Coagulation and inflammation

S. Lipinski; L. Bremer; T. Lammers; F. Thieme; S. Schreiber; P. Rosenstiel

doi:10.5482/ha-1134

Hämostaseologie, Table of Contents

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

Authors

S. Lipinski

¹Institut für Klinische Molekularbiologie, Christian-Albrechts-Universität, Kiel
L. Bremer

¹Institut für Klinische Molekularbiologie, Christian-Albrechts-Universität, Kiel
T. Lammers

²I. Medizinische Klinik, Universitätsklinikum Schleswig-Holstein, Campus Kiel
F. Thieme

²I. Medizinische Klinik, Universitätsklinikum Schleswig-Holstein, Campus Kiel
S. Schreiber

¹Institut für Klinische Molekularbiologie, Christian-Albrechts-Universität, Kiel

²I. Medizinische Klinik, Universitätsklinikum Schleswig-Holstein, Campus Kiel
P. Rosenstiel

¹Institut für Klinische Molekularbiologie, Christian-Albrechts-Universität, Kiel

Abstract

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

Full Text

References

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.
2 Opal SM. Phylogenetic and functional relationships between coagulation and the innate immune response. Crit Care Med 2000; 28 (9 Suppl): S77-S80.
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.
4 Akira S, Takeda K. Toll-like receptor signalling. Nat Rev Immunol 2004; 04: 499-511.
5 Akira S, Uematsu S, Takeuchi O. Pathogen recognition and innate immunity. Cell 2006; 124: 783-801.
6 Levi M, Ten Cate H. Disseminated intravascular coagulation. N Engl J Med 1999; 341: 586-592.
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.
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.
9 Stouthard JM. et al. Interleukin-6 stimulates coagulation, not fibrinolysis, in humans. Thromb Haemost 1996; 76: 738-742.
10 McGilvray ID, Rotstein OD. Role of the coagulation system in the local and systemic inflammatory response. World J Surg 1998; 22: 179-186.
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.
12 Gray E, Thomas S, Mistry Y, Poole S. Inhibition of tissue factor and cytokine release. Haemostasis 1996; 26 (Suppl 1): 92-95.
13 Moons AH, Levi M, Peters RJ. Tissue factor and coronary artery disease. Cardiovasc Res 2002; 53: 313-325.
14 Cermak J. et al. C-reactive protein induces human peripheral blood monocytes to synthesize tissue factor. Blood 1993; 82: 513-520.
15 Levi M. The coagulant response in sepsis and inflammation. Hämostaseologie 2010; 30: 10-12 14–16..
16 Burstein SA. Cytokines, platelet production and hemostasis. Platelets 1997; 08: 93-104.
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.
18 Conway EM, Rosenberg RD. Tumor necrosis factor suppresses transcription of the thrombomodulin gene in endothelial cells. Mol Cell Biol 1988; 08: 5588-5592.
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.
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.
21 Alcaraz A. et al. Activation of the protein C pathway in acute sepsis. Thromb Res 1995; 79: 83-93.
22 Takano S, Kimura S, Ohdama S, Aoki N. Plasma thrombomodulin in health and diseases. Blood 1990; 76: 2024-2029.
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.
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.
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.
26 Clark SR. et al. Platelet TLR4 activates neutrophil extracellular traps to ensnare bacteria in septic blood. Nat Med 2007; 13: 463-469.
27 Brinkmann V. et al. Neutrophil extracellular traps kill bacteria. Science 2004; 303: 1532-1535.
28 Ma AC, Kubes P. Platelets, neutrophils, and neutrophil extracellular traps (NETs) in sepsis. J Thromb Haemost 2008; 06: 415-420.
29 Hardaway RM, Chun B, Rutherford RB. Histologic evidence of disseminated intravascular coagulation in clinical shock. Vasc Dis 1965; 02: 254-265.
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.
31 Engel C. et al. Epidemiology of sepsis in Germany: results from a national prospective multicenter study. Intensive Care Med 2007; 33: 606-618.
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.
33 Levi M, van der Poll T, Buller HR. Bidirectional relation between inflammation and coagulation. Circulation 2004; 109: 2698-2704.
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.
35 Lorente JA. et al. Time course of hemostatic abnormalities in sepsis and its relation to outcome. Chest 1993; 103: 1536-1542.
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.
37 Esmon CT. Interactions between the innate immune and blood coagulation systems. Trends Immunol 2004; 25: 536-542.
38 De Pont AC. et al. Endotoxaemia induces resistance to activated protein C in healthy humans. Br J Haematol 2006; 134: 213-219.
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.
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.
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.
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.
43 Yoshida H, Granger DN. Inflammatory bowel disease: a paradigm for the link between coagulation and inflammation. Inflamm Bowel Dis 2009; 15: 1245-1255.
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.
45 Kaser A, Zeissig S, Blumberg RS. Inflammatory bowel disease. Ann Rev Immunol 2010; 28: 573-621.
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.
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.
48 Miehsler W. et al. Is inflammatory bowel disease an independent and disease specific risk factor for thromboembolism?. Gut 2004; 53: 542-548.
49 Suarez JFCrespo. et al. Thromboembolic complications in inflammatory bowel disease. Gastroenterol Hepatol 1997; 20: 180-183.
50 Larsen TB. et al. Platelets and anticoagulant capacity in patients with inflammatory bowel disease. Pathophysiol Haemost Thromb 2002; 32: 92-96.
51 Bouma BN, Mosnier LO. Thrombin activatable fibrinolysis inhibitor (TAFI) at the interface between coagulation and fibrinolysis. Pathophysiol Haemost Thromb 2003; 33: 375-381.
52 Folwaczny C. Coagulation system and inflammatory bowel disease: therapeutic and pathophysiologic implications. Z Gastroenterol 2002; 40: 991-998.
53 Grignani G, Maiolo A. Cytokines and hemostasis. Haematologica 2000; 85: 967-972.
54 Esmon CT. Crosstalk between inflammation and thrombosis. Maturitas 2008; 61: 122-131.
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.
56 Creasey AA. et al. Tissue factor pathway inhibitor reduces mortality from Escherichia coli septic shock. J Clin Invest 1993; 91: 2850-2860.
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.
58 Danese S. Inflammation and the mucosal microcirculation in inflammatory bowel disease: the ebb and flow. Curr Opin Gastroenterol 2007; 23: 384-389.
59 Boehme MW. et al. Elevated serum levels and reduced immunohistochemical expression of thrombomodulin in active ulcerative colitis. Gastroenterology 1997; 113: 107-117.
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.
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.
62 Koutroubakis IE. Unraveling the mechanisms of thrombosis in inflammatory bowel disease. Am J Gastroenterol 2001; 96: 1325-1327.
63 Danese S. et al. Inflammation and coagulation in inflammatory bowel disease: The clot thickens. Am J Gastroenterol 2007; 102: 174-186.
64 Tsiolakidou G, Koutroubakis IE. Thrombosis and inflammatory bowel disease-the role of genetic risk factors. World J Gastroenterol 2008; 14: 4440-4444.
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.
66 Saibeni S. et al. Increased thrombin generation in inflammatory bowel diseases. Thromb Res 2010; 125: 278-282.
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.
68 Bernhard H. et al. Calibrated automated thrombin generation in paediatric patients with inflammatory bowel disease. Hämostaseologie 2009; 29 (Suppl. 01) S90-S93.
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.
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.
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.
72 Stief TW. et al. Analysis of hemostasis alterations in sepsis. Blood Coagul Fibrinolysis 2007; 18: 179-186.
73 Fox EA, Kahn SR. The relationship between inflammation and venous thrombosis. A systematic review of clinical studies. Thromb Haemost 2005; 94: 362-365.
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.
75 Van Aken BE, den Heijer M, Bos GM. et al. Recurrent venous thrombosis and markers of inflammation. Thromb Haemost 2000; 83: 536-539.
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.
77 Sturn DH. et al. Expression and function of the endothelial protein C receptor in human neutrophils. Blood 2003; 102: 1499-1505.
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.
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.
80 Yoshida H. et al. Role of the protein C pathway in the extraintestinal thrombosis associated with murine colitis. Gastroenterology 2008; 135: 882-888.
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.
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.
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.
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.
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.
86 Derhaschnig U. et al. Evaluation of antiinflammatory and antiadhesive effects of heparins in human endotoxemia. Crit Care Med 2003; 31: 1108-1112.
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.
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.
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.
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.
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.
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.
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.
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.
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.
96 Goode S, Tierney G, Deighton C. Life threatening intra-abdominal sepsis in patients on anti-TNFalpha therapy. Gut 2006; 55: 590-591.
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.
98 Favalli EG. et al. Serious infections during anti- TNFalpha treatment in rheumatoid arthritis patients. Autoimmun Rev 2009; 08: 266-273.
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.
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.
101 Gross V, Andus T, Leser HG. et al. Inflammatory mediators in chronic inflammatory bowel diseases. Klin Wochenschr 1991; 69: 981-987.
102 Hoang P, Fiasse R, Van Heuverzwyn R, Sibille C. Role of cytokines in inflammatory bowel disease. Acta Gastroenterol Belg 1994; 57: 219-223.
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.
104 Bjerregaard LT. et al. Hyperhomocysteinaemia, coagulation pathway activation and thrombophilia in patients with inflammatory bowel disease. Scand J Gastroenterol 2002; 37: 62-67.