Thrombosis associated with malignant disease is a leading cause of morbidity and mortality in cancer patients, yet its pathophysiologic basis remains unknown. In our pilot study to ascertain the association of thrombosis with a potential biomarker, tissue factor-bearing microparticles, the odds ratio for these microparticles in cancer patients with venous thromboembolic events compared with cancer patients without venous thromboembolic events was 4.1. In thrombosis- negative cancer patients with detectable tissue factor-bearing microparticles, the one-year rate of their developing a thrombotic event was 35% versus 0% in the same group without elevated tissue factor-bearing microparticles.
Aim #1 focuses on in vitro studies to determine the functional status of tissue factor expressed on cancer microparticles, and the tissue origin and half-life of these microparticles.
Aim #2 describes a randomized, placebo-controlled interventional clinical trial involving over 100 patients with pancreatic carcinoma to determine whether patients with tumor-derived tissue factor-bearing microparticles will benefit from thromboprophylaxis with unfractionated heparin to reduce venous thromboembolic complications.
In Aim #3, SCID mice with human pancreatic carcinoma xenografts will be used as a mouse model of pancreatic carcinoma. The accumulation of human xenograft-derived tissue factor-bearing microparticles during thrombus formation will be imaged by intravital microscopy to observe the accumulation of human tissue factor in the developing thrombus and the contribution of xenograft-derived tissue factor to thrombus formation. The role of platelet P- selectin in microparticle accumulation will be determined, and the P-selectin ligand on tumor- derived microparticles identified by Western blotting and mass spectroscopy. The results will advance the hypothesis that tissue factor-bearing microparticles are both a biomarker for thrombosis risk in pancreatic carcinoma and that they are central to the pathogenesis of cancer- associated thrombosis. Given the priority of identifying better markers of cancer patients likely to develop thrombosis, the demonstration of the utility of heparin thromboprophylaxis of patients with pancreatic carcinoma who are positive for TF-bearing microparticles will have significant impact in clinical practice by establishing an anticoagulant regimen focused on only cancer patients at high risk of thrombosis.
Tissue factor-bearing microparticles are both a biomarker for thrombosis risk in cancer and likely central to the pathogenesis of cancer-associated thrombosis. Given the priority that identifying better markers of cancer patients likely to develop thrombosis, the demonstration of the utility of heparin thromboprophylaxis of patients with pancreatic carcinoma who are positive for TF-bearing microparticles will have significant impact in clinical practice by establishing an anticoagulant regimen focused on only cancer patients a high risk of thrombosis.
|Proulle, Valerie; Furie, Richard A; Merrill-Skoloff, Glenn et al. (2014) Platelets are required for enhanced activation of the endothelium and fibrinogen in a mouse thrombosis model of APS. Blood 124:611-22|
|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|
|Kroh, Heather K; Panizzi, Peter; Tchaikovski, Svetlana et al. (2011) Active site-labeled prothrombin inhibits prothrombinase in vitro and thrombosis in vivo. J Biol Chem 286:23345-56|
|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|