Transgenic Mouse Models of Venous Thrombosis: Fulfilling the Expectations?

ABSTRACT

During the last 15 years, transgenic mice have been generated that carry defective and/or mutant alleles of the natural anticoagulant pathways and display a spontaneous thrombotic phenotype. With the generation of these mouse lines, better opportunities became available for investigating both existing and novel risk factors for venous thrombosis. In addition, these models could serve as a tool for evaluating novel antithrombotic strategies. This review summarizes these mouse models and evaluates whether they have fulfilled the expectations.

KEYWORDS

Venous thrombosis - natural anticoagulants - knockout mouse - mouse models - factor V Leiden

REFERENCES

• 1 Day S M, Reeve J L, Myers D D, Fay W P. Murine thrombosis models.  Thromb Haemost. 2004;  92 486-494
• 2 Dorffler-Melly J, Schwarte L A, Ince C, Levi M. Mouse models of focal arterial and venous thrombosis.  Basic Res Cardiol. 2000;  95 503-509
• 3 Hogan K A, Weiler H, Lord S T. Mouse models in coagulation.  Thromb Haemost. 2002;  87 563-574
• 4 Mackman N. Mouse models in haemostasis and thrombosis.  Thromb Haemost. 2004;  92 440-443
• 5 Emeis J J, Jirouskova M, Muchitsch E M, Shet A S, Smyth S S, Johnson G J. A guide to murine coagulation factor structure, function, assays, and genetic alterations.  J Thromb Haemost. 2007;  5 670-679
• 6 Carmeliet P, Moons L, Collen D. Mouse models of angiogenesis, arterial stenosis, atherosclerosis and hemostasis.  Cardiovasc Res. 1998;  39 8-33
• 7 Sood R, Weiler H. Embryogenesis and gene targeting of coagulation factors in mice.  Best Pract Res Clin Haematol. 2003;  16 169-181
• 8 Mackman N. Tissue-specific hemostasis in mice.  Arterioscler Thromb Vasc Biol. 2005;  25 2273-2281
• 9 Tsakiris D A, Scudder L, Hodivala-Dilke K, Hynes R O, Coller B S. Hemostasis in the mouse (Mus musculus): a review.  Thromb Haemost. 1999;  81 177-188
• 10 Preissner K T. Hemostatic protease receptors and endothelial cell function: insights from gene targeting in mice.  Semin Thromb Hemost. 2000;  26 451-462
• 11 Car B D, Eng V M. Special considerations in the evaluation of the hematology and hemostasis of mutant mice.  Vet Pathol. 2001;  38 20-30
• 12 Huang Z F, Broze Jr G. Consequences of tissue factor pathway inhibitor gene-disruption in mice.  Thromb Haemost. 1997;  78 699-704
• 13 Huang Z F, Higuchi D, Lasky N, Broze Jr G J. Tissue factor pathway inhibitor gene disruption produces intrauterine lethality in mice.  Blood. 1997;  90 944-951
• 14 Dusse L M, Carvalho M G, Cooper A J, Lwaleed B A. Tissue factor and tissue factor pathway inhibitor: a potential role in pregnancy and obstetric vascular complications?.  Clin Chim Acta. 2006;  372 43-46
• 15 Chan J C, Carmeliet P, Moons L et al.. Factor VII deficiency rescues the intrauterine lethality in mice associated with a tissue factor pathway inhibitor deficit.  J Clin Invest. 1999;  103 475-482
• 16 Pedersen B, Holscher T, Sato Y, Pawlinski R, Mackman N. A balance between tissue factor and tissue factor pathway inhibitor is required for embryonic development and hemostasis in adult mice.  Blood. 2005;  105 2777-2782
• 17 Ishiguro K, Kojima T, Kadomatsu K et al.. Complete antithrombin deficiency in mice results in embryonic lethality.  J Clin Invest. 2000;  106 873-878
• 18 Yanada M, Kojima T, Ishiguro K et al.. Impact of antithrombin deficiency in thrombogenesis: lipopolysaccharide and stress-induced thrombus formation in heterozygous antithrombin-deficient mice.  Blood. 2002;  99 2455-2458
• 19 Dewerchin M, Herault J P, Wallays G et al.. Life-threatening thrombosis in mice with targeted Arg48-to-Cys mutation of the heparin-binding domain of antithrombin.  Circ Res. 2003;  93 1120-1126
• 20 Hayashi M, Matsushita T, Mackman N et al.. Fatal thrombosis of antithrombin-deficient mice is rescued differently in the heart and liver by intercrossing with low tissue factor mice.  J Thromb Haemost. 2006;  4 177-185
• 21 Dewerchin M, Van der E L, Singh I et al.. Inhibition of factor VIII with a partially inhibitory human recombinant monoclonal antibody prevents thrombotic events in a transgenic model of type II HBS antithrombin deficiency in mice.  J Thromb Haemost. 2004;  2 77-84
• 22 Jalbert L R, Rosen E D, Moons L et al.. Inactivation of the gene for anticoagulant protein C causes lethal perinatal consumptive coagulopathy in mice.  J Clin Invest. 1998;  102 1481-1488
• 23 Levi M, Dorffler-Melly J, Reitsma P et al.. Aggravation of endotoxin-induced disseminated intravascular coagulation and cytokine activation in heterozygous protein-C-deficient mice.  Blood. 2003;  101 4823-4827
• 24 Lay A J, Liang Z, Rosen E D, Castellino F J. Mice with a severe deficiency in protein C display prothrombotic and proinflammatory phenotypes and compromised maternal reproductive capabilities.  J Clin Invest. 2005;  115 1552-1561
• 25 Chan J C, Cornelissen I, Collen D, Ploplis V A, Castellino F J. Combined factor VII/protein C deficiency results in intrauterine coagulopathy in mice.  J Clin Invest. 2000;  105 897-903
• 26 Chan J C, Ganopolsky J G, Cornelissen I et al.. The characterization of mice with a targeted combined deficiency of protein c and factor XI.  Am J Pathol. 2001;  158 469-479
• 27 Gu J M, Crawley J T, Ferrell G et al.. Disruption of the endothelial cell protein C receptor gene in mice causes placental thrombosis and early embryonic lethality.  J Biol Chem. 2002;  277 43335-43343
• 28 Zheng X, Li W, Gu J M et al.. Effects of membrane and soluble EPCR on the hemostatic balance and endotoxemia in mice.  Blood. 2007;  109 1003-1009
• 29 Castellino F J, Liang Z, Volkir S P et al.. Mice with a severe deficiency of the endothelial protein C receptor gene develop, survive, and reproduce normally, and do not present with enhanced arterial thrombosis after challenge.  Thromb Haemost. 2002;  88 462-472
• 30 Li W, Zheng X, Gu J M et al.. Extraembryonic expression of EPCR is essential for embryonic viability.  Blood. 2005;  106 2716-2722
• 31 Healy A M, Rayburn H B, Rosenberg R D, Weiler H. Absence of the blood-clotting regulator thrombomodulin causes embryonic lethality in mice before development of a functional cardiovascular system.  Proc Natl Acad Sci U S A. 1995;  92 850-854
• 32 Rosenberg R D. Thrombomodulin gene disruption and mutation in mice.  Thromb Haemost. 1997;  78 705-709
• 33 Weiler-Guettler H, Christie P D, Beeler D L et al.. A targeted point mutation in thrombomodulin generates viable mice with a prethrombotic state.  J Clin Invest. 1998;  101 1983-1991
• 34 Weiler H, Lindner V, Kerlin B et al.. Characterization of a mouse model for thrombomodulin deficiency.  Arterioscler Thromb Vasc Biol. 2001;  21 1531-1537
• 35 Weiler H, Isermann B H. Thrombomodulin.  J Thromb Haemost. 2003;  1 1515-1524
• 36 Dorffler-Melly J, de Kruif M, Schwarte L A et al.. Functional thrombomodulin deficiency causes enhanced thrombus growth in a murine model of carotid artery thrombosis.  Basic Res Cardiol. 2003;  98 347-352
• 37 Isermann B, Hendrickson S B, Hutley K, Wing M, Weiler H. Tissue-restricted expression of thrombomodulin in the placenta rescues thrombomodulin-deficient mice from early lethality and reveals a secondary developmental block.  Development. 2001;  128 827-838
• 38 Isermann B, Hendrickson S B, Zogg M et al.. Endothelium-specific loss of murine thrombomodulin disrupts the protein C anticoagulant pathway and causes juvenile-onset thrombosis.  J Clin Invest. 2001;  108 537-546
• 39 Weiler H. Mouse models of thrombosis: thrombomodulin.  Thromb Haemost. 2004;  92 467-477
• 40 Bertina R M, Koeleman B P, Koster T et al.. Mutation in blood coagulation factor V associated with resistance to activated protein C.  Nature. 1994;  369 64-67
• 41 Yang T L, Cui J, Rehumtulla A et al.. The structure and function of murine factor V and its inactivation by protein C.  Blood. 1998;  91 4593-4599
• 42 Cui J, Eitzman D T, Westrick R J et al.. Spontaneous thrombosis in mice carrying the factor V Leiden mutation.  Blood. 2000;  96 4222-4226
• 43 Schlachterman A, Schuettrumpf J, Liu J H et al.. Leiden improves in vivo hemostasis in murine hemophilia models.  J Thromb Haemost. 2005;  3 2730-2737
• 44 Shen Y, Bodary P F, Vargas F B et al.. Alpha-galactosidase A deficiency leads to increased tissue fibrin deposition and thrombosis in mice homozygous for the factor V Leiden mutation.  Stroke. 2006;  37 1106-1108
• 45 Eitzman D T, Westrick R J, Bi X et al.. Lethal perinatal thrombosis in mice resulting from the interaction of tissue factor pathway inhibitor deficiency and factor V Leiden.  Circulation. 2002;  105 2139-2142
• 46 Yin Z F, Huang Z F, Cui J et al.. Prothrombotic phenotype of protein Z deficiency.  Proc Natl Acad Sci U S A. 2000;  97 6734-6738
• 47 Corral J, Gonzalez-Conejero R, Hernandez-Espinosa D, Vicente V. Protein Z/Z-dependent protease inhibitor (PZ/ZPI) anticoagulant system and thrombosis.  Br J Haematol. 2007;  137 99-108
• 48 Broze Jr G J. Protein Z-dependent regulation of coagulation.  Thromb Haemost. 2001;  86 8-13
• 49 Sood R, Zogg M, Westrick R J et al.. Fetal gene defects precipitate platelet-mediated pregnancy failure in factor V Leiden mothers.  J Exp Med. 2007;  , In press
• 50 Westrick R J, Manning S L, Dobies S L et al.. A sensitized genome-wide ENU mutagenesis screen in the mouse to identify genetic modifiers of thrombosis. Paper presented at: ASH Annual Meeting; 2004; abstracts.  2004;  104 2