Reduced vitamin K status as a potentially modifiable risk factor of severe COVID-19
Anton S M Dofferhoff, M.D Ianthe Piscaer, M.D Leon J Schurgers, PhD Margot P J Visser, M.D Jody M W Van Den Ouweland, Pim A De Jong, M.D Reinoud Gosens, Ph.D Tilman M Hackeng, Ph.D Henny Van Daal, Petra Lux, Cecile Maassen, Esther G A Karssemeijer, Emiel F M Wouters, Loes E M Kistemaker, Ph.D Jona Walk, M.D Rob Janssen
doi:10.1093/cid/ciaa1258/5898121
Indirectly quantified extrahepatic vitamin K status is severely reduced in COVID-19 patients. Data suggest pneumonia-induced vitamin K depletion leading to accelerated elastic fiber damage and thrombosis risk due to impaired vitamin K-dependent activation of MGP and endothelial protein S, respectively.
Authors' contributions RJ developed the theory. ASMD, RJ and LJS designed the study. LJS, PL and CM were responsible for the dp-ucMGP and PIVKA-II; and JMWO and HD for the DES measurements. PAJ performed the CT analyses. HD, EGAK, CV, MPJV and JW analyzed the data, and IP performed the statistical analysis. IP, JW and RJ wrote the first draft of the manuscript. ASMD, LJS, JMWO, PAJ, TMH, RG, LEMK, and EFMW critically revised the manuscript.
Conflict of interest statements LJS reports consultancy fee from Immunodiagnostic systems and grants from NattoPharma. JMWO and RJ are owners of Desmosine.com and RJ is owner of Emphysema Solutions BV. RJ discloses application of a patent on vitamin K in COVID-19 for prognostic and therapeutic purposes. ASMD, IP, JW, MPJV, TMH, PAJ, RG, PL, HD, CM, EGAK, LEMK, CV, and EFMW declare no competing interests. Cardiac or cardiovascular disease (%) 17
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{ 'DOI': '10.1093/cid/ciaa1258',
'ISSN': ['1058-4838', '1537-6591'],
'URL': 'http://dx.doi.org/10.1093/cid/ciaa1258',
'abstract': '<jats:title>Abstract</jats:title>\n'
' <jats:sec>\n'
' <jats:title>Background</jats:title>\n'
' <jats:p>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.</jats:p>\n'
' </jats:sec>\n'
' <jats:sec>\n'
' <jats:title>Methods</jats:title>\n'
' <jats:p>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.</jats:p>\n'
' </jats:sec>\n'
' <jats:sec>\n'
' <jats:title>Results</jats:title>\n'
' <jats:p>dp-ucMGP was elevated in COVID-19 patients compared with controls '
'(P\u2005&lt;\u2005.001), with even higher dp-ucMGP in patients with poor outcomes (P\u2005'
'&lt;\u2005.001). PIVKA-II was normal in 82.1% of patients. dp-ucMGP was correlated with '
'desmosine (P\u2005&lt;\u2005.001) and with coronary artery (P\u2005=\u2005.002) and '
'thoracic aortic (P\u2005&lt;\u2005.001) calcification scores.</jats:p>\n'
' </jats:sec>\n'
' <jats:sec>\n'
' <jats:title>Conclusions</jats:title>\n'
' <jats:p>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.</jats:p>\n'
' </jats:sec>',
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