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, we performed a retrospective observational study of 11,116 patients who presented with suspected 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, sex, or history of smoking. Further, transcriptional profiling of nasopharyngeal (NP) swabs from 650 control and SARS-CoV-2 infected patients demonstrated that in addition to innate Type-I interferon and IL-6 dependent inflammatory immune responses, infection MESHD results in robust engagement and activation of the complement and coagulation pathways. Finally, we conducted a candidate driven genetic association study of severe SARS-CoV-2 disease MESHD. Among the findings, our scan identified putative complement and coagulation associated loci including missense, eQTL and sQTL variants of critical regulators of the complement and coagulation cascades. In addition to providing evidence that complement function modulates SARS-CoV-2 infection MESHD outcome, the data point to putative transcriptional 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, transcriptomics, and genomics to reveal determinants and predictors of immunity, susceptibility, and clinical outcome associated with infection MESHD.