Vitamin K metabolism as the potential missing link between lung damage and thromboembolism in Coronavirus disease 2019

Rob Janssen, Margot P J Visser, Anton S M Dofferhoff, Cees Vermeer, Wim Janssens, Jona Walk, Rob Janssen, Margot P J Visser, Anton S M Dofferhoff, Cees Vermeer, Wim Janssens, Jona Walk

Abstract

Coronavirus disease 2019 (Covid-19), caused by severe acute respiratory syndrome coronavirus (SARS-CoV)-2, exerts far-reaching effects on public health and socio-economic welfare. The majority of infected individuals have mild to moderate symptoms, but a significant proportion develops respiratory failure due to pneumonia. Thrombosis is another frequent manifestation of Covid-19 that contributes to poor outcomes. Vitamin K plays a crucial role in the activation of both pro- and anticlotting factors in the liver and the activation of extrahepatically synthesised protein S which seems to be important in local thrombosis prevention. However, the role of vitamin K extends beyond coagulation. Matrix Gla protein (MGP) is a vitamin K-dependent inhibitor of soft tissue calcification and elastic fibre degradation. Severe extrahepatic vitamin K insufficiency was recently demonstrated in Covid-19 patients, with high inactive MGP levels correlating with elastic fibre degradation rates. This suggests that insufficient vitamin K-dependent MGP activation leaves elastic fibres unprotected against SARS-CoV-2-induced proteolysis. In contrast to MGP, Covid-19 patients have normal levels of activated factor II, in line with previous observations that vitamin K is preferentially transported to the liver for activation of procoagulant factors. We therefore expect that vitamin K-dependent endothelial protein S activation is also compromised, which would be compatible with enhanced thrombogenicity. Taking these data together, we propose a mechanism of pneumonia-induced vitamin K depletion, leading to a decrease in activated MGP and protein S, aggravating pulmonary damage and coagulopathy, respectively. Intervention trials should be conducted to assess whether vitamin K administration plays a role in the prevention and treatment of severe Covid-19.

Keywords: Covid-19; Matrix Gla protein; Protein S; Prothrombin; Vitamin K.

Figures

Graphical abstract
Graphical abstract
Fig. 1.
Fig. 1.
Vitamin K cycle. The vitamin K cycle and the effects of vitamin K antagonists. , Active; , inactive.
Fig. 2.
Fig. 2.
Micronutrient triage theory with regard to vitamin K. Particularly vitamin K1 is preferentially transported to the liver. This implies that the grade of carboxylation in a state of vitamin K deficiency is usually higher for hepatic procoagulant factors, such as factor II, than for endothelial protein S as well as for pulmonary matrix Gla protein (MGP).
Fig. 3.
Fig. 3.
Proposed sequential steps linking severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pneumonia to vitamin K insufficiency, pulmonary damage and thrombogenecity. (1) SARS-CoV-2 enters alveolar type II (ATII) cells. (2) Infected AT2 cells response by up-regulating synthesis of proinflammatory cytokines, including IL-6. (3) This leads to an increase in the number and activation of alveolar macrophages (4) that produce matrix metalloproteinases (MMP), which accelerates degradation of elastic fibres. (5) The increased polarity of partially degraded elastic fibres (6) enhances their affinity for calcium and leads to increased elastic fibre calcium content. (7) Matrix Gla protein (MGP) synthesis is up-regulated in an attempt to protect elastic fibres from calcification and degradation, (8) and the need for vitamin K to carboxylate additional MGP increases. (9) This increased utilisation of vitamin K may induce extrahepatic vitamin K insufficiency, (10a) leading to insufficient carboxylation of pulmonary MGP and (11a) increased pulmonary damage. (10b) The second consequence of extrahepatic vitamin K insufficiency is decreased carboxylation of endothelial protein S, (11b) which increases thrombosis risk.

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