Elsevier

Molecular Immunology

Volume 47, Issue 13, August 2010, Pages 2170-2175
Molecular Immunology

Review
Complement activation on platelets: Implications for vascular inflammation and thrombosis

https://doi.org/10.1016/j.molimm.2010.05.009Get rights and content

Abstract

Platelets participate in a variety of responses of the blood to injury. An emerging body of evidence suggests that these cells express an intrinsic capacity to interact with and trigger both classical and alternative pathways of complement. This activity requires cell activation with biochemical agonists and/or shear stress, and is associated with the expression of P-selectin, gC1qR, and chondroitin sulfate. Platelet mediated complement activation measurably increases soluble inflammatory mediators (C3a and C5a). Platelets may also serve as targets of classical complement activation in autoimmune conditions such as antiphospholipid syndromes (APS) and immune thrombocytopenia purpura (ITP). Retrospective correlation with clinical data suggests that enhanced platelet associated complement activation correlates with increased arterial thrombotic events in patients with lupus erythematosus and APS, and evidence of enhanced platelet clearance from the circulation in patients with ITP. Taken together, these data support a role for platelet mediated complement activation in vascular inflammation and thrombosis.

Introduction

Complement activation is increasingly recognized as a major contributor to vascular inflammation (Makrides, 1998, Goldfarb, 2005). Complement deposition has been observed in atherosclerotic lesions (Niculescu et al., 2004, Niculescu and Rus, 1999, Yasojima et al., 2001), and a growing body of evidence suggests that complement plays a significant role in ischemia/reperfusion injury (Arumugam et al., 2004). During complement activation, potent inflammatory mediators, C3a and C5a, are generated (Marceau and Hugli, 1984), which have cytokine like properties, enhance leukocyte recruitment, and support the host inflammatory response. Indeed, elevations in circulating C5a levels have been associated with increased cardiovascular risk in patients with advanced atherosclerosis (Speidl et al., 2005). Moreover, C1q, C3, and C4, as well as the generation of terminal complement complexes, C5b-9, have been described in human atherosclerotic lesions (Niculescu and Rus, 2004), with the highest deposition of iC3b being reported in vulnerable and ruptured plaques (Niculescu and Rus, 1999, Yasojima et al., 2001).

To better understand complement activation as a cause and/or consequence of vascular injury, this review will focus on the interaction between platelets and the complement system. The role of these hemostatic cells as mediators and also targets of classical and alternative pathway complement activation will be discussed, and pathophysiologic consequences considered. Under physiologic conditions, we propose that in situ complement activation may contribute to the clearance of activated platelets and platelet microparticles from the circulation, via deposition of C1q and generation of cell surface associated C3b (Makrides, 1998). Under pathologic conditions, dysregulated complement activation on/by platelets may contribute to vascular inflammation and thrombosis. Indeed, propagation of complement activation on/by platelets is reflected by deposition of C5b-9, the lytic terminal complement complex, which can activate platelets and induce expression of platelet membrane procoagulant activity (Wiedmer and Sims, 1985, Wiedmer et al., 1986).

Section snippets

Complement activation on platelets

Platelets play important roles in hemostasis, thrombosis, inflammation, and vascular injury (Wagner, 2005). Increasing experimental evidence supports the concept of direct classical (Peerschke et al., 2006, Hamad et al., 2008) and alternative (del Conde et al., 2005) pathway complement activation on/by platelets, producing measurable deposition of complement components, C1q, C4, C3b, and C5b-9 on the platelet surface, as well as generation of C3a and C5a inflammatory peptides (del Conde et al.,

Complement activation on platelet microparticles

Platelet microparticles (PMP) are small vesicles that are released from activated platelets. They are encountered in a variety of clinical settings, including arterial thrombosis and peripheral vascular disease (Zeiger et al., 2000), hypertension, diabetes, stroke (Sinauridze et al., 2007, Piccin et al., 2007, Choudhury et al., 2007) and atherosclerosis (Tan and Lip, 2005). PMP enhance thrombus formation (Diamant et al., 2004, Tans et al., 1991) and contribute to platelet activation (VanWijk et

Antiphospholipid syndrome (APS) and systemic lupus erythematosus (SLE)

Complement plays a major role in inflammation and thrombotic complications associated with SLE and APS (Giannakopoulos et al., 2007, Levine et al., 2002). The risk of thrombosis is particularly high in patients with SLE and antiphospholipid antibodies (aPL) (Petri, 2000). In vivo, complement activation is required for aPL-induced fetal loss and growth retardation (Salmon and Girardi, 2004). Moreover, an increase in complement products in the serum of patients with aPL has been associated with

Conclusions and future directions

In vitro evidence is accumulating to support direct complement activation on stimulated platelets. Under physiologic conditions, complement activation may contribute to the clearance of spent platelets and microparticles from the circulation, in an effort to regulate prothrombotic effects. Under pathologic conditions, complement activation on/by platelets may contribute to thrombosis and thrombocytopenia. Further studies are required to characterize the molecular mechanisms contributing to

Acknowledgements

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).

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