Page 96 - Haematologica May 2022

J. Yu et al.
late that dysregulation of the APC is likely an early event
after SARS-CoV-2 infection. Complement amplification
from classical and lectin pathways following tissue dam-
age, secondary infections, and thrombosis likely exacer-
bate end-organ damage similar to severe forms of aHUS
and CAPS (Figure 7). Preconditions that lead to inflamma-
tion (e.g., obesity, diabetes and vascular disease) or con-
tribute to complement activation (e.g., third-trimester
pregnancy) or dysregulation (age-related macular degener-
ation and other germline complement mutations) may
contribute to a severe phenotype. Indeed, components of
the APC (CFB, CFD, and C3) are elevated in patients with
obesity and insulin resistance.45 Prospective studies corre-
lating SARS-CoV-2 viral load to complement-mediated
cell damage over the course of infection and additional
genetic studies probing for rare variants in complement
regulatory genes are needed. Our data also suggest that for
complement inhibitors to be most effective, they should
be initiated early in the disease process, but this too Health (NIH), National Heart, Lung, and Blood Institute requires prospective study, as is the subject of the ongoing (NHLBI) grant R01 HL 133113 (RAB); NIH grant K08
TACTIC-R study (clinical trials NCT04390464).46
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Disclosures
Contributions
Funding
RAB has served on the advisory board for Alexion Pharmaceutical Inc.; SC has served on boards for Alexion and Sanofi-Genzyme, and her institution has received research fund- ing on her behalf from Takeda.
JY designed and performed experiments, analyzed the data, enrolled patients and wrote the first draft of the manuscript; GFG enrolled patients, analyzed the data, and edited the manuscript; HC designed and performed the heparin binding assay, ana- lyzed the data, and edited the manuscript; XY, SC and EMB interpreted the data and edited the manuscript; RAB designed the study,supervisedtheexperiments,interpretedthedataandwrote portions of the manuscript.
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