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* First Division of Internal Medicine, Medical School, Democritus University of Thrace, Alexandroupolis, Greece;
Foundation for Biomedical Research of the Academy of Athens, Center of Immunology and Transplantations, Athens, Greece; and
Department of Pathology & Laboratory Medicine, School of Medicine, University of Pennsylvania, Philadelphia, PA 19104
Neutrophils and complement are key sentinels of innate immunity and mediators of acute inflammation. Recent studies have suggested that inflammatory processes modulate thrombogenic pathways. To date, the potential cross-talk between innate immunity and thrombosis and the precise molecular pathway by which complement and neutrophils trigger the coagulation process have remained elusive. In this study, we demonstrate that antiphospholipid Ab-induced complement activation and downstream signaling via C5a receptors in neutrophils leads to the induction of tissue factor (TF), a key initiating component of the blood coagulation cascade. TF expression by neutrophils was associated with an enhanced procoagulant activity, as verified by a modified prothrombin time assay inhibited by anti-TF mAb. Inhibition studies using the complement inhibitor compstatin revealed that complement activation is triggered by antiphospholipid syndrome (APS) IgG and leads to the induction of a TF-dependent coagulant activity. Blockade studies using a selective C5a receptor antagonist and stimulation of neutrophils with recombinant human C5a demonstrated that C5a, and its receptor C5aR, mediate the expression of TF in neutrophils and thereby significantly enhance the procoagulant activity of neutrophils exposed to APS serum. These results identify a novel cross-talk between the complement and coagulation cascades that can potentially be exploited therapeutically in the treatment of APS and other complement-associated thrombotic diseases.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by grants from the Governing Board of Academic Hospital of Alexandroupolis (to K.R.), Marie Curie fellowship (to S.R.), Phillip Morris USA and Phillip Morris International (to P.S. and D.M.), and National Institutes of Health Grants GM62134, GM069736, and DK59422 (to J.D.L.).
2 Address correspondence and reprint requests to Dr. Konstantinos Ritis, P.O. Box 205, 68100 Alexandroupolis, Greece; E-mail address: ritis2{at}otenet.gr or Dr. John D. Lambris, Protein Chemistry Laboratory, 401 Stellar-Chance Labs, 422 Curie Boulevard, Department of Pathology & Laboratory Medicine, School of Medicine, University of Pennsylvania, Philadelphia, PA 19104; E-mail address: lambris{at}mail.med.upenn.edu
3 Abbreviations used in this paper: APS, antiphospholipid syndrome; TF, tissue factor; asTF, alternatively spliced variant of human TF; cTF, common TF; rhC5a, recombinant human C5a; mPT, modified prothrombin time; FVII, factor VII.
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