Interaction Between the Coagulation and Complement System
The complement system as a main column of innate immunity and the coagulation system as a main column in hemostasis undergo massive activation early after injury. Interactions between the two cascades have often been proposed but the precise molecular pathways of this interplay are still in the dark. To elucidate the mechanisms involved, the effects of various coagulation factors on complement activation and generation of anaphylatoxins were investigated and summarized in the light of the latest literature. Own in vitro findings suggest, that the coagulation factors FXa, FXIa and plasmin may cleave both C5 and C3, and robustly generate C5a and C3a (as detected by immunoblotting and ELISA). The produced anaphylatoxins were found to be biologically active as shown by a dose-dependent chemotactic response of neutrophils and HMC-1 cells, respectively. Thrombin did not only cleave C5 (Huber-Lang et al. 2006) but also in vitro-generated C3a when incubated with native C3. The plasmin-induced cleavage activity could be dose-dependently blocked by the serine protease inhibitor aprotinin and leupeptine. Theese findings suggest, that various serine proteases belonging to the coagulation system are able to activate the complement cascade independently of the established pathways. Moreover, functional C5a and C3a are generated, both of which are known to be crucially involved in the inflammatory response.
We thank Sonja Albers and Barbara Acker for outstanding laboratory assistance. This work was supported by grants from the Deutsche Forschungsgemeinschaft (DFG HU 823/2-2, HU 823/2-3, European Shock Society/Novo Nordisk Grant 2005) and NIH AI068730.
- Bernard, G.R., Vincent, J.L., Laterre, P.F., LaRosa, S.P., Dhainaut, J.F., Lopez-Rodriguez, A., Steingrub, J.S., Garber, G.E., Helterbrand, J.D., Ely, E.W., Fisher, C.J. (2001) Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 344, 699–709PubMedCrossRefGoogle Scholar
- 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., Ward, P.A. (2006) Generation of C5a in the absence of C3: a new complement activation pathway. Nat Med 12, 682–687PubMedCrossRefGoogle Scholar
- Lambris, : , J.D., Sahu, A., Wetsel, R. (1998) The chemistry and biology of C3, C4, and C5. InVolanakis, J.E., Frank, M. (eds.). The Human Complement System in Health and DiseaseMarcel Dekker, New York, pp. 83–118Google Scholar