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. 2021 Dec 6;73(11):e4039-e4046.
doi: 10.1093/cid/ciaa1258.

Reduced Vitamin K Status as a Potentially Modifiable Risk Factor of Severe Coronavirus Disease 2019

Anton S M Dofferhoff  1 , Ianthe Piscaer  2 , Leon J Schurgers  3 , Margot P J Visser  4 , Jody M W van den Ouweland  5 , Pim A de Jong  6 , Reinoud Gosens  7 , Tilman M Hackeng  3 , Henny van Daal  5 , Petra Lux  3 , Cecile Maassen  3 , Esther G A Karssemeijer  1 , Cees Vermeer  3 , Emiel F M Wouters  2   8 , Loes E M Kistemaker  9 , Jona Walk  1 , Rob Janssen  4
Affiliations

Reduced Vitamin K Status as a Potentially Modifiable Risk Factor of Severe Coronavirus Disease 2019

Anton S M Dofferhoff et al. Clin Infect Dis. .

Abstract

Background: Respiratory failure and thromboembolism are frequent in severe acute respiratory syndrome coronavirus 2-infected patients. Vitamin K activates both hepatic coagulation factors and extrahepatic endothelial anticoagulant protein S, required for thrombosis prevention. In times of vitamin K insufficiency, hepatic procoagulant factors are preferentially activated over extrahepatic proteins. Vitamin K also activates matrix Gla protein (MGP), which protects against pulmonary and vascular elastic fiber damage. We hypothesized that vitamin K may be implicated in coronavirus disease 2019 (COVID-19), linking pulmonary and thromboembolic disease.

Methods: A total of 135 hospitalized COVID-19 patients were compared with 184 historic controls. Inactive vitamin K-dependent MGP (desphospho-uncarboxylated [dp-uc] MGP) and prothrombin (PIVKA-II) were measured inversely related to extrahepatic and hepatic vitamin K status, respectively. Desmosine was measured to quantify the rate of elastic fiber degradation. Arterial calcification severity was assessed using computed tomography.

Results: dp-ucMGP was elevated in COVID-19 patients compared with controls (P < .001), with even higher dp-ucMGP in patients with poor outcomes (P < .001). PIVKA-II was normal in 82.1% of patients. dp-ucMGP was correlated with desmosine (P < .001) and with coronary artery (P = .002) and thoracic aortic (P < .001) calcification scores.

Conclusions: dp-ucMGP was severely increased in COVID-19 patients, indicating extrahepatic vitamin K insufficiency, which was related to poor outcome; hepatic procoagulant factor II remained unaffected. These data suggest pneumonia-induced extrahepatic vitamin K depletion leading to accelerated elastic fiber damage and thrombosis in severe COVID-19 due to impaired activation of MGP and endothelial protein S, respectively.

Keywords: COVID-19; elastic fibers; factor II; matrix Gla protein; vitamin K.

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