, I propose to investigate the association between bloodborne TF-bearing microparticles and cancer-associated thromboembolic disease.
The Specific Aims of this project are (1) to characterize microparticle concentrations in healthy controls and determine the normal distribution of tissue factor bearing microparticles;(2) to determine which malignancies are associated with the highest circulating TF-bearing microparticle concentrations and to assess whether TF-bearing microparticles normalize following surgical resection of a pancreatic adenocarcinoma . TF-bearing microparticle concentrations will also be measured in patients with and without malignancy who present with an acute venous thromboembolic event in order to establish whether elevations in TF-bearing microparticles are unique to patients with malignancy;and lastly, (3) to investigate the causal relationship between elevated TF-bearing microparticle concentrations and thrombosis as identified by screening ultrasound examination. This proposal addresses the molecular basis of thrombosis in cancer patients with the goal of establishing a novel biomarker. Given that thromboembolic events are the second leading cause of death in cancer patients, an improved understanding of the underlying mechanisms of thrombosis would likely translate into improved strategies for both the management and prevention of thrombotic events in cancer.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Mentored Patient-Oriented Research Career Development Award (K23)
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Special Emphasis Panel (ZHL1-CSR-R (O1))
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Werner, Ellen
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Beth Israel Deaconess Medical Center
United States
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Zwicker, Jeffrey I; Liebman, Howard A; Bauer, Kenneth A et al. (2013) Prediction and prevention of thromboembolic events with enoxaparin in cancer patients with elevated tissue factor-bearing microparticles: a randomized-controlled phase II trial (the Microtec study). Br J Haematol 160:530-7
Campigotto, F; Neuberg, D; Zwicker, J I (2012) Biased estimation of thrombosis rates in cancer studies using the method of Kaplan and Meier. J Thromb Haemost 10:1449-51
Campigotto, Federico; Neuberg, Donna; Zwicker, Jeffrey I (2012) Accounting for death as a competing risk in cancer-associated thrombosis studies. Thromb Res 129 Suppl 1:S85-7
Zwicker, Jeffrey I; Trenor 3rd, Cameron C; Furie, Barbara C et al. (2011) Tissue factor-bearing microparticles and thrombus formation. Arterioscler Thromb Vasc Biol 31:728-33
Zwicker, Jeffrey I (2010) Impedance-based flow cytometry for the measurement of microparticles. Semin Thromb Hemost 36:819-23
Zwicker, Jeffrey I (2010) Predictive value of tissue factor bearing microparticles in cancer associated thrombosis. Thromb Res 125 Suppl 2:S89-91
Mantha, S; Bauer, K A; Zwicker, J I (2010) Low molecular weight heparin to achieve live birth following unexplained pregnancy loss: a systematic review. J Thromb Haemost 8:263-8
Zwicker, Jeffrey I; Liebman, Howard A; Neuberg, Donna et al. (2009) Tumor-derived tissue factor-bearing microparticles are associated with venous thromboembolic events in malignancy. Clin Cancer Res 15:6830-40