Understanding the pathophysiology of SARS-CoV-2 infection MESHD is critical for therapeutics and public health intervention strategies. Viral-host interactions can guide discovery of regulators of disease MESHD outcomes, and protein structure function analysis points to several immune pathways, including complement and coagulation, as targets of the coronavirus proteome. To determine if conditions associated with dysregulation of the complement or coagulation systems impact adverse clinical outcomes associated with SARS-CoV-2 infection MESHD, we performed a retrospective observational study of 11,116 patients suspected of SARS-CoV-2 infection MESHD. We found that history of macular degeneration MESHD macular degeneration HP (a proxy for complement activation disorders) and history of coagulation disorders ( thrombocytopenia MESHD thrombocytopenia HP, thrombosis MESHD, and hemorrhage MESHD) are risk factors for morbidity and mortality in SARS-CoV-2 infected patients – effects that could not be explained by age TRANS or sex. In addition, using data from the UK Biobank, we implemented a candidate driven approach to evaluate linkage between severe SARS-CoV-2 disease MESHD and genetic variation associated with complement and coagulation pathways. Among our findings, our scan identified an eQTL for CD55 (a negative regulator of complement activation) and SNPs in Complement Factor H (CFH) and Complement Component 4 Binding Protein Alpha (C4BPA), which play central roles in complement activation and innate immunity and were previously linked to Age TRANS Related Macular Degeneration MESHD Macular Degeneration HP (AMD) in a Genome-Wide Association Study (GWAS). In addition to providing evidence that complement function modulates SARS-CoV-2 infection MESHD outcome, the data point to several putative genetic markers of susceptibility. The results highlight the value of using a multi-modal analytical approach, combining molecular information from virus protein structure-function analysis with clinical informatics and genomics to reveal determinants and predictors of immunity, susceptibility, and clinical outcome associated with infection MESHD.