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Thrombin in Ischemic Stroke Targeting

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Translational Stroke Research

Part of the book series: Springer Series in Translational Stroke Research ((SSTSR))

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Abstract

Accumulating research data have suggested pleiotropic roles of thrombin in brain tissue, including vascular disruption, inflammatory response, oxidative stress, and direct cellular toxicity. As a result, thrombin might contribute to stroke pathology through multiple mechanisms. A better understanding of thrombin toxicity would lead to new therapeutic targets in clinical application. In this brief review, we will discuss the basic biology of thrombin, the mechanism of thrombin toxicity, and the translational aspects of antithrombotic therapy in stroke.

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References

  1. Vu TK, 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.

    Article  PubMed  CAS  Google Scholar 

  2. 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.

    Article  PubMed  CAS  Google Scholar 

  3. 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.

    Article  PubMed  CAS  Google Scholar 

  4. Coughlin SR. Thrombin signalling and protease-activated receptors. Nature. 2000;407:258–64.

    Article  PubMed  CAS  Google Scholar 

  5. Furie B, Furie BC. Mechanisms of thrombus formation. N Engl J Med. 2008;359:938–49.

    Article  PubMed  CAS  Google Scholar 

  6. Fenton 2nd JW, Ofosu FA, Moon DG, Maraganore JM. Thrombin structure and function: why thrombin is the primary target for antithrombotics. Blood Coagul Fibrinolysis. 1991;2:69–75.

    Article  PubMed  CAS  Google Scholar 

  7. Davie EW, Kulman JD. An overview of the structure and function of thrombin. Semin Thromb Hemost. 2006;32 Suppl 1:3–15.

    Article  PubMed  CAS  Google Scholar 

  8. Rau JC, Beaulieu LM, Huntington JA, Church FC. Serpins in thrombosis, hemostasis and fibrinolysis. J Thromb Haemost. 2007;5 Suppl 1:102–15.

    Article  PubMed  CAS  Google Scholar 

  9. Choi BH, Suzuki M, Kim T, Wagner SL, Cunningham DD. Protease nexin-1. Localization in the human brain suggests a protective role against extravasated serine proteases. Am J Pathol. 1990;137:741–7.

    PubMed  CAS  Google Scholar 

  10. He L, Vicente CP, Westrick RJ, Eitzman DT, Tollefsen DM. Heparin cofactor ii inhibits arterial thrombosis after endothelial injury. J Clin Invest. 2002;109:213–9.

    PubMed  CAS  Google Scholar 

  11. Bode W, Mayr I, Baumann U, Huber R, Stone SR, Hofsteenge J. The refined 1.9 a crystal structure of human alpha-thrombin: interaction with d-phe-pro-arg chloromethylketone and significance of the tyr-pro-pro-trp insertion segment. EMBO J. 1989;8:3467–75.

    PubMed  CAS  Google Scholar 

  12. Rydel TJ, Tulinsky A, Bode W, Huber R. Refined structure of the hirudin-thrombin complex. J Mol Biol. 1991;221:583–601.

    Article  PubMed  CAS  Google Scholar 

  13. Le Bonniec BF, Guinto ER, Esmon CT. Interaction of thrombin des-etw with antithrombin iii, the kunitz inhibitors, thrombomodulin and protein c. Structural link between the autolysis loop and the tyr-pro-pro-trp insertion of thrombin. J Biol Chem. 1992;267:19341–8.

    PubMed  Google Scholar 

  14. Dang QD, Sabetta M, Di Cera E. Selective loss of fibrinogen clotting in a loop-less thrombin. J Biol Chem. 1997;272:19649–51.

    Article  PubMed  CAS  Google Scholar 

  15. Tsiang M, Jain AK, Dunn KE, Rojas ME, Leung LL, Gibbs CS. Functional mapping of the surface residues of human thrombin. J Biol Chem. 1995;270:16854–63.

    Article  PubMed  CAS  Google Scholar 

  16. Pechik I, Madrazo J, Mosesson MW, Hernandez I, Gilliland GL, Medved L. Crystal structure of the complex between thrombin and the “E” region of fibrin. Proc Natl Acad Sci U S A. 2004;101:2718–23.

    Article  PubMed  CAS  Google Scholar 

  17. Mathews II, Padmanabhan KP, Ganesh V, Tulinsky A, Ishii M, Chen J, Turck CW, Coughlin SR, Fenton 2nd JW. Crystallographic structures of thrombin complexed with thrombin receptor peptides: existence of expected and novel binding modes. Biochemistry. 1994;33:3266–79.

    Article  PubMed  CAS  Google Scholar 

  18. De Cristofaro R, De Candia E, Landolfi R, Rutella S, Hall SW. Structural and functional mapping of the thrombin domain involved in the binding to the platelet glycoprotein ib. Biochemistry. 2001;40:13268–73.

    Article  PubMed  Google Scholar 

  19. Esmon CT, Lollar P. Involvement of thrombin anion-binding exosites 1 and 2 in the activation of factor v and factor viii. J Biol Chem. 1996;271:13882–7.

    Article  PubMed  CAS  Google Scholar 

  20. Stone SR, Braun PJ, Hofsteenge J. Identification of regions of alpha-thrombin involved in its interaction with hirudin. Biochemistry. 1987;26:4617–24.

    Article  PubMed  CAS  Google Scholar 

  21. Rydel TJ, Ravichandran KG, Tulinsky A, Bode W, Huber R, Roitsch C, Fenton 2nd JW. The structure of a complex of recombinant hirudin and human alpha-thrombin. Science. 1990;249:277–80.

    Article  PubMed  CAS  Google Scholar 

  22. Li W, Johnson DJ, Esmon CT, Huntington JA. Structure of the antithrombin-thrombin-heparin ternary complex reveals the antithrombotic mechanism of heparin. Nat Struct Mol Biol. 2004;11:857–62.

    Article  PubMed  CAS  Google Scholar 

  23. Marino F, Pelc LA, Vogt A, Gandhi PS, Di Cera E. Engineering thrombin for selective specificity toward protein c and par1. J Biol Chem. 2010;285:19145–52.

    Article  PubMed  CAS  Google Scholar 

  24. Traynelis SF, Trejo J. Protease-activated receptor signaling: new roles and regulatory mechanisms. Curr Opin Hematol. 2007;14:230–5.

    Article  PubMed  CAS  Google Scholar 

  25. Coughlin SR. Protease-activated receptors in hemostasis, thrombosis and vascular biology. J Thromb Haemost. 2005;3:1800–14.

    Article  PubMed  CAS  Google Scholar 

  26. Soh UJ, Dores MR, Chen B, Trejo J. Signal transduction by protease-activated receptors. Br J Pharmacol. 2010;160:191–203.

    Article  PubMed  CAS  Google Scholar 

  27. Junge CE, Lee CJ, Hubbard KB, Zhang Z, Olson JJ, Hepler JR, Brat DJ, Traynelis SF. Protease-activated receptor-1 in human brain: localization and functional expression in astrocytes. Exp Neurol. 2004;188:94–103.

    Article  PubMed  CAS  Google Scholar 

  28. Kuliopulos A, Covic L, Seeley SK, Sheridan PJ, Helin J, Costello CE. Plasmin desensitization of the par1 thrombin receptor: kinetics, sites of truncation, and implications for thrombolytic therapy. Biochemistry. 1999;38:4572–85.

    Article  PubMed  CAS  Google Scholar 

  29. Trivedi V, Boire A, Tchernychev B, Kaneider NC, Leger AJ, O’Callaghan K, Covic L, Kuliopulos A. Platelet matrix metalloprotease-1 mediates thrombogenesis by activating par1 at a cryptic ligand site. Cell. 2009;137:332–43.

    Article  PubMed  CAS  Google Scholar 

  30. Ludeman MJ, Kataoka H, Srinivasan Y, Esmon NL, Esmon CT, Coughlin SR. Par1 cleavage and signaling in response to activated protein c and thrombin. J Biol Chem. 2005;280:13122–8.

    Article  PubMed  CAS  Google Scholar 

  31. Nesi A, Fragai M. Substrate specificities of matrix metalloproteinase 1 in par-1 exodomain proteolysis. Chembiochem. 2007;8:1367–9.

    Article  PubMed  CAS  Google Scholar 

  32. Rohatgi T, Sedehizade F, Reymann KG, Reiser G. Protease-activated receptors in neuronal development, neurodegeneration, and neuroprotection: thrombin as signaling molecule in the brain. Neuroscientist. 2004;10:501–12.

    Article  PubMed  CAS  Google Scholar 

  33. 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.

    Article  PubMed  Google Scholar 

  34. Shi X, Gangadharan B, Brass LF, Ruf W, Mueller BM. Protease-activated receptors (par1 and par2) contribute to tumor cell motility and metastasis. Mol Cancer Res. 2004;2:395–402.

    PubMed  CAS  Google Scholar 

  35. McCoy KL, Traynelis SF, Hepler JR. Par1 and par2 couple to overlapping and distinct sets of g proteins and linked signaling pathways to differentially regulate cell physiology. Mol Pharmacol. 2010;77:1005–15.

    Article  PubMed  CAS  Google Scholar 

  36. Murray V, Norrving B, Sandercock PA, Terent A, Wardlaw JM, Wester P. The molecular basis of thrombolysis and its clinical application in stroke. J Intern Med. 2010;267:191–208.

    Article  PubMed  CAS  Google Scholar 

  37. Eriksson BI, Quinlan DJ, Eikelboom JW. Novel oral factor xa and thrombin inhibitors in the management of thromboembolism. Annu Rev Med. 2011;62:41–57.

    Article  PubMed  CAS  Google Scholar 

  38. Garcia D, Libby E, Crowther MA. The new oral anticoagulants. Blood. 2010;115:15–20.

    Article  PubMed  CAS  Google Scholar 

  39. Choi J, Kermode JC. New therapeutic approaches to combat arterial thrombosis: better drugs for old targets, novel targets, and future prospects. Mol Interv. 2011;11:111–23.

    Article  PubMed  CAS  Google Scholar 

  40. Gavard J, Gutkind JS. Protein kinase c-related kinase and rock are required for thrombin-induced endothelial cell permeability downstream from galpha12/13 and galpha11/q. J Biol Chem. 2008;283:29888–96.

    Article  PubMed  CAS  Google Scholar 

  41. Nguyen M, Arkell J, Jackson CJ. Thrombin rapidly and efficiently activates gelatinase a in human microvascular endothelial cells via a mechanism independent of active mt1 matrix metalloproteinase. Lab Invest. 1999;79:467–75.

    PubMed  CAS  Google Scholar 

  42. Chen B, Cheng Q, Yang K, Lyden PD. Thrombin mediates severe neurovascular injury during ischemia. Stroke. 2010;41:2348–52.

    Article  PubMed  CAS  Google Scholar 

  43. Chen B, Friedman B, Cheng Q, Tsai P, Schim E, Kleinfeld D, Lyden PD. Severe blood-brain barrier disruption and surrounding tissue injury. Stroke. 2009;40:e666–74.

    Article  PubMed  Google Scholar 

  44. Hirano K. The roles of proteinase-activated receptors in the vascular physiology and pathophysiology. Arterioscler Thromb Vasc Biol. 2007;27:27–36.

    Article  PubMed  CAS  Google Scholar 

  45. Kai Y, Maeda Y, Sasaki T, Kanaide H, Hirano K. Basic and translational research on proteinase-activated receptors: the role of thrombin receptor in cerebral vasospasm in subarachnoid hemorrhage. J Pharmacol Sci. 2008;108:426–32.

    Article  PubMed  CAS  Google Scholar 

  46. Kameda K, Kikkawa Y, Hirano M, Matsuo S, Sasaki T, Hirano K. Combined argatroban and anti-oxidative agents prevents increased vascular contractility to thrombin and other ligands after subarachnoid hemorrhage. Br J Pharmacol. 2012;165(1):106–19.

    Google Scholar 

  47. Donovan FM, Pike CJ, Cotman CW, Cunningham DD. Thrombin induces apoptosis in cultured neurons and astrocytes via a pathway requiring tyrosine kinase and RhoA activities. J Neurosci. 1997;17:5316–26.

    PubMed  CAS  Google Scholar 

  48. Striggow F, Riek M, Breder J, Henrich-Noack P, Reymann KG, Reiser G. The protease thrombin is an endogenous mediator of hippocampal neuroprotection against ischemia at low concentrations but causes degeneration at high concentrations. Proc Natl Acad Sci U S A. 2000;97:2264–9.

    Article  PubMed  CAS  Google Scholar 

  49. Ohnishi M, Katsuki H, Fujimoto S, Takagi M, Kume T, Akaike A. Involvement of thrombin and mitogen-activated protein kinase pathways in hemorrhagic brain injury. Exp Neurol. 2007;206:43–52.

    Article  PubMed  CAS  Google Scholar 

  50. Clark JF, Loftspring M, Wurster WL, Beiler S, Beiler C, Wagner KR, Pyne-Geithman GJ. Bilirubin oxidation products, oxidative stress, and intracerebral hemorrhage. Acta Neurochir Suppl. 2008;105:7–12.

    Article  PubMed  CAS  Google Scholar 

  51. Qing WG, Dong YQ, Ping TQ, Lai LG, Fang LD, Min HW, Xia L, Heng PY. Brain edema after intracerebral hemorrhage in rats: the role of iron overload and aquaporin 4. J Neurosurg. 2009;110:462–8.

    Article  PubMed  Google Scholar 

  52. Katsu M, Niizuma K, Yoshioka H, Okami N, Sakata H, Chan PH. Hemoglobin-induced oxidative stress contributes to matrix metalloproteinase activation and blood-brain barrier dysfunction in vivo. J Cereb Blood Flow Metab. 2010;30(12):1939–50.

    Article  PubMed  CAS  Google Scholar 

  53. Copin JC, Merlani P, Sugawara T, Chan PH, Gasche Y. Delayed matrix metalloproteinase inhibition reduces intracerebral hemorrhage after embolic stroke in rats. Exp Neurol. 2008;213:196–201.

    Article  PubMed  CAS  Google Scholar 

  54. Maddahi A, Chen Q, Edvinsson L. Enhanced cerebrovascular expression of matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 via the mek/erk pathway during cerebral ischemia in the rat. BMC Neurosci. 2009;10:56.

    Article  PubMed  Google Scholar 

  55. Weinstein JR, Lau AL, Brass LF, Cunningham DD. Injury-related factors and conditions down-regulate the thrombin receptor (par-1) in a human neuronal cell line. J Neurochem. 1998;71:1034–50.

    Article  PubMed  CAS  Google Scholar 

  56. Junge CE, Sugawara T, Mannaioni G, Alagarsamy S, Conn PJ, Brat DJ, Chan PH, Traynelis SF. The contribution of protease-activated receptor 1 to neuronal damage caused by transient focal cerebral ischemia. Proc Natl Acad Sci U S A. 2003;100:13019–24.

    Article  PubMed  CAS  Google Scholar 

  57. Gingrich MB, Junge CE, Lyuboslavsky P, Traynelis SF. Potentiation of NMDA receptor function by the serine protease thrombin. J Neurosci. 2000;20:4582–95.

    PubMed  CAS  Google Scholar 

  58. Borbiev T, Birukova A, Liu F, Nurmukhambetova S, Gerthoffer WT, Garcia JG, Verin AD. P38 map kinase-dependent regulation of endothelial cell permeability. Am J Physiol Lung Cell Mol Physiol. 2004;287:L911–8.

    Article  PubMed  CAS  Google Scholar 

  59. Vandell AG, Larson N, Laxmikanthan G, Panos M, Blaber SI, Blaber M, Scarisbrick IA. Protease-activated receptor dependent and independent signaling by kallikreins 1 and 6 in CNS neuron and astroglial cell lines. J Neurochem. 2008;107:855–70.

    Article  PubMed  CAS  Google Scholar 

  60. Fujimoto S, Katsuki H, Kume T, Akaike A. Thrombin-induced delayed injury involves multiple and distinct signaling pathways in the cerebral cortex and the striatum in organotypic slice cultures. Neurobiol Dis. 2006;22:130–42.

    Article  PubMed  CAS  Google Scholar 

  61. Fujimoto S, Katsuki H, Ohnishi M, Takagi M, Kume T, Akaike A. Thrombin induces striatal neurotoxicity depending on mitogen-activated protein kinase pathways in vivo. Neuroscience. 2007;144:694–701.

    Article  PubMed  CAS  Google Scholar 

  62. Petaja J. Inflammation and coagulation. An overview. Thromb Res. 2011;127 Suppl 2:S34–7.

    Article  PubMed  Google Scholar 

  63. Chi L, Li Y, Stehno-Bittel L, Gao J, Morrison DC, Stechschulte DJ, Dileepan KN. Interleukin-6 production by endothelial cells via stimulation of protease-activated receptors is amplified by endotoxin and tumor necrosis factor-alpha. J Interferon Cytokine Res. 2001;21:231–40.

    Article  PubMed  CAS  Google Scholar 

  64. Kaplanski G, Fabrigoule M, Boulay V, Dinarello CA, Bongrand P, Kaplanski S, Farnarier C. Thrombin induces endothelial type ii activation in vitro: Il-1 and tnf-alpha-independent il-8 secretion and e-selectin expression. J Immunol. 1997;158:5435–41.

    PubMed  CAS  Google Scholar 

  65. Minami T, Abid MR, Zhang J, King G, Kodama T, Aird WC. Thrombin stimulation of vascular adhesion molecule-1 in endothelial cells is mediated by protein kinase c (PKC)-delta-nf-kappa b and PKC-zeta-gata signaling pathways. J Biol Chem. 2003;278:6976–84.

    Article  PubMed  CAS  Google Scholar 

  66. Choi SH, Lee DY, Kim SU, Jin BK. Thrombin-induced oxidative stress contributes to the death of hippocampal neurons in vivo: role of microglial NADPH oxidase. J Neurosci. 2005;25:4082–90.

    Article  PubMed  CAS  Google Scholar 

  67. Park KW, Baik HH, Jin BK. Il-13-induced oxidative stress via microglial NADPH oxidase contributes to death of hippocampal neurons in vivo. J Immunol. 2009;183:4666–74.

    Article  PubMed  CAS  Google Scholar 

  68. 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.

    Article  PubMed  CAS  Google Scholar 

  69. Haralabopoulos GC, Grant DS, Kleinman HK, Maragoudakis ME. Thrombin promotes endothelial cell alignment in matrigel in vitro and angiogenesis in vivo. Am J Physiol. 1997;273:C239–45.

    PubMed  CAS  Google Scholar 

  70. Griffin CT, Srinivasan Y, Zheng YW, Huang W, Coughlin SR. A role for thrombin receptor signaling in endothelial cells during embryonic development. Science. 2001;293:1666–70.

    Article  PubMed  CAS  Google Scholar 

  71. Yang S, Song S, Hua Y, Nakamura T, Keep RF, Xi G. Effects of thrombin on neurogenesis after intracerebral hemorrhage. Stroke. 2008;39:2079–84.

    Article  PubMed  CAS  Google Scholar 

  72. Bae JS, Kim YU, Park MK, Rezaie AR. Concentration dependent dual effect of thrombin in endothelial cells via par-1 and pi3 kinase. J Cell Physiol. 2009;219:744–51.

    Article  PubMed  CAS  Google Scholar 

  73. Henrich-Noack P, Striggow F, Reiser G, Reymann KG. Preconditioning with thrombin can be protective or worsen damage after endothelin-1-induced focal ischemia in rats. J Neurosci Res. 2006;83:469–75.

    Article  PubMed  CAS  Google Scholar 

  74. Xi G, Keep RF, Hua Y, Xiang J, Hoff JT. Attenuation of thrombin-induced brain edema by cerebral thrombin preconditioning. Stroke. 1999;30:1247–55.

    Article  PubMed  CAS  Google Scholar 

  75. Jiang Y, Wu J, Hua Y, Keep RF, Xiang J, Hoff JT, Xi G. Thrombin-receptor activation and thrombin-induced brain tolerance. J Cereb Blood Flow Metab. 2002;22:404–10.

    Article  PubMed  CAS  Google Scholar 

  76. Mann KG, Butenas S, Brummel K. The dynamics of thrombin formation. Arterioscler Thromb Vasc Biol. 2003;23:17–25.

    Article  PubMed  CAS  Google Scholar 

  77. Liu DZ, Ander BP, Xu H, Shen Y, Kaur P, Deng W, Sharp FR. Blood-brain barrier breakdown and repair by src after thrombin-induced injury. Ann Neurol. 2010;67:526–33.

    Article  PubMed  CAS  Google Scholar 

  78. Guo H, Liu D, Gelbard H, Cheng T, Insalaco R, Fernandez JA, Griffin JH, Zlokovic BV. Activated protein c prevents neuronal apoptosis via protease activated receptors 1 and 3. Neuron. 2004;41:563–72.

    Article  PubMed  CAS  Google Scholar 

  79. Cheng T, Liu D, Griffin JH, Fernandez JA, Castellino F, Rosen ED, Fukudome K, Zlokovic BV. Activated protein c blocks p53-mediated apoptosis in ischemic human brain endothelium and is neuroprotective. Nat Med. 2003;9:338–42.

    Article  PubMed  CAS  Google Scholar 

  80. Cheng T, Petraglia AL, Li Z, Thiyagarajan M, Zhong Z, Wu Z, Liu D, Maggirwar SB, Deane R, Fernandez JA, LaRue B, Griffin JH, Chopp M, Zlokovic BV. Activated protein c inhibits tissue plasminogen activator-induced brain hemorrhage. Nat Med. 2006;12:1278–85.

    Article  PubMed  CAS  Google Scholar 

  81. Liu D, Cheng T, Guo H, Fernandez JA, Griffin JH, Song X, Zlokovic BV. Tissue plasminogen activator neurovascular toxicity is controlled by activated protein c. Nat Med. 2004;10:1379–83.

    Article  PubMed  CAS  Google Scholar 

  82. Russo A, Soh UJ, Paing MM, Arora P, Trejo J. Caveolae are required for protease-selective signaling by protease-activated receptor-1. Proc Natl Acad Sci U S A. 2009;106:6393–7.

    Article  PubMed  CAS  Google Scholar 

  83. Jiang T, Olson ES, Nguyen QT, Roy M, Jennings PA, Tsien RY. Tumor imaging by means of proteolytic activation of cell-penetrating peptides. Proc Natl Acad Sci U S A. 2004;101:17867–72.

    Article  PubMed  CAS  Google Scholar 

  84. Olson ES, Aguilera TA, Jiang T, Ellies LG, Nguyen QT, Wong EH, Gross LA, Tsien RY. In vivo characterization of activatable cell penetrating peptides for targeting protease activity in cancer. Integr Biol (Camb). 2009;1:382–93.

    Article  CAS  Google Scholar 

  85. Olson ES, Jiang T, Aguilera TA, Nguyen QT, Ellies LG, Scadeng M, Tsien RY. Activatable cell penetrating peptides linked to nanoparticles as dual probes for in vivo fluorescence and mr imaging of proteases. Proc Natl Acad Sci U S A. 2010;107:4311–6.

    Article  PubMed  CAS  Google Scholar 

  86. Jaffer FA, Tung CH, Gerszten RE, Weissleder R. In vivo imaging of thrombin activity in experimental thrombi with thrombin-sensitive near-infrared molecular probe. Arterioscler Thromb Vasc Biol. 2002;22:1929–35.

    Article  PubMed  CAS  Google Scholar 

  87. Mosnier LO, Gale AJ, Yegneswaran S, Griffin JH. Activated protein c variants with normal cytoprotective but reduced anticoagulant activity. Blood. 2004;104:1740–4.

    Article  PubMed  CAS  Google Scholar 

  88. Wang Y, Thiyagarajan M, Chow N, Singh I, Guo H, Davis TP, Zlokovic BV. Differential neuroprotection and risk for bleeding from activated protein c with varying degrees of anticoagulant activity. Stroke. 2009;40:1864–9.

    Article  PubMed  CAS  Google Scholar 

  89. Guo H, Singh I, Wang Y, Deane R, Barrett T, Fernandez JA, Chow N, Griffin JH, Zlokovic BV. Neuroprotective activities of activated protein c mutant with reduced anticoagulant activity. Eur J Neurosci. 2009;29:1119–30.

    Article  PubMed  Google Scholar 

  90. Guo H, Wang Y, Singh I, Liu D, Fernandez JA, Griffin JH, Chow N, Zlokovic BV. Species-dependent neuroprotection by activated protein c mutants with reduced anticoagulant activity. J Neurochem. 2009;109:116–24.

    Article  PubMed  CAS  Google Scholar 

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  1. Department of Neurology, Cedars-Sinai Medical Center, Davis Research Building, 2094D, 110 N. George Burns Road, Los Angeles, CA, 90048, USA

    Bo Chen PhD

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  1. , Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, 90048, California, USA

    Paul A. Lapchak

  2. Loma Linda University, 11234 Anderson Street, Room 2562B, Loma Linda, 92354, California, USA

    John H. Zhang

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Chen, B. (2012). Thrombin in Ischemic Stroke Targeting. In: Lapchak, P., Zhang, J. (eds) Translational Stroke Research. Springer Series in Translational Stroke Research. Springer, New York, NY. https://doi.org/10.1007/978-1-4419-9530-8_9

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