Anti-thrombotics in thrombosis and cancer.
ABSTRACT Many cancer patients have a reportedly hypercoagulable state, with recurrent thrombosis due to the impact of cancer cells and chemotherapy or radiotherapy on the coagulation cascade. Studies have demonstrated that unfractionated heparin or its low-molecular-weight fractions interfere with various processes involved in tumor growth and metastasis. These include fibrin formation; binding of heparin to angiogenic growth factors, such as basic fibroblast growth factor and vascular endothelial growth factor; modulation of tissue factor; and perhaps other more important modulatory mechanisms, such as enhanced tissue factor pathway inhibitor (TFPI) release and inhibition of various matrix-degrading enzymes. Clinical trials have suggested a clinically relevant effect of low-molecular-weight heparin (LMWH), as compared with unfractionated heparin, on the survival of cancer patients with deep vein thrombosis. Similarly, the impact of warfarin on the survival of cancer patients with thromboembolic disorders was demonstrated. Studies from the author's laboratory demonstrated a significant role for LMWH, warfarin, anti-VIIa, and LMWH-releasable TFPI on the regulation of angiogenesis, tumor growth and tumor metastasis. Thus, modulation of tissue factor/VIIa noncoagulant activities by LMWH, warfarin, anti-VIIa, or TFPI may be a useful therapeutic method for the inhibition of angiogenesis associated with human tumor growth and metastasis. Additionally, antiplatelet drugs may have an impact on tumor metastasis, and the combination of antiplatelets and anticoagulants at adjusted doses may provide greater benefits to cancer patients.
- SourceAvailable from: Moses T Bility01/2008;
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ABSTRACT: The relationship between cancer and thrombosis has been recognized for nearly 150 years. Although the mechanisms underlying this association are not completely understood, there are increasing evidences suggesting a pivotal role of thrombin in cancer biology. This review will focus on the most important pathways by which thrombin may affect cancer growth and dissemination. In addition, the potential role of congenital (i.e., hemophilia) and pharmaceutical (i.e., antithrombotic agents) anticoagulation in cancer incidence and survival will be investigated through the analysis of the published experimental and clinical studies.Seminars in Thrombosis and Hemostasis 02/2012; 38(1):95-101. · 4.22 Impact Factor
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ABSTRACT: Conventional therapy for venous thromboembolism or acute coronary syndrome involves the administration of glycoanticoagulants (heparins) or oligosaccharides (fondaparinux). We evaluated the effects of such drugs on angiogenesis and vasculogenesis-like models. Human umbilical vein endothelial cells or human endothelial progenitor cells were treated with bemiparin, fondaparinux or unfractionated heparin, at concentrations reflecting the doses used in clinical practice. After 24h, cell viability, proliferation, tubule formation and angiogenic molecular mechanisms, such as activation of the serine/threonine kinase AKT, were assessed. In vivo angiogenesis was studied using a Matrigel sponge assay in mice. Bemiparin gave a significant decrease of in vitro angiogenesis as shown by the reduction of endothelial cell tubule network, while both fondaparinux and unfractionated heparin did not show any significant effect. In assays of Matrigel sponge invasion in mice, unfractionated heparin was able to stimulate angiogenesis and, conversely, bemiparin inhibited angiogenesis. Furthermore, both bemiparin and fondaparinux caused a significant reduction in an in vitro vasculogenesis-like model, as demonstrated by the decrease of tubule network after co-seeding of endothelial progenitor cells and human umbilical vein endothelial cells. In addition, unfractionated heparin but not bemiparin was able to increase AKT phosphorylation. In in vitro experiments, bemiparin was the only drug to show an anti-angiogenic and vasculogenic-like effect, unfractionated heparin showed only a trend to increase in angiogenesis assay and fondaparinux affected only the vasculogenesis-like model. Notably, the in vivo experiments corroborated these data. Such results are important for the choice of a patient-tailored therapy.Thrombosis Research 04/2012; 130(3):e113-22. · 2.43 Impact Factor