Seminars in Immunopathology

, Volume 34, Issue 1, pp 151–165 | Cite as

Interactions between coagulation and complement—their role in inflammation

  • Katerina Oikonomopoulou
  • Daniel Ricklin
  • Peter A. Ward
  • John D. LambrisEmail author


The parallel expression of activation products of the coagulation, fibrinolysis, and complement systems has long been observed in both clinical and experimental settings. Several interconnections between the individual components of these cascades have also been described, and the list of shared regulators is expanding. The co-existence and interplay of hemostatic and inflammatory mediators in the same microenvironment typically ensures a successful host immune defense in compromised barrier settings. However, dysregulation of the cascade activities or functions of inhibitors in one or both systems can result in clinical manifestations of disease, such as sepsis, systemic lupus erythematosus, or ischemia–reperfusion injury, with critical thrombotic and/or inflammatory complications. An appreciation of the precise relationship between complement activation and thrombosis may facilitate the development of novel therapeutics, as well as improve the clinical management of patients with thrombotic conditions that are characterized by complement-associated inflammatory responses.


Anaphylatoxin Coagulation Complement Fibrinolysis Inflammation Sepsis 



Atypical hemolytic uremic syndrome


C1 inhibitor


C4b-binding protein


C3a receptor


C5a receptor


C5a receptor-like 2


Decay accelerating factor


Disseminated intravascular coagulation


Dextran sulphate sodium


Hereditary angioedema


High mobility globulin B1


Inflammatory bowel disease






Membrane-attack complex


Mannose-binding lectin-associated serine proteinase


Mannose-binding lectin


Monocytes chemoattractant protein 1


Migration-inhibitory factor


Macrophage inflammatory protein 1


Plasminogen activator inhibitor 1


Proteinase-activated receptor


Paroxysmal nocturnal hemoglobinuria


Systemic inflammatory response syndrome


Systemic lupus erythematosus


Thrombin activatable fibrinolysis inhibitor


Tissue factor


Tumor necrosis factor


Tissue plasminogen activator


Urokinase plasminogen activator


Urokinase plasminogen activator receptor



We thank D. McClellan for editorial assistance. This work was supported by U.S. National Institutes of Health grants AI68730, AI30040 and GM62134 (to J.D.L.), and GM29507, GM61656 (to P.A.W.). K.O. is recipient of a Natural Sciences and Engineering Research Council of Canada postdoctoral fellowship.


  1. 1.
    Reid KB, Porter RR (1981) The proteolytic activation systems of complement. Annu Rev Biochem 50:433–464PubMedGoogle Scholar
  2. 2.
    Ricklin D, Hajishengallis G, Yang K, Lambris JD (2010) Complement: a key system for immune surveillance and homeostasis. Nat Immunol 11:785–797PubMedGoogle Scholar
  3. 3.
    Jackson CM, Nemerson Y (1980) Blood coagulation. Annu Rev Biochem 49:765–811PubMedGoogle Scholar
  4. 4.
    Adams RL, Bird RJ (2009) Review article: coagulation cascade and therapeutics update: relevance to nephrology. Part 1: Overview of coagulation, thrombophilias and history of anticoagulants. Nephrology (Carlton) 14:462–470Google Scholar
  5. 5.
    Francis CW, Marder VJ (1987) Physiologic regulation and pathologic disorders of fibrinolysis. Hum Pathol 18:263–274PubMedGoogle Scholar
  6. 6.
    Kane KK (1984) Fibrinolysis—a review. Ann Clin Lab Sci 14:443–449PubMedGoogle Scholar
  7. 7.
    Rawlings ND, Barrett AJ, Bateman A (2010) MEROPS: the peptidase database. Nucleic Acids Res 38:D227–D233PubMedGoogle Scholar
  8. 8.
    Rawlings ND (2010) Peptidase inhibitors in the MEROPS database. Biochimie 92:1463–1483PubMedGoogle Scholar
  9. 9.
    Barrett AJ, Rawlings ND, Woessner JF (2004) Handbook of proteolytic enzymes. Elsevier Academic Press, San DiegoGoogle Scholar
  10. 10.
    Macfarlane RG (1948) Normal and abnormal blood coagulation: a review. J Clin Pathol 1:113–143Google Scholar
  11. 11.
    Lachmann P (2006) Complement before molecular biology. Mol Immunol 43:496–508PubMedGoogle Scholar
  12. 12.
    Hoffman R, Benz E Jr., Shattil SJ, Furie B, Cohen HJ, Silberstein LE, McGlave P (2005). Hematology: basic principles and practice. Elsevier Churchill Livingstone, PhiladelphiaGoogle Scholar
  13. 13.
    Walsh PN (2004) Platelet coagulation–protein interactions. Semin Thromb Hemost 30:461–471PubMedGoogle Scholar
  14. 14.
    Davie EW, Ratnoff OD (1964) Waterfall sequence for intrinsic blood clotting. Science 145:1310–1312PubMedGoogle Scholar
  15. 15.
    Hoffman M (2003) Remodeling the blood coagulation cascade. J Thromb Thrombolysis 16:17–20PubMedGoogle Scholar
  16. 16.
    Rakic JM, Maillard C, Jost M, Bajou K, Masson V, Devy L, Lambert V, Foidart JM, Noel A (2003) Role of plasminogen activator-plasmin system in tumor angiogenesis. Cell Mol Life Sci 60:463–473PubMedGoogle Scholar
  17. 17.
    Van de Werf FJ, Topol EJ, Sobel BE (2009) The impact of fibrinolytic therapy for ST-segment-elevation acute myocardial infarction. J Thromb Haemost 7:14–20PubMedGoogle Scholar
  18. 18.
    The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group (1995) Tissue plasminogen activator for acute ischemic stroke. N Engl J Med 333:1581–1587Google Scholar
  19. 19.
    Steinhoff M, Buddenkotte J, Shpacovitch V, Rattenholl A, Moormann C, Vergnolle N, Luger TA, Hollenberg MD (2005) Proteinase-activated receptors: transducers of proteinase-mediated signaling in inflammation and immune response. Endocr Rev 26:1–43PubMedGoogle Scholar
  20. 20.
    Riewald M, Ruf W (2003) Proteinase-activated receptor activation by coagulation proteinases. Drug Develop Res 59:400–407Google Scholar
  21. 21.
    Coughlin SR (2000) Thrombin signalling and protease-activated receptors. Nature 407:258–264PubMedGoogle Scholar
  22. 22.
    Kuliopulos A, Covic L, Seeley SK, Sheridan PJ, Helin J, Costello CE (1999) Plasmin desensitization of the PAR1 thrombin receptor: kinetics, sites of truncation, and implications for thrombolytic therapy. Biochemistry 38:4572–4585PubMedGoogle Scholar
  23. 23.
    Laumonnier Y, Syrovets T, Burysek L, Simmet T (2006) Identification of the annexin A2 heterotetramer as a receptor for the plasmin-induced signaling in human peripheral monocytes. Blood 107:3342–3349PubMedGoogle Scholar
  24. 24.
    Li Q, Laumonnier Y, Syrovets T, Simmet T (2007) Plasmin triggers cytokine induction in human monocyte-derived macrophages. Arterioscler Thromb Vasc Biol 27:1383–1389PubMedGoogle Scholar
  25. 25.
    Lambris JD, Ricklin D, Geisbrecht BV (2008) Complement evasion by human pathogens. Nat Rev Microbiol 6:132–142PubMedGoogle Scholar
  26. 26.
    Ricklin D, Lambris JD (2007) Complement-targeted therapeutics. Nat Biotechnol 25:1265–1275PubMedGoogle Scholar
  27. 27.
    Le FG, Kemper C (2009) Complement: coming full circle. Arch Immunol Ther Exp (Warsz) 57:393–407Google Scholar
  28. 28.
    Dunkelberger JR, Song WC (2010) Complement and its role in innate and adaptive immune responses. Cell Res 20:34–50PubMedGoogle Scholar
  29. 29.
    Markiewski MM, Lambris JD (2007) The role of complement in inflammatory diseases from behind the scenes into the spotlight. Am J Pathol 171:715–727PubMedGoogle Scholar
  30. 30.
    Kemper C, Atkinson JP, Hourcade DE (2010) Properdin: emerging roles of a pattern-recognition molecule. Annu Rev Immunol 28:131–155PubMedGoogle Scholar
  31. 31.
    Pangburn MK, Muller-Eberhard HJ (1986) The C3 convertase of the alternative pathway of human complement. Enzymic properties of the bimolecular proteinase. Biochem J 235:723–730PubMedGoogle Scholar
  32. 32.
    Volanakis JE (1989) C3 convertases of complement. Molecular genetics, structure and function of the catalytic domains, C2 and B. Year Immunol 4:218–230PubMedGoogle Scholar
  33. 33.
    Klos A, Tenner AJ, Johswich KO, Ager RR, Reis ES, Kohl J (2009) The role of the anaphylatoxins in health and disease. Mol Immunol 46:2753–2766PubMedGoogle Scholar
  34. 34.
    Kalant D, MacLaren R, Cui W, Samanta R, Monk PN, Laporte SA, Cianflone K (2005) C5L2 is a functional receptor for acylation-stimulating protein. J Biol Chem 280:23936–23944PubMedGoogle Scholar
  35. 35.
    Ward PA (2009) Functions of C5a receptors. J Mol Med 87:375–378PubMedGoogle Scholar
  36. 36.
    Van Lith LH, Oosterom J, Van EA, Zaman GJ (2009) C5a-stimulated recruitment of beta-arrestin2 to the nonsignaling 7-transmembrane decoy receptor C5L2. J Biomol Screen 14:1067–1075PubMedGoogle Scholar
  37. 37.
    Bamberg CE, Mackay CR, Lee H, Zahra D, Jackson J, Lim YS, Whitfeld PL, Craig S, Corsini E, Lu B, Gerard C, Gerard NP (2010) The C5a receptor (C5aR) C5L2 is a modulator of C5aR-mediated signal transduction. J Biol Chem 285:7633–7644PubMedGoogle Scholar
  38. 38.
    Scola AM, Johswich KO, Morgan BP, Klos A, Monk PN (2009) The human complement fragment receptor, C5L2, is a recycling decoy receptor. Mol Immunol 46:1149–1162PubMedGoogle Scholar
  39. 39.
    Megyeri M, Mako V, Beinrohr L, Doleschall Z, Prohaszka Z, Cervenak L, Zavodszky P, Gal P (2009) Complement protease MASP-1 activates human endothelial cells: PAR4 activation is a link between complement and endothelial function. J Immunol 183:3409–3416PubMedGoogle Scholar
  40. 40.
    Pham CT (2006) Neutrophil serine proteases: specific regulators of inflammation. Nat Rev Immunol 6:541–550PubMedGoogle Scholar
  41. 41.
    Dulon S, Leduc D, Cottrell GS, D’Alayer J, Hansen KK, Bunnett NW, Hollenberg MD, Pidard D, Chignard M (2005) Pseudomonas aeruginosa elastase disables proteinase-activated receptor 2 in respiratory epithelial cells. Am J Respir Cell Mol Biol 32:411–419PubMedGoogle Scholar
  42. 42.
    Schmidtchen A, Holst E, Tapper H, Bjorck L (2003) Elastase-producing Pseudomonas aeruginosa degrade plasma proteins and extracellular products of human skin and fibroblasts, and inhibit fibroblast growth. Microb Pathog 34:47–55PubMedGoogle Scholar
  43. 43.
    Jagels MA, Travis J, Potempa J, Pike R, Hugli TE (1996) Proteolytic inactivation of the leukocyte C5a receptor by proteinases derived from Porphyromonas gingivalis. Infect Immun 64:1984–1991PubMedGoogle Scholar
  44. 44.
    Wingrove JA, DiScipio RG, Chen Z, Potempa J, Travis J, Hugli TE (1992) Activation of complement components C3 and C5 by a cysteine proteinase (gingipain-1) from Porphyromonas (Bacteroides) gingivalis. J Biol Chem 267:18902–18907PubMedGoogle Scholar
  45. 45.
    Hajishengallis G, Lambris JD (2010) Crosstalk pathways between Toll-like receptors and the complement system. Trends Immunol 31:154–163PubMedGoogle Scholar
  46. 46.
    Mollnes TE, Garred P, Bergseth G (1988) Effect of time, temperature and anticoagulants on in vitro complement activation: consequences for collection and preservation of samples to be examined for complement activation. Clin Exp Immunol 73:484–488PubMedGoogle Scholar
  47. 47.
    Wiggins RC, Giclas PC, Henson PM (1981) Chemotactic activity generated from the fifth component of complement by plasma kallikrein of the rabbit. J Exp Med 153:1391–1404PubMedGoogle Scholar
  48. 48.
    DiScipio RG (1982) The activation of the alternative pathway C3 convertase by human plasma kallikrein. Immunology 45:587–595PubMedGoogle Scholar
  49. 49.
    Hiemstra PS, Daha MR, Bouma BN (1985) Activation of factor B of the complement system by kallikrein and its light chain. Thromb Res 38:491–503PubMedGoogle Scholar
  50. 50.
    Thoman ML, Meuth JL, Morgan EL, Weigle WO, Hugli TE (1984) C3d-K, a kallikrein cleavage fragment of iC3b is a potent inhibitor of cellular proliferation. J Immunol 133:2629–2633PubMedGoogle Scholar
  51. 51.
    Huber-Lang M, Sarma JV, Zetoune FS, Rittirsch D, Neff TA, McGuire SR, Lambris JD, Warner RL, Flierl MA, Hoesel LM, Gebhard F, Younger JG, Drouin SM, Wetsel RA, Ward PA (2006) Generation of C5a in the absence of C3: a new complement activation pathway. Nat Med 12:682–687PubMedGoogle Scholar
  52. 52.
    Amara U, Flierl MA, Rittirsch D, Klos A, Chen H, Acker B, Bruckner UB, Nilsson B, Gebhard F, Lambris JD, Huber-Lang M (2010) Molecular intercommunication between the complement and coagulation systems. J Immunol 185:5628–5636PubMedGoogle Scholar
  53. 53.
    Del Conde I, Crúz MA, Zhang H, López JA, Afshar-Kharghan V (2005) Platelet activation leads to activation and propagation of the complement system. J Exp Med 201:871–879PubMedGoogle Scholar
  54. 54.
    Ghebrehiwet B, Silverberg M, Kaplan AP (1981) Activation of the classical pathway of complement by Hageman factor fragment. J Exp Med 153:665–676PubMedGoogle Scholar
  55. 55.
    Ghebrehiwet B, Randazzo BP, Dunn JT, Silverberg M, Kaplan AP (1983) Mechanisms of activation of the classical pathway of complement by Hageman factor fragment. J Clin Invest 71:1450–1456PubMedGoogle Scholar
  56. 56.
    Hamad OA, Nilsson PH, Lasaosa M, Ricklin D, Lambris JD, Nilsson B, Ekdahl KN (2010) Contribution of chondroitin sulfate A to the binding of complement proteins to activated platelets. PLoS One 5:e12889PubMedGoogle Scholar
  57. 57.
    Endo Y, Nakazawa N, Iwaki D, Takahashi M, Matsushita M, Fujita T (2009) Interactions of ficolin and mannose-binding lectin with fibrinogen/fibrin augment the lectin complement pathway. J Innate Immun 2:33–42PubMedGoogle Scholar
  58. 58.
    Krarup A, Wallis R, Presanis JS, Gal P, Sim RB (2007) Simultaneous activation of complement and coagulation by MBL-associated serine protease 2. PLoS One 2:e623PubMedGoogle Scholar
  59. 59.
    Gulla KC, Gupta K, Krarup A, Gal P, Schwaeble WJ, Sim RB, O’Connor CD, Hajela K (2010) Activation of mannan-binding lectin-associated serine proteases leads to generation of a fibrin clot. Immunology 129:482–495PubMedGoogle Scholar
  60. 60.
    Platt JL, Dalmasso AP, Lindman BJ, Ihrcke NS, Bach FH (1991) The role of C5a and antibody in the release of heparan sulfate from endothelial cells. Eur J Immunol 21:2887–2890PubMedGoogle Scholar
  61. 61.
    Marcum JA, Atha DH, Fritze LM, Nawroth P, Stern D, Rosenberg RD (1986) Cloned bovine aortic endothelial cells synthesize anticoagulantly active heparan sulfate proteoglycan. J Biol Chem 261:7507–7517PubMedGoogle Scholar
  62. 62.
    Zaferani A, Vives RR, van der PP, Hakvoort JJ, Navis GJ, van GH, Daha MR, Lortat-Jacob H, Seelen MA, van den BJ (2011) Identification of tubular heparan sulfate as a docking platform for the alternative complement component properdin in proteinuric renal disease. J Biol Chem 286:5359–5367Google Scholar
  63. 63.
    Polley MJ, Nachman R (1978) The human complement system in thrombin-mediated platelet function. J Exp Med 147:1713–1726PubMedGoogle Scholar
  64. 64.
    Sims PJ, Wiedmer T (1991) The response of human platelets to activated components of the complement system. Immunol Today 12:338–342PubMedGoogle Scholar
  65. 65.
    Wiedmer T, Sims PJ (1985) Effect of complement proteins C5b-9 on blood platelets. Evidence for reversible depolarization of membrane potential. J Biol Chem 260:8014–8019PubMedGoogle Scholar
  66. 66.
    Ando B, Wiedmer T, Hamilton KK, Sims PJ (1988) Complement proteins C5b-9 initiate secretion of platelet storage granules without increased binding of fibrinogen or von Willebrand factor to newly expressed cell surface GPIIb-IIIa. J Biol Chem 263:11907–11914PubMedGoogle Scholar
  67. 67.
    Wiedmer T, Esmon CT, Sims PJ (1986) Complement proteins C5b-9 stimulate procoagulant activity through platelet prothrombinase. Blood 68:875–880PubMedGoogle Scholar
  68. 68.
    Sims PJ, Faioni EM, Wiedmer T, Shattil SJ (1988) 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 263:18205–18212PubMedGoogle Scholar
  69. 69.
    Hamilton KK, Hattori R, Esmon CT, Sims PJ (1990) Complement proteins C5b-9 induce vesiculation of the endothelial plasma membrane and expose catalytic surface for assembly of the prothrombinase enzyme complex. J Biol Chem 265:3809–3814PubMedGoogle Scholar
  70. 70.
    Peerschke EI, Reid KB, Ghebrehiwet B (1993) Platelet activation by C1q results in the induction of alpha IIb/beta 3 integrins (GPIIb-IIIa) and the expression of P-selectin and procoagulant activity. J Exp Med 178:579–587PubMedGoogle Scholar
  71. 71.
    Skoglund C, Wettero J, Tengvall P, Bengtsson T (2010) C1q induces a rapid up-regulation of P-selectin and modulates collagen-and collagen-related peptide-triggered activation in human platelets. Immunobiology 215:987–995PubMedGoogle Scholar
  72. 72.
    Polley MJ, Nachman RL (1983) Human platelet activation by C3a and C3a des-arg. J Exp Med 158:603–615PubMedGoogle Scholar
  73. 73.
    Gushiken FC, Han H, Li J, Rumbaut RE, fshar-Kharghan V (2009) Abnormal platelet function in C3-deficient mice. J Thromb Haemost 7:865–870PubMedGoogle Scholar
  74. 74.
    Qin X, Krumrei N, Grubissich L, Dobarro M, Aktas H, Perez G, Halperin JA (2003) Deficiency of the mouse complement regulatory protein mCd59b results in spontaneous hemolytic anemia with platelet activation and progressive male infertility. Immunity 18:217–227PubMedGoogle Scholar
  75. 75.
    Hamad OA, Nilsson PH, Wouters D, Lambris JD, Ekdahl KN, Nilsson B (2010) Complement component C3 binds to activated normal platelets without preceding proteolytic activation and promotes binding to complement receptor 1. J Immunol 184:2686–2692PubMedGoogle Scholar
  76. 76.
    Ikeda K, Nagasawa K, Horiuchi T, Tsuru T, Nishizaka H, Niho Y (1997) C5a induces tissue factor activity on endothelial cells. Thromb Haemost 77:394–398PubMedGoogle Scholar
  77. 77.
    Ritis K, Doumas M, Mastellos D, Micheli A, Giaglis S, Magotti P, Rafail S, Kartalis G, Sideras P, Lambris JD (2006) A novel C5a receptor-tissue factor cross-talk in neutrophils links innate immunity to coagulation pathways. J Immunol 177:4794–4802PubMedGoogle Scholar
  78. 78.
    Kambas K, Markiewski MM, Pneumatikos IA, Rafail SS, Theodorou V, Konstantonis D, Kourtzelis I, Doumas MN, Magotti P, DeAngelis RA, Lambris JD, Ritis KD (2008) C5a and TNF-alpha up-regulate the expression of tissue factor in intra-alveolar neutrophils of patients with the acute respiratory distress syndrome. J Immunol 180:7368–7375PubMedGoogle Scholar
  79. 79.
    Tedesco F, Pausa M, Nardon E, Introna M, Mantovani A, Dobrina A (1997) The cytolytically inactive terminal complement complex activates endothelial cells to express adhesion molecules and tissue factor procoagulant activity. J Exp Med 185:1619–1627PubMedGoogle Scholar
  80. 80.
    Sillaber C, Baghestanian M, Bevec D, Willheim M, Agis H, Kapiotis S, Fureder W, Bankl HC, Kiener HP, Speiser W, Binder BR, Lechner K, Valent P (1999) The mast cell as site of tissue-type plasminogen activator expression and fibrinolysis. J Immunol 162:1032–1041PubMedGoogle Scholar
  81. 81.
    Wojta J, Kaun C, Zorn G, Ghannadan M, Hauswirth AW, Sperr WR, Fritsch G, Printz D, Binder BR, Schatzl G, Zwirner J, Maurer G, Huber K, Valent P (2002) C5a stimulates production of plasminogen activator inhibitor-1 in human mast cells and basophils. Blood 100:517–523PubMedGoogle Scholar
  82. 82.
    Wojta J, Huber K, Valent P (2003) New aspects in thrombotic research: complement induced switch in mast cells from a profibrinolytic to a prothrombotic phenotype. Pathophysiol Haemost Thromb 33:438–441PubMedGoogle Scholar
  83. 83.
    Levi M, van der Tom P (2010) Inflammation and coagulation. Crit Care Med 38:S26–S34PubMedGoogle Scholar
  84. 84.
    Levi M, van der Tom P (2005) Two-way interactions between inflammation and coagulation. Trends Cardiovasc Med 15:254–259PubMedGoogle Scholar
  85. 85.
    Markiewski MM, DeAngelis RA, Lambris JD (2006) Liver inflammation and regeneration: two distinct biological phenomena or parallel pathophysiologic processes? Mol Immunol 43:45–56PubMedGoogle Scholar
  86. 86.
    Markiewski MM, DeAngelis RA, Strey CW, Foukas PG, Gerard C, Gerard N, Wetsel RA, Lambris JD (2009) The regulation of liver cell survival by complement. J Immunol 182:5412–5418PubMedGoogle Scholar
  87. 87.
    Shebuski RJ, Kilgore KS (2002) Role of inflammatory mediators in thrombogenesis. J Pharmacol Exp Ther 300:729–735PubMedGoogle Scholar
  88. 88.
    Szotowski B, Antoniak S, Poller W, Schultheiss HP, Rauch U (2005) Procoagulant soluble tissue factor is released from endothelial cells in response to inflammatory cytokines. Circ Res 96:1233–1239PubMedGoogle Scholar
  89. 89.
    Burstein SA, Peng J, Friese P, Wolf RF, Harrison P, Downs T, Hamilton K, Comp P, Dale GL (1996) Cytokine-induced alteration of platelet and hemostatic function. Stem Cells 14(Suppl 1):154–162PubMedGoogle Scholar
  90. 90.
    Verardi S, Page RC, Ammons WF, Bordin S (2007) Differential chemokine response of fibroblast subtypes to complement C1q. J Periodontal Res 42:62–68PubMedGoogle Scholar
  91. 91.
    Lidington EA, Haskard DO, Mason JC (2000) Induction of decay-accelerating factor by thrombin through a protease-activated receptor 1 and protein kinase C-dependent pathway protects vascular endothelial cells from complement-mediated injury. Blood 96:2784–2792PubMedGoogle Scholar
  92. 92.
    Campbell W, Okada N, Okada H (2001) Carboxypeptidase R is an inactivator of complement-derived inflammatory peptides and an inhibitor of fibrinolysis. Immunol Rev 180:162–167PubMedGoogle Scholar
  93. 93.
    Bajzar L, Morser J, Nesheim M (1996) TAFI, or plasma procarboxypeptidase B, couples the coagulation and fibrinolytic cascades through the thrombin-thrombomodulin complex. J Biol Chem 271:16603–16608PubMedGoogle Scholar
  94. 94.
    Levi M, Opal SM (2006) Coagulation abnormalities in critically ill patients. Crit Care 10:222PubMedGoogle Scholar
  95. 95.
    Degen JL, Bugge TH, Goguen JD (2007) Fibrin and fibrinolysis in infection and host defense. J Thromb Haemost 5(Suppl 1):24–31PubMedGoogle Scholar
  96. 96.
    Hecke F, Schmidt U, Kola A, Bautsch W, Klos A, Kohl J (1997) Circulating complement proteins in multiple trauma patients—correlation with injury severity, development of sepsis, and outcome. Crit Care Med 25:2015–2024PubMedGoogle Scholar
  97. 97.
    Markiewski MM, DeAngelis RA, Lambris JD (2008) Complexity of complement activation in sepsis. J Cell Mol Med 12:2245–2254PubMedGoogle Scholar
  98. 98.
    Ward PA, Gao H (2009) Sepsis, complement and the dysregulated inflammatory response. J Cell Mol Med 13:4154–4160PubMedGoogle Scholar
  99. 99.
    Castellheim A, Brekke OL, Espevik T, Harboe M, Mollnes TE (2009) Innate immune responses to danger signals in systemic inflammatory response syndrome and sepsis. Scand J Immunol 69:479–491PubMedGoogle Scholar
  100. 100.
    Daniels R, Nutbeam T (2010) ABC of Sepsis. Blackwell Publishing Ltd, ChichesterGoogle Scholar
  101. 101.
    Rittirsch D, Flierl MA, Ward PA (2008) Harmful molecular mechanisms in sepsis. Nat Rev Immunol 8:776–787PubMedGoogle Scholar
  102. 102.
    Ward PA (2004) The dark side of C5a in sepsis. Nat Rev Immunol 4:133–142PubMedGoogle Scholar
  103. 103.
    Laudes IJ, Chu JC, Sikranth S, Huber-Lang M, Guo RF, Riedemann N, Sarma JV, Schmaier AH, Ward PA (2002) Anti-c5a ameliorates coagulation/fibrinolytic protein changes in a rat model of sepsis. Am J Pathol 160:1867–1875PubMedGoogle Scholar
  104. 104.
    Knoebl P (2010) Blood coagulation disorders in septic patients. Wien Med Wochenschr 160:129–138PubMedGoogle Scholar
  105. 105.
    Gando S (2010) Microvascular thrombosis and multiple organ dysfunction syndrome. Crit Care Med 38:S35–S42PubMedGoogle Scholar
  106. 106.
    Deitch EA (1992) Multiple organ failure. Pathophysiology and potential future therapy. Ann Surg 216:117–134PubMedGoogle Scholar
  107. 107.
    Barie PS, Hydo LJ, Pieracci FM, Shou J, Eachempati SR (2009) Multiple organ dysfunction syndrome in critical surgical illness. Surg Infect (Larchmt) 10:369–377Google Scholar
  108. 108.
    Ten Cate H, Schoenmakers SH, Franco R, Timmerman JJ, Groot AP, Spek CA, Reitsma PH (2001) Microvascular coagulopathy and disseminated intravascular coagulation. Crit Care Med 29:S95–S97PubMedGoogle Scholar
  109. 109.
    Younger JG, Bracho DO, Chung-Esaki HM, Lee M, Rana GK, Sen A, Jones AE (2010) Complement activation in emergency department patients with severe sepsis. Acad Emerg Med 17:353–359PubMedGoogle Scholar
  110. 110.
    Semple JW, Freedman J (2010) Platelets and innate immunity. Cell Mol Life Sci 67:499–511PubMedGoogle Scholar
  111. 111.
    Gawaz M, Dickfeld T, Bogner C, Fateh-Moghadam S, Neumann FJ (1997) Platelet function in septic multiple organ dysfunction syndrome. Intensive Care Med 23:379–385PubMedGoogle Scholar
  112. 112.
    Ekdahl KN, Nilsson B (1995) Phosphorylation of complement component C3 and C3 fragments by a human platelet protein kinase. Inhibition of factor I-mediated cleavage of C3b. J Immunol 154:6502–6510PubMedGoogle Scholar
  113. 113.
    Nilsson-Ekdahl K, Nilsson B (2001) Phosphorylation of C3 by a casein kinase released from activated human platelets increases opsonization of immune complexes and binding to complement receptor type 1. Eur J Immunol 31:1047–1054PubMedGoogle Scholar
  114. 114.
    Hack CE, Nuijens JH, Felt-Bersma RJ, Schreuder WO, Eerenberg-Belmer AJ, Paardekooper J, Bronsveld W, Thijs LG (1989) Elevated plasma levels of the anaphylatoxins C3a and C4a are associated with a fatal outcome in sepsis. Am J Med 86:20–26PubMedGoogle Scholar
  115. 115.
    Rittirsch D, Flierl MA, Nadeau BA, Day DE, Huber-Lang M, Mackay CR, Zetoune FS, Gerard NP, Cianflone K, Kohl J, Gerard C, Sarma JV, Ward PA (2008) Functional roles for C5a receptors in sepsis. Nat Med 14:551–557PubMedGoogle Scholar
  116. 116.
    Hawlisch H, Belkaid Y, Baelder R, Hildeman D, Gerard C, Kohl J (2005) C5a negatively regulates toll-like receptor 4-induced immune responses. Immunity 22:415–426PubMedGoogle Scholar
  117. 117.
    Riedemann NC, Guo RF, Gao H, Sun L, Hoesel M, Hollmann TJ, Wetsel RA, Zetoune FS, Ward PA (2004) Regulatory role of C5a on macrophage migration inhibitory factor release from neutrophils. J Immunol 173:1355–1359PubMedGoogle Scholar
  118. 118.
    Markiewski MM, Nilsson B, Ekdahl KN, Mollnes TE, Lambris JD (2007) Complement and coagulation: strangers or partners in crime? Trends Immunol 28:184–192PubMedGoogle Scholar
  119. 119.
    Wiedmer T, Hall SE, Ortel TL, Kane WH, Rosse WF, Sims PJ (1993) Complement-induced vesiculation and exposure of membrane prothrombinase sites in platelets of paroxysmal nocturnal hemoglobinuria. Blood 82:1192–1196PubMedGoogle Scholar
  120. 120.
    Karpman D, Manea M, Vaziri-Sani F, Stahl AL, Kristoffersson AC (2006) Platelet activation in hemolytic uremic syndrome. Semin Thromb Hemost 32:128–145PubMedGoogle Scholar
  121. 121.
    Coppola L, Guastafierro S, Verrazzo G, Coppola A, De LD, Tirelli A (2002) C1 inhibitor infusion modifies platelet activity in hereditary angioedema patients. Arch Pathol Lab Med 126:842–845PubMedGoogle Scholar
  122. 122.
    Nangaku M, Couser WG (2005) Mechanisms of immune-deposit formation and the mediation of immune renal injury. Clin Exp Nephrol 9:183–191PubMedGoogle Scholar
  123. 123.
    Shushakova N, Tkachuk N, Dangers M, Tkachuk S, Park JK, Hashimoto K, Haller H, Dumler I (2005) Urokinase-induced activation of the gp130/Tyk2/Stat3 pathway mediates a pro-inflammatory effect in human mesangial cells via expression of the anaphylatoxin C5a receptor. J Cell Sci 118:2743–2753PubMedGoogle Scholar
  124. 124.
    Mocco J, Wilson DA, Komotar RJ, Sughrue ME, Coates K, Sacco RL, Elkind MS, Connolly ES Jr (2006) Alterations in plasma complement levels after human ischemic stroke. Neurosurgery 59:28–33PubMedGoogle Scholar
  125. 125.
    Banz Y, Rieben R (2011) Role of complement and perspectives for intervention in ischemia-reperfusion damage. Ann Med doi: 10.3109/07853890.2010.535556
  126. 126.
    Cervera A, Planas AM, Justicia C, Urra X, Jensenius JC, Torres F, Lozano F, Chamorro A (2010) Genetically-defined deficiency of mannose-binding lectin is associated with protection after experimental stroke in mice and outcome in human stroke. PLoS One 5:e8433PubMedGoogle Scholar
  127. 127.
    Lood C, Gullstrand B, Truedsson L, Olin AI, Alm GV, Ronnblom L, Sturfelt G, Eloranta ML, Bengtsson AA (2009) C1q inhibits immune complex-induced interferon-alpha production in plasmacytoid dendritic cells: a novel link between C1q deficiency and systemic lupus erythematosus pathogenesis. Arthritis Rheum 60:3081–3090PubMedGoogle Scholar
  128. 128.
    Robson MG, Walport MJ (2001) Pathogenesis of systemic lupus erythematosus (SLE). Clin Exp Allergy 31:678–685PubMedGoogle Scholar
  129. 129.
    Palatinus A, Adams M (2009) Thrombosis in systemic lupus erythematosus. Semin Thromb Hemost 35:621–629PubMedGoogle Scholar
  130. 130.
    Nilsson B, Korsgren O, Lambris JD, Ekdahl KN (2010) Can cells and biomaterials in therapeutic medicine be shielded from innate immune recognition? Trends Immunol 31:32–38PubMedGoogle Scholar
  131. 131.
    Kourtzelis I, Markiewski MM, Doumas M, Rafail S, Kambas K, Mitroulis I, Panagoutsos S, Passadakis P, Vargemezis V, Magotti P, Qu H, Mollnes TE, Ritis K, Lambris JD (2010) Complement anaphylatoxin C5a contributes to hemodialysis-associated thrombosis. Blood 116:631–639PubMedGoogle Scholar
  132. 132.
    Brenner P, Keller M, Beiras-Fernandez A, Uchita S, Kur F, Thein E, Wimmer C, Hammer C, Schmoeckel M, Reichart B (2010) Prevention of hyperacute xenograft rejection through direct thrombin inhibition with hirudin. Annals of Transplantation: quarterly of the Polish Transplantation Society 15:30–37Google Scholar
  133. 133.
    Freue GV, Sasaki M, Meredith A, Gunther OP, Bergman A, Takhar M, Mui A, Balshaw RF, Ng RT, Opushneva N, Hollander Z, Li G, Borchers CH, Wilson-McManus J, McManus BM, Keown PA, McMaster WR (2010) Proteomic signatures in plasma during early acute renal allograft rejection. Mol Cell Proteomics 9:1954–1967PubMedGoogle Scholar
  134. 134.
    Ingegnoli F, Fantini F, Griffini S, Soldi A, Meroni PL, Cugno M (2010) Anti-tumor necrosis factor alpha therapy normalizes fibrinolysis impairment in patients with active rheumatoid arthritis. Clin Exp Rheumatol 28:254–257PubMedGoogle Scholar
  135. 135.
    Lu F, Fernandes SM, Davis AE III (2010) The role of the complement and contact systems in the dextran sulfate sodium—induced colitis model: the effect of C1 inhibitor in inflammatory bowel disease. Am J Physiol Gastrointest Liver Physiol 298:G878–G883PubMedGoogle Scholar
  136. 136.
    Cugno M, Tedeschi A, Crosti C, Marzano AV (2009) Activation of blood coagulation in autoimmune skin disorders. Expert Rev Clin Immunol 5:605–613PubMedGoogle Scholar
  137. 137.
    Wagner E, Frank MM (2010) Therapeutic potential of complement modulation. Nat Rev Drug Discov 9:43–56PubMedGoogle Scholar
  138. 138.
    Qu H, Ricklin D, Lambris JD (2009) Recent developments in low molecular weight complement inhibitors. Mol Immunol 47:185–195PubMedGoogle Scholar
  139. 139.
    Hillmen P, Muus P, Duhrsen U, Risitano AM, Schubert J, Luzzatto L, Schrezenmeier H, Szer J, Brodsky RA, Hill A, Socie G, Bessler M, Rollins SA, Bell L, Rother RP, Young NS (2007) Effect of the complement inhibitor eculizumab on thromboembolism in patients with paroxysmal nocturnal hemoglobinuria. Blood 110:4123–4128PubMedGoogle Scholar
  140. 140.
    Testa L, Van Gaal WJ, Bhindi R, Biondi-Zoccai GG, Abbate A, Agostoni P, Porto I, Andreotti F, Crea F, Banning AP (2008) Pexelizumab in ischemic heart disease: a systematic review and meta-analysis on 15,196 patients. J Thorac Cardiovasc Surg 136:884–893PubMedGoogle Scholar
  141. 141.
    Flierl MA, Rittirsch D, Nadeau BA, Day DE, Zetoune FS, Sarma JV, Huber-Lang MS, Ward PA (2008) Functions of the complement components C3 and C5 during sepsis. FASEB J 22:3483–3490PubMedGoogle Scholar
  142. 142.
    Ricklin D, Lambris JD (2008) Compstatin: a complement inhibitor on its way to clinical application. Adv Exp Med Biol 632:273–292PubMedGoogle Scholar
  143. 143.
    Chi ZL, Yoshida T, Lambris JD, Iwata T (2010) Suppression of drusen formation by compstatin, a peptide inhibitor of complement C3 activation, on cynomolgus monkey with early-onset macular degeneration. Adv Exp Med Biol 703:127–135PubMedGoogle Scholar
  144. 144.
    Potentia (2007) Potentia Pharmaceuticals announces initiation of Phase I clinical trials to evaluate its lead compound for age-related macular degeneration. Potentia Press Release, April 5, 2007Google Scholar
  145. 145.
    Silasi-Mansat R, Zhu H, Popescu NI, Peer G, Sfyroera G, Magotti P, Ivanciu L, Lupu C, Mollnes TE, Taylor FB, Kinasewitz G, Lambris JD, Lupu F (2010) Complement inhibition decreases the procoagulant response and confers organ protection in a baboon model of Escherichia coli sepsis. Blood 116:1002–1010PubMedGoogle Scholar
  146. 146.
    Thuerer GR, Angevine DM (1949) Influence of dicumarol on streptococcic infection in rabbits. Arch Pathol (Chic) 48:274–277Google Scholar
  147. 147.
    Weiler JM, Linhardt RJ (1991) Antithrombin III regulates complement activity in vitro. J Immunol 146:3889–3894PubMedGoogle Scholar
  148. 148.
    Ranjbaran H, Wang Y, Manes TD, Yakimov AO, Akhtar S, Kluger MS, Pober JS, Tellides G (2006) Heparin displaces interferon-gamma-inducible chemokines (IP-10, I-TAC, and Mig) sequestered in the vasculature and inhibits the transendothelial migration and arterial recruitment of T cells. Circulation 114:1293–1300PubMedGoogle Scholar
  149. 149.
    Baldus S, Rudolph V, Roiss M, Ito WD, Rudolph TK, Eiserich JP, Sydow K, Lau D, Szocs K, Klinke A, Kubala L, Berglund L, Schrepfer S, Deuse T, Haddad M, Risius T, Klemm H, Reichenspurner HC, Meinertz T, Heitzer T (2006) Heparins increase endothelial nitric oxide bioavailability by liberating vessel-immobilized myeloperoxidase. Circulation 113:1871–1878PubMedGoogle Scholar
  150. 150.
    Rao NV, Argyle B, Xu X, Reynolds PR, Walenga JM, Prechel M, Prestwich GD, MacArthur RB, Walters BB, Hoidal JR, Kennedy TP (2010) Low anticoagulant heparin targets multiple sites of inflammation, suppresses heparin—induced thrombocytopenia, and inhibits interaction of RAGE with its ligands. Am J Physiol Cell Physiol 299:C97–C110PubMedGoogle Scholar
  151. 151.
    Davis AE III (2005) The pathophysiology of hereditary angioedema. Clin Immunol 114:3–9PubMedGoogle Scholar
  152. 152.
    Kaplan AP (2010) Enzymatic pathways in the pathogenesis of hereditary angioedema: the role of C1 inhibitor therapy. J Allergy Clin Immunol 126:918–925PubMedGoogle Scholar
  153. 153.
    Antoniu SA (2011) Therapeutic approaches in hereditary angioedema. Clin Rev Allergy Immunol doi: 10.1007/s12016-011-8254-2
  154. 154.
    Petersen SV, Thiel S, Jensen L, Vorup-Jensen T, Koch C, Jensenius JC (2000) Control of the classical and the MBL pathway of complement activation. Mol Immunol 37:803–811PubMedGoogle Scholar
  155. 155.
    Matsushita M, Thiel S, Jensenius JC, Terai I, Fujita T (2000) Proteolytic activities of two types of mannose-binding lectin-associated serine protease. J Immunol 165:2637–2642PubMedGoogle Scholar
  156. 156.
    Jiang H, Wagner E, Zhang H, Frank MM (2001) Complement 1 inhibitor is a regulator of the alternative complement pathway. J Exp Med 194:1609–1616PubMedGoogle Scholar
  157. 157.
    Jansen PM, Eisele B, de Jang I, Chang A, Delvos U, Taylor FB Jr, Hack CE (1998) Effect of C1 inhibitor on inflammatory and physiologic response patterns in primates suffering from lethal septic shock. J Immunol 160:475–484PubMedGoogle Scholar
  158. 158.
    Levi M, Lowenberg E, Meijers JC (2010) Recombinant anticoagulant factors for adjunctive treatment of sepsis. Semin Thromb Hemost 36:550–557PubMedGoogle Scholar
  159. 159.
    Levi M, van der Tom P (2008) The role of natural anticoagulants in the pathogenesis and management of systemic activation of coagulation and inflammation in critically ill patients. Semin Thromb Hemost 34:459–468PubMedGoogle Scholar
  160. 160.
    Crowther MA, Marshall JC (2001) Continuing challenges of sepsis research. JAMA 286:1894–1896PubMedGoogle Scholar
  161. 161.
    Hagiwara S, Iwasaka H, Matsumoto S, Hasegawa A, Yasuda N, Noguchi T (2010) In vivo and in vitro effects of the anticoagulant, thrombomodulin, on the inflammatory response in rodent models. Shock 33:282–288PubMedGoogle Scholar
  162. 162.
    Saito H, Maruyama I, Shimazaki S, Yamamoto Y, Aikawa N, Ohno R, Hirayama A, Matsuda T, Asakura H, Nakashima M, Aoki N (2007) Efficacy and safety of recombinant human soluble thrombomodulin (ART-123) in disseminated intravascular coagulation: results of a phase III, randomized, double-blind clinical trial. J Thromb Haemost 5:31–41PubMedGoogle Scholar
  163. 163.
    Warren BL, Eid A, Singer P, Pillay SS, Carl P, Novak I, Chalupa P, Atherstone A, Penzes I, Kubler A, Knaub S, Keinecke HO, Heinrichs H, Schindel F, Juers M, Bone RC, Opal SM (2001) Caring for the critically ill patient. High-dose antithrombin III in severe sepsis: a randomized controlled trial. JAMA 286:1869–1878PubMedGoogle Scholar
  164. 164.
    Levi M, Schouten M, van der Tom P (2008) Sepsis, coagulation, and antithrombin: old lessons and new insights. Semin Thromb Hemost 34:742–746PubMedGoogle Scholar
  165. 165.
    Opal SM (2000) Therapeutic rationale for antithrombin III in sepsis. Crit Care Med 28:S34–S37PubMedGoogle Scholar
  166. 166.
    Kienast J, Juers M, Wiedermann CJ, Hoffmann JN, Ostermann H, Strauss R, Keinecke HO, Warren BL, Opal SM (2006) Treatment effects of high-dose antithrombin without concomitant heparin in patients with severe sepsis with or without disseminated intravascular coagulation. J Thromb Haemost 4:90–97PubMedGoogle Scholar
  167. 167.
    Sarangi PP, Lee HW, Kim M (2010) Activated protein C action in inflammation. Br J Haematol 148:817–833PubMedGoogle Scholar
  168. 168.
    Bernard GR, Vincent JL, Laterre PF, LaRosa SP, Dhainaut JF, Lopez-Rodriguez A, Steingrub JS, Garber GE, Helterbrand JD, Ely EW, Fisher CJ Jr (2001) Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 344:699–709PubMedGoogle Scholar
  169. 169.
    Levi M, Levy M, Williams MD, Douglas I, Artigas A, Antonelli M, Wyncoll D, Janes J, Booth FV, Wang D, Sundin DP, Macias WL (2007) Prophylactic heparin in patients with severe sepsis treated with drotrecogin alfa (activated). Am J Respir Crit Care Med 176:483–490PubMedGoogle Scholar
  170. 170.
    Xu J, Zhang X, Pelayo R, Monestier M, Ammollo CT, Semeraro F, Taylor FB, Esmon NL, Lupu F, Esmon CT (2009) Extracellular histones are major mediators of death in sepsis. Nat Med 15:1318–1321PubMedGoogle Scholar
  171. 171.
    Goring K, Huang Y, Mowat C, Leger C, Lim TH, Zaheer R, Mok D, Tibbles LA, Zygun D, Winston BW (2009) Mechanisms of human complement factor B induction in sepsis and inhibition by activated protein C. Am J Physiol Cell Physiol 296:C1140–C1150PubMedGoogle Scholar
  172. 172.
    Mosnier LO, Yang XV, Griffin JH (2007) Activated protein C mutant with minimal anticoagulant activity, normal cytoprotective activity, and preservation of thrombin activable fibrinolysis inhibitor-dependent cytoprotective functions. J Biol Chem 282:33022–33033PubMedGoogle Scholar
  173. 173.
    Mosnier LO, Gale AJ, Yegneswaran S, Griffin JH (2004) Activated protein C variants with normal cytoprotective but reduced anticoagulant activity. Blood 104:1740–1744PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Katerina Oikonomopoulou
    • 1
  • Daniel Ricklin
    • 1
  • Peter A. Ward
    • 2
  • John D. Lambris
    • 1
    Email author
  1. 1.Department of Pathology & Laboratory Medicine, School of MedicineUniversity of PennsylvaniaPhiladelphiaUSA
  2. 2.Department of PathologyUniversity of Michigan Medical SchoolAnn ArborUSA

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