Download PDF
Hamostaseologie 2011; 31(02): 94-104
DOI: 10.5482/ha-1134
Review
Schattauer GmbH

Coagulation and inflammation

Molecular insights and diagnostic implicationsGerinnung und EntzündungMolekulare Erkenntnisse und diagnostische Implikationen
S. Lipinski
1   Institut für Klinische Molekularbiologie, Christian-Albrechts-Universität, Kiel
,
L. Bremer
1   Institut für Klinische Molekularbiologie, Christian-Albrechts-Universität, Kiel
,
T. Lammers
2   I. Medizinische Klinik, Universitätsklinikum Schleswig-Holstein, Campus Kiel
,
F. Thieme
2   I. Medizinische Klinik, Universitätsklinikum Schleswig-Holstein, Campus Kiel
,
S. Schreiber
1   Institut für Klinische Molekularbiologie, Christian-Albrechts-Universität, Kiel
2   I. Medizinische Klinik, Universitätsklinikum Schleswig-Holstein, Campus Kiel
,
P. Rosenstiel
1   Institut für Klinische Molekularbiologie, Christian-Albrechts-Universität, Kiel
› Author Affiliations
Further Information

Publication History



09 December 2010

Publication Date:
28 December 2017 (online)

Also available at
    Permissions and Reprints

Summary

Overwhelming evidence has linked inflammatory disorders to a hypercoagulable state. In fact, thromboembolic complications are among the leading causes of disability and death in many acute and chronic inflammatory diseases. Despite this clinical knowledge, coagulation and immunity were long regarded as separate entities. Recent studies have unveiled molecular underpinnings of the intimate interconnection between both systems. The studies have clearly shown that distinct pro-inflammatory stimuli also activate the clotting cascade and that coagulation in turn modulates inflammatory signaling pathways.

In this review, we use evidence from sepsis and inflammatory bowel diseases as a paradigm for acute and chronic inflammatory states in general and rise hypotheses how a systematic molecular understanding of the “inflammation-coagulation” crosstalk may result in novel diagnostic and therapeutic strategies that target the inflammation-induced hypercoagulable state.

Zusammenfassung

Seit langem ist bekannt, dass systemische Entzündungen mit einer gesteigerten Blutgerinnung einhergehen. Tatsächlich besteht für Patienten mit akuten oder chronischen Entzündungserkrankungen ein erhöhtes Morbiditäts- und Sterberisiko durch thrombo- embolische Komplikationen. Entgegen dieser klinischen Befunde wurden Hämostase und Immunität in der Vergangenheit i. d. R. als unabhängige Prozesse betrachtet. Aktuelle Studien zeigen nun molekulare Verbindungen auf und bestätigen das enge Zusammenspiel beider Systeme. Immunzellen wie auch bestimmte pro-entzündliche Botenstoffe führen zu einer Aktivierung der Gerinnungskaskade – und umgekehrt beeinflussen Faktoren der Blutgerinnung die Entzündungsantwort.

Dieser Artikel fasst am Beispiel von Sepsis und chronisch-entzündlichen Darmerkrankungen, stellvertretend für akute und chronische Entzündungen, aktuelle Erkenntnisse zusammen und leitet daraus neue diagnostische und therapeutische Strategien ab, die die entzündungsvermittelte pathologische Gerinnungsaktivierung in Zukunft gezielt unterbinden könnten.

Keywords

Coagulation - inflammation - chronic inflammatory diseases - sepsis - biomarkers

Schlüsselwörter

Gerinnung - Entzündung - chronisch-entzünd- liche Erkrankungen - Sepsis - Biomarker
 

  • References

  • 1 Acosta-Salmon H, Southgate PC. Wound healing after excision of mantle tissue from the Akoya pearl oyster, Pinctada fucata. Comp Biochem Physiol A Mol Integr Physiol 2006; 143: 264-268.
    CrossrefPubMedGoogle Scholar
  • 2 Opal SM. Phylogenetic and functional relationships between coagulation and the innate immune response. Crit Care Med 2000; 28 (9 Suppl): S77-S80.
    CrossrefPubMedGoogle Scholar
  • 3 Means TK. et al. Human lupus autoantibody-DNA complexes activate DCs through cooperation of CD32 and TLR9. J Clin Invest 2005; 115: 407-417.
    CrossrefPubMedGoogle Scholar
  • 4 Akira S, Takeda K. Toll-like receptor signalling. Nat Rev Immunol 2004; 04: 499-511.
    CrossrefPubMedGoogle Scholar
  • 5 Akira S, Uematsu S, Takeuchi O. Pathogen recognition and innate immunity. Cell 2006; 124: 783-801.
    CrossrefPubMedGoogle Scholar
  • 6 Levi M, Ten Cate H. Disseminated intravascular coagulation. N Engl J Med 1999; 341: 586-592.
    CrossrefPubMedGoogle Scholar
  • 7 Vervloet MG, Thijs LG, Hack CE. Derangements of coagulation and fibrinolysis in critically ill patients with sepsis and septic shock. Semin Thromb Hemost 1998; 24: 33-44.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 8 Oukka M. et al. A mammalian homolog of Drosophila schnurri, KRC, regulates TNF receptordriven responses and interacts with TRAF2. Mol Cell 2002; 09: 121-131.
    CrossrefPubMedGoogle Scholar
  • 9 Stouthard JM. et al. Interleukin-6 stimulates coagulation, not fibrinolysis, in humans. Thromb Haemost 1996; 76: 738-742.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 10 McGilvray ID, Rotstein OD. Role of the coagulation system in the local and systemic inflammatory response. World J Surg 1998; 22: 179-186.
    CrossrefPubMedGoogle Scholar
  • 11 Conkling PR, Greenberg CS, Weinberg JB. Tumor necrosis factor induces tissue factor-like activity in human leukemia cell line U937 and peripheral blood monocytes. Blood 1988; 72: 128-133.
    PubMedGoogle Scholar
  • 12 Gray E, Thomas S, Mistry Y, Poole S. Inhibition of tissue factor and cytokine release. Haemostasis 1996; 26 (Suppl 1): 92-95.
    PubMedGoogle Scholar
  • 13 Moons AH, Levi M, Peters RJ. Tissue factor and coronary artery disease. Cardiovasc Res 2002; 53: 313-325.
    CrossrefPubMedGoogle Scholar
  • 14 Cermak J. et al. C-reactive protein induces human peripheral blood monocytes to synthesize tissue factor. Blood 1993; 82: 513-520.
    CrossrefPubMedGoogle Scholar
  • 15 Levi M. The coagulant response in sepsis and inflammation. Hämostaseologie 2010; 30: 10-12 14–16..
    Article in Thieme ConnectPubMedGoogle Scholar
  • 16 Burstein SA. Cytokines, platelet production and hemostasis. Platelets 1997; 08: 93-104.
    CrossrefPubMedGoogle Scholar
  • 17 Bernardo A, Ball C, Nolasco L. et al. Effects of inflammatory cytokines on the release and cleavage of the endothelial cell-derived ultralarge von Willebrand factor multimers under flow. Blood 2004; 104: 100-106.
    CrossrefPubMedGoogle Scholar
  • 18 Conway EM, Rosenberg RD. Tumor necrosis factor suppresses transcription of the thrombomodulin gene in endothelial cells. Mol Cell Biol 1988; 08: 5588-5592.
    CrossrefPubMedGoogle Scholar
  • 19 Klein NJ, Shennan GI, Heyderman RS, Levin M. Alteration in glycosaminoglycan metabolism and surface charge on human umbilical vein endothelial cells induced by cytokines, endotoxin and neutrophils. J Cell Sci 1992; 102: 821-832.
    Google Scholar
  • 20 Fukudome K, Esmon CT. Identification, cloning, and regulation of a novel endothelial cell protein C/activated protein C receptor. J Biol Chem 1994; 269: 26486-26491.
    PubMedGoogle Scholar
  • 21 Alcaraz A. et al. Activation of the protein C pathway in acute sepsis. Thromb Res 1995; 79: 83-93.
    CrossrefPubMedGoogle Scholar
  • 22 Takano S, Kimura S, Ohdama S, Aoki N. Plasma thrombomodulin in health and diseases. Blood 1990; 76: 2024-2029.
    PubMedGoogle Scholar
  • 23 Giebler R, Schmidt U, Koch S. et al. Combined antithrombin III and C1-esterase inhibitor treatment decreases intravascular fibrin deposition and attenuates cardiorespiratory impairment in rabbits exposed to Escherichia coli endotoxin. Crit Care Med 1999; 27: 597-604.
    CrossrefPubMedGoogle Scholar
  • 24 Iba T, Kidokoro A, Yagi Y. The role of the endothelium in changes in procoagulant activity in sepsis. J Am Coll Surg 1998; 187: 321-329.
    CrossrefPubMedGoogle Scholar
  • 25 Levi M, van der Poll T. The role of natural anticoagulants in the pathogenesis and management of systemic activation of coagulation and inflammation in critically ill patients. Semin Thromb Hemost 2008; 34: 459-468.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 26 Clark SR. et al. Platelet TLR4 activates neutrophil extracellular traps to ensnare bacteria in septic blood. Nat Med 2007; 13: 463-469.
    CrossrefPubMedGoogle Scholar
  • 27 Brinkmann V. et al. Neutrophil extracellular traps kill bacteria. Science 2004; 303: 1532-1535.
    CrossrefPubMedGoogle Scholar
  • 28 Ma AC, Kubes P. Platelets, neutrophils, and neutrophil extracellular traps (NETs) in sepsis. J Thromb Haemost 2008; 06: 415-420.
    CrossrefPubMedGoogle Scholar
  • 29 Hardaway RM, Chun B, Rutherford RB. Histologic evidence of disseminated intravascular coagulation in clinical shock. Vasc Dis 1965; 02: 254-265.
    PubMedGoogle Scholar
  • 30 Bone RC. et al. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. Chest 2009; 136 (5 Suppl): e28.
    CrossrefPubMedGoogle Scholar
  • 31 Engel C. et al. Epidemiology of sepsis in Germany: results from a national prospective multicenter study. Intensive Care Med 2007; 33: 606-618.
    CrossrefPubMedGoogle Scholar
  • 32 Armstrong L, Medford AR, Hunter KJ. et al. Differential expression of Toll-like receptor (TLR)-2 and TLR-4 on monocytes in human sepsis. Clin Exp Immunol 2004; 136: 312-319.
    CrossrefPubMedGoogle Scholar
  • 33 Levi M, van der Poll T, Buller HR. Bidirectional relation between inflammation and coagulation. Circulation 2004; 109: 2698-2704.
    CrossrefPubMedGoogle Scholar
  • 34 Fourrier F. et al. Septic shock, multiple organ failure, and disseminated intravascular coagulation. Compared patterns of antithrombin III, protein C, and protein S deficiencies. Chest 1992; 101: 816-823.
    CrossrefPubMedGoogle Scholar
  • 35 Lorente JA. et al. Time course of hemostatic abnormalities in sepsis and its relation to outcome. Chest 1993; 103: 1536-1542.
    CrossrefPubMedGoogle Scholar
  • 36 Boldt J, Papsdorf M, Rothe A. et al. Changes of the hemostatic network in critically ill patients--is there a difference between sepsis, trauma, and neurosurgery patients?. Crit Care Med 2000; 28: 445-450.
    CrossrefPubMedGoogle Scholar
  • 37 Esmon CT. Interactions between the innate immune and blood coagulation systems. Trends Immunol 2004; 25: 536-542.
    CrossrefPubMedGoogle Scholar
  • 38 De Pont AC. et al. Endotoxaemia induces resistance to activated protein C in healthy humans. Br J Haematol 2006; 134: 213-219.
    CrossrefPubMedGoogle Scholar
  • 39 Boehme MW. et al. Release of thrombomodulin from endothelial cells by concerted action of TNFalpha and neutrophils: in vivo and in vitro studies. Immunology 1996; 87: 134-140.
    PubMedGoogle Scholar
  • 40 Levi M, van der Poll T, ten Cate H, van Deventer SJ. The cytokine-mediated imbalance between coagulant and anticoagulant mechanisms in sepsis and endotoxaemia. Eur J Clin Invest 1997; 27: 3-9.
    PubMedGoogle Scholar
  • 41 Voss R, Matthias FR, Borkowski G, Reitz D. Activation and inhibition of fibrinolysis in septic patients in an internal intensive care unit. Br J Haematol 1990; 75: 99-105.
    CrossrefPubMedGoogle Scholar
  • 42 Franco RF. et al. The in vivo kinetics of tissue factor messenger RNA expression during human endo- toxemia: relationship with activation of coagulation. Blood 2000; 96: 554-559.
    PubMedGoogle Scholar
  • 43 Yoshida H, Granger DN. Inflammatory bowel disease: a paradigm for the link between coagulation and inflammation. Inflamm Bowel Dis 2009; 15: 1245-1255.
    CrossrefPubMedGoogle Scholar
  • 44 Rosenstiel P, Sina C, Franke A, Schreiber S. Towards a molecular risk map--recent advances on the etiology of inflammatory bowel disease. Semin Immunol 2009; 21: 334-345.
    CrossrefPubMedGoogle Scholar
  • 45 Kaser A, Zeissig S, Blumberg RS. Inflammatory bowel disease. Ann Rev Immunol 2010; 28: 573-621.
    CrossrefPubMedGoogle Scholar
  • 46 Kjeldsen J, Lassen JF, Brandslund I, Schaffalitzky de Muckadell OB. Markers of coagulation and fibrinolysis as measures of disease activity in inflammatory bowel disease. Scand J Gastroenterol 1998; 33: 637-643.
    CrossrefPubMedGoogle Scholar
  • 47 Bernstein CN, Blanchard JF, Houston DS, Wajda A. The incidence of deep venous thrombosis and pulmonary embolism among patients with inflammatory bowel disease: a population-based cohort study. Thromb Haemost 2001; 85: 430-434.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 48 Miehsler W. et al. Is inflammatory bowel disease an independent and disease specific risk factor for thromboembolism?. Gut 2004; 53: 542-548.
    CrossrefPubMedGoogle Scholar
  • 49 Suarez JFCrespo. et al. Thromboembolic complications in inflammatory bowel disease. Gastroenterol Hepatol 1997; 20: 180-183.
    PubMedGoogle Scholar
  • 50 Larsen TB. et al. Platelets and anticoagulant capacity in patients with inflammatory bowel disease. Pathophysiol Haemost Thromb 2002; 32: 92-96.
    CrossrefPubMedGoogle Scholar
  • 51 Bouma BN, Mosnier LO. Thrombin activatable fibrinolysis inhibitor (TAFI) at the interface between coagulation and fibrinolysis. Pathophysiol Haemost Thromb 2003; 33: 375-381.
    CrossrefPubMedGoogle Scholar
  • 52 Folwaczny C. Coagulation system and inflammatory bowel disease: therapeutic and pathophysiologic implications. Z Gastroenterol 2002; 40: 991-998.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 53 Grignani G, Maiolo A. Cytokines and hemostasis. Haematologica 2000; 85: 967-972.
    PubMedGoogle Scholar
  • 54 Esmon CT. Crosstalk between inflammation and thrombosis. Maturitas 2008; 61: 122-131.
    CrossrefPubMedGoogle Scholar
  • 55 Emerson Jr TE, Fournel MA, Redens TB, Taylor Jr FB. Efficacy of antithrombin III supplementation in animal models of fulminant Escherichia coli endo- toxemia or bacteremia. Am J Med 1989; 87: 27S-33S.
    CrossrefPubMedGoogle Scholar
  • 56 Creasey AA. et al. Tissue factor pathway inhibitor reduces mortality from Escherichia coli septic shock. J Clin Invest 1993; 91: 2850-2860.
    CrossrefPubMedGoogle Scholar
  • 57 Mahmood A. et al. Prevalence of hyperhomocysteinaemia, activated protein C resistance and prothrombin gene mutation in inflammatory bowel disease. Eur J Gastroenterol Hepatol 2005; 17: 739-744.
    CrossrefPubMedGoogle Scholar
  • 58 Danese S. Inflammation and the mucosal microcirculation in inflammatory bowel disease: the ebb and flow. Curr Opin Gastroenterol 2007; 23: 384-389.
    CrossrefPubMedGoogle Scholar
  • 59 Boehme MW. et al. Elevated serum levels and reduced immunohistochemical expression of thrombomodulin in active ulcerative colitis. Gastroenterology 1997; 113: 107-117.
    CrossrefPubMedGoogle Scholar
  • 60 Faioni EM. et al. Expression of endothelial protein C receptor and thrombomodulin in the intestinal tissue of patients with inflammatory bowel disease. Crit Care Med 2004; 32 (5 Suppl|): S266-S270.
    CrossrefPubMedGoogle Scholar
  • 61 Scaldaferri F. et al. Crucial role of the protein C pathway in governing microvascular inflammation in inflammatory bowel disease. J Clin Invest 2007; 117: 1951-1960.
    CrossrefPubMedGoogle Scholar
  • 62 Koutroubakis IE. Unraveling the mechanisms of thrombosis in inflammatory bowel disease. Am J Gastroenterol 2001; 96: 1325-1327.
    CrossrefPubMedGoogle Scholar
  • 63 Danese S. et al. Inflammation and coagulation in inflammatory bowel disease: The clot thickens. Am J Gastroenterol 2007; 102: 174-186.
    CrossrefPubMedGoogle Scholar
  • 64 Tsiolakidou G, Koutroubakis IE. Thrombosis and inflammatory bowel disease-the role of genetic risk factors. World J Gastroenterol 2008; 14: 4440-4444.
    CrossrefPubMedGoogle Scholar
  • 65 Koutroubakis IE. et al. Plasma thrombin-activatable fibrinolysis inhibitor and plasminogen activator inhibitor-1 levels in inflammatory bowel disease. Eur J Gastroenterol Hepatol 2008; 20: 912-916.
    CrossrefPubMedGoogle Scholar
  • 66 Saibeni S. et al. Increased thrombin generation in inflammatory bowel diseases. Thromb Res 2010; 125: 278-282.
    CrossrefPubMedGoogle Scholar
  • 67 Vrij AA, Rijken J, van Wersch JW, Stockbrugger RW. Coagulation and fibrinolysis in inflammatory bowel disease and in giant cell arteritis. Pathophysiol Haemost Thromb 2003; 33: 75-83.
    CrossrefPubMedGoogle Scholar
  • 68 Bernhard H. et al. Calibrated automated thrombin generation in paediatric patients with inflammatory bowel disease. Hämostaseologie 2009; 29 (Suppl. 01) S90-S93.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 69 Shen J. et al. Biomarkers of altered coagulation and fibrinolysis as measures of disease activity in active inflammatory bowel disease: a gender-stratified, cohort analysis. Thromb Res 2009; 123: 604-611.
    CrossrefPubMedGoogle Scholar
  • 70 Kalsch T. et al. Endotoxin-induced effects on platelets and monocytes in an in vivo model of inflammation. Basic Res Cardiol 2007; 102: 460-466.
    CrossrefPubMedGoogle Scholar
  • 71 Edgar JD, Gabriel V, Gallimore JR. et al. A prospective study of the sensitivity, specificity and diagnostic performance of soluble intercellular adhesion molecule 1, highly sensitive C-reactive protein, soluble E-selectin and serum amyloid A in the diagnosis of neonatal infection. BMC Pediatr 2010; 10: 22.
    CrossrefPubMedGoogle Scholar
  • 72 Stief TW. et al. Analysis of hemostasis alterations in sepsis. Blood Coagul Fibrinolysis 2007; 18: 179-186.
    CrossrefPubMedGoogle Scholar
  • 73 Fox EA, Kahn SR. The relationship between inflammation and venous thrombosis. A systematic review of clinical studies. Thromb Haemost 2005; 94: 362-365.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 74 Reitsma PH, Rosendaal FR. Activation of innate immunity in patients with venous thrombosis: the Leiden Thrombophilia Study. J Thromb Haemost 2004; 02: 619-622.
    CrossrefPubMedGoogle Scholar
  • 75 Van Aken BE, den Heijer M, Bos GM. et al. Recurrent venous thrombosis and markers of inflammation. Thromb Haemost 2000; 83: 536-539.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 76 Pereira C, Schaer DJ, Bachli EB. et al. Wnt5A/CaMKII signaling contributes to the inflammatory response of macrophages and is a target for the antiinflammatory action of activated protein C and interleukin-10. Arterioscler Thromb Vasc Biol 2008; 28: 504-510.
    CrossrefPubMedGoogle Scholar
  • 77 Sturn DH. et al. Expression and function of the endothelial protein C receptor in human neutrophils. Blood 2003; 102: 1499-1505.
    CrossrefPubMedGoogle Scholar
  • 78 Cao C. et al. The efficacy of activated protein C in murine endotoxemia is dependent on integrin CD11b. J Clin Invest 2010; 120: 1971-1980.
    CrossrefPubMedGoogle Scholar
  • 79 Bernard GR. et al. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 2001; 344: 699-709.
    CrossrefPubMedGoogle Scholar
  • 80 Yoshida H. et al. Role of the protein C pathway in the extraintestinal thrombosis associated with murine colitis. Gastroenterology 2008; 135: 882-888.
    CrossrefPubMedGoogle Scholar
  • 81 Danese S, Vetrano S, Zhang L. et al. The protein C pathway in tissue inflammation and injury: pathogenic role and therapeutic implications. Blood 2010; 115: 1121-1130.
    CrossrefPubMedGoogle Scholar
  • 82 Levi M. et al. Prophylactic heparin in patients with severe sepsis treated with drotrecogin alfa (activated). Am J Respir Crit Care Med 2007; 176: 483-490.
    CrossrefPubMedGoogle Scholar
  • 83 Agarwal R, Gupta D. Anticoagulation in sepsis: is low-dose heparin as effective as activated protein C?. Intensive Care Med 2005; 31: 1297-1298.
    CrossrefPubMedGoogle Scholar
  • 84 Priglinger U. et al. Prophylactic anticoagulation with enoxaparin: Is the subcutaneous route appropriate in the critically ill?. Crit Care Med 2003; 31: 1405-1409.
    CrossrefPubMedGoogle Scholar
  • 85 Zuo XJ, Nicolaidou E, Okada Y. et al. Antithrombin III inhibits lymphocyte proliferation, immunoglobulin production and mRNA expression of lymphocyte growth factors (IL-2, gamma-IFN and IL-4) in vitro. Transpl Immunol 2001; 09: 1-6.
    CrossrefPubMedGoogle Scholar
  • 86 Derhaschnig U. et al. Evaluation of antiinflammatory and antiadhesive effects of heparins in human endotoxemia. Crit Care Med 2003; 31: 1108-1112.
    CrossrefPubMedGoogle Scholar
  • 87 Vrij AA. et al. Thrombin generation in mesalazine refractory ulcerative colitis and the influence of low molecular weight heparin. J Thromb Thrombolysis 2007; 24: 175-182.
    CrossrefPubMedGoogle Scholar
  • 88 De Bievre MA. et al. Randomized, placebo-controlled trial of low molecular weight heparin in active ulcerative colitis. Inflamm Bowel Dis 2007; 13: 753-758.
    CrossrefPubMedGoogle Scholar
  • 89 Malhotra S. et al. A comparison of observational studies and controlled trials of heparin in ulcerative colitis. Int J Clin Pharmacol Ther 2004; 42: 690-694.
    CrossrefPubMedGoogle Scholar
  • 90 Pastorelli L. et al. Oral, colonic-release low-molecular-weight heparin: an initial open study of Parnaparin-MMX for the treatment of mild-to-moderate left-sided ulcerative colitis. Aliment Pharmacol Ther 2008; 28: 581-588.
    CrossrefPubMedGoogle Scholar
  • 91 Chande N, McDonald JW, Macdonald JK. Unfractionated or low-molecular weight heparin for induction of remission in ulcerative colitis. Cochrane Database Syst Rev 2008; 16: CD006774.
    PubMedGoogle Scholar
  • 92 Hinshaw LB. et al. Study of septic shock in the nonhuman primate: relationship of pathophysiological response to therapy with anti-TNF antibody. Circ Shock 1994; 44: 221-229.
    PubMedGoogle Scholar
  • 93 Hinshaw LB. et al. Lethal Staphylococcus aureus-induced shock in primates: prevention of death with anti-TNF antibody. J Trauma 1992; 33: 568-573.
    CrossrefPubMedGoogle Scholar
  • 94 Hinshaw LB. et al. Survival of primates in LD100 septic shock following therapy with antibody to tumor necrosis factor (TNF alpha). Circ Shock 1990; 30: 279-292.
    PubMedGoogle Scholar
  • 95 Clark MA. et al. Effect of a chimeric antibody to tumor necrosis factor-alpha on cytokine and physiologic responses in patients with severe sepsis--a randomized, clinical trial. Crit Care Med 1998; 26: 1650-1659.
    CrossrefPubMedGoogle Scholar
  • 96 Goode S, Tierney G, Deighton C. Life threatening intra-abdominal sepsis in patients on anti-TNFalpha therapy. Gut 2006; 55: 590-591.
    CrossrefPubMedGoogle Scholar
  • 97 Ho GT. et al. Efficacy and complications of adalimumab treatment for medically-refractory Crohn’s disease: analysis of nationwide experience in Scotland (2004–2008). Aliment Pharmacol Ther 2009; 29: 527-534.
    CrossrefPubMedGoogle Scholar
  • 98 Favalli EG. et al. Serious infections during anti- TNFalpha treatment in rheumatoid arthritis patients. Autoimmun Rev 2009; 08: 266-273.
    CrossrefPubMedGoogle Scholar
  • 99 Ingegnoli F. et al. Inflammatory and prothrombotic biomarkers in patients with rheumatoid arthritis: effects of tumor necrosis factor-alpha blockade. J Autoimmun 2008; 31: 175-179.
    CrossrefPubMedGoogle Scholar
  • 100 Petitpain N. et al. Arterial and venous thromboembolic events during anti-TNF therapy: a study of 85 spontaneous reports in the period 2000–2006. Biomed Mater Eng 2009; 19: 355-364.
    PubMedGoogle Scholar
  • 101 Gross V, Andus T, Leser HG. et al. Inflammatory mediators in chronic inflammatory bowel diseases. Klin Wochenschr 1991; 69: 981-987.
    CrossrefPubMedGoogle Scholar
  • 102 Hoang P, Fiasse R, Van Heuverzwyn R, Sibille C. Role of cytokines in inflammatory bowel disease. Acta Gastroenterol Belg 1994; 57: 219-223.
    PubMedGoogle Scholar
  • 103 Yurekli BP. et al. The search for a common thrombophilic state during the active state of inflammatory bowel disease. J Clin Gastroenterol 2006; 40: 809-813.
    CrossrefPubMedGoogle Scholar
  • 104 Bjerregaard LT. et al. Hyperhomocysteinaemia, coagulation pathway activation and thrombophilia in patients with inflammatory bowel disease. Scand J Gastroenterol 2002; 37: 62-67.
    CrossrefPubMedGoogle Scholar