Page 94 - Haematologica May 2022

J. Yu et al.
and clinical data from 97 patients hospitalized with COVID-19 and found an increase in rare variants associat- ed with thrombotic microangiopathies (several involving the alternative pathway of complement) in patients with severe COVID-19 disease.
Complement amplification in hospitalized patients with COVID-19 is multifactorial. Our previous data adding
recombinant spike protein to normal human serum showed that complement-mediated cell killing was almost entirely through the alternative complement pathway.17 Here, using serum from patients with COVID-19, we find additional contributions from the non-APC pathways. This may be because serum samples in this study were obtained a median of 7 days after testing positive for
Figure 7. Proposed model for complement dysregulation in SARS-CoV-2 infection. Early in infection, the SARS-CoV-2 spike protein binds heparan sulfate on the endothelial cell surface and interferes with the inhibitory function of complement factor H (CFH), leading to alternative pathway of complement dysregulation. Suppression of CFH binding results in increased cleavage of factor B by factor D and generation of Bb. Factor Bb binds to C3b to form the alternative pathway C3 convertase (C3bBb), leading to the cleavage of C3 and generation of the C5 convertase (C4b2a3b or C3bBb3b). The C5 convertase cleaves C5 to generate C5a and C5b, which complexes with C6-9 to form the membrane attack complex (C5b-9). C3a and C5a are anaphylatoxins that recruit inflammatory cells and upregulate the expression of acute phase proteins, such as C-reactive protein. Complement amplification from the classical and lectin pathways follows subsequent tissue damage, secondary infections and thromboses. Formation of antibody-antigen complexes can activate the classical complement pathway by binding to the C1 complex and cleaving C4 and C2 to form the classical C3 convertase (C4b2a). In the lectin pathway, MBL-MASP binds to carbohydrates on the surface of microbes and mediates the cleavage of C2 and C4, to generate the C3 convertase (C4b2a). Preconditions that enhance inflammation (e.g., obesity, diabetes, and vascular disease) or con- tribute to complement activation (e.g., third-trimester pregnancy) or dysregulation (age-related macular degeneration and other germline complement mutations) may contribute to a severe phenotype through upregulation of these pathways. HS: heparan sulfate; MBL-MASP: mannose-binding protein-mannose-binding lectin serine protease; CRP: C-reactive protein.
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