Thromb Haemost 2001; 86(01): 298-307
DOI: 10.1055/s-0037-1616227
Research Article
Schattauer GmbH

Protease-activated Receptors in Vascular Biology

Shaun Coughlin
1   Cardiovascular Research Institute, Departments of Medicine, and Department of Cellular and Molecular Pharmacology University of California, San Francisco, CA, USA
› Author Affiliations
Further Information

Publication History

Publication Date:
12 December 2017 (online)

Summary

G protein-coupled protease-activated receptors (PARs) provide one answer to the question of how coagulation factors and other proteases regulate cellular behaviors. In concert with the coagulation cascade, these receptors provide an elegant mechanism that links mechanical information in the form of tissue injury or vascular leak to cellular responses. Roles for PARs in hemostasis and thrombosis, inflammation, and perhaps even blood vessel development are beginning to emerge. Our current understanding of the role of PARs in platelet and endothelial cell activation and their potential importance in normal and disease states is discussed.

 
  • References

  • 1 Colman RW, Marder VJ, Salzman EW, Hirsh J. Overview of Hemostasis. In: Hemostasis and Thrombosis. Colman RW, Marder VJ, Salzman EW, Hirsh J. eds. Philadelphia: Lippincott; 1994: 3-18.
  • 2 Esmon CT, Fukudome K, Mather T, Bode W, Regan LM, Stearns-Kurosawa DJ, Kurosawa S. Inflammation, sepsis, and coagulation. Haematologica 1999; 84: 254-9.
  • 3 Bevilacqua MP, Gimbrone Jr MA. Inducible endothelial functions in inflammation and coagulation. Semin Thromb Hemost 1987; 13: 425-33.
  • 4 Osterud B. Tissue factor expression by monocytes: regulation and patho-physiological roles. Blood Coagul Fibrinolysis 1998; 9 (Suppl. 01) S9-14.
  • 5 Giesen PL, Rauch U, Bohrmann B, Kling D, Roqué M, Fallon JT, Badimon JJ, Himber J, Riederer MA, Nemerson Y. Blood-borne tissue factor: another view of thrombosis. Proc Natl Acad Sci USA 1999; 96: 2311-5.
  • 6 Coughlin SR. Sol Sherry lecture in thrombosis: how thrombin “talks” to cells: molecular mechanisms and roles in vivo. Arterioscler Thrombos Vasc Biol 1998; 18: 514-8.
  • 7 Davey M, Luscher E. Actions of thrombin and other coagulant and proteolytic enzymes on blood platelets. Nature 1967; 216: 857-8.
  • 8 Brass LF, Manning DR, Cichowski K, Abrams CS. Signaling through G proteins in platelets: to the integrins and beyond. Thromb Haemost 1997; 78: 581-9.
  • 9 Hamberg M, Svensson J, Samuelsson B. Thromboxanes: a new group of biologically active compounds derived from prostaglandin endoperoxides. Proc Natl Acad Sci USA 1975; 72: 2994-8.
  • 10 Stenberg PE, McEver RP, Shuman MA, Jacques YV, Bainton DF. A platelet alpha-granule membrane protein (GMP-140) is expressed on the plasma membrane after activation. J Cell Biol 1985; 101: 880-6.
  • 11 Henn V, Slupsky JR, Gräfe M, Anagnostopoulos I, Förster R, MüllerBerghaus G, Kroczek RA. CD40 ligand on activated platelets triggers an inflammatory reaction of endothelial cells. Nature 1998; 391: 591-4.
  • 12 Hughes PE, Pfaff M. Integrin affinity modulation. Trends Cell Biol 1998; 8: 359-64.
  • 13 Sims PJ, Wiedmer T, Esmon CT, Weiss HJ, Shattil SJ. Assembly of the platelet prothrombinase complex is linked to vesiculation of the platelet plasma membrane. J Biol Chem 1989; 264: 17049-57.
  • 14 Hattori R, Hamilton KK, Fugate RD, McEver RP, Sims PJ. Stimulated secretion of endothelial von Willebrand factor is accompanied by rapid redistribution to the cell surface of the intracellular granule membrane protein GMP-140. J Biol Chem 1989; 264: 7768-71.
  • 15 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.
  • 16 Frenette PS, Mayadas TN, Rayburn H, Hynes RO, Wagner DD. Susceptibility to infection and altered hematopoiesis in mice deficient in both P- and E-selectins. Cell 1996; 84: 563-74.
  • 17 Lum H, Malik AB. Regulation of vascular endothelial barrier function. Am J Physiol 1994; 267: L223-41.
  • 18 Cirino G, Cicala C, Bucci MR, Sorrentino L, Maraganore JM, Stone SR. Thrombin functions as an inflammatory mediator through activation of its receptor. J Exp Med 1996; 183: 821-7.
  • 19 Coughlin SR. How the protease thrombin talks to cells. Proc Natl Acad Sci USA 1999; 96: 11023-7.
  • 20 Vu T-KH, Hung DT, Wheaton VI, Coughlin SR. Molecular cloning of a functional thrombin receptor reveals a novel proteolytic mechanism of receptor activation. Cell 1991; 64: 1057-68.
  • 21 Rasmussen UB, Vouret-Craviari V, Jallat S, Schlesinger Y, Pagers G, Pavirani A, Lecocq JP, Pouyssegur J, Van Obberghen-Schilling E. cDNA cloning and expression of a hamster alpha-thrombin receptor coupled to Ca2+ mobilization. FEBS Letts 1991; 288: 123-8.
  • 22 Chen J, Ishii M, Wang L, Ishii K, Coughlin SR. Thrombin receptor activation: Confirmation of the intramolecular tethered liganding hypothesis and discovery of an alternative intermolecular liganding mode. J Biol Chem 1994; 269: 16041-5.
  • 23 O’Brien PJ, Prevost N, Molino M, Hollinger MK, Woolkalis MJ, Woulfe DS, Brass LF. Thrombin responses in human endothelial cells. Contributions from receptors other than PAR1 include the transactivation of PAR2 by thrombin-cleaved PAR1. J Biol Chem 2000; 275: 13502-9.
  • 24 Offermanns S, Toombs CF, Hu YH, Simon MI. Defective platelet activation in G alpha(q)-deficient mice. Nature 1997; 389: 183-6.
  • 25 Klages B, Brandt U, Simon MI, Schultz G, Offermanns S. Activation of G12/G13 results in shape change and rho/rho kinase-mediated myosin light chain phosphorylation in mouse platelets. J Cell Biol 1999; 144: 745-54.
  • 26 Yang J, Wu J, Kowalska MA, Dalvi A, Prevost N, O’Brien PJ, Manning D, Poncz M, Lucki I, Blendy JA, Brass LF. Loss of signaling through the G protein, Gz, results in abnormal platelet activation and altered responses to psychoactive drugs. Proc Natl Acad Sci USA 2000; 97: 9984-9.
  • 27 Lefkowitz RJ, Pitcher J, Krueger K, Daaka Y. Mechanisms of beta-adrenergic receptor desensitization and resensitization. Adv Pharmacol 1998; 42: 416-20.
  • 28 Hoxie JA, Ahuja M, Belmonte E, Pizarro S, Parton R, Brass LF. Internalization and recycling of activated thrombin receptors. J Biol Chem 1993; 268: 13756-63.
  • 29 Ishii K, Chen J, Ishii M, Koch WJ, Freedman NJ, Lefkowitz RJ, Coughlin SR. Inhibition of thrombin receptor signaling by a G protein-coupled receptor kinase. Functional specificity among G protein-coupled receptor kinases. J Biol Chem 1994; 269: 1125-30.
  • 30 Hein L, Ishii K, Coughlin SR, Kobilka BK. Intracellular targeting and trafficking of thrombin receptors: a novel mechanism for resensitization of a G protein-coupled receptor. J Biol Chem 1994; 269: 27719-26.
  • 31 Trejo J, Hammes SR, Coughlin SR. Termination of signaling by protease-activated receptor-1 is linked to lysosomal sorting. Proc Natl Acad Sci USA 1998; 95: 13698-702.
  • 32 Trejo J, Coughlin SR. The cytoplasmic tails of protease-activated receptor-1 and substance P receptor specify sorting to lysosomes versus recycling. J Biol Chem 1999; 274: 2216-24.
  • 33 Ishii K, Hein L, Kobilka B, Coughlin SR. Kinetics of thrombin receptor cleavage on intact cells. Relation to signaling. J Biol Chem 1993; 268: 9780-6.
  • 34 Hammes SR, Coughlin SR. Protease-activated receptor-1 can mediate responses to SFLLRN in thrombin-desensitized cells: evidence for a novel mechanism for preventing or terminating signaling by PAR1′s tethered ligand. Biochemistry 1999; 38: 2486-93.
  • 35 Bernatowicz MS, Klimas CE, Hartl KS, Peluso M, Allegretto NJ, Seiler SM. Development of potent thrombin receptor antagonist peptides. J Med Chem 1996; 39: 4879-87.
  • 36 Andrade-Gordon P, Maryanoff BE, Derian CK, Zhang HC, Addo MF, Darrow AL, Eckardt AJ, Hoekstra WJ, McComsey DF, Oksenberg D, Reynolds EE, Santulli RJ, Scarborough RM, Smith CE, White KB. Design, synthesis, and biological characterization of a peptide-mimetic antagonist for a tethered-ligand receptor. Proc Natl Acad Sci USA 1999; 96: 12257-62.
  • 37 Quinn MJ, Fitzgerald DJ. Ticlopidine and clopidogrel. Circulation 1999; 100: 1667-72.
  • 38 Savi P, Pereillo JM, Uzabiaga MF, Combalbert J, Picard C, Maffrand JP, Pascal M, Hebert JM. Identification and biological activity of the active metabolite of clopidogrel. Thromb Haemost 2000; 84: 891-6.
  • 39 Ishihara H, Connolly AJ, Zeng D, Kahn ML, Zheng YW, Timmons C, Tram T, Coughlin SR. Protease-activated receptor 3 is a second thrombin receptor in humans. Nature 1997; 386: 502-6.
  • 40 Xu WF, Andersen H, Whitmore TE, Presnell SR, Yee DP, Ching A, Gilbert T, Davie EW, Foster DC. Cloning and characterization of human protease-activated receptor 4. Proc Natl Acad Sci USA 1998; 95: 6642-6.
  • 41 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.
  • 42 Nystedt S, Emilsson K, Wahlestedt C, Sundelin J. Molecular cloning of a potential novel proteinase activated receptor. Proc Natl Acad Sci USA 1994; 91: 9208-12.
  • 43 Molino M, Barnathan ES, Numerof R, Clark J, Dreyer M, Cumashi A, Hoxie JA, Schechter N, Woolkalis M, Brass LF. Interactions of mast cell tryptase with thrombin receptors and PAR-2. J Biol Chem 1997; 272: 4043-9.
  • 44 Camerer E, Røttingen JA, Iversen JG, Prydz H. Coagulation factors VII and X induce Ca2+ oscillations in Madin-Darby canine kidney cells only when proteolytically active. J Biol Chem 1996; 271: 29034-42.
  • 45 Camerer E, Huang W, Coughlin SR. Tissue factor- and Factor X-dependent activation of PAR2 by Factor VIIa. Proc Natl Acad Sci USA 2000; 97: 5255-60.
  • 46 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.
  • 47 Kahn ML, Nakanishi-Matsui M, Shapiro MJ, Ishihara H, Coughlin SR. Protease-activated receptors 1 and 4 mediate activation of human platelets by thrombin. J Clin Invest 1999; 103: 879-87.
  • 48 Hung DT, Vu TK, Wheaton VI, Ishii K, Coughlin SR. Cloned platelet thrombin receptor is necessary for thrombin-induced platelet activation. J Clin Invest 1992; 89: 1350-3.
  • 49 Brass LF, Vassallo RJ, Belmonte E, Ahuja M, Cichowski K, Hoxie JA. Structure and function of the human platelet thrombin receptor. Studies using monoclonal antibodies directed against a defined domain within the receptor N terminus. J Biol Chem 1992; 267: 13795-8.
  • 50 Selak MA, Chignard M, Smith JB. Cathepsin G is a strong platelet agonist released by neutrophils. Biochem J 1988; 251: 293-9.
  • 51 Sambrano GR, Huang W, Faruqi T, Mahrus S, Craik C, Coughlin SR. Cathepsin G activates protease-activated receptor-4 in human platelets. J Biol Chem 2000; 275: 6819-23.
  • 52 Shapiro MJ, Weiss EJ, Faruqi TR, Coughlin SR. Protease-activated receptors 1 and 4 are shutoff with distinct tempos after activation by thrombin. J Biol Chem 2000; 275: 25216-21.
  • 53 Covic L, Gresser AL, Kuliopulos A. Biphasic kinetics of activation and signaling for PAR1 and PAR4 thrombin receptors in platelets. Biochemistry 2000; 39: 5458-67.
  • 54 Kahn ML, Zheng Y-W, 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.
  • 55 Faruqi TR, Weiss EJ, Shapiro MJ, Hung W, Coughlin SR. Structure-function analysis of protease-activated receptor-4 tethered tigand peptides: Determinants of specificity and utility in assays of receptor function. J Biol Chem 2000; 275: 19728-34.
  • 56 Okamura T, Hasitz M, Jamieson GA. Platelet glycocalicin: interaction with thrombin and role as thrombin receptor on the platelet surface. J Biol Chem 1978; 253: 3435-43.
  • 57 Andrews RK, Shen Y, Gardiner EE, Dong JF, López JA, Berndt MC. The glycoprotein Ib-IX-V complex in platelet adhesion and signaling. Thromb Haemost 1999; 82: 357-64.
  • 58 Ware J, Russell SR, Vicente V, Scharf RE, Tomer A, McMillan R, Ruggeri ZM. Nonsense mutation in the glycoprotein Ib alpha coding sequence associated with Bernard-Soulier syndrome. Proc Natl Acad Sci USA 1990; 87: 2026-30.
  • 59 De Marco L, Mazzucato M, Fabris F, De Roia D, Coser P, Girolami A, Vicente V, Ruggeri ZM. Variant Bernard-Soulier syndrome type bolzano. A congenital bleeding disorder due to a structural and functional abnormality of the platelet glycoprotein Ib-IX complex. J Clin Invest 1990; 86: 25-31.
  • 60 De Marco L, Mazzucato M, Masotti A, Fenton JWd, Ruggeri ZM. Function of glycoprotein Ib alpha in platelet activation induced by alpha-thrombin. J Biol Chem 1991; 266: 23776-83.
  • 61 Ruggeri ZM. The platelet glycoprotein Ib-IX complex. Prog Hemost Thromb 1991; 10: 35-68.
  • 62 De Marco L, Mazzucato M, Masotti A, Ruggeri ZM. Localization and characterization of an alpha-thrombin-binding site on platelet glycoprotein Ib alpha. J Biol Chem 1994; 269: 6478-84.
  • 63 De Candia E, Hall SW, Rutella S, Landolfi R, Andrews RK, De Cristofaro R. Binding of thrombin to glycoprotein Ib accelerates the hydrolysis of PAR-1 on intact platelets. J Biol Chem 2001; 276: 4692-8.
  • 64 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.
  • 65 Connolly TM, Condra C, Feng DM, Cook JJ, Stranieri MT, Reilly CF, Nutt RF, Gould RJ. Species variability in platelet and other cellular responsiveness to thrombin receptor-derived peptides. Thromb Haemost 1994; 72: 627-33.
  • 66 Derian CK, Santulli RJ, Tomko KA, Haertlein BJ, Andrade-Gordon P. Species differences in platelet responses to thrombin and SFLLRN. Receptor-mediated calcium mobilization and aggregation and regulation by protein kinases. Thromb Res 1995; 6: 505-19.
  • 67 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.
  • 68 Zimmerman GA, Elstad MR, Lorant DE, McLntyre TM, Prescott SM, Topham MK, Weyrich AS, Whatley RE. Platelet-activating factor (PAF): signalling and adhesion in cell-cell interactions. Adv Exp Med Biol 1996; 416: 297-304.
  • 69 Johnson K, Choi Y, DeGroot E, Samuels I, Creasey A, Aarden L. Potential mechanisms for a proinflammatory vascular cytokine response to coagulation activation. J Immunol 1998; 160: 5130-5.
  • 70 Cunningham MA, Rondeau E, Chen X, Coughlin SR, Holdsworth SR, Tipping PG. Protease-activated receptor 1 mediates thrombin-dependent, cell-mediated renal inflammation in crescentic glomerulonephritis. J Exp Med 2000; 191: 455-62.
  • 71 Lindner JR, Kahn ML, Coughlin SR, Sambrano GR, Schauble E, Bernstein D, Foy D, Hafezi-Moghadam A, Ley K. Delayed onset of inflammation in protease-activated receptor-2-deficient mice. J Immunol 2000; 165: 6504-10.
  • 72 Shivdasani RA, Rosenblatt MF, Zucker FD, Jackson CW, Hunt P, Saris CJ, Orkin SH. Transcription factor NF-E2 is required for platelet formation independent of the actions of thrombopoietin/MGDF in megakaryocyte development. Cell 1995; 81: 695-704.
  • 73 Bugge TH, Xiao Q, Kombrinck KW, Flick MJ, Holmbäck 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.
  • 74 Carmeliet P, Mackman N, Moons L, Luther T, Gressens P, Van Vlaenderen I, Demunck H, Kasper M, Breier G, Evrard P, Müller M, Risau W, Edgington T, Collen D. Role of tissue factor in embryonic blood vessel development. Nature 1996; 383: 73-5.
  • 75 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.
  • 76 Sun WY, Witte DP, Degen JL, Colbert MC, Burkart MC, Holmbäck 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.
  • 77 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.
  • 78 Tsopanoglou NE, Maragoudakis ME. On the mechanism of thrombin-induced angiogenesis. Potentiation of vascular endothelial growth factor activity on endothelial cells by up-regulation of its receptors. J Biol Chem 1999; 274: 23969-76.
  • 79 Coughlin SR. Thrombin signalling and protease-activated receptors. Nature 2000; 407: 258-64.
  • 80 Vu T-KH, Wheaton VI, Hung DT, Coughlin SR. Domains specifying thrombin-receptor interaction. Nature 1991; 353: 674-7.
  • 81 Liu L, Vu T-KH, Esmon CT, Coughlin SR. The region of the thrombin receptor resembling hirudin binds to thrombin and alters enzyme specificity. J Biol Chem 1991; 266: 16977-80.
  • 82 Mathews II, Padmanabhan KP, Ganesh V, Tulinsky A, Ishii M, Chen J, Turck CW, Coughlin SR, Fenton JW. 2nd. Crystallographic structures of thrombin complexed with thrombin receptor peptides: existence of expected and novel binding modes. Biochemistry 1994; 33: 3266-79.
  • 83 Hung DT, Wong YH, Vu T-KH, Coughlin SR. The cloned platelet thrombin receptor couples to at least two distinct effectors to stimulate both phosphoinositide hydrolysis and inhibit adenylyl cyclase. J Biol Chem 1992; 353: 20831-4.
  • 84 Offermanns S, Laugwitz K-L, Spicher K, Schultz G. G proteins of the G12 family are activated via thromboxane A2 and thrombin receptors in human platelets. Proc Natl Acad Sci USA 1994; 91: 504-8.
  • 85 Barr AJ, Brass LF, Manning DR. Reconstitution of receptors and GTP-binding regulatory proteins (G proteins) in Sf9 cells. A direct evaluation of selectivity in receptor. G protein coupling. J Biol Chem 1997; 272: 2223-9.
  • 86 Kozasa T, Jiang X, Hart MJ, Sternweis PM, Singer WD, Gilman AG, Bollag G, Sternweis PC. p115 RhoGEF, a GTPase activating protein for Galpha12 and Galpha13. Science 1998; 280: 2109-11.
  • 87 Hart MJ, Jiang X, Kozasa T, Roscoe W, Singer WD, Gilman AG, Sternweis PC, Bollag G. Direct stimulation of the guanine nucleotide exchange activity of p115 RhoGEF by Galpha13. Science 1998; 280: 2112-4.
  • 88 Fukuhara S, Murga C, Zohar M, Igishi T, Gutkind JS. A novel PDZ domain containing guanine nucleotide exchange factor links heterotrimeric G proteins to Rho. J Biol Chem 1999; 274: 5868-79.
  • 89 Vouret-Craviari V, Boquet P, Pouysségur J, Van Obberghen-Schilling E. Regulation of the actin cytoskeleton by thrombin in human endothelial cells: role of Rho proteins in endothelial barrier function. Molec Biol Cell 1998; 9: 2639-53.
  • 90 Offermanns S, Mancino V, Revel J-P, Simon MI. Vascular system defects and impaired cell chemokinesis as a result of Gα13 deficiency. Science 1997; 275: 533-6.
  • 91 Taylor S, Chae H, Rhee S-G, Exton J. Activation of the B1 isozyme of phospholipase C by a subunits of the Gq class of G proteins. Nature 1991; 350: 516-8.
  • 92 Stoyanov B, Volinia S, Hanck T, Rubio I, Loubtchenkov M, Malek D, Stoyanova S, Vanhaesebroeck B, Dhand R, Nürnberg B. et al. Cloning and characterization of a G protein-activated human phosphoinositide-3 kinase. Science 1995; 269: 690-3.
  • 93 Clapham DE, Neer EJ. G protein beta gamma subunits. Ann Rev Pharmacol Toxicol 1997; 37: 167-203.
  • 94 Leevers SJ, Vanhaesebroeck B, Waterfield MD. Signalling through phosphoinositide 3-kinases: the lipids take centre stage. Curr Opin Cell Biol 1999; 11: 219-25.
  • 95 Prenzel N, Zwick E, Daub H, Leserer M, Abraham R, Wallasch C, Ullrich A. EGF receptor transactivation by G-protein-coupled receptors requires metalloproteinase cleavage of proHB-EGF. Nature 1999; 402: 884-8.
  • 96 Ali H, Tomhave ED, Richardson RM, Haribabu B, Snyderman R. Thrombin primes responsiveness of selective chemoattractant receptors at a site distal to G protein activation. J Biol Chem 1996; 271: 3200-6.
  • 97 Colotta F, Sciacca FL, Sironi M, Luini W, Rabiet MJ, Mantovani A. Expression of monocyte chemotactic protein-1 by monocytes and endothelial cells exposed to thrombin. Am J Pathol 1994; 144: 975-85.
  • 98 Ueno A, Murakami K, Yamanouchi K, Watanabe M, Kondo T. Thrombin stimulates production of interleukin-8 in human umbilical vein endothelial cells. Immunology 1996; 88: 76-81.
  • 99 Palabrica T, Lobb R, Furie BC, Aronovitz M, Benjamin C, Hsu YM, Sajer SA, Furie B. Leukocyte accumulation promoting fibrin deposition is mediated in vivo by P-selectin on adherent platelets. Nature 1992; 359: 848-51.
  • 100 Nystedt S, Ramakrishnan V, Sundelin J. The proteinase-activated receptor 2 is induced by inflammatory mediators in human endothelial cells. Comparison with the thrombin receptor. J Biol Chem 1996; 271: 14910-5.
  • 101 Esmon CT. Introduction: are natural anticoagulants candidates for modulating the inflammatory response to endotoxin?. Blood 2000; 95: 1113-6.
  • 102 Inbal A, Kenet G, Zivelin A, Yermiyahu T, Bronstein T, Sheinfeld T, Tamari H, Gitel S, Eshel G, Duchemin J, Aiach M, Seligsohn U. Purpura fulminans induced by disseminated intravascular coagulation following infection in 2 unrelated children with double heterozygosity for factor V Leiden and protein S deficiency. Thromb Haemost 1997; 77: 1086-9.