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Use of Transgenic Mice in the Study of Thrombosis and Hemostasis

  • Chapter
Antithrombotics

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 132))

Abstract

Hemostasis is a delicate balance between the formation and lysis of insoluble blood clots and is required for the maintenance of vessel integrity. A complex, highly regulated system has evolved for the formation of a platelet plug and fibrin clot at the site of vessel injury, involving interactions between blood platelets, the endothelium, and a cascade of specific proteases. Once hemostasis has been achieved, a second system known as the fibrinolytic pathway is required for lysis and resolution of the fibrin and blood clot, leading to the repair of the damaged tissue and reestablishment of vascular integrity. A shift in the balance between these pathways can result in fatal thrombosis or hemorrhage. Recently, considerable insight into the functions and interactions between these pathways has come from the characterization of genetically altered mice generated by powerful transgenic technologies. This chapter will first briefly review the coagulation and fibrinolytic systems as a framework for discussion of these transgenic animal models.

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References

  • Aimer LO, Ohlin H (1987) Elevated levels of the rapid inhibitor of plasminogen activator (t-PAI) in acute myocardial infarction. Thromb Res 47:335–339

    Article  Google Scholar 

  • Aoki N, Moroi M, Sakata Y, Yoshida N, Matsuda M (1978) Abnormal plasminogen. A hereditary molecular abnormality found in a patient with recurrent thrombosis. J Clin Invest 61:1186–1195

    Article  PubMed  CAS  Google Scholar 

  • Aparicio C, Dahlback B (1996) Molecular mechanisms of activated protein C resistance - properties of factor V isolated from an individual with homozygosity for the Arg506 to Gin mutation in the factor V gene. Biochem J 313:467–472

    PubMed  CAS  Google Scholar 

  • Armentano D, Thompson AR, Darlington G, Woo SLC (1990)Expression of human factor IX in rabbit hepatocytes by retrovirus-mediated gene transfer: potential for gene therapy of hemophilia B. Proc Natl Acad Sci USA 87:6141–6145

    Article  PubMed  CAS  Google Scholar 

  • Aznar J, Estelles A, Tormo G, Sapena P, Tormo V, Blanch S, Espana F (1988) Plasminogen activator inhibitor activity and other fibrinolytic variables in patients with coronary artery disease. Br Heart J 59:535–541

    Article  PubMed  CAS  Google Scholar 

  • Barbash GI, Hod H, Roth A, Miller HI, Rath S, Zahav YH, Modan M, Zivelin A, Laniado S, Seligsohn U (1989) Correlation of baseline plasminogen activator inhibitor activity with patency of the infarct artery after thrombolytic therapy in acute myocardial infarction. Am J Cardiol 64:1231–1235

    Article  PubMed  CAS  Google Scholar 

  • Bi L, Lawler AM, Antonarakis SE, High KA, Gearhart JD, Kazazian HH Jr (1995) Targeted disruption of the mouse factor VIII gene produces a model of haemophilia A. Nat Genet 10:119–121

    Article  PubMed  CAS  Google Scholar 

  • Bugge TH, Flick MJ, Daugherty CC, Degen JL (1995a) Plasminogen deficiency causes severe thrombosis but is compatible with development and reproduction. Genes Dev 9:794–807

    Article  PubMed  CAS  Google Scholar 

  • Bugge TH, Suh TT, Flick MJ, Daugherty CC, Romer J, Solberg H, Ellis V, Dano K, Degen JL (1995b) The receptor for urokinase-type plasminogen activator is not essential for mouse development or fertility. J Biol Chem 270:16886–16894

    Article  PubMed  CAS  Google Scholar 

  • Bugge TH, Flick MJ, Danton MJS, Daugherty CC, Romer J, Dano K, Carmeliet P, Collen D, Degen JL (1996a) Urokinase-type plasminogen activator is effective in fibrin clearance in the absence of its receptor or tissue-type plasminogen activator. Proc Natl Acad Sci USA 93:5899–5904

    Article  PubMed  CAS  Google Scholar 

  • Bugge TH, Kombrinck KW, Flick MJ, Daugherty CC, Danton MJS, Degen JL (1996b) Loss of fibrinogen rescues mice from the pleiotropic effects of plasminogen deficiency. Cell 87:709–719

    Article  PubMed  CAS  Google Scholar 

  • Bugge TH, Xiao Q, Kombrinck KW, Flick MJ, Holmback K, Danton JS, Colbert MC, Witte DP, Fujikawa K, Davie EW, Degen JL (1996c) Fatal embryonic bleeding events in mice lacking tissue factor, the cell-associated initiator of blood coagulation. Proc Natl Acad Sci USA 93:6258–6263

    Article  PubMed  CAS  Google Scholar 

  • Carmeliet P, Collen D (1994) Evaluation of the plasminogen/plasmin system in transgenic mice, Fibrinolysis 8:269–276

    Article  Google Scholar 

  • Carmeliet P, Kieckens L, Schoonjans L, Ream B, Van Nuffelen A, Prendergast GC, Cole MD, Bronson R, Collen D, Mulligan RC (1993a) Plasminogen activator inhibitor-1 gene-deficient mice. I. Generation by homologous recombination and characterization, J Clin Invest 92:2746–2755

    CAS  Google Scholar 

  • Carmeliet P, Stassen JM, Schoonjans L, Ream B, van den Oord J J, De Mol M, Mulligan RC, Collen D (1993b) Plasminogen activator inhibitor-1 gene-deficient mice. II. Effects on hemostasis, thrombosis, and thrombolysis. J Clin Invest 92:2756–2760

    Article  PubMed  CAS  Google Scholar 

  • Carmeliet P, Schoonjans L, Kieckens L, Ream B, Degen JL, Bronson R, De Vos R, van den Oord JJ, Collen D, Mulligan RC (1994) Physiological consequences of loss of plasminogen activator gene function in mice. Nature 368:419–424

    Article  PubMed  CAS  Google Scholar 

  • Carmeliet P, BouchE A, De Clercq C, Janssen S, Pollefeyt S, Wyns S, Mulligan RC, Collen D (1995)Biological effects of disruption of the tissue-type plasminogen activator urokinase-type plasminogen activator, and plasminogen activator inhibitor-1 genes in mice Ann NY Acad Sci 748:367–382

    CAS  Google Scholar 

  • Carmeliet P, Mackman N, Moons L, Luther T, Gressens P, Van Vlaenderen I, Demunck H, Kasper M, Breier G, Evrard P, Muller M, Risau W, Edgington T, Collen D (1996) Role of tissue factor in embryonic blood vessel development. Nature 383:73–75

    Article  PubMed  CAS  Google Scholar 

  • Cui J, O’Shea KS, Purkayastha A, Saunders TL, Ginsburg D (1996a) Fatal haemorrhage and incomplete block to embryogenesis in mice lacking coagulation factor V. Nature 384:66–68

    Article  PubMed  CAS  Google Scholar 

  • Cui J, Purkayastha A, Yang A, Yang T, Gallagher K, Metz A, Ginsburg D (1996b) Spontaneous thrombosis in mice carrying the APC resistance mutation (FV Leiden) introduced by gene targeting. Blood 88:440a (Abstract)

    Google Scholar 

  • Dahlback B (1995a) Factor V gene mutation causing inherited resistance to activated protein C as a basis for venous thromboembolism. J Intern Med 237:221–227

    Article  PubMed  CAS  Google Scholar 

  • Dahlback B (1995b) Resistance to activated protein C, the Arg506 to Gin mutation in the factor V gene, and venous thrombosis. Functional tests and DNA-based assays, pros and cons, Thromb Haemost 73:739–742

    CAS  Google Scholar 

  • Dahlback B (1995c) Molecular genetics of thrombophilia: factor V gene mutation causing resistance to activated protein C as a basis of the hypercoagulable state. J Lab Clin Med 125:566–571

    PubMed  CAS  Google Scholar 

  • Dahlback B, Hildebrand (1994)Inherited resistance to activated protein C is corrected by anticoagulant cofactor activity found to be a property of factor V.Proc Natl Acad Sci USA 91:1396–1400

    Article  PubMed  CAS  Google Scholar 

  • Darrow AL, Fung-Leung W-P, Ye RD, Santulli RJ, Cheung W-F, Derian CK, Burns CL, Damiano BP, Zhou L, Keenan CM, Peterson PA, Andrade-Gordan P (1996) Biological consequences of thrombin receptor deficiency in mice. Thromb Haemost 76:860–866

    PubMed  CAS  Google Scholar 

  • Davie EW, Fujikawa K, Kisiel W (1991)The coagulation cascade: initiation, maintenance, and regulation Biochem 30:10363–10370

    CAS  Google Scholar 

  • De Vries TJ, Kitson JL, Silvers WK, Mintz B (1995) Expression of plasminogen activators and plasminogen activator inhibitors in cutaneous melanomas of transgenic melanoma-susceptible mice. Cancer Res 55:4681–4687

    PubMed  Google Scholar 

  • Dewerchin M, Van Nuffelen A, Wallays G, BouchE A, Moons L, Carmeliet P, Mulligan RC, Collen D (1996) Generation and characterization of urokinase receptor-deficient mice. J Clin Invest 97:870–878

    Article  PubMed  CAS  Google Scholar 

  • Eitzman DT, Krauss JC, Shen T, Cui J, Ginsburg D (1996a) Lack of plasminogen activator inhibitor-1 effect in a transgenic mouse model of metastatic melanoma. Blood 87:4718–4722

    PubMed  CAS  Google Scholar 

  • Eitzman DT, McCoy RD, Zheng X, Fay WP, Shen T, Ginsburg D (1996b) Bleomycininduced pulmonary fibrosis in transgenic mice that either lack or overexpress the murine plasminogen activator inhibitor-1 gene. J Clin Invest 97:232–237

    Article  PubMed  CAS  Google Scholar 

  • Eitzman DT, Fay WP, Ginsburg D (1997) Plasminogen activator inhibitor-1. In: Becker RC (ed) The textbook of coronary thrombosis and thrombolysis. Kluwer Academic Publishers, Boston, p 65

    Google Scholar 

  • Erickson LA, Fici GJ, Lund JE, Boyle TP, Polites HG, Marotti KR (1990) Development of venous occlusions in mice transgenic for the plasminogen activator inhibitor-1 gene. Nature 346:74–76

    Article  PubMed  CAS  Google Scholar 

  • Esmon CT (1989) The roles of protein C and thrombomodulin in the regulation of blood coagulation. J Biol Chem 264:4743–4746

    PubMed  CAS  Google Scholar 

  • Fay WP, Shapiro AD, Shih JL, Schleef RR, Ginsburg D (1992) Complete deficiency of plasminogen-activator inhibitor type 1 due to a frame-shift mutation. N Engl J Med 327:1729–1733

    Article  PubMed  CAS  Google Scholar 

  • Fay WP, Parker AC, Condrey LR, Shapiro AD (1997) Human plasminogen activator inhibitor-1 (PAI-1) deficiency: characterization of a large kindred with a null mutation in the PAI-1 gene. Blood 90:204–208

    PubMed  CAS  Google Scholar 

  • Ginsburg D (1997) Haemophilias and other disorders of haemostasis. In: Rimoin DL, Connor JM, Pyeritz RE (eds) Emery and Rimoin’s principles and practice of medical genetics, vol. II, 3rd edn. Churchill Livingstone, New York, p 1652

    Google Scholar 

  • Griffin JH, Evatt B, Zimmerman TS, Kleiss AJ (1981) Deficiency of protein C in congenital thrombotic disease. J Clin Invest 68:1370–1373

    Article  PubMed  CAS  Google Scholar 

  • Hamsten A, de Faire U, Walldius G, Dahlen G, Szamosi A, Landou C, Blomback M, Wiman B (1987) Plasminogen activator inhibitor in plasma: risk factor for recurrent myocardial infarction. Lancet 2:3–9

    Article  PubMed  CAS  Google Scholar 

  • Hasday JL, Bachwich PR, Lynch JP, Sitrin RG (1988) Procoagulant and plasminogen activator activities of bronchoalveolar fluid in patients with pulmonary sarcoidosis. Exp Lung Res 14:261–278

    Article  PubMed  CAS  Google Scholar 

  • Haverkate F, Samama M (1995) Familial dysfibrinogenemia and thrombophilia. Report on a study of the SSC subcommittee on fibrinogen. Thromb Haemost 73:151–161

    PubMed  CAS  Google Scholar 

  • Healy AM, Rayburn HB, Rosenberg RD, Weiler H (1995) Absence of the bloodclotting regulator thrombomodulin causes embryonic lethality in mice before development of a functional cardiovascular system. Proc Natl Acad Sci USA 92:850–854

    Article  PubMed  CAS  Google Scholar 

  • Ichinose A, Espling ES, Takamatsu J, Saito H, Shinmyozu K, Maruyama I, Petersen TE, Davie EW (1991) Two types of abnormal genes for plasminogen in families with a predisposition for thrombosis. Proc Natl Acad Sci USA 88:115–119

    Article  PubMed  CAS  Google Scholar 

  • Jorgensen M, Bonnevie-Nielsen V (1987) Increased concentration of the fast-acting plasminogen activator inhibitor in plasma associated with familial venous thrombosis. Br J Haematol 65:175–180

    Article  PubMed  CAS  Google Scholar 

  • Kotani I, Sato A, Hayakawa H, Urano T, Takada Y, Takada A (1995) Increased procoagulant and antifibrinolytic activities in the lungs with idiopathic pulmonary fibrosis. Thromb Res 77:493–504

    Article  PubMed  CAS  Google Scholar 

  • Kwaan HC (1992) The plasminogen-plasmin system in malignancy. Cancer Metastasis Rev 11:291–311

    Article  PubMed  CAS  Google Scholar 

  • Lin HF, Maeda N, Smithies O, Straight DL, Stafford DW (1996) Coagulation factor IX-deficient mice developed by gene targeting. Blood 88:657a (Abstract)

    Google Scholar 

  • Marlar RA, Neumann A (1990) Neonatal purpura fulminans due to homozygous protein C or protein S deficiencies. Semin Thromb Hemost 16:299–309

    Article  PubMed  CAS  Google Scholar 

  • Medcalf RL, Kruithof EKO, Schleuning W-D (1988) Plasminogen activator inhibitor 1 and 2 are tumor necrosis factor/cachectin-responsive genes. J Exp Med 168: 751–759

    Article  PubMed  CAS  Google Scholar 

  • Medina R, Socher SH, Han JH, Friedman PA (1989) Interleukin-1, endotoxin or tumor necrosis factor/cachectin enhance the level of plasminogen activator inhibitor messenger RNA in bovine aortic endothelial cells. Thromb Res 54:41–52

    Article  PubMed  CAS  Google Scholar 

  • Moalli R, Doyle JM, Tahhan HR, Hasan FM, Braman SS, Saldeen T (1989) Fibrinolysis in critically ill patients. Am Rev Respir Dis 140:287–293

    Article  PubMed  CAS  Google Scholar 

  • Olofsson BO, Dahlen G, Nilsson TK (1989) Evidence for increased levels of plasminogen activator inhibitor and tissue plasminogen activator in plasma of patients with angiographically verified coronary artery disease. Eur Heart J 10:77–82

    PubMed  CAS  Google Scholar 

  • Oseroff A, Krishnamurti C, Hassett A, Tang D, Alving B (1989) Plasminogen activator and plasminogen activator inhibitor activities in men with coronary artery disease. J Lab Clin Med 113:88–93

    PubMed  CAS  Google Scholar 

  • Paramo J A, Colucci M, Collen D, van de Werf F (1985) Plasminogen activator inhibitor in the blood of patients with coronary artery disease. BMJ (Clin Res Ed) 291:573–574

    Article  CAS  Google Scholar 

  • Paramo JA, Diaz FJ, Rocha E (1988) Plasminogen activator inhibitor activity in bacterial infection. Thromb Haemost 59:451–454

    PubMed  CAS  Google Scholar 

  • Ploplis VA, Carmeliet P, Vazirzadeh S, Van Vlaenderen I, Moons L, Plow EF, Collen D (1995) Effects of disruption of the plasminogen gene on thrombosis, growth, and health in mice. Circulation 92:2585–2593

    PubMed  CAS  Google Scholar 

  • Poggi A, Bellelli E, Castelli MP, Marinacci R, Rella C, Erickson LA, Donati MB, Bini A, Consorzio MNS, Santa Maria Imbaro I (1993) Reduced Lewis lung carcinoma (3LL) metastases in mice transgenic for human plasminogen activator inhibitor-1 (PAI-1). Proc Annu Meet Am Assoc Cancer Res 34: 72 (Abstract)

    Google Scholar 

  • Pyke C, Kristensen P, Ralfkiaer E, Grondahl-Hansen J, Eriksen J, Blasi F, Dano K, Grndahl-Hansen J, Dan K (1991) Urokinase-type plasminogen activator is expressed in stromal cells and its receptor in cancer cells at invasive foci in human colon adenocarcinomas, Am J Pathol 138:1059–1067

    PubMed  CAS  Google Scholar 

  • Rees DC (1996) The population genetics of factor V Leiden (Arg 506 Gin). Br J Haematol 95:79–586

    Article  Google Scholar 

  • Romer J, Bugge TH, Pyke C, Lund LR, Flick MJ, Degen JL, Dano K (1996) Impaired wound healing in mice with a disrupted plasminogen gene. Nature Med 2:287–292

    Article  PubMed  CAS  Google Scholar 

  • Sappino AP, Huarte J, Belin D, Vassalli JD (1989) Plasminogen activators in tissue remodeling and invasion: mRNA localization in mouse ovaries and implanting embryos. J Cell Biol 109:2471–2479

    Article  PubMed  CAS  Google Scholar 

  • Sawdey MS, Loskutoff DJ (1991) Regulation of murine type 1 plasminogen activator inhibitor gene expression in vivo. Tissue specificity and induction by lipopolysaccharide, tumor necrosis factor-a, and transforming growth factor-a. J Clin Invest 88:1346–1353

    Article  PubMed  CAS  Google Scholar 

  • Shirasuna K, Saka M, Hayashido Y, Yoshioka H, Sugiura T, Matsuya T (1993) Extracellular matrix production and degradation by adenoid cystic carcinoma cells: participation of plasminogen activator and its inhibitor in matrix degradation. Cancer Res 53:147–152

    PubMed  CAS  Google Scholar 

  • Soff GA, Sanderowitz J, Gately S, Verrusio E, Weiss I, Brem S, Kwaan HC (1995) Expression of plasminogen activator inhibitor type 1 by human prostate carcinoma cells inhibits primary tumor growth, tumor-associated angiogenesis, and metastasis to lung and liver in an athymic mouse model. J Clin Invest 96:2593–2600

    Article  PubMed  CAS  Google Scholar 

  • Strickland S, Beers WH (1976) Studies on the role of plasminogen activator in ovulation. In vitro response of granulosa cells to gonadotropins, cyclic, nucleotides and prostaglandins. J Biol Chem 251:5694–5702

    PubMed  CAS  Google Scholar 

  • Strickland S, Reich E, Sherman MI (1976) Plasminogen activator in early embryogenesis: enzyme production by trophoblast and parietal endoderm. Cell 9:231–240

    Article  PubMed  CAS  Google Scholar 

  • Suh TT, Holmback K, Jensen NJ, Daugherty CC, Small K, Simon DI, Potter SS, Degen JL (1995) Resolution of spontaneous bleeding events but failure of pregnancy in fibrinogen-deficient mice. Genes Dev 9:2020–2033

    Article  PubMed  CAS  Google Scholar 

  • Tabernero MD, Estells A, Vicente V, Alberca I, Aznar J (1989) Incidence of increased plasminogen activator inhibitor in patients with deep venous thrombosis and or pulmonary embolism. Thromb Res 56:565–570

    Article  PubMed  CAS  Google Scholar 

  • Toomey JR, Kratzer KE, Lasky NM, Broze GJ Jr (1997) Effect of tissue factor deficiency on mouse and tumor development. Proc Natl Acad Sci USA 94:6922–6926

    Article  PubMed  CAS  Google Scholar 

  • Tsirka SE, Gualandris A, Amaral DG, Strickland S (1995) Excitotoxin-induced neuronal degeneration and seizure are mediated by tissue plasminogen activator. Nature 377:340–344

    Article  PubMed  CAS  Google Scholar 

  • Yao S-N, Wilson JM, Nabel EG, Kurachi S, Hachiya HL, Kurachi K (1991) Expression of human factor IX in rat capillary endothelial cells: toward somatic gene therapy for hemophilia B. Proc Natl Acad Sci USA 88:8101–8105

    Article  PubMed  CAS  Google Scholar 

  • Zller B, Svensson PJ, He X, Dahlback B (1994) Identification of the same factor V gene mutation in 47 out of 50 thrombosis-prone families with inherited resistance to activated protein C.J Clin Invest 94:2521–252

    Article  Google Scholar 

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  1. J. M. Pearson
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  2. D. Ginsburg
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Editors and Affiliations

  1. Drug Development, Parke-Davis Pharmaceutical Research Division, Warner-lambert Company, 2800 Plymouth Road, Ann Arbor, MI, 48105, USA

    Andrew C. G. Uprichard M.D. (Vice President) (Vice President)

  2. Vascular and Cardiac Diseases, Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, 2800 Plymouth Road, Ann Arbor, MI, 48105, USA

    Kim P. Gallagher Ph.D.

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© 1999 Springer-Verlag Berlin Heidelberg

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Pearson, J.M., Ginsburg, D. (1999). Use of Transgenic Mice in the Study of Thrombosis and Hemostasis. In: Uprichard, A.C.G., Gallagher, K.P. (eds) Antithrombotics. Handbook of Experimental Pharmacology, vol 132. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-59942-2_6

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  • DOI: https://doi.org/10.1007/978-3-642-59942-2_6

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