Genetic Interactions between the Coagulation and Fibrinolytic Systems

Jay L. Degen

doi:10.1055/s-0037-1616209

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 2001; 86(01): 130-137
DOI: 10.1055/s-0037-1616209

Research Article

Schattauer GmbH

Genetic Interactions between the Coagulation and Fibrinolytic Systems

Jay L. Degen

¹Children’s Hospital Research Foundation and University of Cincinnati College of Medicine, Cincinnati, Ohio, USA

› Institutsangaben

Abstract

Summary

Nearly all of the genes encoding the established coagulation and fibrinolytic factors have been successfully altered or disrupted in transgenic mice. Although comprehensive studies of each of these genetargeted mouse lines are still ongoing, the initial findings have significantly refined our understanding of the roles of selected hemostatic factors in vivo, and occasionally altered long-standing concepts. This review summarizes some of the progress that has been made in the generation and phenotypic characterization of mice lacking key hemostatic factors, including coagulation, fibrinolytic, platelet and endothelial cell-associated factors. New insights regarding the role(s) and interplay of hemostatic factors that have emerged from detailed studies of mice carrying multiple deficits in coagulation and fibrinolytic system components are highlighted.

Key words

Coagulation - fibrinolysis - platelets - gene-targeting

Volltext

Referenzen

References
1 Bugge TH, Xiao Q, Kombrinck KW, Flick MJ, Holmback K, Danton MJ, Colbert MC, Witte DP, Fujikawa K, Davie EW, Degen JL. Fatal embryonic bleeding events in mice lacking tissue factor, the cell-associated initiator of blood coagulation. Proc Natl Acad Sci USA 1996; 93: 6258-63.
2 Toomey JR, Kratzer KE, Lasky NM, Stanton JJ, Broze Jr GJ. Targeted disruption of the murine tissue factor gene results in embryonic lethality. Blood 1996; 88: 1583-7.
3 Toomey JR, Kratzer KE, Lasky NM, Broze Jr GJ. Effect of tissue factor deficiency on mouse and tumor development. Proc Natl Acad Sci USA 1997; 94: 6922-6.
4 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. Role of tissue factor in embryonic blood vessel development. Nature 1996; 383: 73-5.
5 Rosen ED, Chan JC, Idusogie E, Clotman F, Vlasuk G, Luther T, Jalbert LR, Albrecht S, Zhong L, Lissens A, Schoonjans L, Moons L, Collen D, Castellino FJ, Carmeliet P. Mice lacking factor VII develop normally but suffer fatal perinatal bleeding. Nature 1997; 390: 290-4.
6 Dewerchin M, Liang Z, Moons L, Carmeliet P, Castellino FJ, Collen D, Rosen ED. Blood coagulation factor X deficiency causes partial embryonic lethality and fatal neonatal bleeding in mice. Thromb Haemost 2000; 83: 185-90.
7 Denis C, Methia N, Frenette PS, Rayburn H, Ullman-Cullere M, Hynes RO, Wagner DD. A mouse model of severe von Willebrand disease: defects in hemostasis and thrombosis. Proc Natl Acad Sci USA 1998; 95: 9524-9.
8 Wang L, Zoppe M, Hackeng TM, Griffin JH, Lee KF, Verma IM. A factor IX-deficient mouse model for hemophilia B gene therapy. Proc Natl Acad Sci USA 1997; 94: 11563-6.
9 Bi L, Sarkar R, Naas T, Lawler AM, Pain J, Shumaker SL, Bedian V, Kazazian Jr HH. Further characterization of factor VIII-deficient mice created by gene targeting: RNA and protein studies. Blood 1996; 88: 3446-50.
10 Gailani D, Lasky NM, Broze Jr GJ. A murine model of factor XI deficiency. Blood Coagul Fibrinolysis 1997; 8: 134-44.
11 Cui J, O’Shea KS, Purkayastha A, Saunders TL, Ginsburg D. Fatal haemorrhage and incomplete block to embryogenesis in mice lacking coagulation factor V. Nature 1996; 384: 66-8.
12 Sun WY, Witte DP, Degen JL, Colbert MC, Burkart MC, Holmback K, Xiao Q, Bugge TH, Degen SJ. Prothrombin deficiency results in embryonic and neonatal lethality in mice. Proc Natl Acad Sci USA 1998; 95: 7597-602.
13 Xue J, Wu Q, Westfield LA, Tuley EA, Lu D, Zhang Q, Shim K, Zheng X, Sadler JE. Incomplete embryonic lethality and fatal neonatal hemorrhage caused by prothrombin deficiency in mice. Proc Natl Acad Sci USA 1998; 95: 7603-7.
14 Suh TT, Holmback K, Jensen NJ, Daugherty CC, Small K, Simon DI, Potter S, Degen JL. Resolution of spontaneous bleeding events but failure of pregnancy in fibrinogen-deficient mice. Genes Dev 1995; 9: 2020-33.
15 Holmback K, Danton MJ, Suh TT, Daugherty CC, Degen JL. Impaired platelet aggregation and sustained bleeding in mice lacking the fibrinogen motif bound by integrin alpha IIb beta 3. EMBO J 1996; 15: 5760-71.
16 Lin HF, Maeda N, Smithies O, Straight DL, Stafford DW. A coagulation factor IX-deficient mouse model for human hemophilia B. Blood 1997; 90: 3962-6.
17 Kundu RK, Sangiorgi F, Wu LY, Kurachi K, Anderson WF, Maxson R, Gordon EM. Targeted inactivation of the coagulation factor IX gene causes hemophilia B in mice. Blood 1998; 92: 168-74.
18 Bi L, Lawler AM, Antonarakis SE, High KA, Gearhart JD, Kazazian HH. Targeted disruption of the mouse factor VIII gene produces a model of haemophilia A. Nat Genet 1995; 10: 119-21.
19 Healy AM, Rayburn HB, Rosenberg RD, 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 USA 1995; 92: 850-4.
20 Healy AM, Hancock WW, Christie PD, Rayburn HB, Rosenberg RD. Intravascular coagulation activation in a murine model of thrombomodulin deficiency: effects of lesion size, age, and hypoxia on fibrin deposition. Blood 1998; 92: 4188-97.
21 Jalbert LR, Rosen ED, Moons L, Chan JC, Carmeliet P, Collen D, Castellino FJ. Inactivation of the gene for anticoagulant protein C cause lethal perinatal consumptive coagulopathy in mice. J Clin Invest 1998; 102: 1481-8.
22 Huang ZF, Higuchi D, Lasky N, Broze Jr GJ. Tissue factor pathway inhibitor gene disruption produces intrauterine lethality in mice. Blood 1997; 90: 944-51.
23 Huang ZF, Broze Jr G. Consequences of tissue factor pathway inhibitor gene-disruption in mice. Thromb Haemost 1997; 78: 699-704.
24 Ishiguro K, Kojima T, Kadomatsu K, Nakayama Y, Takagi A, Suzuki M, Takeda N, Ito M, Yamamoto K, Matsushita T, Kusugami K, Muramatsu T, Saito H. Complete antithrombin deficiency in mice results in embryonic lethality. J Clin Invest 2000; 106: 873-8.
25 Enjyoji K, Sevigny J, Lin Y, Frenette PS, Christie PD, Esch 2nd JS, Imai M, Edelberg JM, Rayburn H, Lech M, Beeler DL, Csizmadia E, Wagner DD, Robson SC, Rosenberg RD. Targeted disruption of cd39/ATP diphosphohydrolase results in disordered hemostasis and thromboregulation. Nat Med 1999; 5: 1010-7.
26 Connolly AJ, Ishihara H, Kahn ML, Farese Jr RV, Coughlin SR. Role of the thrombin receptor in development and evidence for a second receptor. Nature 1996; 381: 516-9.
27 Coughlin SR. Sol Sherry lecture in thrombosis: how thrombin “talks” to cells: molecular mechanisms and roles in vivo. Arterioscler Thromb Vasc Biol 1998; 18: 514-8.
28 Kahn ML, Zheng YW, Huang W, Bigornia V, Zeng D, Moff S, Farese Jr RV, Tam C, Coughlin SR. A dual thrombin receptor system for platelet activation. Nature 1998; 394: 690-4.
29 Offermanns S, Toombs CF, Hu YH, Simon MI. Defective platelet activation in G alpha(q)-deficient mice. Nature 1997; 389: 183-6.
30 Hodivala-Dilke KM, McHugh KP, Tsakiris DA, Rayburn H, Crowley D, Ullman-Cullere M, Ross FP, Coller BS, Teitelbaum S, Hynes RO. Beta3-integrin-deficient mice are a model for Glanzmann thrombasthenia showing placental defects and reduced survival. J Clin Invest 1999; 103: 229-38.
31 Subramaniam M, Frenette PS, Saffaripour S, Johnson RC, Hynes RO, Wagner DD. Defects in hemostasis in P-selectin-deficient mice. Blood 1996; 87: 1238-42.
32 Ware J, Russell S, Ruggeri ZM. Generation and rescue of a murine model of platelet dysfunction: the Bernard-Soulier syndrome. Proc Natl Acad Sci USA 2000; 97: 2803-8.
33 Cheng AM, Rowley B, Pao W, Hayday A, Bolen JB, Pawson T. Syk tyrosine kinase required for mouse viability and B-cell development. Nature 1995; 378: 303-6.
34 Turner M, Mee PJ, Costello PS, Williams O, Price AA, Duddy LP, Furlong MT, Geahlen RL, Tybulewicz VL. Perinatal lethality and blocked B-cell development in mice lacking the tyrosine kinase Syk. Nature 1995; 378: 298-302.
35 Kiefer F, Brumell J, Al-Alawi N, Latour S, Cheng A, Veillette A, Grinstein S, Pawson T. The Syk protein tyrosine kinase is essential for Fcgamma receptor signaling in macrophages and neutrophils. Mol Cell Biol 1998; 18: 4209-20.
36 Judd BA, Myung PS, Leng L, Obergfell A, Pear WS, Shattil SJ, Koretzky GA. Hematopoietic reconstitution of SLP-76 corrects hemostasis and platelet signaling through alpha IIbbeta 3 and collagen receptors. Proc Natl Acad Sci USA 2000; 97: 12056-61.
37 Obergfell A, Judd BA, del Pozo MA, Schwartz MA, Koretzky GA, Shattil SJ. The molecular adapter SLP-76 relays signals from platelet integrin IIb 3 to the actin cytoskeleton. J Biol Chem 2001; 276: 5916-23.
38 Pivniouk V, Tsitsikov E, Swinton P, Rathbun G, Alt FW, Geha RS. Impaired viability and profound block in thymocyte development in mice lacking the adaptor protein SLP-76. Cell 1998; 94: 229-38.
39 Clements JL, Lee JR, Gross B, Yang B, Olson JD, Sandra A, Watson SP, Lentz SR, Koretzky GA. Fetal hemorrhage and platelet dysfunction in SLP-76-deficient mice. J Clin Invest 1999; 103: 19-25.
40 Tronik-Le Roux D, Roullot V, Poujol C, Kortulewski T, Nurden P, Marguerie G. Thrombasthenic mice generated by replacement of the integrin alpha(IIb) gene: demonstration that transcriptional activation of this megakaryocytic locus precedes lineage commitment. Blood 2000; 96: 1399-408.
41 Weiler-Guettler H, Christie PD, Beeler DL, Healy AM, Hancock WW, Rayburn H, Edelberg JM, Rosenberg RD. A targeted point mutation in thrombomodulin generates viable mice with a prethrombotic state. J Clin Invest 1998; 101: 1983-91.
42 Cui J, Eitzman DT, Westrick RJ, Christie PD, Xu ZJ, Yang AY, Purkayastha AA, Yang TL, Metz AL, Gallagher KP, Tyson JA, Rosenberg RD, Ginsburg D. Spontaneous thrombosis in mice carrying the factor V leiden mutation. Blood 2000; 96: 4222-6.
43 Yin ZF, Huang ZF, Cui J, Fiehler R, Lasky N, Ginsburg D, Broze Jr GJ. Prothrombotic phenotype of protein Z deficiency. Proc Natl Acad Sci USA 2000; 97: 6734-8.
44 Carmeliet P, Schoonjans L, Kieckens L, Ream B, Degen J, Bronson R, De Vos R, van den Oord JJ, Collen D, Mulligan RC. Physiological consequences of loss of plasminogen activator gene function in mice. Nature 1994; 368: 419-24.
45 Carmeliet P, Stassen JM, Schoonjans L, Ream B, van den Oord JJ, De Mol M, Mulligan RC, Collen D. Plasminogen activator inhibitor-1 gene-deficient mice. II. Effects on hemostasis, thrombosis, and thrombolysis. J Clin Invest 1993; 92: 2756-60.
46 Bugge TH, Flick MJ, Daugherty CC, Degen JL. Plasminogen deficiency causes severe thrombosis but is compatible with development and reproduction. Genes Dev 1995; 9: 794-807.
47 Bugge TH, Suh TT, Flick MJ, Daugherty CC, Romer J, Solberg H, Ellis V, Dano K, Degen JL. The receptor for urokinase-type plasminogen activator is not essential for mouse development or fertility. J Biol Chem 1995; 270: 16886-94.
48 Ploplis VA, French EL, Carmeliet P, Collen D, Plow EF. Plasminogen deficiency differentially affects recruitment of inflammatory cell populations in mice. Blood 1998; 91: 2005-9.
49 Dewerchin M, Nuffelen AV, Wallays G, Bouche A, Moons L, Carmeliet P, Mulligan RC, Collen D. Generation and characterization of urokinase receptor-deficient mice. J Clin Invest 1996; 97: 870-8.
50 Lijnen HR, Okada K, Matsuo O, Collen D, Dewerchin M. Alpha2-anti-plasmin gene deficiency in mice is associated with enhanced fibrinolytic potential without overt bleeding. Blood 1999; 93: 2274-81.
51 Dougherty KM, Pearson JM, Yang AY, Westrick RJ, Baker MS, Ginsburg D. The plasminogen activator inhibitor-2 gene is not required for normal murine development or survival. Proc Natl Acad Sci USA 1999; 96: 686-91.
52 Suh TT, Nerlov C, Dano K, Degen JL. The murine urokinase-type plasminogen activator receptor gene. J Biol Chem 1994; 269: 25992-8.
53 Roy SN, Procyk R, Kudryk BJ, Redman CM. Assembly and secretion of recombinant human fibrinogen. J Biol Chem 1991; 266: 4758-63.
54 Ni H, Denis CV, Subbarao S, Degen JL, Sato TN, Hynes RO, Wagner DD. Persistence of platelet thrombus formation in arterioles of mice lacking both von Willebrand factor and fibrinogen. J Clin Invest 2000; 106: 385-92.
55 Bugge TH, Kombrinck KW, Flick MJ, Daugherty CC, Danton MJ, Degen JL. Loss of fibrinogen rescues mice from the pleiotropic effects of plasminogen deficiency. Cell 1996; 87: 709-19.
56 Collen D. The plasminogen (fibrinolytic) system. Thromb Haemost 1999; 82: 259-70.
57 Ploplis VA, Carmeliet P, Vazirzadeh S, Van Vlaenderen I, Moons L, Plow EF, Collen D. Effects of disruption of the plasminogen gene on thrombosis, growth, and health in mice. Circulation 1995; 92: 2585-93.
58 Romer J, Bugge TH, Pyke C, Lund LR, Flick MJ, Degen JL, Dano K. Impaired wound healing in mice with a disrupted plasminogen gene. Nat Med 1996; 2: 287-92.
59 Drew AF, Kaufman AH, Kombrinck KW, Danton MJ, Daugherty CC, Degen JL, Bugge TH. Ligneous conjunctivitis in plasminogen-deficient mice. Blood 1998; 91: 1616-24.
60 Drew AF, Schiman HL, Kombrinck KW, Bugge TH, Degen JL, Kaufman AH. Persistent corneal haze after excimer laser photokeratectomy in plasminogen-deficient mice. Invest Ophthalmol Vis Sci 2000; 41: 67-72.
61 Lund LR, Bjorn SF, Sternlicht MD, Nielsen BS, Solberg H, Usher PA, Osterby R, Christensen IJ, Stephens RW, Bugge TH, Dano K, Werb Z. Lactational competence and involution of the mouse mammary gland require plasminogen. Development 2000; 127: 4481-92.
62 Kao WW, Kao CW, Kaufman AH, Kombrinck KW, Converse RL, Good WV, Bugge TH, Degen JL. Healing of corneal epithelial defects in plasminogen- and fibrinogen-deficient mice. Invest Ophthalmol Vis Sci 1998; 39: 502-8.
63 Akassoglou K, Kombrinck KW, Degen JL, Strickland S. Tissue plasminogen activator-mediated fibrinolysis protects against axonal degeneration and demyelination after sciatic nerve injury. J Cell Biol 2000; 149: 1157-66.
64 Bezerra JA, Bugge TH, Melin-Aldana H, Sabla G, Kombrinck KW, Witte DP, Degen JL. Plasminogen deficiency leads to impaired remodeling after a toxic injury to the liver. Proc Natl Acad Sci USA 1999; 96: 15143-8.
65 Creemers E, Cleutjens J, Smits J, Heymans S, Moons L, Collen D, Daemen M, Carmeliet P. Disruption of the plasminogen gene in mice abolishes wound healing after myocardial infarction. Am J Pathol 2000; 156: 1865-73.
66 Tsirka SE, Bugge TH, Degen JL, Strickland S. Neuronal death in the central nervous system demonstrates a non-fibrin substrate for plasmin. Proc Natl Acad Sci USA 1997; 94: 9779-81.
67 Tsirka SE, Rogove AD, Bugge TH, Degen JL, Strickland S. An extracellular proteolytic cascade promotes neuronal degeneration in the mouse hippocampus. J Neurosci 1997; 17: 543-52.
68 Coleman JL, Gebbia JA, Piesman J, Degen JL, Bugge TH, Benach JL. Plasminogen is required for efficient dissemination of B. burgdorferi in ticks and for enhancement of spirochetemia in mice. Cell 1997; 89: 1111-9.
69 Coleman JL, Benach JL. The generation of enzymatically active plasmin on the surface of spirochetes. Methods 2000; 21: 133-41.
70 Gebbia JA, Monco JC, Degen JL, Bugge TH, Benach JL. The plasminogen activation system enhances brain and heart invasion in murine relapsing fever borreliosis. J Clin Invest 1999; 103: 81-7.
71 Goguen JD, Bugge T, Degen JL. Role of the pleiotropic effects of plasminogen deficiency in infection experiments with plasminogen-deficient mice. Methods 2000; 21: 179-83.
72 Heymans S, Luttun A, Nuyens D, Theilmeier G, Creemers E, Moons L, Dyspersin GD, Cleutjens JP, Shipley M, Angellilo A, Levi M, Nube O, Baker A, Keshet E, Lupu F, Herbert JM, Smits JF, Shapiro SD, Baes M, Borgers M, Collen D, Daemen MJ, Carmeliet P. Inhibition of plasminogen activators or matrix metalloproteinases prevents cardiac rupture but impairs therapeutic angiogenesis and causes cardiac failure. Nat Med 1999; 5: 1135-42.
73 Drew AF, Tucker HL, Kombrinck KW, Simon DI, Bugge TH, Degen JL. Plasminogen is a critical determinant of vascular remodeling in mice. Circ Res 2000; 87: 133-9.
74 Chen ZL, Strickland S. Neuronal death in the hippocampus is promoted by plasmin-catalyzed degradation of laminin. Cell 1997; 91: 917-25.
75 Chen ZL, Indyk JA, Bugge TH, Kombrinck KW, Degen JL, Strickland S. Neuronal death and blood-brain barrier breakdown after excitotoxic injury are independent processes. J Neurosci 1999; 19: 9813-20.
76 Wang YF, Tsirka SE, Strickland S, Stieg PE, Soriano SG, Lipton SA. Tissue plasminogen activator (tPA) increases neuronal damage after focal cerebral ischemia in wild-type and tPA-deficient mice. Nat Med 1998; 4: 228-31.
77 Tsirka SE, Gualandris A, Amaral DG, Strickland S. Excitotoxin-induced neuronal degeneration and seizure are mediated by tissue plasminogen activator. Nature 1995; 377: 340-4.
78 Plow EF, Ginsberg MH. Specific and saturable binding of plasma fibronectin to thrombin-stimulated human platelets. J Biol Chem 1981; 256: 9477-82.
79 Thiagarajan P, Kelly KL. Exposure of binding sites for vitronectin on platelets following stimulation. J Biol Chem 1988; 263: 3035-8.
80 Lawler J, Hynes RO. The structure of human thrombospondin, an adhesive glycoprotein with multiple calcium-binding sites and homologies with several different proteins. J Cell Biol 1986; 103: 1635-48.
81 Ruggeri ZM. Mechanisms initiating platelet thrombus formation. Thromb Haemost 1997; 78: 611-6.
82 Bonnefoy A, Hantgan R, Legrand C, Frojmovic MM. A model of platelet aggregation involving multiple interactions of Thrombospondin-1, Fibrinogen and GPIIbIIIa receptor. J Biol Chem 2001; 276: 5605-12.
83 Ruggeri ZM, Dent JA, Saldivar E. Contribution of distinct adhesive interactions to platelet aggregation in flowing blood. Blood 1999; 94: 172-8.
84 Goto S, Ikeda Y, Saldivar E, Ruggeri ZM. Distinct mechanisms of platelet aggregation as a consequence of different shearing flow conditions. J Clin Invest 1998; 101: 479-86.
85 Bugge TH, Flick MJ, Danton MJ, Daugherty CC, Romer J, Dano K, Carmeliet P, Collen D, Degen JL. 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 1996; 93: 5899-904.
86 Chan JC, Carmeliet P, Moons L, Rosen ED, Huang ZF, Broze Jr GJ, Collen D, Castellino FJ. Factor VII deficiency rescues the intrauterine lethality in mice associated with a tissue factor pathway inhibitor deficit. J Clin Invest 1999; 103: 475-82.
87 Chan JC, Cornelissen I, Collen D, Ploplis VA, Castellino FJ. Combined factor VII/protein C deficiency results in intrauterine coagulopathy in mice. J Clin Invest 2000; 105: 897-903.
88 Chan JC, Ganopolsky JG, Cornelissen I, Suckow MA, Sandoval-Cooper MJ, Brown EC, Noria F, Gailani D, Rosen ED, Ploplis VA, Castellino FJ. The characterization of mice with a targeted combined deficiency of protein C and Factor XI. Am J Pathol 2001; 158: 469-79.
89 Yang TL, Cui J, Taylor JM, Yang A, Gruber SB, Ginsburg D. Rescue of fatal neonatal hemorrhage in factor V deficient mice by low level trans-gene expression. Thromb Haemost 2000; 83: 70-7.
90 Ploplis VA, Wilberding J, McLennan L, Liang Z, Cornelissen I, DeFord ME, Rosen ED, Castellino FJ. A total fibrinogen deficiency is compatible with the development of pulmonary fibrosis in mice. Am J Pathol 2000; 157: 703-8.
91 Connolly AJ, Suh DY, Hunt TK, Coughlin SR. Mice lacking the thrombin receptor, PAR1, have normal skin wound healing. Am J Pathol 1997; 151: 1199-204.
92 Coughlin SR. Thrombin signalling and protease-activated receptors. Nature 2000; 407: 258-64.
93 Ishihara H, Zeng D, Connolly AJ, Tam C, Coughlin SR. Antibodies to protease-activated receptor 3 inhibit activation of mouse platelets by thrombin. Blood 1998; 91: 4152-7.
94 Nakanishi-Matsui M, Zheng YW, Sulciner DJ, Weiss EJ, Ludeman MJ, Coughlin SR. PAR3 is a cofactor for PAR4 activation by thrombin. Nature 2000; 404: 609-13.
95 Angelillo-Scherrer A, de Frutos PG, Aparicio C, Melis E, Savi P, Lupu F, Arnout J, Dewerchin M, Hoylaerts MF, Herbert JM, Collen D, Dahl-bäck B, Carmeliet P. Deficiency or inhibition of Gas6 causes platelet dysfunction and protects mice against thrombosis. Nat Med 2001; 7: 215-21.
96 Zheng X, Saunders TL, Camper SA, Samuelson LC, Ginsburg D. Vitronectin is not essential for normal mammalian development and fertility. Proc Natl Acad Sci USA 1995; 92: 12426-30.
97 Eitzman DT, Westrick RJ, Nabel EG, Ginsburg D. Plasminogen activator inhibitor-1 and vitronectin promote vascular thrombosis in mice. Blood 2000; 95: 577-80.
98 Fay WP, Parker AC, Ansari MN, Zheng X, Ginsburg D. Vitronectin inhibits the thrombotic response to arterial injury in mice. Blood 1999; 93: 1825-30.
99 Mayadas TN, Johnson RC, Rayburn H, Hynes RO, Wagner DD. Leukocyte rolling and extravasation are severely compromised in P selectin-deficient mice. Cell 1993; 74: 541-54.
100 Carmeliet P, Kieckens L, Schoonjans L, Ream B, van Nuffelen A, Prendergast G, Cole M, Bronson R, Collen D, Mulligan RC. Plasminogen activator inhibitor-1 gene-deficient mice. I. Generation by homologous recombination and characterization. J Clin Invest 1993; 92: 2746-55.