Preprint Article Version 1 This version is not peer-reviewed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)

How to cite: Dofferhoff, A.S.; Piscaer, I.; Schurgers, L.J.; Walk, J.; van den Ouweland, J.M.; Hackeng, T.M.; Lux, P.; Maassen, C.; Karssemeijer, E.G.; Wouters, E.F.; Janssen, R. Reduced Vitamin K Status as A Potentially Modifiable Prognostic Risk Factor in COVID-19. Preprints 2020, 2020040457 (doi: 10.20944/preprints202004.0457.v1). Dofferhoff, A.S.; Piscaer, I.; Schurgers, L.J.; Walk, J.; van den Ouweland, J.M.; Hackeng, T.M.; Lux, P.; Maassen, C.; Karssemeijer, E.G.; Wouters, E.F.; Janssen, R. Reduced Vitamin K Status as A Potentially Modifiable Prognostic Risk Factor in COVID-19. Preprints 2020, 2020040457 (doi: 10.20944/preprints202004.0457.v1).

Abstract

Introduction: Coronavirus 2019 (COVID-19) is caused by the severe acute respiratory syndrome coronavirus-2. The majority of patients have at most mild symptoms, however, a significant proportion develops respiratory failure. COVID-19 may also progress beyond the lungs. Coagulopathy and thromboembolism are prevalent in severe COVID-19 and relate to decreased survival. Coagulation is an intricate balance between clot promoting and dissolving processes in which vitamin K plays a well-known role. We hypothesized that vitamin K status is reduced in patients with severe COVID-19. Methods: Vitamin K status was assessed by measuring desphospho-uncarboxylated matrix Gla protein (dp-ucMGP; inversely related to vitamin K status) and the rate of elastin degradation by measuring desmosine. We included 123 patients who were admitted with COVID-19 and 184 controls. Results: Dp-ucMGP levels were significantly elevated in COVID-19 patients (1,673Å}1,584 pmol/L) compared to controls (536±291 pmol/L; p<0.0005). Dp-ucMGP levels were significantly higher in COVID-19 patients with unfavorable outcome compared to those with less severe disease. Furthermore, dp-ucMGP and desmosine levels were significantly associated (r=0.65; p<0.0005). Conclusions: Vitamin K status was reduced in patients with COVID-19 and related to poor prognosis. Also, low vitamin K status seems to be associated with accelerated elastin degradation. An intervention trial is now needed to assess whether vitamin K administration improves outcome in patients with COVID-19.

Subject Areas

COVID-19; vitamin K; vitamin K antagonists; SARS-CoV-2; matrix Gla protein; desmosine; protein C; protein S

Comments (4)

Comment 1
Received: 16 May 2020
Commenter: Edward Lynam
The commenter has declared there is no conflict of interests.
Comment: This finding could be very significant. When following the pandemic in Japan, one should note its low R0 without any vigorous non-pharmaceutical interventions. Japan has a significant portion of its population which eats natto, a rich source of Vitamin K2-MK7 not found in the diets of most other countries. The enhancement of innate immunity could be leading to a resistance to infection in a sizable portion of their population. In contrast, once infected, Japanese people seem to have a similar death and severe illness rate as anywhere else. It could be the portion of their population not protected by Vitamin K status are allowing a more limited pandemic outcome there.

If Vitamin K2-MK7 could protect a high portion of the population from spread, it could represent a means of controlling the pandemic. If this can be demonstrated, someone should get the Nobel Prize.
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Response 1 to Comment 1
Received: 20 May 2020
Commenter: Rob Janssen
Commenter's Conflict of Interests: RJ discloses application of a patent for vitamin K status as a prognostic and therapeutic biomarker in COVID-19.
Comment: Thank you for your interest in our work. Natto is indeed a food product containing high concentrations of vitamin K2. A Japanese colleague told me a similar story that in Japanese regions in which natto consumption is high, there would be less Covid-19-related morbidity and mortality. I did not have the chance to verify this observation, but it may be very relevant.
Comment 2
Received: 19 May 2020
Commenter: Rosa Fasching
The commenter has declared there is no conflict of interests.
Comment: So, there is a reduction of vitamin k ? Pls take a look for E. coli (EcN/Mutaflor), problem solved.
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Response 1 to Comment 2
Received: 20 May 2020
Commenter: Rob Janssen
Commenter's Conflict of Interests: RJ discloses application of a patent for vitamin K status as a prognostic and therapeutic biomarker in COVID-19.
Comment: Thank you for your suggestion and interest in our work. It would be very interesting to evaluate your hypothesis.

We think that the most likely reasons for the extreme extrahepatic vitamin K deficiency that we found in severe Covid-19 patients are:
1. enhanced vitamin K utilization in the lungs to activate MGP for the protection of partially degraded elastic fibers
2. poor vitamin K consumption
3. calcified and/or partially degraded pulmonary elastic fibers at baseline, which have increased vulnerability to SARS-CoV-2-induced proteolytic activity, which will upregulate MGP synthezis and need for vitamin K to activate this additional MGP.

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