Semin Thromb Hemost 2000; 26(5): 451-462
DOI: 10.1055/s-2000-13201
Copyright © 2000 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel.: +1(212) 584-4662

Hemostatic Protease Receptors and Endothelial Cell Function: Insights from Gene Targeting in Mice

Klaus T. Preissner
  • Institute for Biochemistry, Fachbereich Humanmedizin, Justus-Liebig-Universität, Giessen, Germany
Further Information

Publication History

Publication Date:
31 December 2000 (online)

ABSTRACT

Hemostasis constitutes a major defense system of our body that maintains blood flow in the circulation and prevents life-threatening blood loss. The endothelium plays a crucial dynamic role as a protective interface between blood and the underlying tissues during this process. Following vessel wall injury with initial platelet adhesion and aggregation to exposed subendothelial extracellular matrix, the initiation, amplification, and control of hemostasis depend on structurally unrelated membrane-associated receptors for blood coagulation proteases including tissue factor, G protein-coupled protease-activatable receptors, thrombomodulin, or protein C receptor. In addition to their regulatory role in hemostasis, the respective (pro-)enzyme ligands such as factors VIIa and Xa, thrombin, and protein C mediate specific signaling pathways in vascular cells related to migration, proliferation, or adhesion. The functional importance of these receptors beyond hemostasis has been manifested by various lethal or pathological phenotypes in knock-out mice. These protease receptors thereby provide important molecular links in the vascular system and serve to integrate hemostasis with endothelial cell functions that are relevant for the (patho-) physiological responses to inflammatory challenges, injury, or infection.

REFERENCES

  • 1 Risau W. Mechanisms of angiogenesis.  Nature . 1997;  386 671-674
  • 2 Springer T A. Traffic signals for lymphocyte recirculation and leukocyte emigration: The multistep paradigm.  Cell . 1994;  76 301-314
  • 3 Zimmerman G A, McIntyre T M, Prescott S M. Adhesion and signalling in vascular cell-cell interactions.  J Clin Invest . 1996;  98 1699-1702
  • 4 May A E, Neumann F J, Preissner K T. The relevance of blood cell-vessel wall adhesive interactions for vascular thrombotic disease.  Thromb Haemost . 1999;  82 962-970
  • 5 Cines D B, Pollak E S, Buck C A. Endothelial cells in physiology and in the pathophysiology of vascular disorders.  Blood . 1998;  91 3527-3561
  • 6 Bu G, Warshawsky I, Schwartz A L. Cellular receptors for the plasminogen activators.  Blood . 1994;  83 3427-3436
  • 7 Anderson R GW. The caveolae membrane system.  Annu Rev Biochem . 1998;  67 199-225
  • 8 Schnitzer J E, McIntosh D P, Dvorak A M, Liu J, Oh P. Separation of caveolae from associated microdomains of GPI-anchored proteins.  Science . 1995;  269 1435-1439
  • 9 Blasi F. uPA, uPAR, PAI-1: Key intersection of proteolytic, adhesive and chemotactic highways?.  Immunol Today . 1997;  18 415-417
  • 10 Carmeliet P, Collen D. Role of the plasminogen/plasmin system in thrombosis, hemostasis, restenosis and atherosclerosis.  Trends Cardiovasc Med . 1995;  5 117-122
  • 11 Carmeliet P, Collen D. Development and disease in proteinase-deficient mice: Role of the plasminogen, matrix metalloproteinase and coagulation system.  Thromb Res . 1998;  91 255-286
  • 12 Konigsberg W H, Nemerson Y. Molecular cloning of the cDNA for human tissue factor.  Cell . 1988;  52 639-640
  • 13 Martin D MA, Boys C WG, Ruf W. Tissue factor: Molecular recognition and cofactor function.  FASEB J . 1995;  9 852-859
  • 14 Morrissey J H, Neuenschwander P F, Huang Q. Factor VIIa-tissue factor: Functional importance of protein-membrane interactions.  Thromb Haemost . 1997;  78 112-116
  • 15 Ruf W, Edgington T S. Structural biology of tissue factor, the initiator of thrombogenesis in vivo.  FASEB J . 1994;  8 385-390
  • 16 Gailani D, Broze G J. Factor XI activation in a revised model of blood coagulation.  Science . 1991;  253 909-911
  • 17 Giesen P L, Rauch U, Bohrmann B. Blood-borne tissue factor: Another view of thrombosis.  Proc Natl Acad Sci USA . 1999;  96 2311-2315
  • 18 Holzmuller H, Moll T, Hofer-Warbinek R. A transcriptional repressor of the tissue factor gene in endothelial cells.  Arterioscler Thromb Vasc Biol . 1999;  19 1804-1811
  • 19 Weiss H J, Turitto V T, Baumgartner H R, Nemerson Y, Hoffmann T. Evidence for the presence of tissue factor activity on subendothelium.  Blood . 1989;  73 968-975
  • 20 Contrino J, Hair G, Kreutzer D L, Rickles F R. In situ detection of tissue factor in vascular endothelial cells: Correlation with the malignant phenotype of human breast disease.  Nat Med . 1996;  2 209-215
  • 21 Drake T A, Cheng J, Chang A, Taylor F B. Expression of tissue factor, thrombomodulin, and E-selectin in baboons with lethal Escherichia coli sepsis.  Am J Pathol . 1993;  142 1458-1470
  • 22 Wilcox J N, Smith K M, Schwartz S M, Gordon D. Localization of tissue factor in the normal vessel wall and in the atherosclerotic plaque.  Proc Natl Acad Sci USA . 1989;  86 2839-2843
  • 23 Annex B H, Denning S M, Channon K M. Differential expression of tissue factor protein in directional atherectomy specimens from patients with stable and unstable coronary syndromes.  Circulation . 1995;  91 619-622
  • 24 Kaikita K, Takeya M, Ogawa H. Co-localization of tissue factor and tissue factor pathway inhibitor in coronary atherosclerosis.  J Pathol . 1999;  188 180-188
  • 25 Brand K, Banka C L, Mackman N. Oxidized LDL enhances lipopolysaccharide-induced tissue factor expression in human adherent monocytes.  Arterioscler Thromb . 1994;  14 790-797
  • 26 Taubman M B, Fallon J T, Schecter A D. Tissue factor in the pathogenesis of atherosclerosis.  Thromb Haemost . 1997;  78 200-204
  • 27 Bauer K A. Activation of the factor VII-tissue factor pathway.  Thromb Haemost . 1997;  78 108-111
  • 28 Mulder A B, Smit J W, Blom N R. Association of smooth muscle cell tissue factor with caveolae.  Blood . 1996;  88 1306-1313
  • 29 Lupu C, Goodwin C A, Westmuckett A D. Tissue factor pathway inhibitor in endothelial cells colocalizes with glycolipid microdomains/caveolae. Regulatory mechanism(s) of the anticoagulant properties of the endothelium.  Arterioscler Thromb Vasc Biol . 1997;  17 2964-2974
  • 30 Sevinsky J R, Rao L VM, Ruf W. Ligand-induced protease receptor translocation into caveolae: A mechanism for regulating cell surface proteolysis of the tissue factor-dependent coagulation pathway.  J Cell Biol . 1996;  133 293-304
  • 31 Huang Z-F, Higuchi D, Lasky N, Broze G J. Tissue factor pathway inhibitor gene disruption produces intrauterine lethality in mice.  Blood . 1997;  90 944-951
  • 32 Zhang Y, Deng Y, Wendt T. Intravenous somatic gene transfer with antisense tissue factor restores blood flow by reducing tumor necrosis factor-α-induced tissue factor expression and fibrin deposition in mouse meth-a sarcomas.  J Clin Invest . 1996;  97 2213-2224
  • 33 Bugge T H. Fatal embryonic bleeding events in mice lacking tissue factor, the cell-associated initiator of blood coagulation.  Proc Natl Acad Sci USA . 1996;  93 6258-6263
  • 34 Carmeliet P, Mackman N, Moons L. Role of tissue factor in embryonic blood vessel development.  Nature . 1996;  383 73-75
  • 35 Toomey J R, Kratzer K E, Lasky N M, Stanton J J, Broze G J. Targeted disruption of the murine tissue factor gene results in embryonic lethality.  Blood . 1996;  88 1583-1587
  • 36 Toomey J R, Kratzer K E, Lasky N M, Broze G J. Effect of tissue factor deficiency on mouse and tumor development.  Proc Natl Acad Sci USA . 1997;  94 6922-6926
  • 37 Parry G CN, Erlich J H, Carmeliet P, Luther T, Mackman N. Low levels of tissue factor are compatible with development and hemostasis in mice.  J Clin Invest . 1998;  101 560-569
  • 38 Erlich J, Parry G C, Fearns C. Tissue factor is required for uterine hemostasis and maintenance of the placental labyrinth during gestation.  Proc Natl Acad Sci USA . 1999;  96 8138-8143
  • 39 Clauss M, Grell M, Fangmann C. Synergistic induction of endothelial tissue factor by tumor necrosis factor and vascular endothelial growth factor: Functional analysis of the tumor necrosis factor receptors.  FEBS Lett . 1996;  390 334-338
  • 40 Zhang Y, Deng Y, Luther T. Tissue factor controls the balance of angiogenic and antiangiogenic properties of tumor cells in mice.  J Clin Invest . 1994;  94 1320-1327
  • 41 Rosen E D, Chan J C, Idusogie E. Mice lacking factor VII develop normally but suffer fatal perinatal bleeding.  Nature . 1997;  390 290-294
  • 42 Chan J CY, Carmeliet P, Moons L. Factor VII deficiency rescues the intrauterine lethality in mice associated with a tissue factor pathway inhibitor deficit.  J Clin Invest . 1999;  103 475-482
  • 43 Ruf W, Mueller B M. Tissue factor signaling.  Thromb Haemost . 1999;  82 175-182
  • 44 Edgington T S, Dickinson C D, Ruf W. The structural basis of function of the TF-VIIa complex in the cellular initiation of coagulation.  Thromb Haemost . 1997;  78 401-405
  • 45 Bromberg M E, Sundaram R, Homer R J, Garen A, Konigsberg W H. Role of tissue factor in metastatsis: Functions of the cytoplasmic and extracellular domains of the molecule.  Thromb Haemost . 1999;  82 88-92
  • 46 Zioncheck T F, Roy S, Vehar G A. The cytoplasmic domain of tissue factor is phosphorylated by a protein kinase-C-dependent mechanism.  J Biol Chem . 1992;  267 3561-3564
  • 47 Mueller B M, Reisfeld R A, Edgington T S, Ruf W. Expression of tissue factor by melanoma cells promotes efficient hematogenous metastasis.  Proc Natl Acad Sci USA . 1992;  89 11832-11836
  • 48 Mueller B M, Ruf W. Requirement for binding of catalytically factor VIIa in tissue factor-dependent experimental metastasis.  J Clin Invest . 1998;  101 1372-1378
  • 49 Ott I, Fischer E G, Miyagi Y, Möller B M, Ruf W. A role of tissue factor in cell adhesion and migration mediated by interaction with actin-binding protein 280.  J Cell Biol . 1998;  140 1241-1253
  • 50 Randolph G J, Luther T, Albrecht S, Magdolen V, Muller W A. Role of tissue factor in adhesion of mononuclear phagocytes to and trafficking through endothelium in vitro.  Blood . 1998;  92 4167-4177
  • 51 Brinkman H J, Mertens K, Holthuis J. The activation of human blood coagulation factor X on the surface of endothelial cells: A comparison with various vascular cells, platelets and monocytes.  Br J Haematol . 1994;  87 332-342
  • 52 Stern D M, Knitter G, Kisiel W, Nawroth P P. In vivo evidence of intravascular binding sites for coagulation factor IX.  Br J Haematol . 1987;  66 227-232
  • 53 Tijburg P, Ryan J, Stern D M. Activation of the coagulation mechanism on tumor necrosis factor-stimulated cultured endothelial cells and their extracellular matrix. The role of flow and factor IX/IXa.  J Biol Chem . 1991;  266 12067-12074
  • 54 Cheung W F, van den Born J, Köhn K. Identification of the endothelial cell binding site for factor IX.  Proc Natl Acad Sci USA . 1996;  93 11068-11073
  • 55 Stern D M, Nawroth P P, Kisiel W. A coagulation pathway on bovine aortic segments leading to generation of factor Xa and thrombin.  J Clin Invest . 1984;  74 1910-1921
  • 56 Etingin O R, Silverstein R L, Friedman H M, Hajjar D P. Viral activation of the coagulation cascade: Molecular interactions at the surface of infected endothelial cells.  Cell . 1990;  61 657-662
  • 57 Altieri D C, Etingin O R, Fair D S. Structurally homologous ligand binding of integrin Mac-1 and viral glycoprotein C receptors.  Science . 1991;  254 1200-1202
  • 58 Cui J, O'Shea K S, Purkayastha A, Saunders T L, Ginsburg D. Fatal haemorrhage and incomplete block to embryogenesis in mice lacking coagulation factor V.  Nature . 1996;  384 66-68
  • 59 Nichols W C, Seligsohn U, Zivelin A. Mutations in the ER-Golgi intermediate compartment protein ERGIC-53 cause combined deficiency of coagulation factors V and VIII.  Cell . 1998;  93 61-70
  • 60 Altieri D C. Coagulation assembly on leukocytes in transmembrane signaling and cell adhesion.  Blood . 1993;  81 569-579
  • 61 Altieri D C. Xa receptor EPR-1.  FASEB J . 1995;  9 860-865
  • 62 Bouchard B A, Catcher C S, Thrash B R, Adida C, Tracy P B. Effector cell protease receptor-1, a platelet activation-dependent membrane protein, regulates prothrombinase-catalyzed thrombin generation.  J Biol Chem . 1997;  272 9244-9251
  • 63 Gajdusek C, Carbon S, Ross R, Nawroth P, Stern D. Activation of coagulation releases endothelial cell mitogens.  J Cell Biol . 1986;  103 419-428
  • 64 Altieri D C. Proteases and protease receptors in modulation of leukocyte effector functions.  J Leukoc Biol . 1995;  58 120-127
  • 65 Herbert J M, Bono F, Herault J P. Effector protease receptor 1 mediates the mitogenic activity of factor Xa for vascular smooth muscle cells in vitro and in vivo.  J Clin Invest . 1998;  101 993-1000
  • 66 Cirino G, Cicala C, Bucci M. Factor Xa as an interface between coagulation and inflammation: Molecular mimicry of factor Xa association with effector cell protease receptor-1 induces acute inflammation in vivo.  J Clin Invest . 1997;  99 2446-2451
  • 67 Hattori R, Hamilton K K, Fugate R D, McEver R P, Sims P J. Stimulated secretion of endothelial vWF is accompanied by rapid redistribution to the cell surface of the intracellular granule membrane protein GMP-140.  J Biol Chem . 1989;  264 7768-7771
  • 68 Colotta F, Sciacca F L, Sironi M. Expression of monocyte chemotactic protein-1 by monocytes and endothelial cells exposed to thrombin.  Am J Pathol . 1994;  144 975-985
  • 69 McNamara C A, Sarembock I J, Gimple L W. Thrombin stimulates proliferation of cultured rat aortic smooth muscle cells by a proteolytically activated receptor.  J Clin Invest . 1993;  91 94-98
  • 70 Herbert J M, Dupuy E, Laplace M C. Thrombin induces endothelial cell growth via both a proteolytic and a non-proteolytic pathway.  Biochem J . 1994;  303 227-231
  • 71 Kanthou C, Benzakour O. Cellular effects of thrombin and their signalling pathways.  Cell Pharmacol . 1995;  2 293-302
  • 72 Coughlin S R. Molecular mechanisms of thrombin signaling.  Semin Hematol . 1994;  31 270-277
  • 73 Coughlin S R. Protease-activated receptors and platelet function.  Thromb Haemost . 1999;  82 353-356
  • 74 Scarborough R M, Naughton M A, Teng W. Tethered ligand agonist peptides. Structural requirements for thrombin receptor activation reveal mechanism of proteolytic unmasking of agonist function.  J Biol Chem . 1992;  267 13146-13149
  • 75 Trejo J, Hammes S R, Coughlin S R. Termination of signaling by protease-activated receptor-1 is linked to lysosomal sorting.  Proc Natl Acad Sci USA . 1998;  95 13698-13702
  • 76 Vu T-KV, Hung D T, Wheaton V I, Coughlin S R. Molecular cloning of a functional thrombin receptor reveals a novel proteolytic mechanism of receptor activation.  Cell . 1991;  64 1057-1068
  • 77 Ishihara H, Connolly A J, Zeng D. Protease-activated receptor 3 is a second thrombin receptor in humans.  Nature . 1997;  386 502-506
  • 78 Kahn M L, Zheng Y W, Huang W. A dual thrombin receptor system for platelet activation.  Nature . 1998;  394 690-694
  • 79 Xu W F, Andersen H, Whitmore T E. Cloning and characterization of human protease-activated receptor-4.  Proc Natl Acad Sci USA . 1998;  95 6642-6646
  • 80 Coughlin S R. How the protease thrombin talks to cells.  Proc Natl Acad Sci USA . 1999;  96 11023-11027
  • 81 Connolly A J, Ishihara H, Kahn M L, Farese R V, Coughlin S R. Role of the thrombin receptor in development and evidence for a second receptor.  Nature . 1996;  381 516-519
  • 82 Xue J, Nu Q, Westfield L A. Incomplete embryonic lethality and fatal neonatal hemorrhage caused by prothrombin deficiency in mice.  Proc Natl Acad Sci USA . 1998;  95 7603-7607
  • 83 Suh T T, Holmbäck K, Jensen N J. Resolution of spontaneous bleeding events but failure of pregnancy in fibrinogen-deficient mice.  Genes Dev . 1995;  9 2020-2033
  • 84 Shivdasani R A, Rosenblatt M F, Zucker F D. Transcription factor NF-E2 is required for platelet formation independent of the actions of thrombopoietin/MGDF in megakaryocyte development.  Cell . 1995;  81 695-704
  • 85 Even-Ram S, Uziely B, Cohen P. Thrombin receptor overexpression in malignant and physiological invasion processes.  Nature Med . 1998;  4 909-914
  • 86 Nystedt S, Emilsson K, Wahlestedt C, Sundelin J. Molecular cloning of a potential proteinase activated receptor.  Proc Natl Acad Sci USA . 1994;  91 9208-9212
  • 87 Brass L F, Molino M. Protease-activated G protein-coupled receptors on human platelets and endothelial cells.  Thromb Haemost . 1997;  78 234-241
  • 88 Alm A K, Norstrom E, Sundelin J, Nystedt S. Stimulation of proteinase activated receptor-2 causes endothelial cells to promote blood coagulation in vitro.  Thromb Haemost . 1999;  81 984-988
  • 89 Woolkalis M J, DeMelfi T M, Blanchard N, Hoxie J A, Brass L F. Regulation of thrombin receptors on human umbilical vein endothelial cells.  J Biol Chem . 1999;  270 9868-9875
  • 90 Sambrano G R, Coughlin S R. The carboxyl tail of protease-activated receptor-1 is required for chemotaxis. Correlation of signal termination and directional migration.  J Biol Chem . 1999;  274 20178-20184
  • 91 Molino M, Woolkalis M J, Reavey-Cantwell J. Endothelial cell thrombin receptors and PAR-2. Two protease-activated receptors located in a single cellular environment.  J Biol Chem . 1997;  272 11133-11141
  • 92 Bar-Shavit R, Kahn A, Wilner G D, Fenton J W. Monocyte chemotaxis: Stimulation by specific exosite region in thrombin.  Science . 1983;  220 728-731
  • 93 Bar-Shavit R, Kahn A J, Mann K G, Wilner G D. Identification of a thrombin sequence with growth factor activity on macrophages.  Proc Natl Acad Sci USA . 1986;  83 976-980
  • 94 Bar-Shavit R, Kahn A J, Mann K G, Wilner G D. Growth promoting effects of esterolytically inactive thrombin.  J Cell Biol . 1986;  32 261-272
  • 95 Bar-Shavit R, Sabbah V, Lampugnani M G. An Arg-Gly-Asp sequence within thrombin promotes endothelial cell adhesion.  J Cell Biol . 1991;  112 335-344
  • 96 Bar-Shavit R, Eskohjido Y, Fenton J W, Esko J D, Vlodavsky I. Thrombin adhesive properties: Induction by plasmin and heparan sulfate.  J Cell Biol . 1993;  123 1279-1287
  • 97 Esmon C T. The protein C pathway: new insights.  Thromb Haemost . 1997;  78 70-74
  • 98 Ostrovsky L, Woodman R C, Payne D, Teoh D, Kubes P. Antithrombin III prevents and rapidly reverses leukocyte recruitment in ischemia/reperfusion.  Circulation . 1997;  96 2302-2310
  • 99 Wen D, Dittmann W A, Ye R D. Human thrombomodulin: Complete cDNA sequence and chromosome localization of the gene.  Biochemistry . 1987;  26 4350-4357
  • 100 Suzuki K, Kusumoto H, Deyashiki Y. Structure and expression of human thrombomodulin, a thrombin receptor on endothelium acting as a cofactor for protein C activation.  EMBO J . 1987;  6 1891-1897
  • 101 Parkinson J F, Koyama T, Bang N U, Preissner K T. Thrombomodulin: An anticoagulant cell surface proteoglycan with physiologically relevant glycosaminoglycan moiety. In: Lane DA, Björk I, Lindahl U, eds. Heparin and Related Polysaccharides New York: Plenum, 1992: 177-188
  • 102 Ye J, Esmon C T, Johnson A E. The chondroitin sulfate moiety of thrombomodulin binds a second molecule of thrombin.  J Biol Chem . 1993;  268 2373-2379
  • 103 Preissner K T, Koyama T, Tschopp J, Müller-Berghaus G. Domain structure of the endothelial cell receptor thrombomodulin as deduced from modulation of its anticoagulant functions. Evidence for a glycosaminoglycan-dependent secondary binding site for thrombin.  J Biol Chem . 1990;  265 4915-4922
  • 104 Bourin M C, Lindahl U. Glycosaminoglycans and the regulation of blood coagulation.  Biochem J . 1993;  289 313-330
  • 105 Koyama T, Parkinson J F, Aoki N. Relationship between post-translational glycosylation and anticoagulant function of secretable recombinant mutants of human thrombomodulin.  Br J Haematol . 1991;  78 515-522
  • 106 Esmon C T. Thrombomodulin as a model of molecular mechanism that modulate protease specificity and function at the vessel surface.  FASEB J . 1995;  9 946-955
  • 107 Sadler J E. Thrombomodulin structure and function.  Thromb Haemost . 1997;  78 392-395
  • 108 Conway E M, Pollefeyt S, Collen D, Steiner-Mosonyi M. The amino terminal lectin-like domain of thrombomodulin is required for constitutive endocytosis.  Blood . 1997;  89 652-661
  • 109 Braat E AM, Los P, Rijken D C. The inactivation of single-chain urokinase-type plasminogen activator by thrombin in a plasma milieu:effect of thrombomodulin.  Blood Coagul Fibrinolysis . 1998;  9 419-427
  • 110 Nesheim M, Wang W, Boffa M. Thrombin, thrombomodulin and TAFI in the molecular link between coagulation and fibrinolysis.  Thromb Haemost . 1997;  78 386-391
  • 111 Rezaie A R, Cooper S T, Church F C, Esmon C T. Protein C inhibitor is a potent inhibitor of the thrombin-thrombomodulin complex.  J Biol Chem . 1995;  270 25336-25339
  • 112 Preissner K T. Physiological role of vessel wall related antithrombotic mechanisms: Contribution of endogenous and exogenous heparin-like components to the anticoagulant potential of the endothelium.  Haemostasis . 1990;  20 30-49
  • 113 Haley P E, Doyle M F, Mann K G. The activation of bovine protein C by factor Xa.  J Biol Chem . 1989;  264 16303-16310
  • 114 Wu Q Y, Tsiang M, Lentz S R, Sadler J E. Ligand specificity of human thrombomodulin-equilibrium binding of human thrombin, meizothrombin, and factor Xa to recombinant thrombomodulin.  J Biol Chem . 1992;  267 7083-7088
  • 115 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 USA . 1995;  92 850-854
  • 116 Imada M, Imada S, Iwasaki H. Fetomodulin: Marker surface protein of fetal development which is modulatable by cyclic AMP.  Dev Biol . 1987;  122 483-491
  • 117 Imada S, Yamaguchi H, Nagumo M. Identification of fetomodulin, a surface marker protein of fetal development, as thrombomodulin by gene cloning and functional assays.  Dev Biol . 1990;  140 113-122
  • 118 Maruyama I, Bell C E, Majerus P W. Thrombomodulin is found on endothelium of arteries, veins, capillaries, and lymphatics, and on syncytiotrophoblast of human placenta.  J Cell Biol . 1985;  101 363-371
  • 119 Zhang Y, Weiler-Guettler H. Thrombomodulin modulates growth of tumor cells independent of its anticoagulant activity.  J Clin Invest . 1998;  101 1301-1309
  • 120 Conway E M. Structure-function analyses of thrombomodulin by gene-targeting in mice: The cytoplasmic domain is not required for normal fetal development.  Blood . 1999;  93 3442-3450
  • 121 Fukudome K, Esmon C T. Identification, cloning, and regulation of a novel endothelial cell protein C/activated protein C receptor.  J Biol Chem . 1994;  269 26486-26491
  • 122 Esmon C T. Endothelial protein C receptor.  Thromb Haemost . 1999;  82 251-258
  • 123 Mitro L Z, Taylor F BJ, Ferrell G, Esmon C T. Human protein C receptor is present primarily on endothelium of large blood vessels: Implications for the control of the protein C pathway.  Circulation . 1997;  96 3633-3640
  • 124 Kurosawa S, Stearns-Kurosawa D J, Hidari N, Esmon C T. Identification of functional endothelial protein C receptor in human plasma.  J Clin Invest . 1997;  100 411-418
  • 125 Jalbert L R, Rosen E D, Moons L. Inactivation of the gene for anticoagulant protein C causes lethal perinatal consumptive coagulopathy in mice.  J Clin Invest . 1998;  102 1481-1497
  • 126 Reitsma P H. Protein C deficiency: From gene defects to disease.  Thromb Haemost . 1997;  78 344-350
  • 127 Svensson P J, Dahlbäck B. Resistance to activated protein C as a basis for venous thrombosis.  N Engl J Med . 1994;  330 517-522
  • 128 Bertina R M, Koeleman B PC, Koster T. Mutation in blood coagulation factor V associated with resistance to activated protein C.  Nature . 1994;  369 64-67
  • 129 Öhlin A K, Norlund N, Marlar R A. Thrombomodulin gene variations and thromboembolic disease.  Thromb Haemost . 1997;  78 396-400
  • 130 Borgel D, Gandrille S, Aiach M. Protein S deficiency.  Thromb Haemost . 1997;  78 351-356
  • 131 Taylor J, Chang A, Esmon C T. Protein C prevents the coagulopathic and lethal effects of Escherichia coli infusion in the baboon.  J Clin Invest . 1987;  79 918-925
  • 132 Simmonds R E, Lane D A. Structural and functional implications of the intron/exon organization of the human endothelial cell protein C/activated protein C receptor (EPCR) gene: Comparison with the structure of CD1/major histocompatibility complex alpha1 and alpha2 domains.  Blood . 1999;  94 632-641
  • 133 Esmon C T. They're not just for clots anymore: The idenfication of the blood-clotting inhibitor, protein S, as a ligand for a previously ``orphan'' family of receptor tyrosine kinases demonstrates a new role for clotting and anti-clotting proteins in regulating cell proliferation.  Curr Biol . 1995;  5 743-746
  • 134 Benzakour O, Formstone C, Rahman S. Evidence for a protein S receptor(s) on human vascular smooth muscle cells.  Biochem J . 1995;  308 481-485
  • 135 Manfioletti G, Brancolini C, Avanzi G, Schneider C. The protein encoded by a growth arrest-specific gene (gas6) is a new member of the vitamin K-dependent proteins related to protein S, a negative coregulator in the blood coagulation cascade.  Mol Cell Biol . 1993;  13 4976-4985
  • 136 Stitt T N, Conn G, Gore M. The anticoagulation factor protein S and its relative, Gas6, are ligands for the tyro 3/Axl family of receptor tyrosine kinases.  Cell . 1995;  80 661-670
  • 137 He X, Shen L, Bjartell A, Dahlbäck B. Th gene encoding vitamin K-dependent anticoagulant protein S is expressed in multiple rabbit organs as demonstrated by northern blotting, in situ hybridization, and immunohistochemistry.  J Histochem Cytochem . 1995;  43 85-96
  • 138 Benzakour O, Kanthou C, Kanse S M, Preissner K T. Identification of annexin II as a receptor for the anti-coagulant factor, protein S, in human vascular smooth muscle cells.  Thromb Haemost . 1999;  82(Suppl) 215(Abst)
  • 139 Cesarman G M, Guevara C A, Hajjar K A. An endothelial cell receptor for plasminogen tissue-plasminogen activator (t-PA). 2. Annexin II-mediated enhancement of t-PA-dependent plasminogen activation.  J Biol Chem . 1994;  269 21198-21203
  • 140 Chung C Y, Murphy-Ullrich J E, Erickson H P. Mitogenesis, cell migration, and loss of focal adhesions induced by tenascin-C interacting with its cell surface receptor, annexin II.  Mol Biol Cell . 1996;  7 883-892
  • 141 Dahlbäck B. Interaction between complement component C4b-binding protein and the vitamin K-dependent protein S. A link between blood coagulation and the complement system.  Scand J Clin Lab Invest . 1985;  45 33-41
  • 142 Menell J S, Cesarman G M, Jacovina A T. Annexin II and bleeding in acute promyelocytic leukemia.  N Engl J Med . 1999;  340 994-1004
  • 143 Weiler-Guettler H, Christie P D, Beeler D L. A targeted point mutation in thrombomodulin generates viable mice with a prethrombotic state.  J Clin Invest . 1998;  101 1983-1991
  • 144 Dreyfus M, Magny J F, Bridey F. Treatment of homozygous protein C deficiency and neonatal purpura fulminans with a purified protein C concentrate.  N Engl J Med . 1991;  325 1565-1568
  • 145 Richardson M A, Gerlitz B, Grinnell B W. Enhancing protein C interaction with thrombin results in a clot-activated anticoagulant.  Nature . 1992;  360 261-264
  • 146 O'Reilly M S, Pirie-Shepherd S, Lane W S, Folkman J. Antiangiogenic activity of the cleaved conformation of the serpin antithrombin.  Science . 1999;  285 1926-1928
  • 147 Mansuy I M, van der Putten H, Schmid P. Variable and multiple expression of protease nexin-1 during mouse organogenesis and nervous system development.  Development . 1993;  119 1119-1134
  • 148 Hoffman M, Pratt C W, Brown R L, Church F C. Heparin cofactor II-proteinase reaction products exhibit neutrophil chemoattractant activity.  Blood . 1989;  73 1682-1685
  • 149 Carmeliet P, Moons L, Collen D. Mouse models of angiogenesis, arterial stenosis, atherosclerosis and hemostasis.  Cardiovasc Res . 1998;  39 8-33
  • 150 Degen J L. Haemostatic factors and inflammatory disease.  Thromb Haemost . 1999;  82 858-864
  • 151 Carmeliet P, Moons L, Dewerchin M. Insights in vessel development and vascular disorders using targeted inactivation and transfer of vascular endothelial growth factor, the tissue factor receptor, and the plasminogen system.  Ann NY Acad Sci . 1997;  811 191-206
  • 152 Huang X, Molema G, King S. Tumor infarction in mice by antibody-directed targeting of tissue factor to tumor vasculature.  Science . 1997;  275 547-550