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, 2005
; Peerschke et al., 2006
Complement activation requires platelet stimulation and is associated with the expression of P-selectin (del Conde et al., 2005
) and gC1qR (Peerschke et al., 2006
) on the platelet surface, as well as the secretion of chondroitin sulfate (Hamad et al., 2008
) from internal platelet stores. P-selectin has been associated with activation of the alternative complement pathway, whereas gC1qR and chondroitin sulfate activate the classical pathway. Platelet mediated complement activation can be detected on adherent platelets and activated platelets in suspension, following in vitro exposure to purified complement components, normal plasma or serum, by flow cytometry or ELISA methods.
The intrinsic capacity of platelets to activate complement on /near their surface when exposed to plasma or serum is proportional to the extent of platelet activation (Peerschke et al., 2006
). Platelets activated by weak agonists such as ADP and epinephrine support less complement activation than platelets activated by thrombin or arachidonic acid. In addition to chemical agonists, platelets exposed to shear stress (1800 sec-1
for 60 min) support complement activation. Interestingly, platelets activated by shear stress appear to preferentially activate the classical complement pathway. In contrast, platelets activated by agonists such as thrombin or its receptor activation peptide (TRAP6
), which induce alpha granule secretion and P-selectin expression on the platelet surface, appear to support predominantly alternative pathway activation. This may reflect the secretion of C1 inhibitor (Schmaier et al., 1993
), a potent inhibitor of C1s in the classical pathway, from platelet alpha granules. Indeed, an inverse correlation has been noted between C4 activation on/by platelets and P-selectin expression on their surface (Peerschke et al, 2006
Classical pathway complement activation on/by platelets does not require immune complex formation at the platelet surface. Activation of C4 has been observed following exposure of activated platelets to purified C1 and C4 as well as to normal serum (), and is significantly reduced or absent in C1 depleted serum (Peerschke et al., 2006
). In contrast, both classical pathway and alternative pathways participate in C3b deposition on activated platelets. Thus, reductions in C3b deposition on platelets relative to normal serum are noted with either C1 or Factor B depleted serum (Peerschke et al., 2006
). We believe that these findings reflect the intrinsic capacity of platelets to activate complement (). As described in subsequent sections, platelets also serve as targets of immune mediated complement activation.
Figure 1 Complement activation on/by platelets and platelet microparticles. Results are of typical experiments. Deposition of activated complement components on platelets and microparticles was evaluated by flow cytometry using monoclonal antibodies to C1q, C4d, (more ...)
Figure 2 Proposed mechanisms of complement activation on/by activated platelets. Panel A depicts the intrinsic capacity of platelets to activate the classical and alternative pathways of complement. Panel B demonstrates immune mediated enhanced complement activation (more ...)
Although, studies of complement activation on/by platelets to date have been conducted exclusively in in vitro closed systems, evidence of in vivo complement deposition on platelets has been presented also. Platelet associated C4d has been reported in approximately 18% of patients with systemic lupus erythematosus (Navratil et al., 2006
), and preliminary studies by the authors (EIBP, BG) demonstrate detectable levels of C4d, iC3b and C5b-9 on circulating platelets in approximately 14% of patients with coronary artery disease (n=5/35) (unpublished observations). These findings suggest complement activation on/by platelets in disorders associated with vascular inflammation and thrombosis, and lend strong support for the continued investigation of the physiologic and pathologic relevance of platelet mediated complement activation and its regulation.