Intravascular hemolysis induces complement system activation

Complement activation during intravascular hemolysis: Implication for sickle cell disease and hemolytic transfusion reactions

“…Finally, in vivo experimental settings where heme levels were increased in the circulation in relatively more-pathophysiologically relevant ways, i.e. by intravascular hemolysis or injection of aged RBC, revealed efficacy of hemopexin in preventing mortality (113) and complement activation (56). In the latter study, decrease of acute kidney injury markers in C3 -/mice revealed the impact of complement activation on kidney injury during hemolysis.…”

“…These C3b/C3d deposits and RBC lysis were efficiently inhibited by the C3b-binding peptide Cp40, derived from compstatin (102). More recently, we showed that heme induces alternative complement pathway activation directly in serum and on endothelial cells (56,58), by promoting hydrolysis of C3 and formation of a fluid phase C3 convertase. C3a, C5a and sC5b9 are detected in sera in a dose-dependent manner of heme concentration (Figure 3).…”

“…Subsequently, few reports have mentioned C3 fragments deposition in kidneys in humans and in a mouse model of SCD (54,55). More recently, Merle et al demonstrated the presence of tissue deposits of C3 activation fragments and C5b-9 in kidney biopsies of SCD nephropathy patients and in kidneys of two mouse models of SCD -HbSS Townes and SAD (56). Further, Vercellotti et al, confirmed and extended the notion that complement contributes to the tissue injury in SCD.…”

“…The C3b regulator Factor H prevented the adhesion of sickle red cells to the endothelium, normalizing speed transition times. Although no data is available for the expression of the membrane complement regulators and anaphylatoxin receptors on patients' endothelium, in vitro experiments showed that heme-exposed endothelium decreases the expression of CD46 and CD55 and upregulation of C3aR and C5aR (56,(58)(59)(60).…”

“…Given its amount in the circulation (1 g/L), albumin could keep heme away from other proteins and could neutralize its harmful properties. Nevertheless, only minor beneficial effects are provided in vitro by albumin regarding oxidative reaction (110) and complement activation (56). Moreover, a broad number of studies have depicted pro-inflammatory processes upon injection of heme or heme/albumin in WT and SCD mouse models, excluding such substantial inhibitory capacity of albumin, despite its high plasma content (46,105,106,111,112).…”