FREE NEJM E-TOC    HOME   |   SUBSCRIBE   |   CURRENT ISSUE   |   PAST ISSUES   |   COLLECTIONS   |   Search Term  Advanced Search

Sign in | Get NEJM's E-Mail Table of Contents — Free | Subscribe

Previous Volume 320:1165-1172 May 4, 1989 Number 18 Next

	Add to Personal Archive Add to Citation Manager Notify a Friend E-mail When Cited PubMed Citation

Abstract

To evaluate the effect of endotoxin on the fibrinolytic response, we administered Escherichia coli endotoxin (4 ng per kilogram of body weight) intravenously to 19 healthy volunteers and measured fibrinolytic proteins, protease inhibitors, neutrophil elastase, and von Willebrand factor in serial blood samples obtained over 24 hours. One hour after endotoxin administration, the level of tissue plasminogen activator (t-PA) antigen rose from 10 to 23 ng per milliliter, peaking at 52 ng per milliliter at three hours. The level of alpha 2-plasmin inhibitor-plasmin complexes increased sevenfold, peaking at three hours. Plasminogen-activator inhibitor-1 activity rose more slowly, from 7 U per milliliter to a maximum of 49 U per milliliter at five hours. The concentrations of neutrophil elastase and von Willebrand antigen were unchanged at one hour, increased approximately threefold by 3 hours, and remained elevated at 24 hours. None of these measures changed in a control group (n = 5) given intravenous saline instead of endotoxin. We studied t-PA functional activity in four subjects. The level of activity rose rapidly, from 1.2 ng per milliliter at base line to 8.3 ng per milliliter at one hour and 13.9 ng per milliliter at two hours; it was undetectable at three hours. This increase in plasminogen activator activity was abolished in vitro by incubation of t-PA with an antiserum specific for human t-PA, suggesting that t-PA may be directly responsible for plasmin generation in the response to endotoxin. We conclude from this study of healthy subjects that endotoxin activates the fibrinolytic system, beginning with release of t-PA in the blood within one hour. The early activation of plasmin by endotoxin may prevent thrombosis, and the increase in fibrinolysis is then offset by the release of plasminogen activator inhibitor.

Source Information

Critical Care Medicine Department, National Institutes of Health, Bethesda, Md. 20892.

This article has been cited by other articles:

• Bahador, M., Cross, A. S. (2007). Review: From therapy to experimental model: a hundred years of endotoxin administration to human subjects. Innate Immunity 13: 251-279 [Abstract]  
• Komissarov, A. A., Zhou, A., Declerck, P. J. (2007). Modulation of Serpin Reaction through Stabilization of Transient Intermediate by Ligands Bound to {alpha}-Helix F. J. Biol. Chem. 282: 26306-26315 [Abstract] [Full Text]  
• Abraham, E. (2005). Effects of Recombinant Human Activated Protein C in Human Models of Endotoxin Administration. Proc Am Thorac Soc 2: 243-247 [Abstract] [Full Text]  
• Zeerleder, S., Hack, C. E., Wuillemin, W. A. (2005). Disseminated Intravascular Coagulation in Sepsis. Chest 128: 2864-2875 [Abstract] [Full Text]  
• van der Poll, T., Levi, M., Nick, J. A., Abraham, E. (2005). Activated Protein C Inhibits Local Coagulation after Intrapulmonary Delivery of Endotoxin in Humans. Am. J. Respir. Crit. Care Med. 171: 1125-1128 [Abstract] [Full Text]  
• Yamamoto, K., Takeshita, K., Kojima, T., Takamatsu, J., Saito, H. (2005). Aging and plasminogen activator inhibitor-1 (PAI-1) regulation: implication in the pathogenesis of thrombotic disorders in the elderly. Cardiovasc Res 66: 276-285 [Abstract] [Full Text]  
• Pleiner, J., Schaller, G., Mittermayer, F., Zorn, S., Marsik, C., Polterauer, S., Kapiotis, S., Wolzt, M. (2004). Simvastatin Prevents Vascular Hyporeactivity During Inflammation. Circulation 110: 3349-3354 [Abstract] [Full Text]  
• Renckens, R., Weijer, S., de Vos, A. F., Pater, J. M., Meijers, J. C., Hack, C. E., Levi, M., van der Poll, T. (2004). Inhibition of Plasmin Activity by Tranexamic Acid Does Not Influence Inflammatory Pathways During Human Endotoxemia. Arterioscler. Thromb. Vasc. Bio. 24: 483-488 [Abstract] [Full Text]  
• Lynn, M., Wong, Y. N., Wheeler, J. L., Kao, R. J., Perdomo, C. A., Noveck, R., Vargas, R., D'Angelo, T., Gotzkowsky, S., McMahon, F. G., Wasan, K. M., Rossignol, D. P. (2004). Extended in Vivo Pharmacodynamic Activity of E5564 in Normal Volunteers with Experimental Endotoxemia. J. Pharmacol. Exp. Ther. 308: 175-181 [Abstract] [Full Text]  
• Zeerleder, S., Caliezi, C., van Mierlo, G., Eerenberg-Belmer, A., Sulzer, I., Hack, C. E., Wuillemin, W. A. (2003). Administration of C1 Inhibitor Reduces Neutrophil Activation in Patients with Sepsis. CVI 10: 529-535 [Abstract] [Full Text]  
• Prabhakaran, P., Ware, L. B., White, K. E., Cross, M. T., Matthay, M. A., Olman, M. A. (2003). Elevated levels of plasminogen activator inhibitor-1 in pulmonary edema fluid are associated with mortality in acute lung injury. Am. J. Physiol. Lung Cell. Mol. Physiol. 285: L20-L28 [Abstract] [Full Text]  
• Aird, W. C. (2003). The Hematologic System as a Marker of Organ Dysfunction in Sepsis. Mayo Clin Proc. 78: 869-881 [Abstract]  
• Fiuza, C., Bustin, M., Talwar, S., Tropea, M., Gerstenberger, E., Shelhamer, J. H., Suffredini, A. F. (2003). Inflammation-promoting activity of HMGB1 on human microvascular endothelial cells. Blood 101: 2652-2660 [Abstract] [Full Text]  
• Yamamoto, K., Shimokawa, T., Yi, H., Isobe, K.-i., Kojima, T., Loskutoff, D. J., Saito, H. (2002). Aging Accelerates Endotoxin-Induced Thrombosis : Increased Responses of Plasminogen Activator Inhibitor-1 and Lipopolysaccharide Signaling with Aging. Am. J. Pathol. 161: 1805-1814 [Abstract] [Full Text]  
• Yan, S. B., Helterbrand, J. D., Hartman, D. L., Wright, T. J., Bernard, G. R. (2001). Low Levels of Protein C Are Associated With Poor Outcome in Severe Sepsis. Chest 120: 915-922 [Abstract] [Full Text]  
• Horton, M. R., Olman, M. A., Bao, C., White, K. E., Choi, A. M. K., Chin, B.-Y., Noble, P. W., Lowenstein, C. J. (2000). Regulation of plasminogen activator inhibitor-1 and urokinase by hyaluronan fragments in mouse macrophages. Am. J. Physiol. Lung Cell. Mol. Physiol. 279: L707-L715 [Abstract] [Full Text]  
• de Jonge, E., Dekkers, P. E. P., Creasey, A. A., Hack, C. E., Paulson, S. K., Karim, A., Kesecioglu, J., Levi, M., van Deventer, S. J. H., van der Poll, T. (2000). Tissue factor pathway inhibitor dose-dependently inhibits coagulation activation without influencing the fibrinolytic and cytokine response during human endotoxemia. Blood 95: 1124-1129 [Abstract] [Full Text]  
• Taylor, F. JR, Haddad, P.A., Kinasewitz, G., Chang, A., Peer, G., Allen, R. C. (2000). Luminescence studies of the phagocyte response to endotoxin infusion into normal human subjects: multiple discriminant analysis of luminescence response and correlation with phagocyte morphologic changes and release of elastase. Innate Immunity 6: 3-15 [Abstract]  
• Mattila, K.J., Asikainen, S., Wolf, J., Jousimies-Somer, H., Valtonen, V., Nieminen, M. (2000). Age, Dental Infections, and Coronary Heart Disease. JDR 79: 756-760 [Abstract]  
• Pernerstorfer, T., Hollenstein, U., Hansen, J.-B., Knechtelsdorfer, M., Stohlawetz, P., Graninger, W., Eichler, H.-G., Speiser, W., Jilma, B. (1999). Heparin Blunts Endotoxin-Induced Coagulation Activation. Circulation 100: 2485-2490 [Abstract] [Full Text]  
• Levi, M., ten Cate, H. (1999). Disseminated Intravascular Coagulation. NEJM 341: 586-592 [Full Text]  
• van Mourik, J. A., Boertjes, R., Huisveld, I. A., Fijnvandraat, K., Pajkrt, D., van Genderen, P. J.J., Fijnheer, R. (1999). von Willebrand Factor Propeptide in Vascular Disorders: A Tool to Distinguish Between Acute and Chronic Endothelial Cell Perturbation. Blood 94: 179-185 [Abstract] [Full Text]  
• Kupferwasser, L. I., Hafner, G., Mohr-Kahaly, S., Erbel, R., Meyer, J.u., Darius, H. (1999). The presence of infection-related antiphospholipid antibodies in infective endocarditis determines a major risk factor for embolic events. J Am Coll Cardiol 33: 1365-1371 [Abstract] [Full Text]  
• Yamamoto, K., de Waard, V., Fearns, C., Loskutoff, D. J. (1998). Tissue Distribution and Regulation of Murine von Willebrand Factor Gene Expression In Vivo. Blood 92: 2791-2801 [Abstract] [Full Text]  
• KERMARREC, N., ZUNIC, P., BELOUCIF, S., BENESSIANO, J., DROUET, L., PAYEN, D. (1998). Impact of Inhaled Nitric Oxide on Platelet Aggregation and Fibrinolysis in Rats with Endotoxic Lung Injury . Role of Cyclic Guanosine 5'-monophosphate. Am. J. Respir. Crit. Care Med. 158: 833-839 [Abstract] [Full Text]  
• Barbui, T., Finazzi, G., Falanga, A. (1998). The Impact of All-trans-Retinoic Acid on the Coagulopathy of Acute Promyelocytic Leukemia. Blood 91: 3093-3102 [Full Text]  
• KAYAL, S., JAIS, J.-P., AGUINI, N., CHAUDIERE, J., LABROUSSE, J. (1998). Elevated Circulating E-Selectin, Intercellular Adhesion Molecule 1, and von Willebrand Factor in Patients with Severe Infection. Am. J. Respir. Crit. Care Med. 157: 776-784 [Abstract] [Full Text]  
• Jourdain, M, Carrette, O, Tournoys, A, Fourrier, F, Mizon, C, Mangalaboyi, J, Goudemand, J, Mizon, J, Chopin, C (1997). Effects of inter-alpha-inhibitor in experimental endotoxic shock and disseminated intravascular coagulation. Am. J. Respir. Crit. Care Med. 156: 1825-1833 [Abstract] [Full Text]  
• Pajkrt, D., Manten, A., van der Poll, T., Tiel-van Buul, M. M.C., Jansen, J., Wouter ten Cate, J., J.H. van Deventer, S. (1997). Modulation of Cytokine Release and Neutrophil Function by Granulocyte Colony-Stimulating Factor During Endotoxemia in Humans. Blood 90: 1415-1424 [Abstract] [Full Text]  
• van der Poll, T., Coyle, S. M., Levi, M., Jansen, P. M., Dentener, M., Barbosa, K., Buurman, W. A., Hack, C. E., ten Cate, J. W., Agosti, J. M., Lowry, S. F. (1997). Effect of a Recombinant Dimeric Tumor Necrosis Factor Receptor on Inflammatory Responses to Intravenous Endotoxin in Normal Humans. Blood 89: 3727-3734 [Abstract] [Full Text]  
• Pajkrt, D., van der Poll, T., Levi, M., Cutler, D. L., Affrime, M. B., van den Ende, A., Wouter ten Cate, J., J.H. van Deventer, S. (1997). Interleukin-10 Inhibits Activation of Coagulation and Fibrinolysis During Human Endotoxemia. Blood 89: 2701-2705 [Abstract] [Full Text]  
• Christ, G., Hufnagl, P., Kaun, C., Mundigler, G., Laufer, G., Huber, K., Wojta, J., Binder, B. R. (1997). Antifibrinolytic Properties of the Vascular Wall: Dependence on the History of Smooth Muscle Cell Doublings In Vitro and In Vivo. Arterioscler. Thromb. Vasc. Bio. 17: 723-730 [Abstract] [Full Text]  
• Macko, R. F., Ameriso, S. F., Gruber, A., Griffin, J. H., Fernandez, J. A., Barndt, R., Quismorio, F. P., Weiner, J. M., Fisher, M. (1996). Impairments of the Protein C System and Fibrinolysis in Infection-Associated Stroke. Stroke 27: 2005-2011 [Abstract] [Full Text]  
• Kario, K., Matsuo, T., Kobayashi, H., Matsuo, M., Sakata, T., Miyata, T. (1995). Activation of Tissue Factor–Induced Coagulation and Endothelial Cell Dysfunction in Non–Insulin-Dependent Diabetic Patients With Microalbuminuria. Arterioscler. Thromb. Vasc. Bio. 15: 1114-1120 [Abstract] [Full Text]  
• Joseph, J., Scopelitis, E. (1994). Seronegative Antiphospholipid Syndrome Associated with Plasminogen Activator Inhibitor. Lupus 3: 201-203 [Abstract]  
• Levi, M., Cate, H. t., van der Poll, T., van Deventer, S. J. H. (1993). Pathogenesis of Disseminated Intravascular Coagulation in Sepsis. JAMA 270: 975-979 [Abstract]  
• da Silva, A. M. T., Kaulbach, H. C., Chuidian, F. S., Lambert, D. R., Suffredini, A. F., Danner, R. L. (1993). Shock and Multiple-Organ Dysfunction after Self-Administration of Salmonella Endotoxin. NEJM 328: 1457-1460 [Full Text]  
• Parrillo, J. E. (1993). Pathogenetic Mechanisms of Septic Shock. NEJM 328: 1471-1478 [Full Text]  
• Bone, R. C. (1992). Modulators of Coagulation: A Critical Appraisal of Their Role in Sepsis. Arch Intern Med 152: 1381-1389 [Abstract]  
• Greenman, R. L., Schein, R. M. H., Martin, M. A., Wenzel, R. P., Maclntyre, N. R., Emmanuel, G., Chmel, H., Kohler, R. B., McCarthy, M., Plouffe, J., Russell, J. A., XOMA Sepsis Study Group, , Hollender, E., Immerman, R., Pfaller, M., Sheetz, C., Jebson, P., Houston, A., Rehak, D., Empson, P., Ireland, J., Narain, S., Rashkin, J. E., Jacobs, R. A., Octavio, J., Coleman, R., Kenyon, V. S., Yangco, B. G., Toney, J. F., Edwards, J., Crislip, M., Quenzer, R. W., Trenholme, G. M., Schmitt, B. A., Grossman, J. E., Daley, C. L., Chambers, H. F., Iannini, P. B., Graziano, T., Dandurand, R., Schieiter, G., Kunkel, M., Pankey, G. A., Mayeur, B., Abadie-Kemmerly, S., Zachery, J., Meadors, M., Coco, J., Sanders, C. V., George, W. L., Gardner, S., Finegold, S., Bernard, G. R., Bogden, P., Bello, E., Ellrodt, A. G., Dauer, J., Riedinger, M. S., Meyers, B. R., Iberti, T., Rissing, J. P., Nelson, D., Luu, Q., Campbell, G. D., Olsen, K., Carvalho, A., Brown, A. E., Schmitt, H. J., Brown, S., Schentag, J. J., Wels, P. B., Wing, P. E., Welage, L. S., Quintiliani, R., Chandrasekar, P. H., Ratzan, K. R., Dunn, D. L., Gorelick, K., Wedel, N., Saks, S., Hannigan, J., Ackerman, S. K., Scannon, P. J., Salsburg, D., Webb, C. D. (1991). A Controlled Clinical Trial of E5 Murine Monoclonal IgM Antibody to Endotoxin in the Treatment of Gram-Negative Sepsis. JAMA 266: 1097-1102 [Abstract]  
• Parrillo, J. E., Parker, M. M., Natanson, C., Suffredini, A. F., Danner, R. L., Cunnion, R. E., Ognibene, F. P. (1990). Septic Shock in Humans: Advances in the Understanding of Pathogenesis, Cardiovascular Dysfunction, and Therapy. ANN INTERN MED 113: 227-242 [Abstract]