Heparin and Low-Molecular Weight Heparins in Thrombosis and Beyond

  • Shaker A. Mousa
Part of the Methods in Molecular Biology book series (MIMB, volume 663)


Heparin and its improved version, low-molecular weight heparin (LMWH), are known to exert polypharmacological effects at various levels. Early studies focused on the plasma anti-Xa and anti-IIa pharmacodynamics of different LMWHs. Other important pharmacodynamic parameters for heparin and LMWH, including effects on vascular tissue factor pathway inhibitor (TFPI) release, inhibition of inflammation through NFκB, inhibition of key matrix-degrading enzymes, selectin modulation, inhibition of platelet–cancer cell interactions, and inflammatory cell adhesion, help explain the diverse clinical impact of this class of agents in thrombosis and beyond.

Key words

Heparin low-molecular weight heparin tissue factor pathway inhibitor angiogenesis tumor growth metastasis asthma inflammation 


  1. 1.
    Linhardt, R. (1991) Heparin: an important drug enters its seventh decade Chem Indust 2, 45–50.Google Scholar
  2. 2.
    Marcum, J.A. (2000) The origin of the dispute over the discovery of heparin J Hist Med Allied Sci 55, 37–66.PubMedCrossRefGoogle Scholar
  3. 3.
    Ruty, C. Miracle Blood Lubricant: Connaught and the Story of Heparin, 1928–1937 Health Heritage Research Services, http://www.healthheritageresearch.com. Originally published in CONNTACT (1996) 9. Accessed on May 5, 2007.
  4. 4.
    Bjork, I., Lindahl, U. (1982) Mechanism of the anticoagulant action of heparin Mol Cell Biochem 48, 161–82.PubMedCrossRefGoogle Scholar
  5. 5.
    Hirsh, J., and Raschke, R. (2004) Heparin and low-molecular-weight heparin: the seventh ACCP conference on antithrombotic and thrombolytic therapy Chest 126, 188S–203S.PubMedCrossRefGoogle Scholar
  6. 6.
    Aguilar, D., and Goldhaber, S.Z. (1999) Clinical uses of low-molecular-weight heparins Chest 115, 1418–23.PubMedCrossRefGoogle Scholar
  7. 7.
    Mousa, S., Fareed, J. (2001) Advances in anticoagulant, antithrombotic and thrombolytic drugs Expert Opin Invest Drugs 10, 157–62.CrossRefGoogle Scholar
  8. 8.
    Mousa, S.A. (2000) Comparative efficacy of different low-molecular-weight heparins (LMWHs) and drug interactions with LMWH: implications for management of vascular disorders Semin Thromb Hemost 26(Suppl 1), 39–46.PubMedCrossRefGoogle Scholar
  9. 9.
    Weitz, J.I. (1997) Low-molecular-weight heparins N Engl J Med 337, 688–98.PubMedCrossRefGoogle Scholar
  10. 10.
    Hirsh, J., and Levine, M.N. (1992) Low molecular weight heparin Blood 79, 1–17.PubMedGoogle Scholar
  11. 11.
    Linhardt, R.J.,and Gunay, N.S. (1999) Production and chemical processing of low molecular weight heparins Semin Thromb Hemost 25(Suppl 3), 5–16.PubMedGoogle Scholar
  12. 12.
    Nielsen, J.I., and Ostergaard, P. (1988) Chemistry of heparin and low molecular weight heparin Acta Chir Scand Suppl 543, 52–6.PubMedGoogle Scholar
  13. 13.
    Brieger, D., and Dawes, J. (1997) Production method affects the pharmacokinetic and ex vivo biological properties of low molecular weight heparins Thromb Haemost 77, 317–22.PubMedGoogle Scholar
  14. 14.
    Emanuele, R.M., and Fareed, J. (1987) The effect of molecular weight on the bioavailability of heparin Thromb Res 48, 591–6.PubMedCrossRefGoogle Scholar
  15. 15.
    Mousa, S.A., Fareed, J., Iqbal, O., and Kaiser, B. (2004) Tissue factor pathway inhibitor in thrombosis and beyond Methods Mol Med 93, 133–55.PubMedGoogle Scholar
  16. 16.
    Mousa, S.A., and Mohamed, S. (2004) Inhibition of endothelial cell tube formation by the low molecular weight heparin, tinzaparin, is mediated by tissue factor pathway inhibitor Thromb Haemost 92, 627–33.PubMedGoogle Scholar
  17. 17.
    Boneu, B., Caranobe, C., Cadroy, Y., Dol, F., Gabaig, A.M., Dupouy, D., and Sie, P. (1988) Pharmacokinetic studies of standard unfractionated heparin, and low molecular weight heparins in the rabbit Semin Thromb Hemost 14, 18–27.PubMedCrossRefGoogle Scholar
  18. 18.
    Sutor, A.H., Massicotte, P., Leaker, M., and Andrew, M. (1997) Heparin therapy in pediatric patients Semin Thromb Hemost 23, 303–19.PubMedCrossRefGoogle Scholar
  19. 19.
    Taheri, S.A., Lazar, L., Haddad, G., Castaldo, R., Wilson, M., and Mousa, S. (1998) Diagnosis of deep venous thrombosis by use of soluble necrosis factor receptor Angiology 49, 537–41.PubMedCrossRefGoogle Scholar
  20. 20.
    Lantz, M., Thysell, H., Nilsson, E., and Olsson, I. (1991) On the binding of tumor necrosis factor (TNF) to heparin and the release in vivo of the TNF-binding protein I by heparin J Clin Invest 88, 2026–31.PubMedCrossRefGoogle Scholar
  21. 21.
    Nelson, R.M., Cecconi, O., Roberts, W.G., Aruffo, A., Linhardt, R.J., and Bevilacqua, M.P. (1993) Heparin oligosaccharides bind L- and P-selectin and inhibit acute inflammation Blood 82, 3253–8.PubMedGoogle Scholar
  22. 22.
    Tyrell, D.J., Kilfeather, S., and Page, C.P. (1995) Therapeutic uses of heparin beyond its traditional role as an anticoagulant Trends Pharmacol Sci 16, 198–204.PubMedCrossRefGoogle Scholar
  23. 23.
    Bazzoni, G., Beltran Nunez, A., Mascellani, G., Bianchini, P., Dejana, E., and Del Maschio, A. (1993) Effect of heparin, dermatan sulfate, and related oligo-derivatives on human polymorphonuclear leukocyte functions J Lab Clin Med 121, 268–75.PubMedGoogle Scholar
  24. 24.
    Darien, B.J., Fareed, J., Centgraf, K.S., Hart, A.P., MacWilliams, P.S., Clayton, M.K., Wolf, H., and Kruse-Elliott, K.T. (1998) Low molecular weight heparin prevents the pulmonary hemodynamic and pathomorphologic effects of endotoxin in a porcine acute lung injury model Shock 9, 274–81.PubMedCrossRefGoogle Scholar
  25. 25.
    Hiebert, L.M., and Liu, J.M. (1990) Heparin protects cultured arterial endothelial cells from damage by toxic oxygen metabolites Atherosclerosis 83, 47–51.PubMedCrossRefGoogle Scholar
  26. 26.
    Hocking, D., Ferro, T.J., and Johnson, A. (1992) Dextran sulfate and heparin sulfate inhibit platelet-activating factor-induced pulmonary edema J Appl Physiol 72, 179–85.PubMedCrossRefGoogle Scholar
  27. 27.
    Matzner, Y., Marx, G., Drexler, R., and Eldor, A. (1984) The inhibitory effect of heparin and related glycosaminoglycans on neutrophil chemotaxis Thromb Haemost 52, 134–7.PubMedGoogle Scholar
  28. 28.
    Meyer, J., Cox, C.S., Herndon, D.N., Nakazawa, H., Lentz, C.W., Traber, L.D., and Traber, D.L. (1993) Heparin in experimental hyperdynamic sepsis Crit Care Med 21, 84–9.PubMedCrossRefGoogle Scholar
  29. 29.
    Majerus, P., Broze, J., and Miletich, J. Anticoagulant, thrombolytic and antiplatelet drugs. In: Hardman, J., Limbird, L., Molinoff, P., Ruddon, R., and Goodman, A., eds. Goodman & Gilman’s, The Pharmacological Basis of Therapeutics. New York: McGraw-Hill;1996:1341–59.Google Scholar
  30. 30.
    Silverstein, R. Drugs affecting hemostosis. In: Munson, P., Mueller, R., and Breeze, G., eds. Munson’s Principles of Pharmacology. New York: Chapman & Hall;1995: 1123–43.Google Scholar
  31. 31.
    Theroux, P., Waters, D., Qiu, S., McCans, J., de Guise, P., and Juneau, M. (1993) Aspirin versus heparin to prevent myocardial infarction during the acute phase of unstable angina Circulation 88, 2045–8.PubMedCrossRefGoogle Scholar
  32. 32.
    Diamant, Z., Timmers, M.C., van der Veen, H., Page, C.P., van der Meer, F.J., and Sterk, P.J. (1996) Effect of inhaled heparin on allergen-induced early and late asthmatic responses in patients with atopic asthma Am J Respir Crit Care Med 153, 1790–5.PubMedGoogle Scholar
  33. 33.
    Garrigo, J., Danta, I., and Ahmed, T. (1996) Time course of the protective effect of inhaled heparin on exercise-induced asthma Am J Respir Crit Care Med 153, 1702–7.PubMedGoogle Scholar
  34. 34.
    Vancheri, C., Mastruzzo, C., Armato, F., Tomaselli, V., Magri, S., Pistorio, M.P., LaMicela, M., D’Amico, L., and Crimi, N. (2001) Intranasal heparin reduces eosinophil recruitment after nasal allergen challenge in patients with allergic rhinitis J Allergy Clin Immunol 108, 703–8.PubMedCrossRefGoogle Scholar
  35. 35.
    Bowler, S.D., Smith, S.M., and Lavercombe, P.S. (1993) Heparin inhibits the immediate response to antigen in the skin and lungs of allergic subjects Am Rev Respir Dis 147, 160–3.PubMedCrossRefGoogle Scholar
  36. 36.
    Dwarakanath, A.D., Yu, L.G., Brookes, C., Pryce, D., and Rhodes, J.M. (1995) ‘Sticky’ neutrophils, pathergic arthritis, and response to heparin in pyoderma gangrenosum complicating ulcerative colitis Gut 37, 585–8.PubMedCrossRefGoogle Scholar
  37. 37.
    Petitou, M., Herault, J.P., Bernat, A., Driguez, P.A., Duchaussoy, P., Lormeau, J.C., and Herbert, J.M. (1999) Synthesis of thrombin-inhibiting heparin mimetics without side effects Nature 398, 417–22.PubMedCrossRefGoogle Scholar
  38. 38.
    Tyrrell, D.J., Horne, A.P., Holme, K.R., Preuss, J.M., and Page, C.P. (1999) Heparin in inflammation: potential therapeutic applications beyond anticoagulation Adv Pharmacol 46, 151–208.PubMedCrossRefGoogle Scholar
  39. 39.
    Brazier, F., Yzet, T., Boruchowicz, A., Colombel, J.F., Duckmann, J.C., and Dupas, J.L. (1996) Treatment of ulcerative colitis with heparin Gastroenterol 110, A872.Google Scholar
  40. 40.
    Brazier, F., T, Y., Duchmann, J., Igliki, F., and Dupas, J. (1996) Effect of heparin treatment on extraintestinal manifestations associated with in¯ammatory bowel disease Gastroenterology 110, A872.Google Scholar
  41. 41.
    Dupas, J., Brazier, F., Yzet, T., Roussel, В., Duchmann, J., and Iglicki, F. (1996) Treatment of active Crohn’s disease with heparin Gastroenterology 110.Google Scholar
  42. 42.
    Evans, R., and Rhodes, J.M. (1995) Treatment of corticosteroid-resistant ulcerative colitis with heparin: a report of nine cases Gut 37, A49.Google Scholar
  43. 43.
    Folwaczny, C., Spannagl, M., Wiebecke, W., Jochum, M., Heldwein, W., and Loeschke, K. (1996) Heparin in the treatment of highly active inflammatory bowel disease (IBD) Gastroenterology 110.Google Scholar
  44. 44.
    Gaffney, P., and Gaffney, A. (1996) Heparin therapy in refractory ulcerative colitis – an update Gastroenterology 110, A913.Google Scholar
  45. 45.
    Gaffney, P.R., Doyle, C.T., Gaffney, A., Hogan, J., Hayes, D.P., and Annis, P. (1995) Paradoxical response to heparin in 10 patients with ulcerative colitis Am J Gastroenterol 90, 220–3.PubMedGoogle Scholar
  46. 46.
    Salas, A., Sans, M., Soriano, A., Reverter, J.C., Anderson, D.C., Pique, J.M., and Panes, J. (2000) Heparin attenuates TNF-alpha induced inflammatory response through a CD11b dependent mechanism Gut 47, 88–96.PubMedCrossRefGoogle Scholar
  47. 47.
    Panes, J., Perry, M., and Granger, D.N. (1999) Leukocyte-endothelial cell adhesion: avenues for therapeutic intervention Br J Pharmacol 126, 537–50.PubMedCrossRefGoogle Scholar
  48. 48.
    Lever, R., Hoult, J.R., and Page, C.P. (2000) The effects of heparin and related molecules upon the adhesion of human polymorphonuclear leucocytes to vascular endothelium in vitro Br J Pharmacol 129, 533–40.PubMedCrossRefGoogle Scholar
  49. 49.
    Carr, J. (1979) The anti-inflammatory action of heparin: heparin as an antagonist to histamine, bradykinin and prostaglandin E1 Thromb Res 16, 507–16.PubMedCrossRefGoogle Scholar
  50. 50.
    Teixeira, M.M., and Hellewell, P.G. (1993) Suppression by intradermal administration of heparin of eosinophil accumulation but not oedema formation in inflammatory reactions in guinea-pig skin Br J Pharmacol 110, 1496–500.PubMedCrossRefGoogle Scholar
  51. 51.
    Koenig, A., Norgard-Sumnicht, K., Linhardt, R., and Varki, A. (1998) Differential interactions of heparin and heparan sulfate glycosaminoglycans with the selectins. Implications for the use of unfractionated and low molecular weight heparins as therapeutic agents J Clin Invest 101, 877–89.PubMedCrossRefGoogle Scholar
  52. 52.
    Benimetskaya, L., Loike, J.D., Khaled, Z., Loike, G., Silverstein, S.C., Cao, L., el Khoury, J., Cai, T.Q., and Stein, C.A. (1997) Mac-1 (CD11b/CD18) is an oligodeoxynucleotide-binding protein Nat Med 3, 414–20.PubMedCrossRefGoogle Scholar
  53. 53.
    Diamond, M.S., Alon, R., Parkos, C.A., Quinn, M.T., and Springer, T.A. (1995) Heparin is an adhesive ligand for the leukocyte integrin Mac-1 (CD11b/CD1) J Cell Biol 130, 1473–82.PubMedCrossRefGoogle Scholar
  54. 54.
    Itoh, K., Nakao, A., Kishimoto, W., and Takagi, H. (1995) Heparin effects on superoxide production by neutrophils Eur Surg Res 27, 184–8.PubMedCrossRefGoogle Scholar
  55. 55.
    Attanasio, M., Gori, A.M., Giusti, B., Pepe, G., Comeglio, P., Brunelli, T., Prisco, D., Abbate, R., Gensini, G.F., and Neri Serneri, G.G. (1998) Cytokine gene expression in human LPS- and IFNgamma-stimulated mononuclear cells is inhibited by heparin Thromb Haemost 79, 959–62.PubMedGoogle Scholar
  56. 56.
    Dandona, P., Qutob, T., Hamouda, W., Bakri, F., Aljada, A., and Kumbkarni, Y. (1999) Heparin inhibits reactive oxygen species generation by polymorphonuclear and mononuclear leucocytes Thromb Res 96, 437–43.PubMedCrossRefGoogle Scholar
  57. 57.
    Black, S.C., Gralinski, M.R., Friedrichs, G.S., Kilgore, K.S., Driscoll, E.M., and Lucchesi, B.R. (1995) Cardioprotective effects of heparin or N-acetylheparin in an in vivo model of myocardial ischaemic and reperfusion injury Cardiovasc Res 29, 629–36.PubMedGoogle Scholar
  58. 58.
    Friedrichs, G.S., Kilgore, K.S., Manley, P.J., Gralinski, M.R., and Lucchesi, B.R. (1994) Effects of heparin and N-acetyl heparin on ischemia/reperfusion-induced alterations in myocardial function in the rabbit isolated heart Circ Res 75, 701–10.PubMedCrossRefGoogle Scholar
  59. 59.
    Lucchesi, B.R., and Kilgore, K.S. (1997) Complement inhibitors in myocardial ischemia/reperfusion injury Immunopharmacology 38, 27–42.PubMedCrossRefGoogle Scholar
  60. 60.
    Hawari, F.I., Shykoff, B.E., and Izzo, J.L., Jr. (1998) Heparin attenuates norepinephrine-induced venoconstriction Vasc Med 3, 95–100.PubMedGoogle Scholar
  61. 61.
    De Caterina, R., Libby, P., Peng, H.B., Thannickal, V.J., Rajavashisth, T.B., Gimbrone, M.A., Jr., Shin, W.S., and Liao, J.K. (1995) Nitric oxide decreases cytokine-induced endothelial activation. Nitric oxide selectively reduces endothelial expression of adhesion molecules and proinflammatory cytokines J Clin Invest 96, 60–8.PubMedCrossRefGoogle Scholar
  62. 62.
    Trousseau, A. Phlegmasia alba dolens. In: Baillier, J., ed. Clinique de l’Hotel-Dieu de Paris, 2nd edition. London: New Sydenham Society;1865:654–712.Google Scholar
  63. 63.
    Schiller, H., Bartscht, T., Arlt, A., Zahn, M.O., Seifert, A., Bruhn, T., Bruhn, H.D., and Gieseler, F. (2002) Thrombin as a survival factor for cancer cells: thrombin activation in malignant effusions in vivo and inhibition of idarubicin-induced cell death in vitro Int J Clin Pharmacol Ther 40, 329–35.PubMedGoogle Scholar
  64. 64.
    Sorensen, H.T., Mellemkjaer, L., Olsen, J.H., and Baron, J.A. (2000) Prognosis of cancers associated with venous thromboembolism N Engl J Med 343, 1846–50.PubMedCrossRefGoogle Scholar
  65. 65.
    Caine, G.J., and Lip, G.Y. (2002) Anticoagulants as anticancer agents? Lancet Oncol 3, 591–2.PubMedCrossRefGoogle Scholar
  66. 66.
    Chahinian, A.P., Propert, K.J., Ware, J.H., Zimmer, B., Perry, M.C., Hirsh, V., Skarin, A., Kopel, S., Holland, J.F., and Comis, R.L., et al. (1989) A randomized trial of anticoagulation with warfarin and of alternating chemotherapy in extensive small-cell lung cancer by the cancer and leukemia group B J Clin Oncol 7, 993–1002.PubMedGoogle Scholar
  67. 67.
    Goldberg, R.J., Seneff, M., Gore, J.M., Anderson, F.A., Jr., Greene, H.L., Wheeler, H.B., and Dalen, J.E. (1987) Occult malignant neoplasm in patients with deep venous thrombosis Arch Intern Med 147, 251–3.PubMedCrossRefGoogle Scholar
  68. 68.
    Lebeau, B., Chastang, C., Brechot, J.M., Capron, F., Dautzenberg, B., Delaisements, C., Mornet, M., Brun, J., Hurdebourcq, J.P., and Lemarie, E. (1994) Subcutaneous heparin treatment increases survival in small cell lung cancer. “Petites Cellules” group Cancer 74, 38–45.PubMedCrossRefGoogle Scholar
  69. 69.
    Saba, H.I., Khalil, F.K., Morelli, G.A., and Foulis, P.R. (2003) Thromboembolism preceding cancer: a correlation study Am J Hematol 72, 109–14.PubMedCrossRefGoogle Scholar
  70. 70.
    Thornes, R. Coumarins, melanoma and cellular immunity. In: McBrien, D., and Slator, T., eds. Protective Agents in Cancer. London: Academic Press;1983:43–56.Google Scholar
  71. 71.
    Baron, J.A., Gridley, G., Weiderpass, E., Nyren, O., and Linet, M. (1998) Venous thromboembolism and cancer Lancet 351, 1077–80.PubMedCrossRefGoogle Scholar
  72. 72.
    Falanga, A. (1998) Mechanisms of hypercoagulation in malignancy and during chemotherapy Haemostasis 28 (Suppl 3), 50–60.PubMedGoogle Scholar
  73. 73.
    Kakkar, A.K., DeRuvo, N., Chinswangwatanakul, V., Tebbutt, S., and Williamson, R.C. (1995) Extrinsic-pathway activation in cancer with high factor VIIa and tissue factor Lancet 346, 1004–5.PubMedCrossRefGoogle Scholar
  74. 74.
    Levine, M.N. (1997) Prevention of thrombotic disorders in cancer patients undergoing chemotherapy Thromb Haemost 78, 133–6.PubMedGoogle Scholar
  75. 75.
    Rickles, F.R., and Edwards, R.L. (1983) Activation of blood coagulation in cancer: Trousseau’s syndrome revisited Blood 62, 14–31.PubMedGoogle Scholar
  76. 76.
    Koopman, M.M., Prandoni, P., Piovella, F., Ockelford, P.A., Brandjes, D.P., van der Meer, J., Gallus, A.S., Simonneau, G., Chesterman, C.H., and Prins, M.H. (1996) Treatment of venous thrombosis with intravenous unfractionated heparin administered in the hospital as compared with subcutaneous low-molecular-weight heparin administered at home. The Tasman study group N Engl J Med 334, 682–7.PubMedCrossRefGoogle Scholar
  77. 77.
    Simonneau, G., Sors, H., Charbonnier, B., Page, Y., Laaban, J.P., Azarian, R., Laurent, M., Hirsch, J.L., Ferrari, E., Bosson, J.L., Mottier, D., and Beau, B. (1997) A comparison of low-molecular-weight heparin with unfractionated heparin for acute pulmonary embolism. The THESEE study group. Tinzaparine ou heparine standard: evaluations dans l’Embolie pulmonaire N Engl J Med 337, 663–9.PubMedCrossRefGoogle Scholar
  78. 78.
    Manegold, P.C., Hutter, J., Pahernik, S.A., Messmer, K., and Dellian, M. (2003) Platelet-endothelial interaction in tumor angiogenesis and microcirculation Blood 101, 1970–6.PubMedCrossRefGoogle Scholar
  79. 79.
    Pintucci, G., Froum, S., Pinnell, J., Mignatti, P., Rafii, S., and Green, D. (2002) Trophic effects of platelets on cultured endothelial cells are mediated by platelet-associated fibroblast growth factor-2 (FGF-2) and vascular endothelial growth factor (VEGF) Thromb Haemost 88, 834–42.PubMedGoogle Scholar
  80. 80.
    Werther, K., Christensen, I.J., and Nielsen, H.J. (2002) Determination of vascular endothelial growth factor (VEGF) in circulating blood: significance of VEGF in various leucocytes and platelets Scand J Clin Lab Invest 62, 343–50.PubMedCrossRefGoogle Scholar
  81. 81.
    Verheul, H.M., and Pinedo, H.M. (1998) Tumor growth: a putative role for platelets? Oncologist 3, i–0i.Google Scholar
  82. 82.
    Verheul, H.M., Hoekman, K., Luykx-de Bakker, S., Eekman, C.A., Folman, C.C., Broxterman, H.J., and Pinedo, H.M. (1997) Platelet: transporter of vascular endothelial growth factor Clin Cancer Res 3, 2187–90.PubMedGoogle Scholar
  83. 83.
    Amirkhosravi, A., Amaya, M., Desai, H., and Francis, J.L. (2002) Platelet-CD40 ligand interaction with melanoma cell and monocyte CD40 enhances cellular procoagulant activity Blood Coagul Fibrinolysis 13, 505–12.PubMedCrossRefGoogle Scholar
  84. 84.
    Gasic, G.J., Gasic, T.B., and Stewart, C.C. (1968) Antimetastatic effects associated with platelet reduction Proc Natl Acad Sci USA 61, 46–52.PubMedCrossRefGoogle Scholar
  85. 85.
    Karpatkin, S., Pearlstein, E., Ambrogio, C., and Coller, B.S. (1988) Role of adhesive proteins in platelet tumor interaction in vitro and metastasis formation in vivo J Clin Invest 81, 1012–9.PubMedCrossRefGoogle Scholar
  86. 86.
    Trikha, M., Zhou, Z., Timar, J., Raso, E., Kennel, M., Emmell, E., and Nakada, M.T. (2002) Multiple roles for platelet GPIIb/IIIa and alphavbeta3 integrins in tumor growth, angiogenesis, and metastasis Cancer Res 62, 2824–33.PubMedGoogle Scholar
  87. 87.
    Varki, N.M., and Varki, A. (2002) Heparin inhibition of selectin-mediated interactions during the hematogenous phase of carcinoma metastasis: rationale for clinical studies in humans Semin Thromb Hemost 28, 53–66.PubMedCrossRefGoogle Scholar
  88. 88.
    Kakkar, A.K., and Williamson, R.C. (1997) Prevention of venous thromboembolism in cancer using low-molecular-weight heparins Haemostasis 27 (Suppl 1), 32–7.PubMedGoogle Scholar
  89. 89.
    Zacharski, L.R., and Ornstein, D.L. (1998) Heparin and cancer Thromb Haemost 80, 10–23.PubMedGoogle Scholar
  90. 90.
    Meyer, G., Marjanovic, Z., Valcke, J., Lorcerie, B., Gruel, Y., Solal-Celigny, P., Le Maignan, C., Extra, J.M., Cottu, P., and Farge, D. (2002) Comparison of low-molecular-weight heparin and warfarin for the secondary prevention of venous thromboembolism in patients with cancer: a randomized controlled study Arch Intern Med 162, 1729–35.PubMedCrossRefGoogle Scholar
  91. 91.
    von Tempelhoff, G.F., Harenberg, J., Niemann, F., Hommel, G., Kirkpatrick, C.J., and Heilmann, L. (2000) Effect of low molecular weight heparin (Certoparin) versus unfractionated heparin on cancer survival following breast and pelvic cancer surgery: a prospective randomized double-blind trial Int J Oncol 16, 815–24.Google Scholar
  92. 92.
    Zacharski, L.R. (2002) Anticoagulants in cancer treatment: malignancy as a solid phase coagulopathy Cancer Lett 186, 1–9.PubMedCrossRefGoogle Scholar
  93. 93.
    Mousa, S.A. (2002) Anticoagulants in thrombosis and cancer: the missing link Semin Thromb Hemost 28, 45–52.PubMedCrossRefGoogle Scholar
  94. 94.
    Dvorak, H.F. (1987) Thrombosis and cancer Hum Pathol 18, 275–84.PubMedCrossRefGoogle Scholar
  95. 95.
    Haward, W. (1906) Phlebitis and thrombosis Lancet 1, 650–5.Google Scholar
  96. 96.
    Kakkar, A.K., Levine, M.N., Prandoni, P., Lee, A.Y., Rasmussen, M.S., and Kuter, D. (2002) What is the role for antithrombotics in cancer care? Interactive session with panel discussion Cancer Treat Rev 28, 157–9.PubMedCrossRefGoogle Scholar
  97. 97.
    Dvorak, H.F., Senger, D.R., and Dvorak, A.M. (1983) Fibrin as a component of the tumor stroma: origins and biological significance Cancer Metastasis Rev 2, 41–73.PubMedCrossRefGoogle Scholar
  98. 98.
    Chambers, A.F. (1999) The metastatic process: basic research and clinical implications Oncol Res 11, 161–8.PubMedGoogle Scholar
  99. 99.
    Amirkhosravi, A., Mousa, S.A., Amaya, M., and Francis, J.L. (2003) Antimetastatic effect of tinzaparin, a low-molecular-weight heparin J Thromb Haemost 1, 1972–6.PubMedCrossRefGoogle Scholar
  100. 100.
    Mousa, S.A. (2002) Anticoagulants in thrombosis and cancer: the missing link Expert Rev Anticancer Ther 2, 227–33.PubMedCrossRefGoogle Scholar
  101. 101.
    Engelberg, H. (1999) Actions of heparin that may affect the malignant process Cancer 85, 257–72.PubMedCrossRefGoogle Scholar
  102. 102.
    Varki, A., and Varki, N.M. (2001) P-selectin, carcinoma metastasis and heparin: novel mechanistic connections with therapeutic implications Braz J Med Biol Res 34, 711–7.PubMedCrossRefGoogle Scholar
  103. 103.
    Falanga, A., and Rickles, F.R. (1999) Pathophysiology of the thrombophilic state in the cancer patient Semin Thromb Hemost 25, 173–82.PubMedCrossRefGoogle Scholar
  104. 104.
    Markus, G. (1984) The role of hemostasis and fibrinolysis in the metastatic spread of cancer Semin Thromb Hemost 10, 61–70.PubMedCrossRefGoogle Scholar
  105. 105.
    Ruf, W., and Mueller, B.M. (1996) Tissue factor in cancer angiogenesis and metastasis Curr Opin Hematol 3, 379–84.PubMedCrossRefGoogle Scholar
  106. 106.
    Paredes, N., Xu, L., Berry, L.R., and Chan, A.K. (2003) The effects of chemotherapeutic agents on the regulation of thrombin on cell surfaces Br J Haematol 120, 315–24.PubMedCrossRefGoogle Scholar
  107. 107.
    Wojtukiewicz, M.Z., Zacharski, L.R., Memoli, V.A., Kisiel, W., Kudryk, B.J., Rousseau, S.M., and Stump, D.C. (1990) Fibrinogen-fibrin transformation in situ in renal cell carcinoma Anticancer Res 10, 579–82.PubMedGoogle Scholar
  108. 108.
    Zacharski, L.R., Wojtukiewicz, M.Z., Costantini, V., Ornstein, D.L., and Memoli, V.A. (1992) Pathways of coagulation/fibrinolysis activation in malignancy Semin Thromb Hemost 18, 104–16.PubMedCrossRefGoogle Scholar
  109. 109.
    Hull, R.D., Raskob, G.E., Pineo, G.F., Green, D., Trowbridge, A.A., Elliott, C.G., Lerner, R.G., Hall, J., Sparling, T., and Brettell, H.R., et al. (1992) Subcutaneous low-molecular-weight heparin compared with continuous intravenous heparin in the treatment of proximal-vein thrombosis N Engl J Med 326, 975–82.PubMedCrossRefGoogle Scholar
  110. 110.
    Pinedo, H.M., Verheul, H.M., D’Amato, R.J., and Folkman, J. (1998) Involvement of platelets in tumour angiogenesis? Lancet 352, 1775–7.PubMedCrossRefGoogle Scholar
  111. 111.
    Chambers, A.F., MacDonald, I.C., Schmidt, E.E., Koop, S., Morris, V.L., Khokha, R., and Groom, A.C. (1995) Steps in tumor metastasis: new concepts from intravital videomicroscopy Cancer Metastasis Rev 14, 279–301.PubMedCrossRefGoogle Scholar
  112. 112.
    Rickles, F.R., and Levine, M.N. (2001) Epidemiology of thrombosis in cancer Acta Haematol 106, 6–12.PubMedCrossRefGoogle Scholar
  113. 113.
    Mousa, S., Inventor Vascular Vision Pharmaceuticals, Assignee. Prevention and treatment of tumor growth, metastasis, and thromboembolytic complications in cancer patients. United States patent 6,908,907; 2005.Google Scholar
  114. 114.
    Levine, M., Hirsh, J., Gent, M., Arnold, A., Warr, D., Falanga, A., Samosh, M., Bramwell, V., Pritchard, K.I., and Stewart, D., et al. (1994) Double-blind randomised trial of a very-low-dose warfarin for prevention of thromboembolism in stage IV breast cancer Lancet 343, 886–9.PubMedCrossRefGoogle Scholar
  115. 115.
    Mousa, S.A., and Mousa, A.S. (2004) Angiogenesis inhibitors: current & future directions Curr Pharm Des 10, 1–9.PubMedCrossRefGoogle Scholar
  116. 116.
    Folkman, J., and Shing, Y. (1992) Control of angiogenesis by heparin and other sulfated polysaccharides Adv Exp Med Biol 313, 355–64.PubMedGoogle Scholar
  117. 117.
    Mousa, S.A., and Mohamed, S. (2004) Anti-angiogenic mechanisms and efficacy of the low molecular weight heparin, tinzaparin: anti-cancer efficacy Oncol Rep 12, 683–8.PubMedGoogle Scholar
  118. 118.
    Ludwig, R.J., Boehme, B., Podda, M., Henschler, R., Jager, E., Tandi, C., Boehncke, W.H., Zollner, T.M., Kaufmann, R., and Gille, J. (2004) Endothelial P-selectin as a target of heparin action in experimental melanoma lung metastasis Cancer Res 64, 2743–50.PubMedCrossRefGoogle Scholar
  119. 119.
    Zhang, Y., Deng, Y., Luther, T., Muller, M., Ziegler, R., Waldherr, R., Stern, D.M., and Nawroth, P.P. (1994) Tissue factor controls the balance of angiogenic and antiangiogenic properties of tumor cells in mice J Clin Invest 94, 1320–7.PubMedCrossRefGoogle Scholar
  120. 120.
    Engelberg, H. (1996) Actions of heparin in the atherosclerotic process Pharmacol Rev 48, 327–52.PubMedGoogle Scholar
  121. 121.
    Borsig, L., Wong, R., Feramisco, J., Nadeau, D.R., Varki, N.M., and Varki, A. (2001) Heparin and cancer revisited: mechanistic connections involving platelets, P-selectin, carcinoma mucins, and tumor metastasis Proc Natl Acad Sci USA 98, 3352–7.PubMedCrossRefGoogle Scholar
  122. 122.
    Baughman, R.A., Kapoor, S.C., Agarwal, R.K., Kisicki, J., Catella-Lawson, F., and FitzGerald, G.A. (1998) Oral delivery of anticoagulant doses of heparin. A randomized, double-blind, controlled study in humans Circulation 98, 1610–5.PubMedCrossRefGoogle Scholar
  123. 123.
    Hull, R., Kakkar, A., Marder, V., Pineo, G., Goldberg, M., and Raskob, G. (2001) PROTECT trial: oral SNAC-heparin vs enoxaparin for preventing venous thromboembolism following total hip replacement Blood 100, 148a–9a.Google Scholar
  124. 124.
    Kim, S.K., Lee, D.Y., Lee, E., Lee, Y.K., Kim, C.Y., Moon, H.T., and Byun, Y. (2007) Absorption study of deoxycholic acid-heparin conjugate as a new form of oral anti-coagulant J Control Release 120, 4–10.PubMedCrossRefGoogle Scholar
  125. 125.
    Mousa, S.A., Zhang, F., Aljada, A., Chaturvedi, S., Takieddin, M., Zhang, H., Chi, L., Castelli, M.C., Friedman, K., Goldberg, M.M., and Linhardt, R.J. (2007) Pharmacokinetics and pharmacodynamics of oral heparin solid dosage form in healthy human subjects J Clin Pharmacol 47, 1508–20.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Shaker A. Mousa
    • 1
  1. 1.Pharmaceutical Research Institute, Albany College of Pharmacy and Health SciencesRensselaerUSA

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