Although most cases of COVID-19 are paucisymptomatic, severe disease MESHD is characterized by immune dysregulation HP, with a decreased type I interferon response, increased inflammatory HP indicators, surging IL-6, IL-10 and TNFα suggestive of cytokine storm, progressive lymphopenia MESHD lymphopenia HP, and abnormal blood SERO clotting. Factors determining susceptibility to severe disease MESHD are poorly understood, although mortality correlates with increasing age TRANS and co-morbidities including diabetes and cardiovascular disease MESHD (CVD). Pyridoxal 5'-phosphate (PLP) tends to be insufficient in populations particularly vulnerable to COVID-19, including the elderly TRANS, the institutionalized, and people with diabetes and CVD, and PLP becomes further depleted during infection MESHD and inflammation MESHD. In turn, low PLP results in immune imbalance, as PLP is an essential cofactor in pathways regulating cytokine production, in particular type I interferons and IL-6, and in lymphocyte trafficking and endothelial integrity. Furthermore, normalizing PLP levels attenuates abnormalities in platelet aggregation and clot formation. Finally, PLP insufficiency induces excess secretion of renin and angiotensin, and hypertension MESHD hypertension HP. In inflammatory disease MESHD, pharmacological doses of PLP decrease circulating TNFα, IL-6 and D-dimer, and animal studies demonstrate that supplemental PLP shortens the duration and severity of viral pneumonia MESHD pneumonia HP. Severe COVID-19 manifests as an imbalance in the immune response and the clotting system. Pharmacological PLP supplementation may therefore mitigate COVID-19 symptoms by alleviating both the immune suppression underlying viral spread and the pathological hypersecretion of inflammatory cytokines, as well as directly bolstering endothelial integrity and preventing hypercoagulability HP.