Platelet Mediated Complement Activation

  • Ellinor I.B. Peerschke
  • Wei Yin
  • Berhane Ghebrehiwet
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 632)


The complement system comprises a series of proteases and inhibitors that are activated in cascade-like fashion during host defense (Makrides 1998). A growing body of evidence supports the hypothesis that immune mechanisms, including complement activation, are involved in inflammatory conditions associated with vascular injury (Acostan et al. 2004; Giannakopoulos et al. 2007), and disseminated intravascular coagulation associated with massive trauma (Huber-Lang, this volume). We propose that platelets and platelet derived microparticles focus complement to sites of vascular injury where regulated complement activation participates in clearing terminally activated platelets and microparticles from the circulation, and dysregulated complement activation contributes to inflammation and thrombosis. Given the central role of platelets in hemostasis and thrombosis, it is not surprising that activated complement components have been demonstrated in many types of atherosclerotic and thrombotic vascular lesions (Torzewsjki et al. 2007; Niculescu et al. 2004).


Complement Activation Complement Component Classical Complement Pathway Terminal Complement Complex Induce Tissue Factor Expression 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



This work was supported in part by grants HL67211 (EIBP) and AI060866 (BG) from the National Institutes of Health, and an American Heart Association Heritage Affiliate postdoctoral award # 0625900T (WY).


  1. Acostan, J., Qin, X., and Halperin, J. (2004) Complement and complement regulatory proteins as potential molecular targets for vascular diseases. Curr. Pharm. Dis. 10, 203–211CrossRefGoogle Scholar
  2. Allegretti, M., Moriconi., ABeccari, A.R., Di Bitondo, R., Bizzarri, C., Bertini, R., and Colotta, F. (2005) Targeting C5a: recent advances in drug discover. Curr. Med. Chem. 12, 217–236PubMedGoogle Scholar
  3. Arumugam, T.V., Shields, I.A., Woodruff, T.M., Granger, D.N., and Taylor, S.M. (2004) The role of the complement system in ischemia-reperfusion injury. Shock 21, 401–409PubMedCrossRefGoogle Scholar
  4. Barry, O.P., Pratico, D., Savani, R.C., and FitzGerald, G.A. (1998) Modulation of monocyte-endothelial cell interactions by platelet microparticles.. J. Clin. Invest102, 136–144PubMedCrossRefGoogle Scholar
  5. Buerke, M., Prufer, D., Dahm, M., Oelert, H., Meyer, J., and Darius, H. (1998) Blocking of classical complement pathway inhibits endothelial adhesion molecules expression and preserves ischemic myocardium from reperfusion injury. J. Pharmacol. Exp. Ther. 286, 429–438PubMedGoogle Scholar
  6. Davis III, A.D. and Kenney, D.M. (1979) Properdin factor D; effects on thrombin-induced platelet aggregation. J. Clin. Invest. 64, 721–728CrossRefGoogle Scholar
  7. Dedio, J., Jahnen-Dechent, W., Bachmann, M., and Muller-Esterl, W. (1998) The multiligand binding protein gC1qR, putative C1q receptor, is a mitochondrial protein. J. Immunol. 160, 3534–3542PubMedGoogle Scholar
  8. Del Conde, I., Cruz, M.A., Zhang, H., Lopez, J.A., and Afshar-Kharghan, V. (2005) Platelet activation leads to activation and propagation of the complement system. J. Exp. Med. 201, 871–879PubMedCrossRefGoogle Scholar
  9. Devine, D.V. and Rosse, W.F. (1987) Regulation of the activity of platelet-bound C3 convertase of the alternative pathway of complement by platelet factor H. Proc. Natl. Acad. Sci. USA 84, 5873–5877PubMedCrossRefGoogle Scholar
  10. Gawaz, M., Ott, I., Reininger, A.J., Heinzmann, U., and Neumann, F.J. (1996) Agglutination of isolated platelet membranes. Arterioscler. Thromb. Vasc. Biol. 16, 621–627PubMedCrossRefGoogle Scholar
  11. George, J.N., Pickett, E.B., Saucerman, S., McEver, R.P., Kunicki, T.J., Kieffer, N., and Newman, P.J. (1986) Platelet surface glycoproteins. Studies on resting and activated platelets and platelet membrane microparticles in normal subjects, and observations in patients during adult respiratory distress syndrome and cardiac surgery. J. Clin. Invest. 78, 340–348PubMedCrossRefGoogle Scholar
  12. Ghebrehiwet, B. and Peerschke, E.I.B. (1998) Structure and function of gC1qR a multiligand binding membrane protein. Immunobiology 199, 225–238PubMedCrossRefGoogle Scholar
  13. Ghebrehiwet, B., Lim, B.L., Peerschke, E.I.B., Willis, A.C., and Reid, K.B.M. (1994) Isolation of cDNA cloning, and overexpression of a 33-kDa cell surface glycoprotein that binds to the globular heads of C1q. J. Exp. Med. 179, 1809–1821PubMedCrossRefGoogle Scholar
  14. Ghebrehiwet, B., Lim, B.L., Kumar, R., Feng, X., and Peerschke, E.I.B. (2001) gC1qR/p33 a member of a new class of multifunctional and multicompartmental cellular proteins, is involved in inflammation and infection. Immunol. Rev. 180, 65–77PubMedCrossRefGoogle Scholar
  15. Ghebrehiwet, B., Cebada Mora, C., Tantral, L., Jesty, J., and Peerschke, E.I.B. (2006) gC1qR/p33 serves as a molecular bridge between the complement and contact activation systems and is an important catalyst in inflammation. Adv. Exp. Med. Biol. 586, 95–105PubMedCrossRefGoogle Scholar
  16. Giannakopoulos, B., Passam, F., Rahgozar, S., and Krillis, S.A. (2007) Current concepts on the pathogenesis of the antiphospholipid syndrome. Blood 109, 422–430PubMedCrossRefGoogle Scholar
  17. Gnatenko, D.V., Dunn, J.J., McCorkle, S.R., Weissmann, D., Perrotta, P.L., and Bahou, W.E. (2003) Transcript profiling of human platelets using microarray and serial analysis of gene expression. Blood 101, 2285–2293PubMedCrossRefGoogle Scholar
  18. Huber-Lang, M., Sarma, J.V., Zetoune, F.S., Rittirsch, D., Neff, T.A., McGuire, S.R., Lambris, J.D., Warner, R.L., Flierl, M.A., Hoesel, L.M., Gebhard, F., Younger, J.G., Drouin, S.M., Wetsel, R.A., and Ward, P.A. (2006) Generation of C5a in the absence of C3: a new complement activation pathway. Nat. Med. 12, 682–687PubMedCrossRefGoogle Scholar
  19. Ikeda, K., Nagasawa, K., Horiuchi, T., Nishizaka, H., and Niho, Y. (1997) C5a induced tissue factor activity on endothelial cells. Thromb. Haemost. 77, 394–398PubMedGoogle Scholar
  20. Jiang, J., Zhang, Y., Krainer, A., and Xu, R.M. (1999) Crystal structure of p32, a doughnut-shaped acidic mitochondrial matrix protein. Proc. Natl. Acad. Sci. U S A 96, 3572–3577CrossRefGoogle Scholar
  21. Kansas, G.S. (1996) Selectins and their ligands: current concepts and controversies. Blood 88, 3259–3287PubMedGoogle Scholar
  22. Kaplan, A.P., Silverberg, M., and Ghebrehiwet, B. (1986) The intrinsic coagulation/kinin pathway – the classical complement pathway and their interactions. Adv. Exp. Med. Biol. 198, 1311–1325Google Scholar
  23. Kovacsovics, T., Tschopp, J., Kress, A., and Isliker, H. (1985) Antibody independent activation of C1, the first component of complement by cardiolipin. J. Immunol. 135, 2695–2700PubMedGoogle Scholar
  24. Laine, P., Pentikainen, M.O., Wurzner, R., Penttila, A., Paavonen, T., Meri, S., and Kovanen, P.T. (2002) Evidence for complement activation in ruptured coronary plaques in acute myocardial infarction. Am. J. Cardiol. 90, 404–408PubMedCrossRefGoogle Scholar
  25. Mack, W.J., Sughrue, M.W., Ducruet, A.F., Mocco, J., Sosunov, S.A., Hassid, B.G., Silverberg, J.Z., Ten, V.S., Pinsky, D.J., and Connolly Jr., E.S. (2006). Temporal pattern of C1q deposition after transient focal cerebral ischemia. Wiley InterScience ( doi:10, 1002/jnr.20775
  26. Mahdi, F., Mader, Z.S., Figueroa, C.D., and Schmaier, A.H. (2002) Factor XII interacts with multiprotein assembly of urokinase plasminogen activator receptor, gC1qR and cytokeratin 1 on endothelial cell membranes. Blood 15, 3585–3596CrossRefGoogle Scholar
  27. Makrides, S.C. (1998) Therapeutic inhibition of the complement system. Pharmacol. Rev. 150, 59–87Google Scholar
  28. Markiewski, M.M. and Lambris, J.D. (2007) The role of complement in inflammatory diseases from behind the scenes into the spotlight. Am. J. Pathol. 171, 715–727PubMedCrossRefGoogle Scholar
  29. Markiewski, M.M., Nilsson, B., Ekdahl, K.N., Mollnes, T.E., and Lambris, J.D. (2007) Complement and coagulation: strangers or partners in crime? Trends Immunol. 28, 184–192PubMedCrossRefGoogle Scholar
  30. Martinez, M.C., Tesse, A., Zobairi, F., and Andriantsitohaina, R. (2005) Shed membrane microparticles from circulating and vascular cells in regulating vascular function. Am. J. Physiol. Heart Circ. Physiol. 288, H1004–H1009PubMedCrossRefGoogle Scholar
  31. Mause, S.F., von Hundelshausen, P., Zernecke, A., Koenen, R.R., and Weber, C. (2005) Platelet microparticles: a transcellular delivery system for RANTES promoting monocyte recruitment on endothelium. Arteriscler. Thromb. Vasc. Biol. 25, 1512–1518CrossRefGoogle Scholar
  32. Mevorach, D., Mascarenhas, J.O., Gershoev, D., and Eldon, K.B. (1998) Complement dependent clearance of apoptotic cells by human macrophages. J. Exp. Med. 188, 2313–2320PubMedCrossRefGoogle Scholar
  33. Monsinjon, T., Gasque, P., Chan, P., Ischenko, A., Brady, J.J., and Fontaine, M.C. (2003) Regulation by complement C3a and C5a anaphylatoxins of cytokine production in human umbilical vein endothelial cells. FASEB J. 17, 1003–1014PubMedCrossRefGoogle Scholar
  34. Morel, O., Toti, F., Hugel, B., and Freyssinet, J.M. (2004) Cellular microparticles: a disseminated storage pool of bioactive vascular effectors. Curr. Opin. Hematol. 11, 156–164PubMedCrossRefGoogle Scholar
  35. Muhlfelder, T.W., Miemetz, J., Kreutzer, D., Beebe, D., Ward, P.A., and Rosenfeld, S.I. (1979) C5 chemotactic fragment induces leukocyte production of tissue factor activity: a link between complement and coagulation. J. Clin. Invest. 63, 147–150PubMedCrossRefGoogle Scholar
  36. Navratil, J.S., Manzi, S., Kao, A.H., Krishnaswami, S., Liu, C.C., Ruffing, M.J., Shaw, P.S., Nilson, A.C., Dryden, E.R., Johnson, J.J., and Ahearn, J.M. (2006). Platelet C4d is highly specific for systemic lupus erythematosus. Arthritis and Rheum. 54, 670–674CrossRefGoogle Scholar
  37. Niculescu, F., Niculescu, T., and Rus, H. (2004) C5b-9 terminal complement complex assembly on apoptotic cells in human arterial wall with atherosclerosis. Mol. Immunol. 36, 949–955CrossRefGoogle Scholar
  38. Niculescu, F., and Rus, H. (1999) Complement activation and atherosclerosis. Mol. Immunol. 36, 949–955PubMedCrossRefGoogle Scholar
  39. Patel, S., Thelander, E.M., Hernandez, M., Montenegro, J., Hassing, H., Burton, C., Mundt, S., Hermanowski-Vosatka, A., Wright, S.D., Chao, Y.S., and Detmers, P.A. (2001) ApoE. −/− mice develop atherosclerosis in the absence of complement component C5. Biochem. Biophys Res. Commun. 286, 164–170Google Scholar
  40. Peerschke, E.I., and Ghebrehiwet, B. (1997) C1q augments platelet activation in response to aggregated Ig. J. Immunol. 159, 5594–5598PubMedGoogle Scholar
  41. Peerschke, E.I.B., Reid, K.B.M., and 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, 579–587PubMedCrossRefGoogle Scholar
  42. Peerschke, E.I.B., Reid, K.B.M., and Ghebrehiwet, B. (1994) Identification of a novel 33-kDa C1q-binding site on human blood platelets. J. Immunol. 152, 5896–5901PubMedGoogle Scholar
  43. Peerschke, E.I.B., Murphy, T.K., and Ghebrehiwet, B. (2003) Activation-dependent surface expression of gC1qR/p33 on human blood platelets. Thromb. Haemost. 90, 331–339Google Scholar
  44. Peerschke, E.I.B., Petrovan, R.J., Ghebrehiwet, B., and Ruf, W. (2004) Tissue factor pathway inhibitor-2 (TFPI-2) recognizes the complement and kininogen binding protein gC1qR/p33 (gC1qR): implications for vascular inflammation. Thromb. Haemost. 92, 811–819PubMedGoogle Scholar
  45. Peerschke, E.I.B., Yin, W., Grigg, S.E., and Ghebrehiwet, B. (2006) Blood platelets activate the classical pathway of human complement. J Thromb Haemost 4, 2035–2042PubMedCrossRefGoogle Scholar
  46. Peerschke , E.I.B., Yin, W., Alpert, D.R., Salmon, J.E., Roubey, R.A.S., and Ghebrehiwet, B. (2007). Enhanced serum complement activation on platelets is associated with arterial thrombosis in patients with systemic lupus erythematosus (SLE) and antiphospholipid antibodies (aPL) (abstract). Blood 110, 448aGoogle Scholar
  47. Perez-Pujol, S., Marker, P.H., and Key, N.S. (2007) Platelet microparticles are heterogeneous and highly dependent on the activation mechanism: studies using a new digital flow cytometer. Cytometry 71A, 38–45CrossRefGoogle Scholar
  48. Polley, M.J., and Nachman, R.L. (1978) The human complement system in thrombin-mediated platelet function. J. Exp. Med. 147, 1713–1726PubMedCrossRefGoogle Scholar
  49. Polley, M.J., and Nachman, R.L. (1979) Human complement in thrombin-mediated platelet function: uptake of the C5b-9 complex. J. Exp. Med. 150, 633–645PubMedCrossRefGoogle Scholar
  50. Polley, M.J., and Nachman, R.L. (1983) Human platelet activation by C3a and C3a des-arg. J. Exp. Med. 158, 603–615PubMedCrossRefGoogle Scholar
  51. Schaiff, W.T., and Eisenberg, P.R. (1997) Direct induction of complement activation by pharmacologic activation of plasminogen. Coron. Artery Dis. 8, 9–18PubMedCrossRefGoogle Scholar
  52. Schmaier, A.H., Amenta, S., Xiong, T., Heda, G.D., and Gewirtz, A.M. (1993) Expression of C1 Inhibitor. Blood 82, 465–474PubMedGoogle Scholar
  53. Seidl, W.S., Exner, M., Amighi, J., Kastl, S.P., Zorn, G., Maurer, G., Wagner, O., Huber, K., Minar, E., Wojta, J., and Schillinger, M. (2005) Complement component C5a predicts future cardiovascular events in patients with advanced atherosclerosis. Europ. Heart.. J26, 2294–2299CrossRefGoogle Scholar
  54. Sinauridze, E.I., Kireev, D.A., Popenko, N.Y., Pichugin, A.V., Panteleev, M.A., Krymskaya, O.V., and Ataullakhanov, F.I. (2007) Platelet microparticle membrane have 50 – 100 fold higher specific procoagulant activity than activated platelets. Thromb Haemost; 97, 425–434PubMedGoogle Scholar
  55. Shenghe, C., and Davie III, A.E. (2003) Complement regulatory protein C1 inhibitor binds to selectins and interferes with endothelial-leukocyte adhesion. J. Immunol. 171, 4786–4791Google Scholar
  56. Torzewsjki, J., Bowher, D.E., Wlatenberger, J., and Fitzsimmons, C. (2007) Processes in atherogenesis: complement activation. Atherosclerosis 132,131–138CrossRefGoogle Scholar
  57. Vaziri-Sani, F., Hellwage, J., Zipfel, P.F., Sjoholm, A.G., Iancu, R., and Karpman, D. (2004) Factor H binds to washed human platelets. J. Thromb. Haemost. 3, 154–162CrossRefGoogle Scholar
  58. Vermes, I., Haanen, C., Steffen-Nakken, H., and Reutelingsperger, C. (1995) A novel assay of apoptosis : flow cytometric detection of phosphatidylserine expression on early apoptotic cells using fluorescein-labeled Annexin V. J. Immunol. Methods 184, 39–51PubMedCrossRefGoogle Scholar
  59. Vlaicu, R., Niculescu, F., Rus, H.G., and Cristea A. (1985) Immunohistochemical localization of the terminal C5b-9 complement complex in human aortic fibrous plaque. Atherosclerosis 57, 163–177PubMedCrossRefGoogle Scholar
  60. Wiedmer, T., Esmon, C.T., and Sims, P.J. (1986) Complement proteins C5b-9 stimulate procoagulant activity through platelet prothrombinase. Blood 68, 875–880PubMedGoogle Scholar
  61. Yin, W., Ghebrehiwet, B., and Peerschke, E.I.B. (2008) Expression of complement components and inhibitors on platelet microparticles. Platelets 19, 225–233PubMedCrossRefGoogle Scholar
  62. Zimmerman, T.S., and Kolb, N.P. (1976) Human platelet-initiated formation and uptake of the C5-9 complex of human complement. J. Clin. Invest. 57, 203–211PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • Ellinor I.B. Peerschke
    • 1
  • Wei Yin
    • 2
  • Berhane Ghebrehiwet
    • 3
  1. 1.Department of PathologyThe Mount Sinai School of MedicineNew YorkUSA
  2. 2.Department of Mechanical and Aerospace EngineeringOklahoma State UniversityStillwaterUSA
  3. 3.Departments of Medicine and PathologyStony Brook UniversityStony BrookUSA

Personalised recommendations