Complement proteins C5b-9 stimulate procoagulant activity through platelet prothrombinase

Abstract

The capacity of platelets treated with nonlytic concentrations of the C5b-9 proteins to catalyze prothrombin activation and thereby trigger clot formation has been investigated. When suspended in the presence of exogenous factors Xa and Va, gel-filtered platelets treated with purified C5b-9 proteins catalyzed prothrombin to thrombin conversion at rates up to tenfold above controls, and exceeded by up to fourfold the prothrombinase activity observed for thrombin-stimulated platelets. In the absence of added factor Va, C5b-9 assembly on the platelet surface significantly shortened the lag period before prothrombinase expression that was observed for untreated platelets and increased the maximum catalytic rate of thrombin formation. A comparison with other platelet stimuli revealed that the C5b-9-induced activation of platelet prothrombinase closely paralleled the effects mediated by calcium ionophore A23187. Our data suggest that the C5b-9 proteins promote the release of platelet factor V and the assembly of the prothrombinase complex, thereby potentiating the effects of thrombin on the activation of prothrombinase. Membrane assembly of the C5b-9 proteins was also observed to markedly accelerate the rate of platelet-catalyzed plasma clotting, suggesting a direct link between C5b-9-mediated prothrombinase activation and procoagulant activity accompanying immunologic damage to the platelet.

Properdin: a tightly regulated critical inflammatory modulator

“…Theoretical reasons for this potent effect stem from the potential for multiple positive feedback loops involved in PGA formation that were alluded to in the previous section: (i) platelets and neutrophils mutually enhance each other's activation, thus any factor that enhances the activation of one cell has the potential to indirectly activate the other; (ii) platelets are both activated by complement, [171][172][173][174][175][176] and activate the alternative pathway in a properdin-dependent manner 31 ;…”

Reincarnation of ancient links between coagulation and complement

“…Platelets, endothelial cells, and leukocytes are sensitive to activation by sublytic concentrations of C5b-9 (sC5b-9), thereby providing a mechanism for complement-mediated activation/amplification of the hemostatic system. sC5b-9 induces 'flipping' of the phospholipid membranes of endothelial cells and platelets that favors binding of factor Va, prothrombinase assembly, and generation of thrombin [109][110][111] (Fig. 1 Panel Ea).…”

Complement activation on platelets correlates with a decrease in circulating immature platelets in patients with immune thrombocytopenic purpura

“…Complement fixation in the test system, measured following incubation of immobilized platelets with the standard reference plasma pool, reflects this intrinsic platelet activity, and was considered baseline. Amplification of complement activation by C5b-9 generation in the test system and direct C5b-9 mediated platelet stimulation (Wiedmer et al, 1986) was prevented by using fixed platelets. EDTA, an inhibitor of classical and alternative pathways of complement, prevented the association of activated complement components with platelets, except C1q, demonstrating that the assay measures de novo complement activation at or near the immobilized platelet surface.…”