Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Efficacy of anticoagulants and platelet inhibitors in cancer-induced thrombosis Melissa E. Cloonan, Marianne DiNapoli and Shaker A. Mousa The efficacy of anticoagulants, low-molecular-weight heparins (LMWHs), the antiplatelet glycoprotein IIb/IIIa antagonist, or combinations on cancer-activated thrombosis was determined using thromboelastography. The LMWHs tinzaparin and enoxaparin (0.179, 1.79, 17.9 mg) were incubated in human citrated whole blood (n U 4) and then activated by calcium chloride (11 mmol/l) or Colo205 (cell count 10 5 ). Concentrations of 9.9, 17.9 and 179 mg glycoprotein IIb/IIIa antagonist, XV454, and combinations with each LMWH were carried out and activated under the same conditions. The experiment was repeated with tissue factor substituting for the Colo205 to induce platelet/fibrin clot formation. Parameters tested in the thrombelastography analysis included clotting time, rate of clot formation due to fibrin formation, clot kinetics, and clot strength related to platelet count (maximum amplitude). Tinzaparin (1.79 mg), enoxaparin (1.79 mg), and XV454 (17.9 mg) significantly reduced the angle by 64, 26 and 27%, respectively, in cancer-induced clotting. Significant reductions in the maximum amplitude occurred in tinzaparin 1.79 mg (31%), enoxaparin 1.79 mg (11%), and XV454 17.9 mg (59%). An overall antithrombotic additive effect occurred when each LMWH (1.79 mg) was combined with XV454 (17.9 mg). The results between cancer-activated and tissue factor-activated blood were similar. The study concludes that an additive effect is present between LMWHs and a glycoprotein IIb/IIIa antagonist in reducing cancer- mediated thrombosis. Blood Coagul Fibrinolysis 18:341– 345 ß 2007 Lippincott Williams & Wilkins. Blood Coagulation and Fibrinolysis 2007, 18:341–345 Keywords: cancer-induced thrombosis, glycoprotein IIb/IIIa inhibitor, low-molecular-weight heparins, thromboelastography, thrombosis, tissue factor Pharmaceutical Research Institute at Albany College of Pharmacy, Albany, New York, USA Correspondence to Shaker A. Mousa, PhD, MBA, FACC, FACB, Pharmaceutical Research Institute at Albany College of Pharmacy, 106 New Scotland Avenue, Albany, NY 12208, USA Tel: +1 518 694 7397; fax: +1 518 694 7392; e-mail: mousas@acp.edu Received 29 March 2005 Revised 2 February 2006 Accepted 10 February 2006 Introduction The relationship between coagulation and malignancy has been identified for over a century [1]. Hypercoagul- ability in cancer patients is the result of cancer cells and chemotherapy chronically activating the coagulation cascade [2]. Thrombotic diseases, such as deep vein thrombosis and pulmonary embolism, are more frequent in patients with cancer compared with patients without [3]. Additionally, Goldberg et al. [4] demonstrated that deep vein thrombosis and pulmonary embolism occurred more frequently in precancerous patients compared with patients who did not develop malignancy. Thrombosis may therefore be an indicator, as well as a result, of cancer; this further strengthens the relationship between hypercoagulation and malignancy. Cancer-induced thrombosis is known to occur by activat- ing both platelets and the coagulation cascade. Tumor cells elicit an immune response by invading and dama- ging host tissue. The immune response causes the release of several platelet activators or agonists from the tumor, damaged tissues, and the platelets themselves, which leads to platelet activation [5]. Activation of the coagu- lation cascade is caused primarily by tissue factor (TF) released by the tumor cells. TF binds to activated factor VII, which initiates the cascade and fibrin production [6]. In addition to activating the coagulation pathway, tumor TF also leads to the direct activation of platelets. The activated platelets bind to the fibrinogen present within the fibrin clot via the glycoprotein IIb/IIIa receptor on the surface of the platelets, which leads to aggregation [5] and strengthening of the fibrin clot. In addition to clot formation, coagulation and platelet activation may be significant in tumor growth and metas- tasis. Activated platelets are known to release angiogenic growth factors, which may contribute to tumor angiogen- esis [7]. Likewise, various factors that regulate angiogen- esis are related to the coagulation cascade [8]. The cancer-induced clot, which consists of fibrin and activated platelets, therefore contains the growth factors necessary for tumor growth and metastasis due to angiogenesis. As a result, a positive feedback loop occurs between the tumor and cancer-induced clot, which releases growth factors to promote angiogenesis [2]. The use of anticoagulants, such as heparin and low- molecular-weight heparin (LMWH), has been reviewed as possible treatment for malignancy and metastasis. Studies have demonstrated the ability of heparin to delay the growth of implanted primary tumors, as well as to inhibit metastasis [8]. Tinzaparin, a LMWH used to treat deep vein thrombosis [9], has been demonstrated to be effective in releasing TF pathway inhibitor from Original article 341 0957-5235 ß 2007 Lippincott Williams & Wilkins