Infusion of Phospholipid Vesicles Amplifies the Local Thrombotic Response to TNF and Anti-Protein C into a Consumptive Response

Summary

Inflammation often is considered a contributing factor to both thrombosis and disseminated intravascular coagulation. The molecular mechanisms that dictate which of these clinical manifestations will result from the inflammatory stimulus remain obscure. Bacterial infection and certain tumors are common initiators of the disseminated intravascular coagulant response. Complement activation resulting from bacterial infection shares with selected tumors the capacity to generate or release membrane particles that lack functional adhesion receptors and hence could circulate to amplify a disseminated intravascular coagulant response. We developed a model of venous thrombosis that resulted in localized thrombus formation without disseminated intravascular coagulation. The model involves infusion of tumor necrosis factor, blockade of protein C and a partial decrease in venous flow caused by ligation of the superficial femoral vein without obstruction of the deep femoral vein. Infusion of phospholipid vesicles into this model resulted in amplification of a localized thrombotic response into a consumptive response.

Seven different groups of animals were studied. The first three groups established the conditions necessary to produce deep vein thrombosis. The second four groups established the conditions necessary to produce disseminated intravascular coagulation. The infusion of phospholipid vesicles plus tumor necrosis factor and anti-protein C antibody resulted in consumption of fibrinogen, the production of thrombin/antithrombin complexes, a fall in platelet count, and venous thrombosis. Without ligation and catheterization phospholipid vesicles failed to produce the consumptive response. We conclude, therefore, that phospholipid vesicles can amplify a local thrombotic response into a consumptive response, and that vesiculation accompanying inflammation is one means by which localized coagulant activity may be amplified to produce disseminated intravascular coagulation.

• References

• 1 Nawroth PP, Stem DM. Modulation of endothelial cell hemostatic properties by tumor necrosis factor. J Exp Med 1986; 163: 740-745
• 2 Moore KL, Esmon CT, Esmon NL. Tumor necrosis factor leads to internalization and degradation of thrombomodulin from the surface of bovine aortic endothelial cells in culture. Blood 1989; 73: 159-165
• 3 Comp PC, Doray D, Patton D, Esmon CT. An abnormal plasma distribution of protein S occurs in functional protein S deficiency. Blood 1986; 67: 504-508
• 4 Colucci M, Paramo JA, Collen D. Generation in plasma of fast-acting inhibitor of plasminogen activator in response to endotoxin stimulation. J Clin Invest 1985; 75: 818-821
• 5 McEver R. Role of endothelium in the inflammatory response. In: Critical Care Shoemaker WC, Taylor RW. eds. The Society of Critical Medicine. State of the Art, 12th Edition; Fullerton, CA: 1991: 121-141
• 6 Taylor Jr FB, Esmon CT, Chang A. Primate model of deep vein thrombosis induced by inflammatory mediators. Circulation 1990 82. III-770 (abstr).
• 7 Wakefield TW, Wrobleski SK, Sarpa MS, Taylor Jr FB, Esmon CT, Cheng A, Greenfield LJ. Deep venous thrombosis in the baboon: An experimental model. J Vase Surg 1991; 14: 588-598
• 8 Taylor Jr FB, Hoogendoom 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 1992; 79: 1720-1728
• 9 Sack Jr GH, Levin J, Bell WR. Trousseau’s syndrome and other manifestations of chronic disseminated coagulopathy in patients with neoplasms: Clinical, pathologic, and therapeutic features. (Baltimore) Medicine 1977; 56: 1-13
• 10 Neame PB, Kelton JG, Walker IR, Stewart IO, Nossel HL, Hirsh J. Thrombocytopenia in septicemia: The role of disseminated intravascular coagulation. Blood 1980; 56: 88-94
• 11 Srichaikul TS, Nimmanitaya N, Artchararit T, Siriasawakul T, Sungpeuk P. Fibrinogen metabolism and disseminated intravascular coagulation in Dengue Hemorrhagic Fever. Am J Trop Med Hygiene 1977; 26 (03) 525-531
• 12 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
• 13 Dvorak HF, Quay SC, Orenstein NS, Dvorak AM, Hahn P, Bitzer AM. Tumor shedding and coagulation. Science 1981; 212: 923-927
• 14 de Boer JP, Creasey AA, Chang A, Roem D, Eerenberg AJM, Hack CE, Taylor Jr FB. Activation of the complement system in baboons challenged with live Escherichia coli: Correlation with mortality and evidence for a biphasic activation pattern. Infect Immun 1993; 61 (10) 4293-4301
• 15 Bokisch VA, Top Jr FH, 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
• 16 Sims PJ, Faioni EM, Wiedmer T, Shattil SJ. Complement proteins C5b-9 cause release of membrane vesicles from the platelet surface that are enriched in the membrane receptor for coagulation factor Va and express prothrombinase activity. J Biol Chem 1988; 263: 18205-8212
• 17 Wiedmer T, Esmon CT, Sims PJ. Complement proteins C5b-9 stimulate procoagulant activity through platelet prothrombinase. Blood 1986; 68: 875-880
• 18 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
• 19 Owen WG, Esmon CT, Jackson CM. The conversion of prothrombin to thrombin. Characterization of the reaction products formed during the activation of bovine prothrombin. J Biol Chem 1974; 249: 594-605
• 20 Steams DJ, Kurosawa S, Sims PJ, Esmon NL, Esmon CT. The interaction of a Ca²⁺-dependent monoclonal antibody with the protein C activation peptide region: Evidence for obligatory Ca²⁺ binding to both antigen and antibody. J Biol Chem 1988; 263: 826-832
• 21 Steams DJ, Kurosawa S, Esmon CT. Micro-thrombomodulin: Residue 310-486 from the epidermal growth factor precursor-homology domain of thrombomodulin will accelerate protein C activation. J Biol Chem 1989; 264: 3352-3356
• 22 Taylor Jr FB, 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: 918-925
• 23 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
• 24 Rezaie AR, Fiore EM, Neuenschwander PF, Esmon CT, Morrissey JH. Expression and purification of a soluble tissue factor fusion protein with an epitope for an unusual calcium-dependent antibody. Protein Exp Purif 1992; 3: 453-460
• 25 Barenholz Y, Gibbes D, Litman BJ, Goll J, Thompson D, Carlson FD. A simple method for the preparation of homogeneous phospholipid vesicles. Biochem J 1977; 16: 2806-2811
• 26 Hougie C. Methods for estimating fibrinogen concentration, thrombin time test. In: Hematology Williams WJ, Beutler E, Erslev AJ, Lichtman MA. eds. McGraw-Hill, New York, NY: 1983: 1667
• 27 Wellcome Research Laboratories. Fibrinogen degradation products Thrombo-Wellcotest (rapid latex kit). Purley, Surrey, UK: Southern Press; 1984
• 28 Gretch DR, Suter M, Stinski MF. The use of biotinylated monoclonal antibodies and streptavidin affinity chromatography to isolate herpes virus. Anal Biochem 1987; 163: 270-277
• 29 Esmon CT, Taylor Jr FB, Snow TR. Inflammation and coagulation: Linked processes potentially regulated through a common pathway mediated by protein C. Thromb Haemost 1991; 66: 160-165
• 30 Beutler B, Cerami A. The history, properties, and biological effects of cachectin. Biochemistry 1988; 27: 7575-7582
• 31 Comp PC, Esmon CT. Recurrent venous thromboembolism in patients with partial deficiency of protein S. N Engl J Med 1984; 311: 1525-1528
• 32 Loike JD, Silverstein R, Wright SD, Weitz JI, Huang AJ, Silverstein SC. The role of protected extracellular compartments in interactions between leukocytes, and platelets, and fibrin/fibrinogen matrices. Annals of New York Academy of Science 1992; 667: 167-173
• 33 Northeast ADR, Bumand KG. The response of the vessel wall to thrombosis: The in vivo study of venous thrombolysis. Annals of New York Academy of Science 1992; 667: 127-150
• 34 Peerschke EIB, Reid KBM. Induction of Alphallb/Beta integrins (GPIIb-IIIa) and expression of procoagulant activity. Thromb Haemost 1993; 69 (06) 785 (abstr).
• 35 Gemmell CH, Sefton MV, Yeo EL. Human platelet microparticle generation requires platelet bound fibrinogen: Ligand fidelity of GPIIb-IIIa. Thromb Haemost 1993; 69 (06) 700 (abstr).
• 36 Zimmerman TS, Muller-Eberhard HJ. Blood coagulation initiation by a complement-mediated pathway. J Exp Med 1971; 134: 1601-1607
• 37 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 (06) 1198 (abstr).
• 38 Galli M, Grassi A, Barbui T. Platelet-derived micro vesicles in patients with antiphospholipid antibodies. Thromb Haemost 1993; 69 (06) 541 (abstr).
• 39 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 (06) 912 (abstr)
• 40 He S, Hinshaw L, Emerson T, Kosanke S, White G, Randolph MM, Chang ACK, Duerr M, Peer G, Passey R, Flournoy DJ, Blick K, Taylor Jr FB. Retrospective study comparing the pathophysiology of antibiotic treated and untreated Escherichia-coli-infused and Staphylococcus-aureus infused baboons. Circ Shock 1993; 41 (02) 88-102