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.
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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. · 3.13 Impact Factor
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ABSTRACT: Deep venous thrombosis (DVT) and pulmonary embolism (PE) are possible sources of morbidity and mortality in patients with musculoskeletal neoplasms (MSN). To compare the efficacy of aspirin (ASA) and pneumatic compression devices (PCD) to low-molecular-weight heparin (LMWH) and PCD in patients undergoing orthopedic procedures for MSN of the pelvis or lower extremity. Of 348 patients who met the study criteria, 195 were treated with ASA/PCD and 153 with LMWH/PCD. There were 18 DVT including 8 in ASA/PCD group and 10 in LMWH/PCD group. There were four PEs, all in the LMWH/PCD group. We found no significant difference in DVT rate between ASA/PCD and LMWH/PCD when used for prophylaxis against thromboembolic complications. Our analysis shows that procedures of the thigh, soft tissue resections, and malignant disease were more often managed with ASA/PCD while joint arthroplasty, procedures of the hip/pelvis, and metastatic disease were more often managed with LMWH/PCD. DVT prophylaxis in orthopedic oncology remains a complex topic in which physicians must balance the risks of thromboembolic disease against the risks of post-operative complications.Journal of Surgical Oncology 09/2010; 102(3):276-81. · 2.64 Impact Factor
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ABSTRACT: Recent prospective clinical trials of low molecular weight heparins (LMWHs) have demonstrated that these agents may provide significant advantages in terms of progression-free and overall survival in certain subgroups of cancer patients. The mechanisms of improved survival associated with LMWHs are not known, and may involve direct and/or indirect effects on tumor growth. The purpose of this study was to investigate the effects of LMWH and a sulfated non-anticoagulant LMWH (S-NACH) on tumor chemotherapeutic uptake and chemoresponse. LMWH and S-NACH were tested for their ability to reduce tumor growth and tumor-associated angiogenesis using three different in vivo models. Biodistribution studies were undertaken to determine the effect of these agents on uptake of paclitaxel (PACL) and doxorubicin (Dox) by breast cancer tumor xenografts. LMWH and S-NACH (10 mg/kg s.c. daily) effectively limited tumor growth of human A549 lung adenocarcinoma xenografts in the nude mouse. In an MDA453/LCC6 breast tumor xenograft model, PACL plus S-NACH showed significant (p < 0.01) tumor growth suppression and improved survival when compared to PACL alone. LMWH increased [(124-)I]-PACL uptake into MDA453/LCC6 tumors, with tumor:muscle ratios several fold greater than that of [(124-)I]-PACL alone 24 h post-injection. Similarly, LMWH and S-NACH significantly (p < 0.01) increased the uptake of Dox by 1.5-2 fold in MCF7 Dox-resistant tumor xenografts. Protocols utilizing adjuvant or neo-adjuvant therapy with LMWH or S-NACH could lead to increased tumor chemo responsiveness, potentially overcoming tumor chemoresistance.Anticancer research 02/2011; 31(2):411-9. · 1.71 Impact Factor