Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed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

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 (10)

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.
Comment 3
Received: 5 June 2020
Commenter: Gordon Shotwell
The commenter has declared there is no conflict of interests.
Comment: I'm wondering if you controlled for vitamin D status. There's some evidence that vitamin D is important to Covid-19, and it's also involved in vitamin K physiology.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5613455/
https://github.com/GShotwell/vitamin_d_covid
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Response 1 to Comment 3
Received: 7 June 2020
Commenter: Rob Janssen
Commenter's Conflict of Interests: RJ discloses application of a patent on vitamin K in Covid-19 for prognostic and therapeutic purposes.
Comment: This is a very good suggestion. We are currently measuring 25(OH)D levels in this cohort of Covid-19 patients. Hopefully, we can report these results next week on Preprints.
Comment 4
Received: 6 June 2020
Commenter: Erik Painter
The commenter has declared there is no conflict of interests.
Comment: Natto is high in K2 (1,034.0μg per 100 g). In Japan, every morning millions of people eat a bowl of rice topped with nattō (normally about 50 gms) for breakfast – it’s a staple. The fermented beans can easily be bought at every convenience store and supermarket in the country. Besides K2, natto has 11% fats, 5% fiber, and 5% sugar which might help absorption. The average consumption is 4100 gm/year.
Miso soup also has K2 (not as high -6%DV) and most people have it twice a day, 34gms of miso.
Aomori Prefecture has the highest nattō consumption, about 1.5 nattō packs per week (150 gms), 6800 gms/year. It has a population of 1.249 million. It has had one death from covid-19, and 27 confirmed cases. It has had little shutdown. Schools closed from April 20 to May 7.
Miyagi, Niigata, Gunma, and Ibaraki Prefecture also have high consumption. Miyagi has had 88 cases and one death (2.306 million). Niigata has had 82 cases and no deaths (Population: 2.227 million). Gunma as had 151 cases and 19 deaths (Population: 1.938 million). Ibaraki has had 168 cases and 10 deaths (Population: 2.871 million).
The lowest natto consumption areas in Japan still eat about 2200gms per year.
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Comment 5
Received: 8 June 2020
Commenter: Dr Kevin Maguire
The commenter has declared there is no conflict of interests.
Comment: The result is not at all significant. The conclusion is wrong. What am i missing?

"[X] levels were significantly higher in COVID-19 patients (1,673±1,584 pmol/L) compared to healthy controls (536±291 pmol/L, p<0.0005)."
Using the propagation of errors formula:
100% correlation: (1137 +/- 1581)
0% correlation: (1137 +/- 1610)

So not significant. It's completely wrong to say this result is significant. The quoted p-value is not explained and seems impossible.
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Response 1 to Comment 5
Received: 9 June 2020
Commenter: Rob Janssen
Commenter's Conflict of Interests: RJ discloses application of a patent on vitamin K in Covid-19 for prognostic and therapeutic purposes.
Comment: This is nonsense and not worthwhile responding to. You did not have any access to our data set, and I don't know where you were taught statistics...

We are going to submit our article today for peer review. If accepted, we'll make our data set public so everyone with statistical knowledge can perform their own tests.
Comment 6
Received: 15 June 2020
Commenter: Puya Dehgani-Mobaraki
The commenter has declared there is no conflict of interests.
Comment: This is an amazing work, and I think that the thoughts are crucial for the balance of the levels.
Focusing just on the activity of Vit K on liver will move the relationship that Vitamin K represents on blood vessels and lungs.
Since the lockdown announcement our lifestyle changed so much, and we never considered the possibility that this would have led to and imbalance of our entire system.
Now the key is to look at prevention and get our body prepared to fight against the Monster.
I would love to collaborate for a study on this, we are actually working on the final demonstration of the neurotropism of the virus through the olfactory cells to prove that our paper on the Lancet was correct (but already published a study on autopsies that confirming on 32).
Great effort, my compliments
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