Reduced vitamin K status as a potentially modifiable risk factor of severe COVID-19

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

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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BACKGROUND: Respiratory failure and thromboembolism are frequent in SARS-CoV-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: 135 hospitalized COVID-19 patients were compared with 184 historical controls. Poor outcome was defined as invasive ventilation and/or death. Inactive vitamin K-dependent MGP (dp-ucMGP) 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 by computed tomography.

RESULTS: Dp-ucMGP was elevated in COVID-19 patients compared to controls (p<0.001), with even higher dp-ucMGP in patients with poor outcomes (p<0.001). PIVKA-II was normal in 82.1% of patients. Dp-ucMGP was correlated with desmosine (p<0.001), and coronary artery (p=0.002) and thoracic aortic (p<0.001) calcification scores.

CONCLUSIONS: Dp-ucMGP was severely increased in COVID-19 patients, indicating extrahepatic vitamin K insufficiency, which was related to poor outcome while hepatic procoagulant factor II remained unaffected. These data suggest a mechanism of 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. A clinical trial could assess whether vitamin K administration improves COVID-19 outcomes.

Original languageEnglish
Pages (from-to)e4039–e4046
Number of pages8
JournalClinical Infectious Diseases
Issue number11
Early online date27-Aug-2020
Publication statusPublished - Dec-2021

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