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

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 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.

Original languageEnglish
Pages (from-to)E4039-E4046
Number of pages8
JournalClinical Infectious Diseases
Issue number11
Early online date27 Aug 2020
Publication statusPublished - 1 Dec 2021


  • COVID-19
  • elastic fibers
  • factor II
  • matrix Gla protein
  • vitamin K
  • LUNG

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