A Phase 2, Double Blind, Randomized, Placebo-controlled Clinical Trial to Investigate the Safety and Effects of Oral Vitamin K2 Supplementation in COVID-19

The outbreak of coronavirus 2019 disease (COVID-19) has a major impact on health care worldwide. This infectious disease is caused by the severe acute respiratory syndrome coronavirus (SARS-CoV-2). The majority of individuals who contract COVID-19 have mild symptoms, but a significant part develops respiratory failure due to severe pneumonia and/or acute respiratory distress syndrome (ARDS). The virus may also have extra pulmonary manifestations, including coagulopathy and venous thromboembolism, associated with decreased survival. The pathogenesis of this coagulopathy, and the links between pulmonary and thromboembolic manifestations of COVID-19 are incompletely understood. In KOVIT trial, the roll of vitamin K in the pathogenesis of these manifestations will be elucidated.

Vitamin K in coagulation and elastic fiber metabolism

Coagulation is an intricate balance between clot promoting and dissolving processes in which vitamin K plays an important role. Pro-coagulation factors II, VII, IX and X depend on vitamin K for carboxylation to fulfill their biological function. Besides this, vitamin K is also cofactor of anticoagulant protein C and protein S. A significant proportion of protein S is extrahepatically synthesized in endothelial cells, in contrast to the pro-coagulant factors and protein C. Protein S plays a local suppressive role against thrombosis.

Matrix Gla protein (MGP) is also vitamin K-dependent but not involved in intravascular coagulation. MGP has been generally studied as an inhibitor of vascular mineralization, and its role in the pulmonary compartment seems to be comparable. Besides preventing soft tissue calcification, it also protects against elastic fiber degradation. Elastic fibers are fundamental matrix components in lungs and have high calcium affinity. Degradation and mineralization of elastic fibers are related processes. Desphospho-uncarboxylated MGP (dp-ucMGP) i.e. inactive MGP is a robust biomarker of extrahepatic vitamin K status since it is inversely associated with vitamin K.

Insufficiency of vitamin K may develop within days of poor intake, particularly in pathological conditions of increased vitamin K utilization. During times of scarcity, micronutrients are reserved for use in processes that form the greatest threat to short-term survival. With regard to vitamin K insufficiency, it appears to be preferentially transported to the liver for the activation (via carboxylation) of procoagulant factors at the expense of extrahepatic vitamin K-dependent proteins such as MGP and protein S (figure 1).