Randomized Controlled Clinical Trial to Investigate Effects of Vitamin K2 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).

Assessment of vitamin K status

In nature, vitamin K is found in food as vitamin K1 (phylloquinone) and vitamin K2 (menaquinones). Measuring circulating levels of these two forms of vitamin K is technically feasible but the value of such measurements is limited. Quantification of vitamin K-dependent proteins that have not been carboxylated yet, is a valuable method reflecting the functional deficit of vitamin K1 and K2. Determination of dp-ucMGP levels as well as the ratio between uncarboxylated and carboxylated osteocalcin are validated assays of extrahepatic vitamin K status.

Dp-ucMGP is a biomarker of extrahepatic vitamin K status. High dp-ucMGP reflects low vitamin K status and vice versa. Although increasing vitamin K consumption decreases the amount of dp-ucMGP. Circulating dp-ucMGP concentration can best be regarded as a reflection of the total extrahepatic vitamin K deficit, which refers to the amount of vitamin K that is needed to carboxylate all the uncarboxylated vitamin K-dependent proteins in the body. Hepatic vitamin K status is usually quantified by measuring levels of protein induced by vitamin K absence (PIVKA)-II (i.e. uncarboxylated prothrombin).

Rationale for study treatment

Recently, a reduced vitamin K status was found, as quantified by dp-ucMGP, in patients suffering from COVID-19 as compared to controls. In these patients, low vitamin K status was also associated with poor outcome (defined as the need for invasive ventilation or death) and accelerated elastic fiber degradation (quantified by plasma (iso)desmosine (DES) a byproduct of elastin degradation). In contrast, hepatic vitamin K status, measured by inactive factor II (also called protein-induced by vitamin K absence (PIVKA)-II) was unaffected in most patients (figure 2). Considering the preferential activation of hepatic over extrahepatic proteins.

In COVID-19, inflammation causes pulmonary elastic fiber damage, which could also lead to an upregulation of MGP and a draining of extrahepatic vitamin K. The significant correlation between increased dp-ucMGP levels, and elastic fiber degeneration and poor prognosis supports the theory that vitamin K insufficiency contributes to pulmonary pathology.

Hypothesis

It is hypothesized that improving vitamin K-status by vitamin K supplementation could have favorable effects on both pulmonary damage and coagulation abnormalities in COVID-19 patients.

Objective

The objective of the KOVIT trial is to evaluate the safety of oral vitamin K2 supplementation in patients suffering from COVID-19 requiring hospital admission.