Novel antithrombotics based on modulation of the protein C pathway

Coronary Artery Disease

Volumn 9, Issue 2-3, 1998, Pages 89-97

  Grinnell, Brian W ^a   Betty Yan, S ^a  

^a ELI LILLY AND COMPANY   (United States)

Author keywords

Antithrombotics; Coagulation; Protein C; Thrombin; Thrombomodulin

Indexed keywords

ACTIVATED PROTEIN C; ANTICOAGULANT AGENT; NEW DRUG; PROTEIN C; THROMBIN DERIVATIVE; THROMBOMODULIN;

PRIORITY JOURNAL; REVIEW;

EID: 15144361590     PISSN: 09546928     EISSN: None     Source Type: Journal    
DOI: 10.1097/00019501-199802000-00005     Document Type: Review

References (137)

1. Esmon CT. Molecular events that control the protein C anticoagulant pathway. Thromb Haemost 1993, 70:29-35.
2. Esmon CT. The protein C anticoagulant pathway. Arterioscler Thromb 1992, 12:135-145.
3. Walker FJ. Protein S and thrombotic diseases. Proc Soc Exp Biol Med 1992, 200:285-295.
4. Furie B, Furie BC. Molecular and cellular biology of blood coagulation. N Engl J Med 1992, 326:800-806.
5. Clouse LH, Comp PC. The regulation of hemostasis: the protein C system. N Engl J Med 1986, 314:1298-1304.
6. Yan SB, Grinnell BW. Recombinant human protein C, protein S and thrombomodulin as antithrombotics. Perspect Drug Discov Design 1994, 1:503-520.
7. Yan SB, Grinnell BW. Antithrombotic and anti-inflammatory agents of the protein C anticoagulant pathway. Annu Rep Med Chem 1994, 11:103-112.
8. Esmon CT, Taylor FB, Snow TR. Inflammation and coagulation: linked processes potentially regulated through a common pathway mediated by protein C. Thromb Haemost 1991, 66:160-165.
9. Esmon CT, Schwarz HP. An update on clinical and basic aspects of the protein C anticoagulant pathway. Trends Cardiovasc Med 1995, 5:141-148.
10. Grinnell BW, Berg DT, Walls J, Yan SB. Trans-activated expression of fully gamma-carboxylated recombinant human protein C, an antithrombotic factor. Biotechnology 1987, 5:1189-1192.
11. Grinnell BW, Berg DT, Walls J, Yan SB. Expression and characterization of fully functional recombinant human protein C from the human kidney cell line 293. In: Suttie JW, editor. Current advances in vitamin K research. New York: Elsevier Science Publishing Company; 1988. pp. 191-198.
12. Yan SCB, Grinnell BW, Wold F. Post-translational modifications of protein: some problems left to solve. Trends Biochem Sci 1989, 14:264-268.
13. Yan SB, Razzano P, Chao YB, Walls JD, Berg DT, McClure DB, et al. Characterization and novel purification of recombinant human protein C from three mammalian cell lines. Biotechnology 1990, 8:655-661.
14. Grinnell BW, Walls JD, Gerlitz B, Berg DT, McClure DB, Ehrlich H, et al Native and modified recombinant human protein C. Function secretion and posttranslational modifications. In: Bruley D, Drohan W, editors. Protein C and related anticoagulants. Houston: Gulf Publishing Co.; 1990. pp. 13-46.
15. Berg DT, McClure DB, Grinnell BW. High-level expression of secreted proteins from cell adapted to serum-free suspension culture. Biotechnology 1993, 6:972-978.
16. Berg DT, McClure DB, Grinnell BW. E1a-responsive mammalian host/vector system for the stable high-level expression of secreted proteins. Nucl Acids Res 1992, 20:5485-5486.
17. Walls JD, Berg DT, Yan SB, Grinnell BW. Amplification of multicistronic plasmids in the human 293 cell line and secretion of correctly processed recombinant human protein C. Gene 1989, 81:139-149.
18. Berg DT, McClure DB, Walls JD, Yan SB, Grinnell BW. Viral transformation increases vitamin K-dependent gamma-carboxylation of glutamate. Exp Cell Res 1991, 192:32-40.
19. McClure DB, Walls JD, Grinnell BW. Post-translational processing events in the secretion pathway of human protein C, a complex vitamin K-dependent antithrombotic factor. J Biol Chem 1992, 267:19710-19717.
20. Gerlitz B, Parkinson JF, Bang NU, Grinnell BW. Effect of mutation of Asp71 on human protein C activation and function. J Cell Biochem 1990, 14E:201.
21. Grinnell BW, Walls JD, Gerlitz B. Glycosylation of human protein C affects its secretion, processing, functional actvities and activation by thrombin. J Biol Chem 1991, 226:9778-9785.
22. Grinnell BW, Hermann RB, Yan SB. Human protein C inhibits selectin-mediated cell adhesion. Role of unique fucosylated oligosaccharide. Glycobiology 1994, 4:221-225.
23. Gruber A, Hanson SR, Kelly AW, Yan SB, Bang N, Griffin JH, et al. Inhibition of thrombus formation by activated recombinant protein C in a primate model of arterial athrombosis. Circulation 1990, 82:578-585.
24. Yan SB, Chao YB, vanHalbeek H. Novel Asn-linked oligosaccharides terminating in GalNAcb(1-4)[Fuca(1-3)]GalNAcb(1-2) are present in recombinant human protein C expressed in human kidney 293 cells. Glycobiology 1993, 3:597-608.
25. Gruber A, Griffin JH, Harker LA, Hanson SR. Inhibition of platelet-dependent thrombus formation by human activated protein C in a primate model. Blood 1989, 73:639-642.
26. Hanson SR, Griffin JH, Harker LA, Kelly AB, Esmon CT, Gruber A. Antithrombotic effects of thrombin-induced activation of endogenous protein C in primates. J Clin Invest 1993, 92:2003-2012.
27. Araki H, Nishi K, Ishihara N, Okajima K. Inhibitory effects of activated protein C and heparin on thrombotic arterial occlusion in rat mesenteric arteries. Thrombosis Res 1991, 62:209-216.
28. Arnlijots B, Bergqvist D, Dahlback B. Inhibition of microarterial thrombosis by bovine activated protein C in a rabbit model. Thromb Haemost 1993, 69:[Abstract 161].
29. Romisch J, Diehl K-H, Reiner G, Paques E-P. Activated protein C: antithrombotic properties and influence on fibrinolysis in an animal model. Fibrinolysis 1991, 5:191-196.
30. Krishnamurti C, Young GD, Barr CF, Colleton CA, Alving BM. Enhancement of tissue plasminogen activator-induced fibrinolysis by activated protein C in endotoxin-treated rabbits. J Lab Clin Med 1991, 118:523-530.
31. Gruber A, Harker LA, Hanson SR, Kelly AB, Griffin JH. Antithrombotic effects of combining activated protien C and urokinase in nonhuman primates. Circulation 1991, 84:2454-2462.
32. Oda Y, Tsumoto K, Mizokami H. Inhibitory effect of activated protein C on the experimental cerebral infarction in rabbits. Thromb Haemost 1993, 69:[Abstract 665].
33. Snow TR, Deal MT, Dickey DT, Esmon CT. Protein C activation following coronary artery occlusion in the in situ porcine heart. Circulation 1991, 84:293-299.
34. Emerick SC, Murayama H, Yan SB, Long GL, Harms CS, Marks CA, et al. Preclinical pharmacology of activated protein C. In: Holcenberg JS and Winkelhake JL (editors) The pharmacology and toxicology of proteins. New York: Anal R. Liss, Inc.; 1987. pp. 351-367.
35. Wakefield TW, Wrobleski SK, Sarpa MS, Taylor FB, Esmon CT, Cheng A, et al. Deep venous thrombosis in the baboon: an experimental model. J Vasc Surg 1991, 4:588-598.
36. Dreyfus M, Masterson M, David M, Rivard GE, Muller F, Kreuz W, et al. Replacement therapy with a monoclonal antibody purified protein C concentrate in newborns with severe congenital protein C deficiency. Semin Thromb Hemost 1995, 21:371-381.
37. Muller FM, Ehrenthal W, Hafner G, Schranz D. Purpura fulminans in severe congenital protein C deficiency: monitoring of treatment with protein C concentrate. Eur J Pediatr 1996, 155:20-25.
38. Gibaldi M. Anatomy of an antibody, and related misadventures in developing an effective treatment for septic shock. Pharmacotherapy 1993, 13:302-308.
39. Quezado ZM, Natanson C, Ailing DW, Banks SM, Koev CA, Elin RJ, et al. A controlled trial of HA-1A in a canine model of Gram-negative septic shock. JAMA 1993, 269:2221-2227.
40. Natanson C. Anti-inflammatory therapies to treat sepsis and septic shock: a reassessment. Crit Care Med 1997, 25:1095-1100.
41. van der Poll T, Coyle SM, Levi M, Jansen PM, Dentener M, Barbosa K, et al. Effect of a recombinant dimeric tumor necrosis factor receptor on inflammatory responses to intravenous endotoxin in normal humans. Blood 1997, 89:3727-3734.
42. Levi M, ten Cate H, van der Poll T, van Deventer SJH. Pathogenesis of disseminated intravascular coagulation in sepsis. JAMA 1993, 270:975-979.
43. Carvalho AC, Freeman NJ. How coagulation defects alter outcome in sepsis. survival may depend on reversing procoagulant conditions. J Crit Illness 1994, 9:51-75.
44. Roman J, Velasco F, Fernandez F, Fernandez M, Villalba R, Rubio V, et al. Protein C, protein S and C4b-binding protein in neonatal severe infection and septic shock. J Perinat Med 1992, 20:111-116.
45. Fourrier F, Chopin C, Goudemand J, Hendrycx S, Caron C, Rime A, et al. Septic shock, multiple organ failure and disseminated intravascular coagulation: compared patterns of antighrombin III, protein C and protein S deficiencies. Chest 1992, 101:816-823.
46. Hesselvik JF, Malm J, Dahlback B, Blomback M. Protein C, protein S and C4b-binding protein in severe infection and septic shock. Thromb Haemost 1991, 65:126-129.
47. Leclerc F, Hazelzet J, Jude B, Hofhuis W, Hue V, Martinot A, et al. Protein C and S deficiency in severe infectious purpura of children: a collaborative study of 40 cases. Intens Care Med 1992, 18: 202-205.
48. Alcaraz A, Espana F, Sanchez-Cuenaca J, Zuazu I, Estelles A, Aznar J, et al. Activation of the protein C pathway in acute sepsis. Thromb Res 1995, 79:83-93.
49. Fijnvandraat K, Derkx B, Peters M, Bijlmer R, Sturk A, Prins MH, et al. Coagulation activation and tissue necrosis in meningococcal septic shock: severely reduced protein C levels predict a high mortality. Thromb Haemost 1995, 73:15-20.
50. Massignon D, Lepape A, Bienvenu J, Barbier Y, Boileau C, Caeur P. Coagulation/fibrinolysis balance in septic shock related to cytokines and clinical state. Haemostasis 1994, 24:36-48.
51. Wuillemin WA, Fijnvandraat K, Derkx BHF, Peters M, Vreede W, ten Cate H, et al. Activation of the intrinsic pathway of coagulation in children with meningococcal septic shock. Thromb Haemost 1995, 74:1436-1441.
52. Mesters RM, Mannucci PM, Coppola R, Keller T, Ostermann H, Kienast J. Factor VIIa and antithrombin III activity during severe sepsis and septic shook in neutropenic patients. Blood 1996, 88:881-886.
53. Taylor FB, Chang A, Ferrell G, Mather T, Catlett R, Blick K, et al. C4b-binding protein exacerbates the host response to E. coli. Blood 1991, 78:357-363.
54. Drake TA, Cheng J, Chang A, Taylor FB. Expression of tissue factor, thrombomodulin and E-selectin in baboons with lethal E. coli sepsis. Am J Pathol 1993, 142:1458-1470.
55. Taylor FB, Chang A, Hinshaw LB, Esmon CT, Archer LT, Belter BK. A model for thrombin protection against endotoxin. Thromb Res 1984, 36:177-185.
56. Moore KL, Esmon CT, Esmon NL. Tumor necrosis factor leads to the internalization and degradation of thrombomodulin from the surface of bovine aortic endothelial cells in culture. Blood 1989, 73:159-165.
57. Hancock WW, Tanaka K, Salem HH, Tilney NL, Atkins RC, Kupiec-Weglinski JW. TNF as a mediator of cardiac transplant rejection, including effects on the intragraft protein C/protein S/thrombomodulin pathway. Transplant Proc 1991, 23:235-237.
58. Taylor FB, Chank A, Esmon CT, D'Angelo A, Vigano-D'Angelo S, Blick FE. Protein C prevents the coagulopathic and lethal effects of E. coli infusion in the baboon. J Clin Invest 1987, 79:918-925.
59. Taylor FB, Chang ACK, Peer GT, Mather T, Blick K, Catlett R, et al. DEFR-factor Xa blocks disseminated intravascular coagulation initiated by E. coli without preventing shock or organ damage. Blood 1991, 78:364-368.
60. Taylor FB, Chang A, Ruf W, Morrissey JH, Hinshaw L, Catlett R, et al. Lethal E. coli septic shock is prevented by blocking tissue factor with monoclonal antibody. Circ Shock 1991, 33:127-134.
61. Hairo WD, Ruby EI, Gordon BG, Patil KD, Stephens LC, Kotulak GD, et al. Multiple organ dysfunction syndrome in bone marrow transplantation. JAMA 1995, 274:1289-1295.
62. Rivard GE, David M, Farrell C, Schwarz HP. Treatment of purpura fulminans in meningococcemia with protein C concentrate. J Pediatr 1995, 126:646-652.
63. Rintala E, Seppala O, Kotilainen P, Rasi V. Protein C in the treatment of coagulopathy in meningococcal disease. Lancet 1996, 347:1767.
64. Smith OP, White B, Rafferty M. Successful treatment of meningococcal induced protein C deficiency/purpura fulminans in children with protein C concentrate and heparin. Thromb Haemost 1997, 97:419.
65. Powars D, Larsen R, Johnson J, Hulbert T, Sun T, Patch M, et al. Epidemic meningococcemia and purpura fulminans with induced protein C deficiency. Clin Infect Dis 1993, 17:254-261.
66. Gerson WT, Dickerman JD, Bovill EG, Golden E. Severe acquired protein C deficiency in purpura fulminans associated with disseminated intravascular coagulation: treatment with protein C concentrate. Pediatrics 1993, 91:418-422.
67. Okajima K, Imamura H, Koga S, Masayasu I, Takatsuki K, Aoki N. Treatment of patients with disseminated intravascular coagulation by protein C. Am J Hematol 1990, 33:277-278.
68. Okajima K, Koga S, Kaji M, Inoue M, Nakagaki T, Funastsu A, et al. Effect of protein C and activated protein C on coagulation and fibrinolysis in normal human subjects. Thromb Haemost 1990, 63: 48-53.
69. Hancock WW, Bach FH. Immunobiology and therapeutic applications of protein C/protein S/thrombomodulin in human and experimental allotransplantation and xenotransplantation. Trends Cardiovasc Med 1997, 7:174-183.
70. Coughlin SR, Vu T-KH, Hung DT, Wheaton VI. Characterization of a functional thrombin receptor. Issues and opportunities. J Clin Invest 1992, 89:351-355.
71. Hancock WW, Tsuchida A, Hau H, Thomson NM, Salem HH. The anticoagulants protein C and protein S display potent antiinflammatory and immunosuppressive effects relevant to tranplant biology and therapy. Transplant Proc 1992, 24:2302-2303.
72. Grey S, Hau H, Salem H, Hancock WW. Selective effects of protein C on activation of human monocytes by lipopolysaccharide, interferon-gamma or PMA: modulation of effects on CD11b and CD14 but not CD25 or CD54 induction. Transplant Proc 1993, 25:2913-2914.
73. Grey ST, Hancock WW. Inhibition of LPS-induced activation of human monocytes by activated protein C (APC) occurs through a novel mechanism. J Leukoc Biol 1993, 114:A487.
74. Redl H, Dinges HP, Buurman WA, vanderLinden CJ, Pober JS, Cotran RS, et al. Expression of endothelial leukocyte adhesion molecule-1 in septic but not traumatic/hypovolemic shock in the baboon. Am J Pathol 1991, 139:461-466.
75. Newman W, Beall LD, Carson CW, Hunder GG, Graben N, Randhawa ZI, et al. Soluble E-selectin is found in supernatants of activated endothelial cells and is elevated in the serum of patients with septic shock. J Immunol 1993, 150:644-654.
76. Bevilacqua MP, Nelson RM. Selectins. J Clin Invest 1993, 91:379-387.
77. Kukielka GL, Lane CL, Manning AM, Michael LH, Entman ML, Smith CW, et al. Induction of myocardial ELAM-1 by ischemia and reperfusion. FASEB J 1992, 6:1060A.
78. Fukudome K, Esmon CT. Molecular cloning and expression of murine and bovine endothelial cell protein C/activated protein C receptor (EPCR). J Biol Chem 1995, 270:5571-5577.
79. Kurosawa S, Stearns-Kurosawa DJ, Hidari N, Esmon CT. Identification of functional endothelial protein C receptor in human plasma. J Clin Invest 1997, 100:411-418.
80. Hahn RA, MacDonald BR, Chastain M, Grinnell BW, Simpson PJ. Evaluation of activated protein C on canine infarct size in a nonthrombotic model of myocardial reperfusion injury. J Pharmacol Exp Ther 1996, 276:1104-1110.
81. O'Leary EC, Schelm JA, Simpson PJ. Activated recombinant human protein C does not attenuate recruitment of neutrophils in rat models of acute inflammation. J Pharmacol Exp Ther 1995, 273:193-198.
82. Ehrlich HJ, Jaskunas SR, Grinnell BW, Yan SB, Bang NU. Direct expression of recombinant activated human protein C, a serine protease. J Biol Chem 1989, 264:14298-14304.
83. Richardson MA, Gerlitz B, Grinnell BW. Charge reversal at the P3′ position in protein C optimally enhances thrombin affinity and activation rate. Protein Sci 1994, 3:711-712.
84. Ehrlich HJ, Grinnell BW, Jaskunas SR, Esmon CT, Yan SB, Bang NU. Recombinant human protein C derivatives: altered response to calcium resulting in enhanced activation by thrombin. EMBO J 1990, 9:2367-2373.
85. Richardson MA, Gerlitz B, Grinnell BW. Enhancing protein C interaction with thrombin results in a clot-activated antcoagulant. Nature 1992, 360:261-264.
86. 2+ for rapid activation by the thrombin-thrombomodulin complex. J Biol Chem 1994, 269:3151-3154.
87. Rezaie AR, Esmon CT. The function of calcium in protein C activation by thrombin and thrombin-thrombomodulin complex can be distinguished by mutational analysis of protein C derivatives. J Biol Chem 1992, 267:26104-26109.
88. Kurz KD, Smith T, Wilson A, Gerlitz B, Richardson MA, Grinnell BW. Antithrombotic efficacy in the guinea pig of a derivative of human protein C with enhanced activation by thrombin. Blood 1997, 89:534-540.
89. Esmon NL. Thrombomodulin. Progr Hemost Thromb 1989, 9:29-55.
90. Dittman WA. Thrombomodulin-biology and potential cardiovascular applications. Trends Cardiovasc Med 1991, 1:331-336.
91. Sadler JE, Lentz SR, Sheehan JP, Tsiang M, Wu Q. Structure-function relationships of the thrombin-thrombomodulin interaction. Haemostasis 1993, 23:183-193.
92. Sadler JE. Thrombomodulin structure and function. Thromb Haemost 1997, 78:392-395.
93. Amiral J, Fareed J. Thromboembolic disease: biochemical mechanisms and new possibilities of biological diagnosis. Semin Thromb Hemost 1996, 22 (suppl 1): 41-48.
94. Blann A, Seigneur M. Soluble markers of endothelial cell function. Clin Hemorh Microcirc 1997, 17:3-11.
95. Parkinson JF, Grinnell BW, Moore RE, Hoskins J, Vlahos CJ, Bang NU. Stable expression of a secretable deletion mutant of recombinant human thrombomodulin in mammalian cells. J Biol Chem 1990, 265:12602-12610.
96. Ogata M, Wakita K, Kimura K, Marumoto Y, Oh-i K, Shimizu S. High level expression of recombinant human soluble thrombomodulin in serum free medium by CHO-K1 cells. Appl Microbiol Biotech 1993, 38:520-525.
97. Parkinson JF, Vlahos CJ, Yan SB, Bang NU. Recombinant human thrombomodulin: regulation of cofactor activity and anticoagulant function by a glycosaminoglycan side chain. Biochem J 1992, 283: 151-157.
98. Yamamoto S, Mizozuchi T, Tamaki T, Ohkuchi M, Kimura S, Aoki N. Urinary thrombomodulin, its isolation and characterization. J Biochem 1993, 113:433-440.
99. Gerlitz B, Hassell T, Vlahos C, Parkinson JF, Bang NU, Grinnell BW. Identification of the predominant glycosaminoglycan-attachment site in soluble recombinant human thrombomodulin: potential regulation of functionality by glycosyltransferase competition for serine 474. Biochem J 1993, 295:131-140.
100. Mohn M, Gonda Y, Oka M, Aoki Y, Gomi K, Kiyota T, et al. The antithrombotic effects of recombinant human soluble thrombomodulin (rhsTM) on tissue factor-induced disseminated intravascular coagulation in crab-eating monkeys. Blood Coagul Fibrinol 1997, 8:274-283.
101. Uchiba M, Okajima K, Murakami K, Johno M, Okabe H, Takatsuki K. Recombinant thrombomodulin prevents endotoxin-induced lung injury in rats by inhibiting leukocyte activation. Am J Physiol 1996, 217:L470-L475.
102. Takahashi Y, Hosaka Y, Niina H, Nagasawa K, Naotsuka M, Sakai K, et al. Soluble thrombomodulin purified from human urine exhibits a potent anticoagulant effect in vitro and in vivo. Thromb Haemost 1995, 73:805-811.
103. Aoki Y, Ohishi R, Takei R, Matsuzaki O, Mohri M, Saitoh K, et al. Effects of recombinant human soluble thrombomodulin (rhs-TM) on a rat model of disseminated intravascular coagulation with decreased levels of plasma antithrombin III. Thromb Haemost 1994, 71:452-455.
104. Mohri M, Oka M, Aoki Y, Gonda Y, Hirata S, Gomi K, et al. Intravenous extended infusion of recombinant human soluble thrombomodulin prevented tissue factor-induced disseminated intravascular coagulation in rats. Am J Hematol 1994, 45:298-303.
105. Ono M, Nawa K, Marumoto Y. Antithrombotic effects of recombinant human soluble thrombomodulin in a rat model of vascular shunt thrombosis. Thromb Haemost 1994, 72:421-425.
106. Solis MM, Vitti M, Cook J, Young D, Glase C, Light D, et al. Recombinant soluble human thrombomodulin: a randomized, blinded assessment of prevention of venous thrombosis and effects on hemostatic parameters in a rat model. Thromb Res 1994, 73:385-394.
107. Gonda Y, Hirata S, Saitoh K, Aoki Y, Mohri M, Gomi K, et al. Antithrombotic effect of recombinant human soluble thrombomodulin on endotoxin-induced disseminated intravascular coagulation in rats. Thromb Res 1993, 71:325-335.
108. Solis MM, Cook C, Cook J, Glaser C, Light D, Morse J, et al. Intravenous recombinant soluble human thrombomodulin prevents venous thrombosis in a rat model. J Vasc Surg 1991, 14:599-604.
109. Gomi K, Zushi M, Honda G, Kawahara S, Matsuzaki O, Kanabayashi T, et al. Antithrombotic effect of recombinant human thrombomodulin on thrombin-induced thromboembolism in mice. Blood 1990, 75:1369-1399.
110. Rosenberg RD. Thrombomodulin gene disruption and mutation in mice. Thromb Haemost 1997, 78:705-709.
111. Weiler-Guettler H, Aird WC, Husain M, Rayburn H, Rosenberg RD. Targeting of transgene expression to the vascular endothelium of mice by homologous recombination at the thrombomodulin locus. Circ Res 1996, 78:180-187.
112. Wu Q, Sheehan JP, Tsiang M, Lentz SR, Birktoft JJ, Sadler JE. Single amino acid substitutions dissociate fibrinogen-clotting and thrombomodulin-binding activities of human thrombin. Proc Natl Acad Sci USA 1991, 88:6775-6779.
113. Le Bonniec BF, Esmon CT. Glu-192-Gln substitution in thrombin mimics the catalytic switch induce by thrombomodulin. Proc Natl Acad Sci USA 1991, 88:7371-7375.
114. LeBonniec BF, MacGillivray RTA, Esmon CT. Thrombin Glu-39 restricts the P′3 specificity to nonacidic residues. J Biol Chem 1991, 266:13796-13803.
115. Tsiang M, Jain AK, Dunn KE, Rojas ME, Leung LLK, Gibbs CS. Functional mapping of the surface residues of human thrombin. J Biol Chem 1995, 270:16854-16863.
116. Gibbs CS, Coutre SE, Tsiang M, Li W-X, Jain AK, Dunn KE, et al. Conversion of thrombin into an anticoagulant by protein engineering. Nature 1995, 378:413-416.
117. Tsiang M, Paborsky LR, Li W-X, Jain AK, Mao CT, Dunn KE, et al. Protein engineering thrombin for optimal specificity and potency of anticoagulant activity in vivo. Biochemistry 1996, 35:16450-16457.
118. Leung LLK, Gibbs CS. Modulation of thrombin's procoagulant and anticoagulant properties. Thromb Haemost 1997, 78:577-580.
119. Rezaie AR, Olson ST. Contribution of lysine 60f to S1′ specificity of thrombin. Biochemistry 1997, 36:1026-1033.
120. Dang QD, Sebetta M, Di Cera E. Selective loss of fibrinogen clotting in a loop-less thrombin. J Biol Chem 1997, 272:19649-19651.
121. Ye J, Esmon NL, Eson CT, Johnson AE. The active site of thrombin is altered upon binding to thrombomodulin. J Biol Chem 1991, 266:23016-23021.
122. Ye J, Esmon NL, Esmon CT, Johnson AE. The active site of thrombin is altered upon binding to thrombomodulin: two distinct structural changes are detected by fluorescence, but only one correlates with protein C activation. J Biol Chem 1991, 266:23016-23021.
123. Musci G, Berliner LJ, Esmon CT. Evidence for multiple conformational changes in the active center of thrombin induced by complex formation with thrombomodulin. Biochemistry 1988, 27:769-773.
124. Grinnell BW, Gerlitz B, Berg DT. Identification of a region in protein C involved in thrombomodulin-stimulated activation by thrombin: potential repulsion at anion-binding site I in thrombin. Biochem J 1994, 303:929-933.
125. Wells CM, Di Cera E. Thrombin is a sodium activated enzyme. Biochemistry 1992, 31:11721 -11730.
126. + binding site of thrombin. J Biol Chem 1995, 270:22089-22092.
127. Dang QD, Vindigni A, DiCera E. An allosteric switch controls the procoagulant and anticoagulant activities of thrombin. Proc Natl Acad Sci USA 1995, 92:5977-5981.
128. +-induced allosteric regulation of catalytic activity in serine proteases. Proc Natl Acad Sci USA 1996, 93:10653-10656.
129. Dang QD, Guinto ER, Cera ED. Rational engineering of activity and specificity in a serine protease. Nature Biotechnology 1997, 15: 146-149.
130. Musci G, Berliner LJ. Ligands which effect human protein C activation by thrombin. J Biol Chem 1987, 262:13889-13891.
131. Conery BG, Berliner LJ. Binding subsites in human thrombin. Biochemisty 1983, 22:369-374.
132. Berliner LJ, Shen YYL. Physical evidece for an apolar binding site near the catalytic center of human alpha-thrombin. Biochemistry 1977, 16:4622-4626.
133. Berg DT, Wiley MR, Grinnell BW. Enhanced protein C activation and inhibition of fibrinogen cleavage by a thrombin modulator. Science 1996, 273:1389-1391.
134. Liu LW, 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, 266:16977-16980.
135. Bajzar L, Manuel R, Nesheim ME. Purification and characterization of TAFI, a thromin-activable fibrinolysis inhibitor. J Biol Chem 1995, 270:14477-14484.
136. Dahlback B. Resistance to activated protein C as risk factor for thrombosis: molecular mechanisms, laboratory investigation, and clinical management. Semin Hematol 1997, 34:217-234.
137. Rees DC. The population genetics of factor V Leiden (Arg506Gln). Br J Haematol 1996, 95:579-586.