A Survey of Venous Thrombosis Models

  • Walter P. Jeske
  • Omer Iqbal
  • Jawed Fareed
  • Brigitte Kaiser
Part of the Methods In Molecular Medicine™ book series (MIMM, volume 93)


Animal models have played a crucial role in the development of new antithrombotic drugs during the past few decades. Through the use of these animal models, the differentiation between the anticoagulant and antithrombotic effects was first recognized. Drugs that were unable to produce a prolongation of blood clotting time were found to produce antithrombotic effects in animal models, and a recognition that endogenous effects in the intact animal resulting from the metabolic transformation of the drug and/or release of antithrombotic substances was appreciated. Without the use of intact animal models, such an observation would not have been possible.


Thrombus Formation Vessel Segment Prothrombin Complex Concentrate Antithrombotic Agent Rose Bengal 
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  1. 1.
    Jeske, W. P., Iqbal, O., Fareed, J., and Kaiser, B. (2003) A survey of animal models to develop novel antithrombotic agents, in New Therapeutic Agents in Thrombosis and Thrombolysis, 2nd ed. (Sasahara, A. A. and Loscalzo, J., eds.), Marcel Dekker, Inc., New York, pp. 9–32.Google Scholar
  2. 2.
    Wessler, S., Reimer, S. M., and Sheps, M. C. (1959) Biologic assay of a thrombosisinducing activity in human serum. J. Appl. Physiol. 14, 943–946.PubMedGoogle Scholar
  3. 3.
    Meuleman, D. G., Hobbelen, P. M., Van Dinther, T. G., Vogel, G. M., Van Boeckel, C. A., and Moelker, H. C. (1991) Antifactor Xa activity and antithrombotic activity in rats of structural analogues of the minimum antithrombin III binding sequence: discovery of compounds with a longer duration of action than the natural pentasaccharide. Semin. Thromb. Hemost. 17 (Suppl. 1), 112–117.PubMedGoogle Scholar
  4. 4.
    Carrie, D., Caranobe, C., Saivin, S., Houin, G., Petitou, M., Lormeau, J. C, et al. (1994) Pharmacokinetic and antithrombotic properties of two pentasaccharides with high affinity to antithrombin III in the rabbit: comparison with CY 216. Blood 84(8), 2571–2577.PubMedGoogle Scholar
  5. 5.
    Bara, L., Bloch, M. F., and Samama, M. M. (1992) A comparative study of recombinant hirudin and standard heparin in the Wessler model. Thromb. Res. 68(2), 167–174.PubMedCrossRefGoogle Scholar
  6. 6.
    Saivin, S., Petitou, M., Lormeau, J. C, Dupouy, D., Sie, P., Caranobe, C, et al. (1992) Pharmacological properties of a low molecular weight butyryl heparin derivative (C4-CY 216) with long lasting effects. Thromb. Haemostasis 67(3), 346–351.Google Scholar
  7. 7.
    Thomas, D. P., Gray, E., and Merton, R. E. (1990) Potentiation of the antithrombotic action of dermatan sulfate by small amounts of heparin. Thromb. Haemostasis 64(2), 290–293.Google Scholar
  8. 8.
    Walenga, J. M., Fareed, J., Petitou, M., Samama, M., Lormeau, J. C., and Choay, J. (1986) Intravenous antithrombotic activity of a synthetic heparin pentasaccharide in a human serum induced stasis thrombosis model. Thromb. Res. 43(2), 243–248.PubMedCrossRefGoogle Scholar
  9. 9.
    Peyrou, V., Lormeau, J. C., Caranobe, C., Gabaig, A. M., Crepon, B., Saivin, S., et al. (1994) Pharmacologic properties of CY 216 and of its ACLM and BCLM components in the rabbit. Thromb. Haemostasis 72(2), 268–274.Google Scholar
  10. 10.
    Saivin, S., Caranobe, C., Petitou, M., Lormeau, J. C., Level, M., Crepon, B., et al. (1992) Antithrombotic activity, bleeding effect and pharmacodynamics of a succinyl derivative of dermatan sulfate in rabbits. Br. J. Haematol. 80(4), 509–513.PubMedCrossRefGoogle Scholar
  11. 11.
    Walenga, J. M., Petitou, M., Lormeau, J. C., Samama, M., Fareed, J., and Choay, J. (1987) Antithrombotic activity of a synthetic heparin pentasaccharide in a rabbit stasis thrombosis model using different thrombogenic challenges. Thromb. Res. 46(2), 187–198.PubMedCrossRefGoogle Scholar
  12. 12.
    Vlasuk, G. P., Ramjit, D., Fujita, T., Dunwiddie, C. T., Nutt, E. M., Smith, D. E., et al. (1991) Comparison of the in vivo anticoagulant properties of standard heparin and the highly selective factor Xa inhibitors antistasin and tick anticoagulant peptide (TAP) in a rabbit model of venous thrombosis. Thromb. Haemostasis 65(3), 257–262.Google Scholar
  13. 13.
    Bacher, P., Walenga, J. M., Iqbal, O., Bajusz, S., Breddin, K., and Fareed, J. (1993) The antithrombotic and anticoagulant effects of a synthetic tripeptide and recombinant hirudin in various animal models. Thromb. Res. 71(4), 251–263.PubMedCrossRefGoogle Scholar
  14. 14.
    Millet, J., Theveniaux, J., and Brown, N. L. (1994) The venous antithrombotic profile of naroparcil in the rabbit. Thromb. Haemostasis 72(6), 874–879.Google Scholar
  15. 15.
    Callas, D. D., Bacher, P., and Fareed, J. (1995) Studies on the thrombogenic effects of recombinant tissue factor. In vivo versus ex vivo findings. Semin. Thromb. Hemost. 21(2), 166–176.PubMedCrossRefGoogle Scholar
  16. 16.
    Fareed, J., Walenga, J. M., Kumar, A., and Rock, A. (1985) A modified stasis thrombosis model to study the antithrombotic actions of heparin and its fractions. Semin. Thromb. Hemost. 11(2), 155–175.PubMedCrossRefGoogle Scholar
  17. 17.
    Bacher, P., Welzel, D., Iqbal, O., Hoppensteadt, D., Callas, D., Walenga, J. M., et al. (1992) The thrombolytic potency of LMW-heparin compared to urokinase in a rabbit jugular vein clot lysis model. Thromb. Res. 66, 151–158.PubMedCrossRefGoogle Scholar
  18. 18.
    Raake, W. and Elling, H. (1989) Rat jugular vein hemostasis—a new model for testing antithrombotic agents. Thromb. Res. 53, 73–77.PubMedCrossRefGoogle Scholar
  19. 19.
    Raake, W., Klauser, R. J., Meinetsberger, E., Zeiller, P., and Elling, H. (1991) Pharmacologic profile of the antithrombotic and bleeding actions of sulfated lactobionic acid amides. Semin. Thromb. Hemost. 17 (Suppl. 1), 129–135.PubMedGoogle Scholar
  20. 20.
    Hayes, J. M., Jeske, W., Callas, D., Iqbal, O., and Fareed, J. (1996) Comparative intravenous antithrombotic actions of heparin and site directed thrombin inhibitors in a jugular vein clamping model. Thromb. Res. 82(2), 187–191.PubMedCrossRefGoogle Scholar
  21. 21.
    Kaiser, B. (1995) Effect of tissue factor pathway inhibitor (TFPI) on venous thrombus formation and rethrombosis after lysis in the jugular veins of rabbits. Thromb. Haemostasis 73(6), 944.Google Scholar
  22. 22.
    Kaiser, B., Simon, A., and Markwardt, F. (1990) Antithrombotic effects of recombinant hirudin in experimental angioplasty and intravascular thrombolysis. Thromb. Haemostasis 63(1), 44–47.Google Scholar
  23. 23.
    Lyle, E. M., Fujita, T., Conner, M. W., Connolly, T. M., Vlasuk, G. P., and Lynch, J. L. (1995) Effect of inhibitors of factor Xa or platelet adhesion, heparin, and aspirin on platelet deposition in an atherosclerotic rabbit model of angioplasty injury. J. Pharmacol. Toxicol. Methods 33(1), 53–61.PubMedCrossRefGoogle Scholar
  24. 24.
    Katsuragawa, M., Fujiwara, H., Kawamura, A., Htay, T., Yoshikuni, Y., Mori, K., et al. (1993) An animal model of coronary thrombosis and thrombolysis—comparisons of vascular damage and thrombus formation in the coronary and femoral arteries after balloon angioplasty. Jpn. Circ. J. 57(10), 1000–1006.PubMedCrossRefGoogle Scholar
  25. 25.
    Kaiser, B. and Markwardt, F. (1986) Experimental studies on the antithrombotic action of a highly effective synthetic thrombin inhibitor. Thromb. Haemostasis 55(2), 194–196.Google Scholar
  26. 26.
    Heras, M., Chesebro, J. H., Penny, W. J., Bailey, K. R., Lam, J. Y. T., Holmes, D. R., et al. (1988) Importance of adequate heparin dosage in arterial angioplasty in a porcine model. Circulation 78, 654–660.PubMedCrossRefGoogle Scholar
  27. 27.
    Harker, L. A. (1987) Role of platelets and thrombosis in mechanisms of acute occlusion and restenosis after angioplasty. Am. J. Cardiol. 60, 20B–28B.PubMedCrossRefGoogle Scholar
  28. 28.
    Kurz, K. D., Main, B. W., and Sandusky, G. I. (1990) Rat model of arterial thrombosis induced by ferric chloride. Thromb. Res. 60, 269–280.PubMedCrossRefGoogle Scholar
  29. 29.
    Schumacher, W. A., Heran, C. L., Steinbacher, T. E., Youssef, S., and Ogletree, M. L. (1993) Superior activity of a thromboxane receptor antagonist as compared with aspirin in rat models of arterial and venous thrombosis. J. Cardiovasc. Pharmacol. 22, 526–533.PubMedCrossRefGoogle Scholar
  30. 30.
    Elg, M., Gustafsson, D., and Carlsson, S. (1999) Antithrombotic effects and bleeding time of thrombin inhibitors and warfarin in the rat. Thromb. Res. 94(3), 187–197.PubMedCrossRefGoogle Scholar
  31. 31.
    Deschenes, I., Finkle, C. D., and Winocour, P. D. (1998) Effective use of BCH-2763, a new potent injectable direct thrombin inhibitor, in combination with tissue plasminogen activator (tPA) in a rat arterial thrombolysis model. Thromb. Haemostasis 80(1), 186–191.Google Scholar
  32. 32.
    Roesken, F., Ruecker, M., Vollmar, B., Boeckel, N., Morgenstern, E., and Menger, M. D. (1997) A new model for quantitative in vivo microscopic analysis of thrombus formation and vascular recanalisation: the ear of the hairless (hr/hr) mouse. Thromb. Haemostasis 78(5), 1408–1414.Google Scholar
  33. 33.
    Sanaibadi, A. R., Umemura, K., Matsimoto, N., Sakuma, S., and Nakashima, M. (1995) Vessel wall injury and arterial thrombosis induced by a photochemical reaction. Thromb. Haemostasis 73, 868–872.Google Scholar
  34. 34.
    Hokamura, K., Umemura, K., Makamura, N., Watanabe, M., Takashima, T., and Nakashima, M. (1998) Effect of lipo-pro-prostaglandin EI, AS-013, on rat inner ear microcirculatory thrombosis. Prostaglandins Leukot. Essen. Fatty Acids 59(3), 203–207.CrossRefGoogle Scholar
  35. 35.
    Weichert, W. and Breddin, H. K. (1988) Effect of low-molecular-weight heparin on laser-induced thrombus formation in rat mesenteric vessels. Haemostasis 18S3, 55–63.Google Scholar
  36. 36.
    Yamashita, T., Tsuda, Y., Konishi, Y., Okada, Y., Matsuoka, A., Giddings, J. C, et al. (1998) The antithrombotic effect of potent bifunctional thrombin inhibitors based on hirudin sequence, P551 and P532, on He-Ne laser-induced thrombosis in rat mesenteric microvessels. Thromb. Res. 90(5), 199–206.PubMedCrossRefGoogle Scholar
  37. 37.
    Yamamoto, J., Ishii, I., Okita, N., Sasaki, Y., Yamashita, T., Matsuoka, A., et al. (1997) The differential involvement of von Willebrand factor, fibrinogen and fibronectin in acute experimental thrombosis in rat cerebral and mesenteric microvessels. Jpn. J. Phys. 47(5), 431–441.CrossRefGoogle Scholar
  38. 38.
    Yamashita, T., Tsuji, T., Matsuoka, A., Giddings, J. C., and Yamamoto, J. (1997) The antithrombotic effect of synthetic low molecular weight human factor Xa inhibitor, DX-9065a, on He-Ne laser-induced thrombosis in rat mesenteric microvessels. Thromb. Res. 85(1), 45–51.PubMedCrossRefGoogle Scholar
  39. 39.
    Herbert, J. M., Bernat, A., and Maffrand, J. P. (1992) Importance of platelets in experimental venous thrombosis in rats. Blood 80, 2281–2286.PubMedGoogle Scholar
  40. 40.
    Berry, C. N., Girard, D., Lochot, S., and Lecoffre, C. (1994) Antithrombotic actions of argatroban in rat models of venous, “mixed” and arterial thrombosis, and its effects on the tail transection bleeding time. Br. J. Pharmacol. 113, 1209–1214.PubMedGoogle Scholar
  41. 41.
    Seth, P., Kumari, R., Dikshit, M., and Srimal, R. C. (1994) Effect of platelet activating factor antagonists in different models of thrombosis. Thromb. Res. 76, 503–512.PubMedCrossRefGoogle Scholar
  42. 42.
    Fu, K., Izquierdo, R., Vandevender, D., Warpeha, R. L., Wolf, H., and Fareed, J. (1997) Topical application of low molecular weight heparin in a rabbit traumatic anastomosis model. Thromb. Res. 86(5), 355–361.PubMedCrossRefGoogle Scholar
  43. 43.
    Korompilias, A. V., Chen, L. E., Seaber, A. V., and Urbaniak, J. R. (1997) Antithrombotic potencies of enoxaparin in microvascular surgery: influence of dose and administration methods on patency rate or crushed arterial anastomoses. J. Hand Surg. 22(3), 540–546.CrossRefGoogle Scholar
  44. 44.
    Stockmans, F., Stassen, J. M., Vermylen, J., Hoylaerts, M. F., and Nystrom, A. (1997) A technique to investigate mural thrombus formation in arteries and veins: II. Effects of aspirin, heparin, r-hirudin and G-4120. Ann. Plastic Surg. 38(1), 63–68.CrossRefGoogle Scholar
  45. 45.
    Van Wyk, V., Neethling, W. M. L., Badenhorst, P. N., and Kotze, H. F. (1998) r-Hirudin inhibits platelet-dependent thrombosis during cardiopulmonary bypass in baboons. J. Cardiovasc. Surg. 39, 633–639.Google Scholar
  46. 46.
    Dewanjee, M. K., Wu, S. M., and Hsu, L. C. (2000) Effect of heparin reversal and fresh platelet transfusion on platelet emboli post-cardiopulmonary bypass surgery in a pig model. ASAIO J. 46, 313–318.PubMedCrossRefGoogle Scholar
  47. 47.
    Dewanjee, M. K., Wu, S., Kapadvanjwala, M., et al. (1996) Reduction of platelet thrombi and emboli by L-arginine infusion during cardiopulmonary bypass in a pig model. J. Thromb. Thrombolysis 3, 339–356.Google Scholar
  48. 48.
    Walenga, J. M., Bakhos, M., Messmore, H. L., Fareed, J., and Pifarre, R. (1991) Potential use of recombinant hirudin as an anticoagulant in a cardiopulmonary bypass model. Ann. Thorac. Surg. 51, 271–277.PubMedCrossRefGoogle Scholar
  49. 49.
    Henny, Ch. P., TenCate, H., TenCate, J. W., Moulijn, A. C., Sie, T. H., Warren, P., et al. (1985) A randomized blind study comparing standard heparin and a new low molecular weight heparinoid in cardiopulmonary bypass surgery in dogs. J. Clin. Lab. Med. 106, 187–196.Google Scholar
  50. 50.
    Murray, W. G. (1985) A preliminary study of low molecular weight heparin in aortocoronay bypass surgery, in Low molecular weight heparin in surgical practice (Master of surgery thesis) (Murray, W G.), University of London, London, UK, 266.Google Scholar

Copyright information

© Humana Press Inc. 2004

Authors and Affiliations

  • Walter P. Jeske
    • 1
    • 2
    • 3
  • Omer Iqbal
    • 2
  • Jawed Fareed
    • 2
  • Brigitte Kaiser
    • 4
  1. 1.Department of Thoracic-Cardiovascular SurgeryLoyola University Medical CenterMaywood
  2. 2.Department of PathologyLoyola University Medical CenterMaywood
  3. 3.Cardiovascular InstituteMaywood
  4. 4.Center for Vascular Biology and Medicine ErfurtFriedrich Schiller University JenaErfurtGermany

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