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Adv Exp Med Biol. Author manuscript; available in PMC 2009 July 22.

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Published in final edited form as:
Adv Exp Med Biol. 2008 ; 632: 71–79.

Interaction Between the Coagulation and Complement System
Umme Amara1, Daniel Rittirsch1, Michael Flierl1, Uwe Bruckner2, Andreas Klos3, Florian
Gebhard1, John D. Lambris4, and MarkusHuber-Lang1
J.D. Lambris
1Department

of Traumatology, Hand-, Plastic-, and Reconstructive Surgery, University Hospital of
Ulm, Ulm, Germany, markus.huber-lang@uni-klinik-ulm.de 2Division of Experimental Surgery,
University Hospital of Ulm, Ulm, Germany, uwe.bruckner@uni-ulm.de 3Department of Medical
Microbiology, Medical School Hannover, Hannover, Germany, klos.andreas@mh-hannover.de4Department of Pathology, University of Pennsylvania, 401 Stellar Chance, Philadelphia, PA 19104,
USA, lambris@mail.med.upenn.edu.

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Abstract
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 proposedbut 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 cleavageactivity 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 inflammatoryresponse.

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1 Introduction
The complement system as a key sentinel of innate immunity and the coagulation system as
main actor in hemostasis belong both to the “first line of defense” against injurious stimuli and
invaders (Choi et al. 2006). Being descended from a common ancestor, interactions between
both cascades have often been proposed, but the precise molecularpathways of this cross-talk
have remained elusive. Immediately after severe trauma, massive activation of a series of
cascading enzymatic reactions results in fibrin deposition as well as synchronic fibrinolysis
(Lampl et al. 1994), which often causes an uncontrolled, systemic inflammatory response
(SIRS) (Levi et al. 2004). Furthermore, both cascades contain series of serine-proteases withevidence of some shared activators and inhibitors, such as factor (F) XIIa, which is able to
activate C1q, and thereby the classical pathway of complement. Similarly, the C1 esterase
inhibitor acts not only as inhibitor of all three established complement pathways (classical:
C1q/r/s, lectin: MBL, and alternative: C3b) but also of the endogenous coagulation activation
path (kallikrein, FXIIa)(Davis 2004). Previously it has been shown that thrombin, generated
at inflammatory sites in response to complement activation, is a physiological agonist for the
PKC-dependent pathway of decay accelerating factor (DAF) regulation in terms of a negative

Amara et al.

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feedback loop preventing thrombosis during inflammation (Lidington et al. 2000). The...