**Background:** Despite extensive research into COVID-19 pathogenesis, the mechanisms underlying severe complications remain incompletely understood. Vitamin D (VitD) deficiency is highly prevalent worldwide—affecting 30–60% of European populations and 80% of people in the Middle East—and has been linked to unfavorable COVID-19 outcomes. This review explores the physiological role of VitD in hemostasis and immunity, and how hypovitaminosis D may contribute to the incidence, progression, and thrombotic complications of COVID-19.
**Methods:** This is a narrative review synthesizing evidence from observational studies, clinical trials, and preclinical research on the interplay between VitD status, immune function, coagulation pathways, and COVID-19-associated thrombosis. The authors examine pathophysiological pathways including inflammatory cytokine cascades, platelet abnormalities, coagulation system aberrations, endothelial dysfunction (ED), complement activation, and the renin–angiotensin–aldosterone system (RAAS).
**Key Results:** The review reports that serum VitD levels less than 50 nmol/l are present in 30–60% of European populations and 80% of Middle Eastern populations, with levels below 30 nmol/l in over 10% of Europeans. Each 10 nmol/l decrease in VitD levels increases the odds of acute respiratory tract infection by 1.02 (95% CI: 0.97–1.07). Hypovitaminosis D is associated with an increased CD4/CD8 ratio, reducing the capacity to produce activated CD8+ T-lymphocytes needed to attack virally infected cells. COVID-19 patients have been reported to have low regulatory T-lymphocyte (T-reg) levels, which can be raised by VitD supplementation. Nearly 20–50% of hospitalized COVID-19 patients have aberrant coagulation profiles including prolonged prothrombin time, thrombocytopenia, high D-dimer, and low fibrinogen levels. Disseminated intravascular coagulation (DIC) is responsible for 71.4% of COVID-19-related mortality. The active form of VitD (1,25(OH)₂D₃) upregulates anticoagulant glycoprotein thrombomodulin and downregulates tissue factor expression. VitD also suppresses NF-κB signaling, reduces proinflammatory cytokines (IL-6, TNF-α), and enhances endothelial nitric oxide (NO) bioavailability. Complement activation is widespread in severe COVID-19, with C5b-9, C4d, and MASP-2 deposits in pulmonary microvasculature. C3-deficient mice showed less respiratory dysfunction despite equivalent viral loads. Daily or weekly VitD supplementation without additional bolus doses showed protective effects against acute respiratory tract infection, stronger in those with baseline 25-VitD levels of 25 nmol/l, whereas single large bolus doses in ICU patients failed to protect against pneumonia, ARDS, sepsis, shock, or respiratory failure.
**Clinical Implications:** The review proposes that hypovitaminosis D plays an important role in nurturing multiple mechanisms of COVID-19-associated coagulopathy, including inflammatory cytokine overproduction, endothelial dysfunction, complement activation, platelet hyperactivity, neutrophil extracellular trap (NET) formation, tissue hypoxia, and oxidative stress. Normalizing VitD levels is essential for balanced immune function and maintaining pulmonary epithelium health. The authors suggest that correction of hypovitaminosis D with once-daily dosing may protect against upper respiratory tract infections and decrease COVID-19 complications, though they acknowledge this claim needs more support. Understanding VitD's role in protecting against coagulopathy, vasculopathy, inflammation, oxidative stress, and endothelial dysfunction could lead to new therapeutic strategies for preventing and treating COVID-19 complications.