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. These 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.
Amara
Umme
U
Department of Traumatology, Hand-, Plastic-, and Reconstructive Surgery, University Hospital of Ulm, Ulm, Germany.
Rittirsch
Daniel
D
Flierl
Michael
M
Bruckner
Uwe
U
Klos
Andreas
A
Gebhard
Florian
F
Lambris
John D
JD
Huber-Lang
Markus
M
D000706:Anaphylatoxins / Q000276:immunology; D000818:Animals; D001777:Blood Coagulation / Q000276:immunology*; D003167:Complement Activation / Q000276:immunology; D015922:Complement C1q / Q000276:immunology; D003175:Complement C2 / Q000276:immunology; D003176:Complement C3 / Q000276:immunology; D015926:Complement C3a / Q000276:immunology; D003181:Complement C4 / Q000276:immunology; D015934:Complement C4a / Q000276:immunology; D003182:Complement C5 / Q000276:immunology; D015936:Complement C5a / Q000276:immunology; D011415:Complement Factor B / Q000276:immunology; D003165:Complement System Proteins / Q000276:immunology*; D004347:Drug Interactions; D015945:Factor XIa / Q000276:immunology; D015951:Factor Xa / Q000276:immunology; D005341:Fibrinolysin / Q000276:immunology; D006487:Hemostasis / Q000276:immunology; D006801:Humans; D008954:Models, Biological; D012697:Serine Endopeptidases / Q000276:immunology; D013917:Thrombin / Q000276:immunology; D014945:Wound Healing / Q000276:immunology
D000706:Anaphylatoxins; D003175:Complement C2; D003176:Complement C3; D003181:Complement C4; D003182:Complement C5; D015922:Complement C1q; D015926:Complement C3a; D015934:Complement C4a; D015936:Complement C5a; D003165:Complement System Proteins; D012697:Serine Endopeptidases; D015945:Factor XIa; D011415:Complement Factor B; D013917:Thrombin; D015951:Factor Xa; D005341:Fibrinolysin