Preprint Article Version 2 Preserved in Portico This version is not peer-reviewed

Reduced Vitamin K Status as A Potentially Modifiable Prognostic Risk Factor in COVID-19

Version 1 : Received: 24 April 2020 / Approved: 25 April 2020 / Online: 25 April 2020 (03:13:45 CEST)
Version 2 : Received: 29 May 2020 / Approved: 29 May 2020 / Online: 29 May 2020 (04:16:20 CEST)

A peer-reviewed article of this Preprint also exists.

Journal reference: Clinical Infectious Diseases 2020
DOI: 10.1093/cid/ciaa1258

Abstract

Background: A significant proportion of SARS-CoV-2-infected patients develops respiratory failure. Thromboembolism is also prevalent in coronavirus disease 2019 (Covid-19). Vitamin K plays a role in coagulation and possibly also in lung diseases. We therefore hypothesized that vitamin K is implicated in Covid-19 pathogenesis. Methods: 134 Covid-19 patients and 184 controls were included. Inactive vitamin K-dependent matrix Gla protein (i.e.dp-ucMGP) and prothrombin (i.e. PIVKA-II) were measured, which are inversely related to respectively extrahepatic and hepatic vitamin K status. Desmosine was measured to quantify elastic fiber degradation. Lung involvement and arterial calcifications severity were assessed by computed tomography. Results Dp-ucMGP was elevated in Covid-19 patients compared to controls (P=0.001). Higher dp-ucMGP was found in Covid-19 patients with poor compared to better outcomes (P=0.002). PIVKA-II was normal in 81.8%, mildly elevated in 14.0% and moderately elevated in 4.1% of Covid-19 patients not using vitamin K antagonists. Dp-ucMGP in Covid-19 patients was correlated with desmosine (P<0.001), thoracic aortic calcification (P<0.001) but not with pneumonia severity. Conclusions: Extrahepatic vitamin K status was severely reduced in Covid-19 patients, as reflected by elevated inactive MGP, and related to poor outcome. Procoagulant prothrombin activity remained preserved in the majority of Covid-19 patients, which is compatible with the increased thrombogenicity that is frequently observed in severe Covid-19. Impaired MGP activation was linked to accelerated elastic fiber degradation and premorbid vascular calcifications. A trial should assess whether increasing MGP and protein S activity by vitamin K administration improves Covid-19 outcomes.

Subject Areas

Covid-19; desmosine; dp-ucMGP; elastic fibers; factor II; matrix Gla protein; PIVKA-II; protein S; vitamin K; vitamin K antagonist

Comments (2)

Comment 1
Received: 29 May 2020
Commenter: Rob Janssen
Commenter's Conflict of Interests: Author
Comment: In addition to dp-ucMGP to assess extrahepatic vitamin K status, hepatic/procoagulant vitamin K status was assessed by measuring PIVKA-II. The manuscript text was revised. Figures were added explaining vitamin K metabolism as well as proposed pathomechanistic sequential steps from SARS-CoV-2 virus cell enty to acceleration of elastic fiber degradation and vitamin K insufficiency. Chest CT scans were automatically assessed, whereas only SARS-CoV-2 pneumonia severity was subjectively assessed in version 1.0. 
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Comment 2
Received: 6 July 2020
Commenter: Elisabeth C. Faas
The commenter has declared there is no conflict of interests.
Comment: Great article. Did you consider the common use of a blood thinner. Given to the 'geranium' people. Boven de 70 standaard bloedverdunner en maagzuurremmer. Spinazie en maagzuurremmer!!!
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