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Baboon Model of E. coli Sepsis: Role of Phospholipid Microparticles in DIC

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Sepsis

Abstract

This chapter describes our experience with primate models of E. coli sepsis with emphasis on the responses of the hemostatic system, the mechanism of these responses, and the role of phospholipid microparticles in mediating disseminated intravascular coagulation (DIC). Understanding the principles of how the hemostatic system responds to inflammatory stress depends on viewing this system as a collection of mediator and regulator factors all of which are integrated with each other to control either the patency or the integrity of the cardiovascular system.

The first section of this chapter describes these four functional domains: coagulant versus anticoagulant and fibrinolytic versus antifibrinolytic domains. The functions of all four of which are regulated by thrombin through its interaction with either the endothelium or platelets. This is followed by a review of modulators, which influence the balance between the four functional domains. Emphasis is placed on how modulators such as estrogen, interleukin-6, etc., act to influence the balance between procoagulant mediators (i.e., factor Xa plus phospholipid microparticles) and anticoagulant and fibrinolytic regulators (protein C, plasminogen activator).

The second section describes how this system responds to inflammatory stress in a series of reconstitution and intervention studies. Attention is given to the role of phospholipid microparticles, and to defining those clinical pathophysiologic settings in which the hemostatic system is a link in a lethal chain of events versus those in which it acts in parallel (epiphenomenon).

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References

  1. Taylor FB, Kosanke S, Emerson T, et al. Retrospective description and experimental reconstitution of three different responses of the baboon to lethal E. coli. Shock 1994; 42:92–103.

    Google Scholar 

  2. Taylor FB Jr. Baboon models of three variants of hemostatic response to inflammatory stimuli. In: Brigham KL, ed. Endotoxin and the Lungs. New York: Marcel Dekker, 1994:171.

    Google Scholar 

  3. Esmon CT. The roles of protein C and thrombomodulin in the regulation of blood coagulation. J Biol Chem 1989; 264:4743.

    Google Scholar 

  4. Esmon CT, Fukudome K, Mather T, Bode W, Esmon NL, Regan LM, Stearns-Kurosawa DJ, Kurosawa S. Inflammation-The protein C pathway. 3rd International Symposium on Fibrogen-Hemostasis, Inflammation and Cardiovascular Disease, Ulm, Germany, May 3–4, 1996.

  5. Hanss M, Collen D. Secretion of tissue-type plasminogen activator and plasminogen activator inhibitor by cultured human endothelial cells: Modulation by thrombin, endotoxin, and histamine. J Lab Clin Med 1987;109:97.

    Google Scholar 

  6. Loskutoff DJ, Edgington TS. Synthesis of a fibrinolytic activator and inhibitor of endothelial cells. Proc Natl Acad Sci USA 1977;74:3903.

    Google Scholar 

  7. Collen D. On the regulation and control of fibrinolysis. Thromb & Haemost 1980;43:77–89.

    Google Scholar 

  8. Tesfamariam B. Free radicals in diabetic endothelial cell dysfunction. Free Radicals in Biol and Med 1994;16:383–391.

    Google Scholar 

  9. Read MA, Meyrick BO. Effects of endotoxin on lung endothelium. In: KL Brigham, ed. Endotoxin and the Lungs. New York: Marcel Dekker, 1994:83.

    Google Scholar 

  10. Old LJ. Tumor necrosis factor. Sci Amer 1988;258:59.

    Google Scholar 

  11. Nawroth PP, Stern DM. Modulation of endothelial cell hemostatic properties by tumor necrosis factor. J Exp Med 1986;163:740.

    Google Scholar 

  12. Pohlman TH, Stannes KA, Beatley PG, Ochs DD, Harlan JM. An endothelial cell surface factor(s) induced in vitro by lipopolysaccharide, interleukin 1, tumor necrosis factor-a in-creases neutrophil adherence by a CD2–18–dependent mechanism. J Immunol 1986;136:4548.

    Google Scholar 

  13. Davis EW, Fujikawa K, Kisiel W. The coagulation cascade. Initiation, maintenance, and regulation. Biochemistry 1991; 30:10366.

    Google Scholar 

  14. Booth NA, Anderson JA, Bennett B. Platelet release proteins which inhibit plasminogen activators. J Clin Path 1985;38:825.

    Google Scholar 

  15. Erickson LA, Ginsberg MG, Loskutoff DJ. Detection and partial characterization of an inhibitor of plasminogen activator in human platelets. J Clin Invest 1984;74:1465.

    Google Scholar 

  16. Sprengos ED, Kluft C. Plasminogen activator inhibitors. Blood 1987;69:381–387.

    Google Scholar 

  17. Drake TA, Cheng J, Chang ACK, Taylor FB Jr. Expression of tissue factor, thrombomodulin and E-selectin in baboons with lethal E. coli sepsis. Am J Pathol 1983;142:1458.

    Google Scholar 

  18. Taylor FB Jr, Hoogendorn H, Chang ACK, Peer G, Nesheim ME, Catlett R, Stump DC, Giles AR. Anticoagulant and fibrinolytic activities are promoted, not retarded, in vivo after thrombin generation in the presence of a monoclonal antibody that inhibits activation of protein C. Blood 1991;79:1720–1728.

    Google Scholar 

  19. Unpublished observation. Effects of anti protein C and anti t-PA antibodies on the response to LD100 E. coli.

  20. George JN, El-Harake. Thrombocytopenia due to enhanced platelet destruction by nonimmunologic mechanisms. In: Beutler E, Lichtman M, Coller B, Kipps TJ, eds. Williams Hematology, 5th ed. New York: McGraw-Hill Inc, 1996:1290.

    Google Scholar 

  21. Taylor FB Jr, Chang AK, Peer G, Li A, Burstein S. IL-6 Amplifies the coagulopathic response of the baboon to E. coli. 15th Congress of the International Society on Thrombosis and Haemostasis, Jerusalem, Israel, June 11–16, 1995.

  22. Kruithof EKO, Mestries JC, Gascon MP, Ythier A. The coagulation and fibrinolytic responses of baboons after in vivo thrombin generation-effect of Interleukin 6. Thromb & Haemost 1997;77(5):905–910.

    Google Scholar 

  23. Taylor F, Chang ACK, Ferrell G, Mather T, Catlett R, Blick K, Esmon CT. C4b-binding protein exacerbates the host response to E. coli. Blood 1987;78(15):918.

    Google Scholar 

  24. Taylor FB Jr, Dahlback B, Esmon CT, Chang ACK, Lockhart MS, Hatanaka K. The role of free protein S and C4bBP protein in regulation of the coagulant response to E. coli. Blood 1995;86:2642.

    Google Scholar 

  25. Dahlback B. Interaction between vitamin K-dependent protein S and the complement protein, C4b-binding protein. A link between coagulation and the complement system. Semin Thromb Hemost 1984;10:139.

    Google Scholar 

  26. Creasey AA, Chang ACK, Fiegen L, Wun TC, Taylor FB, Jr., Hinshaw LB. Tissue factor pathway inhibitor (TFPI) reduces mortality from Escherichia coli septic shock. J Clin Invest 1993;91(6):2850–2860.

    Google Scholar 

  27. Carr C, Bild GS, Chang ACK, Peer GT, Palmier MO, Frazier RB, Gustafson ME, Wun TC, Creasey AA, Hinshaw LB, Taylor FB Jr., Galluppi GR. Recombinant E. coli-derived tissue factor pathway inhibitor reduces coagulopathic and lethal effects in the baboon gram-negative model of septic shock. Circ Shock 1995;44:126.

    Google Scholar 

  28. Taylor FB Jr, Emerson TE Jr, Jordan R, Chang ACK, Blick KE. Antithrombin-III prevents the lethal effects of Escherichia coli infusion in baboons. Circ Shock 1988;26:227.

    Google Scholar 

  29. Bajzar L, Taylor F, Tracy PB. A baboon model can be used to assess the physiologic function of TAFI. Thromb & Haemost 1997;(Suppl):596 (Abstr OC-2434).

    Google Scholar 

  30. Anguo L, Chang ACK, Peer GT, Hinshaw LB, FB Taylor Jr. Comparison of the capacity of rhTNF-a and Escherichia coli to induce procoagulant activity by baboon mononuclear cells in vivo and in vitro. Shock 1996;5:274–279.

    Google Scholar 

  31. Taylor FB Jr, He SE, Chang ACK, Box J, Ferrell G, Lee D, Lockhart M, Peer G, Esmon CT. Infusion of phospholipid vesicles amplifies the local thrombotic response to TNF and anti-protein C into a consumptive response. Thromb & Haemost 1996;75(4):578–584.

    Google Scholar 

  32. Taylor FB, Chang AKC, Peer G, Ezban M, Hedner U. Active site inhibited factor VIIa (DEGR VIIa) attenuates the coagulant and interleukin-6 and-8 but not tumor necrosis factor responses of the baboon to LD100 E. coli. Blood 1998;91(5):1609–1615.

    Google Scholar 

  33. Virchow R. Phlagose und thrombose in gefassystein. In: Virchow R, ed. Gesammelte Abhandlungen fur Wissenschaftlichen Medicin. Frankfurt: Von Meidingen Sohn, 1856:458–636.

    Google Scholar 

  34. Slack SM, Cui Y, Turitto VT. The effects of flow on blood coagulation and thrombosis. Thromb Haemost 1993;1:129–133.

    Google Scholar 

  35. Bokisch VA, Top FH Jr, Russell PK, Dixon FJ, Muller-Eberhard HJ. The potential pathogenic role of complement in Dengue hemorrhagic shock syndrome. N Engl J Med 1973;289:996–1003.

    Google Scholar 

  36. Dvorak HF, Van De Water L, Bitzer AM, Dvorak AM, Anderson D, Harvey VS, Bach R, Davis GL, De Wolf W, Carvalho ACA. Procoagulant activity associated with plasma membrane vesicles shed by cultured tumor cells. Cancer Res 1983;43:4434–4443.

    Google Scholar 

  37. Wiedmer T, Esmon CT, Sims PJ. Complement proteins C5b-9 stimulate procoagulant activity through platelet prothrombinase. Blood 1986;68:875–880.

    Google Scholar 

  38. Ando B, Wiedmer T, Hamilton KK, Sims PJ. Complement protein C5b-9 initiates secretion of platelet storage granules without increased binding of fibrinogen on von Willebrand factor to newly expressed cell surfaces GPIIb-IIIa. J Biol Chem 1988;263:11907–11914.

    Google Scholar 

  39. Peerschke EIB, Reid KBM. Induction of AlphaIIb/Beta integrins (GPIIb-IIIa) and expression of procoagulant activity. Thromb Haemost 1993;69(6):785 (Abstract).

    Google Scholar 

  40. Gemmell CH, Sefton MV, Yeo EL.Human plateletmicroparticle generation requires platelet bound fibrinogen: Ligand fidelity ofGPIIb-IIIa.ThrombHaemost 1993;69(6):700 (Abstract).

    Google Scholar 

  41. Zimmerman TS, Müller-Eberhard HJ. Blood coagulation initiation by a complement-mediated pathway. J Exp Med 1971;134:1601–1607.

    Google Scholar 

  42. Holme PA, Solum NO, Brosstad F. Clinical significance of platelet-derived microvesicles, demonstration of their presence in patients suffering from disseminated intravascular coagulation (DIC). Thromb Haemost 1993;69(6):1198 (Abstract).

    Google Scholar 

  43. Galli M, Grassi A, Barbui T. Platelet-derivedmicrovesicles in patients with antiphospholipid antibodies. ThrombHaemost 1993;69(6):541 (Abstract).

    Google Scholar 

  44. Warkentin TE, Hayward CPM, Santos AV, Kelton JG. Platelet-derived microparticles are found in vivo in patients with heparin-induced thrombocytopenia. Thromb Haemost 1993;69(6):912 (Abstract).

    Google Scholar 

  45. He S, Hinshaw L, EmersonT, Kosanke S, White G, Randolph MM, Chang ACK, Duerr M, Peer G, Passey R, Flournoy DJ, Blick K, Taylor FB Jr. Restrospective study comparing the pathophysiology of antibiotic treated and untreated Escherichia-coli-infused and Staphylococcus-aureus infused baboons. Circ Shock 1993;41(2):88–102.

    Google Scholar 

  46. Taylor FB Jr, Esmon CT, Hinshaw LB. Summary of staging, mechanisms, and intervention studies in the baboon model of E. coli sepsis. J Trauma 1991;30(Suppl):S-197.

    Google Scholar 

  47. Taylor FB Jr. Studies of the natural history and mechanism of the primate (baboon) response to Escherichia coli. In: Ryan JL, Morrison DC, eds. Bacterial Endotoxic Lipopolysaccharides, vol. 2., Immunopharmacology and Pathophysiology, Boca Raton, FL: CRCPress, 1991:239.

    Google Scholar 

  48. Voss BL, DeBault LE, Blick KE, Chang ACK, Steiers DL, Hinshaw LB, Taylor FB. Sequential renal alterations in septic shock in the primate. Circ Shock 1991;33:142.

    Google Scholar 

  49. Randolf MM, White GL, Kosanke SD, Bild G, Carr C, Galluppi G, Hinshaw LB, Taylor FB Jr. Attenuation of tissue thrombosis and hemorrhage by ala-TFPI does not account for its protection against E. coli (A comparative study of treated and untreated non-surviving baboons challenged with LD100E. coli). Thromb Haemost 1998;79:1048–1053.

    Google Scholar 

  50. Taylor FB Jr, Chang ACK, Mather T, Blick K, Catlett R, Esmon CT. DEGR-factor Xa blocks disseminated intravascular coagulation initiated by E. coli without preventing shock or organ damage. Blood 1991;78:364.

    Google Scholar 

  51. Hinshaw LB, Tekamp-Olsen P, Chang ACK, et al. Survival of primates in LD100 septic shock following therapy and antibody to tumor necrosis factor (TNF). Circ Shock 1990;30:279.

    Google Scholar 

  52. Taylor FB Jr, Chang ACK, Ruf W, Morrissey JH, Hinshaw LB, Blick KE, Edgington TS. Lethal E. coli septic shock is prevented by blocking tissue factor with monoclonal antibody. Circ Shock 1991;33:127.

    Google Scholar 

  53. Taylor FB Jr. Role of tissue factor and factor VIIa in the coagulant and inflammatory response to LD100 Escherichia coli in the baboon. Haemostasis 1996;26(Suppl 1):83–91.

    Google Scholar 

  54. Rottingen JA, Enden T, Camerer E, Iversen JG, Prydz H. Binding of human factor VIIa to tissue factor induces cytosolic Ca21 signals in J82 cells, transfected COS-1 cells, Madin-Darby canine kidney cells and in human endothelial cells induced to synthesize tissue factor. J Biol Chem 1995;270:4650.

    Google Scholar 

  55. Camerer E, Rottingen JA, Iversen JG, Prydz H. Coagulation factors VII and X induce Ca21 oscillations in Madin-Darby canine kidney cells only when proteolytically active. J Biol Chem 1996;271:29034.

    Google Scholar 

  56. Taylor FB Jr, Chang A, Esmon CT, D' Angelo A, Vigano-D' Angelo S, Blick KE. Protein C prevents the coagulopathic and lethal effects of Escherichia coli infusion in the baboon. J Clin Invest 1987;79:918.

    Google Scholar 

  57. Sandset PM, Warm-Cramer BJ, Rao LV, Maki SL, Rapaport SI. Immunodepletion of extrinsic pathway inhibitor sensitizes rabbits to endotoxin-induced intravascular coagulation. Blood 1991;78:1496–1502.

    Google Scholar 

  58. Taylor FB Jr. Role of tissue factor in the coagulant and inflammatory response to LD100 E. coli sepsis and in the early diagnosis of DIC in the baboon. In: Muller-Berghaus G, et al., eds. DIC: Pathogenesis, Diagnosis and Therapy of Disseminated Intravascular Fibrin Formation. New York: Elsevier Science, 1993:19–32.

    Google Scholar 

  59. Broze GJ Jr. Tissue factor pathway inhibitor and current concept of blood coagulation. Blood Coagul Fibrinol 1995;6:S7–S13.

    Google Scholar 

  60. Rapaport SI. The extrinsic pathway inhibitor: A regulator of tissue factor-dependent blood coagulation. Thromb & Haemost 1991;66(1):6–15.

    Google Scholar 

  61. Kurosawa S, Stearns-Kurosawa DJ, Hidari N, Esmon CT. Identification of functional endothelial protein C receptor in human plasma. J Clin Invest 1995; abstract.

  62. Davie EW. Biochemical and molecular aspects of the coagulation cascade. Thromb Haemostas 1995;74:1–6.

    Google Scholar 

  63. Bom VJJ, Bertina RM. The contributions of Ca21, phospholipids, and tissue factor apoprotein to the activation of human blood coagulation factor X by activated factor VII. Biochem J 1990;265:327–336.

    Google Scholar 

  64. Marcum IA, Rosenberg RD. Anticoagulantly active heparin-like molecules from vascular tissue. Biochemistry 1984; 23:1730.

    Google Scholar 

  65. Calandra T, Bucala R. Macrophage migration inhibitory factor: A counter-regulator of glucocorticoid action and critical mediator of septic shock. J Inflamm 1996;47:39–51.

    Google Scholar 

  66. Hinshaw LB, Beller BK, Chang ACK, Murray CK, Flournoy DJ, Passey RB, Archer LT. Corticosteroid/Antibiotic treatment of adrenalectomized dogs challenged with lethal E. coli. Circ Shock 1985;16:265–277.

    Google Scholar 

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  1. Oklahoma Medical Research Foundation, Oklahoma City, OK, USA

    F.B Taylor Jr. M.D.

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Taylor, F. Baboon Model of E. coli Sepsis: Role of Phospholipid Microparticles in DIC. Sepsis 3, 125–134 (1999). https://doi.org/10.1023/A:1017243016351

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