Is complement the culprit behind COVID-19 vaccine-related adverse reactions?
Complement is a host innate immune sentinel comprising over 50 proteins that can be swiftly activated through any of three initiating pathways (classical, lectin, or alternative) that sense microbial invaders or other inflammatory cues, such as immune complexes. In fact, complement activation has been implicated as a perpetrator of immune complexdriven thromboinflammation in autoimmune pathologies such as the antiphospholipid syndrome, a systemic disorder that increases risk for blood clots (6). Prompted by the striking findings in patients who developed VITT after a single dose of adenoviral-associated vaccine, we posit here that the observed thrombotic complications may partly reflect immune complextriggered complement activation through the classical pathway. PF4-containing immune complexes can be recognized by C1q, a soluble pattern recognition molecule of the classical pathway that binds to the Fc portion of IgG molecules. Anti-PF4 complexdriven classical pathway activation can lead to C3 activation, alternative pathwaymediated amplification of complement responses, and downstream generation of potent proinflammatory mediators and effectors (C3a, C5a and membrane attack complex) that can potentiate thromboinflammation (7). In fact, the thrombogenic capacity of distinct complement activation fragments has been linked to a broad spectrum of immune-related mechanisms that underpin the immunothrombosis of severe COVID-19 (7, 8). Considering that certain allelic combinations of complement gene polymorphisms within the population confer differential susceptibility to deregulated complement activity, it is tempting to speculate that these vaccinated individuals may represent cases where complement deregulation occurs due to genetic alterations that result in ineffective host regulatory control (9). Deregulated complement responses can perpetuate a vicious cycle of inflammatory tissue damage that renders the vascular endothelium and platelet/monocyte compartment more thrombogenic. In this regard, circulating anti-PF4 immune complexes may well serve as a first hit that ignites complement activation, in a way similar to complement-mediated thrombotic microangiopathies (10). The fact that a fraction of these anti-PF4 autoantibodies may recognize antigenic complexes between PF4 and polyanionic structures (such as GAGs or heparan sulfate) raises the possibility that these immune complexes may skew the binding of endogenous complement regulators to host polyanionic surfaces, thereby altering the capacity of these surfaces to withstand autologous complement attack. C3 activation may play a pivotal pathogenic role in this vaccine-induced immunothrombotic phenotype. C3-opsonized anti-PF4 immune complexes can enhance the phagocytic and inflammatory properties of monocytes and neutrophils through the synergistic engagement of FcR and complement receptors, thereby increasing the thrombogenic milieu in the vasculature (Figure 1). C3 fragment deposition on the endothelium and on platelets/neutrophils can potentiate thromboinflammatory responses by promoting CR3-dependent platelet-neutrophil interactions that favor platelet adhesion and clotting (11). Also, C3aR signaling on platelets can further drive thrombotic responses (12). Of note, it has been shown that PF4heparin complexes, a hallmark of HIT pathology, can potently activate C3 in the fluid phase and C3 inhibitors such as Cp40 can abrogate C3 activation triggered by HIT-associated PF4heparin complexes (13). In line with this, the Cp40-based drug candidate AMY-101 has been shown to effectively decrease both neutrophils and neutrophil extracellular trap (NET) formation, two major drivers of HIT-associated thrombosis, in patients with COVID-19 (7, 1416).