@article{Yu_Gerber_Chen_Yuan_Chaturvedi_Braunstein_Brodsky_2022, place={Pavia, Italy}, title={Complement dysregulation is associated with severe COVID-19 illness}, volume={107}, url={https://haematologica.org/article/view/haematol.2021.279155}, DOI={10.3324/haematol.2021.279155}, abstractNote={<p>Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) may manifest as thrombosis, stroke, renal failure, myocardial infarction, and thrombocytopenia, reminiscent of other complement- mediated diseases. Multiple clinical and preclinical studies have implicated complement in the pathogenesis of COVID-19 illness. We previously found that the SARS-CoV-2 spike protein activates the alternative pathway of complement (APC) in vitro through interfering with the function of complement factor H, a key negative regulator of APC. Here, we demonstrated that serum from 58 COVID-19 patients (32 patients with minimal oxygen requirement, 7 on high flow oxygen, 17 requiring mechanical ventilation and 2 deaths) can induce complementmediated cell death in a functional assay (the modified Ham test) and increase membrane attack complex (C5b-9) deposition on the cell surface. A positive modified Ham assay (&gt;20% cell-killing) was present in 41.2% COVID-19 patients requiring intubation (n=7/17) and only 6.3% in COVID-19 patients requiring minimal oxygen support (n=2/32). C5 and factor D inhibition effectively mitigated the complement amplification induced by COVID-19 patient serum. Increased serum factor Bb level was associated with disease severity in COVID-19 patients, suggesting that APC dysregulation plays an important role. Moreover, SARS-CoV-2 spike proteins directly block complement factor H from binding to heparin, which may lead to complement dysregulation on the cell surface. Taken together, our data suggest that complement dysregulation contributes to the pathogenesis of COVID-19 and may be a marker of disease severity.</p&gt;}, number={5}, journal={Haematologica}, author={Yu, Jia and Gerber, Gloria F. and Chen, Hang and Yuan, Xuan and Chaturvedi, Shruti and Braunstein, Evan M. and Brodsky, Robert A.}, year={2022}, month={May}, pages={1095-1105} }