Managing the Mortality & Morbidity of COVID19: The Case for Vitamin K2 Supplementation
Connecting the Dots
Introduction
The SARS-CoV-2 pandemic continues to plague the world leaving us with millions dead and many more suffering from long term symptoms, a condition that we now class as LongCOVID or Longhaulers. Thankfully, there are a variety of vaccines available, albeit in limited supplies in some countries, to limit infection rates. On the flip side, this is a cagey virus, with concerns that the SARS-CoV-2 virus is staying ahead of us by morphing into variants that evade our immune defenses.
That leaves us with a massive need to understand the pathology of the COVID19 and to plug in all the tools we can support in order to manage it, to limit its mortality and morbidity.
One essential nutrient that has got a lot of attention is Vitamin D. Deservedly so, as we know that the the poorest outcomes to SARS-CoV-2 infection occur in those with the lowest levels of vitamin D (Vitamin D and Risk For Severe COVID19). Further, while limited, clinical trials with supplemental Vitamin D suggest that length of hospitalization, death rates, and long term consequences of COVID19 can be improved by Vitamin D3 supplementation (Supplemental Vit D Reduces COVID19 Symptoms).
In essence, Vitamin D3 supplementation is a cheap & effective intervention to help in the management of COVID19.
The question posed in this article is can Vitamin K play a similar role, and what would be the mechanisms behind that suggestion.
What is Vitamin K?
There are several forms of Vitamin K.
Vitamin K1 or phylloquinone, is primarily active in the liver where it is activates coagulation factors and is largely obtained in our diet from leafy greens.
Vitamin K2 or menaquinone or MK7, is derived from certain bacteria and hence fermented foods, cheese curds and some fish is largely found outside of the liver (extra-hepatic). Generally our diet is insufficient in Vitamin K2 and supplementation is suggested as it plays an important role in metabolic processes promoting bone mineralization and soft tissue decalcification i.e., moves calcium out of arteries, lungs and into bone (Vitamin K and Osteoporosis). Vitamin K2 has a longer half-life than Vitamin K1.
Additionally, MK7, but not Vitamin K1, has an anti-inflammatory role. Hence these forms of Vitamin K need to be discussed separately. There are other minor forms of Vitamin K but let’s focus this discussion on Vitamin K2 (MK-7).
Hallmarks of COVID19
While clearly the inhalation of the SARS-CoV-2 virus leads to respiratory infection and compromised oxygenation is a primary driver of hospitalization in COVID19 patients. This is because a primary binding site of the SARS-CoV-2 virus is the ACE2 receptor that is prevalent in the lining of the respiratory tract. However, ACE2 is also ubiquitous in the lining of blood vessels, the endothelium, as well as in other tissues like heart, nerves and the kidneys. Indeed, the virus is regarded as having devastating effects on vascular and cardiac health (SARS-CoV-2 effects on heart and blood vessels)
So many have suggested that the impact of SARS-COV-2 infections must include a framework that it is a vascular disease, not just a pulmonary problem. Further, these vascular interactions play a major role in the long term complications of COVID19 including Brain Fog/Dementia and compromised organ function (Brain Fog and COVID19).
Part of these vascular driven complications center on blood clots, with coagulopathy being a central driver of the vascular events. Related to this, age is a major risk factor for poor outcomes along with cardiovascular disease in various forms
Hypertension
Diabetes
Obesity
Kidney Disease
Consistent in these diseases is a increase in the calcification of elastic fibers and a subsequent degradation of these proteins (Vitamin K & Cardiovascular Disease Mortality).
MK7 and COVID19 Outcomes.
We have already discussed how MK7 is not easy to get in your diet, but in COVID19 patients extra-hepatic levels of MK7 are severely suppressed (Reduced Vit K status in COVID19). This suggests that the low levels MK7 may be prognostic for COVID19 outcomes and imminently treatable through supplementation. However, in order to distinguish this as being either a driver of the pathology or a coincidental finding one must dive a little deeper into the mechanisms of action of MK7, particularly in the vasculature.
The matrix of the vasculature (and lungs) includes fibers that are far more elastic than collagen - these include elastin and Tenascin X. These contribute the healthy movement of these tissues under pressure (breathing or with heart contractions).
Two critical proteins, Matrix Gla protein (MGP) and Protein S play an important role in the health of these elastic fibers in lungs and arteries. The active form MGP regulates the calcification of these elastic fibers. Vitamin K2 converts the uncarboxylated inactive version of MGP (dp-uc MGP) into the active form, and activated MGP limits the calcification of the elastic fibers.
Vitamin K2 is critical for keeping elastic fibers from being excessively mineralized and degraded by proteolytic enzymes called MMPs. The other benefit of MK7 is that it diverts this calcification away from arteries and lungs to the bones (by activating MGP), where it promotes mineralization.
In aging or cardiovascular disease, the stiffness of the heart and blood vessels reflets and excessive mineralization of these elastic fibers, consistent with inadequate Vitamin K2.
Half of the production of Protein S occurs in endothelial cells (Vitamin K2, Protein S and vasculature in COVID19), a target of the SARS-COV-2 virus as this is where the vascular ACE2 docking site exists. Protein S acts as an anticoagulant by inactivating procoagulant factor V (Balance of Pro- and Anti-Coagulation Factors in the Pathology of COVID19).
When levels of activated MGP and Protein S are suppressed, as is the case for inadequate MK7, then the body converts into a state of excessive coagulopathy. This is typical of COVID19 patients. Central to this connection is that SARS-CoV-2 infection dramatically lowers Vitamin K2 tissue reserves.
The Impact of Oxidative Stress, Inflammation & the Cytokine Surge
The combination of the SARS-CoV-2 infection and the hypoxia associated with it produces an oxidative stress with excessive production of free radicals and oxidants. In turn, these oxidants active the master gene switch for inflammation known as NF-kB. The immune response to SARS-CoV-2 which includes infiltrating lymphocytes, macrophages and granulocytes which also produce oxidants to further ramp up the response. Some of the inflammatory products that are regulated by the NF-kB gene switch are TNF alpha and IL-6, which are leaders of the so called CYTOKINE STORM with COVID19.
Additionally a family of proteases called MMPs (matrix metalloproteases) are generated in this soup of oxidants, cytokines and inflammation that typify this infection. Of primary interest is MMP-9 which acts to chop up matrix proteins, including elastic fibers. Indeed, we know that levels of a fragmented elastic fibers are elevated in COVID19 along with MMP-9 and MMP-2 levels (Raised levels of MMP9 MMP2 in COVID19 ); a response that is reversed by MK7 supplementation.
Janssen R et al. British Journal of Nutrition , Volume 126 , Issue 2 , 28 July 2021 , pp. 191 - 198
Essentially, as it relates to the health of elastic fibers in lungs and arteries, inflammatory cytokines, MMPs and oxidative stress work in opposition to Vitamin K2. The cytokine surge promotes a coagulopathy state and Vitamin K2 suppresses it.
In some individuals, the SARS-CoV-2 virus wins this battle.
What About Vitamin D?
While a relationship between adequate levels of Vitamin D and COVID19 outcomes exists, one may ponder if there is a relationship between Vitamin D and K2? In regards to immune activation there is one. Low levels of both vitamins are associated with poor outcomes in SARS-CoV-2 infections and both vitamins suppress the activation of NF-kB, the master gene switch for inflammation and production of MMPs.
There is more evidence, via classic clinical trials that Vitamin D supplementation improves outcomes in COVID19 patients (Vitamin D & the treatment of COVID19). By contrast, to my knowledge there are no such trials completed for Vitamin K2.
Hence, while there are numerous well defined points of interaction between low Vitamin K2 and poor outcomes in COVID19, we do not have solid evidence that supplementing with Vitamin K2 will have an effect on morbidity and mortality.
Next Steps
Given that MK7 has great benefits in limiting vascular and pulmonary calcification of soft tissues, as well as redirecting calcium to the bones, these solid health-promoting actions should be considered as excellent therapeutic approaches especially in older demographics. With the dietary intake of Vitamin D2 being somewhat limited and many having a state of insufficiency, the use of supplements makes a lot of sense.
That is justified in the normal setting but the conversation takes on new twists in this era of SARS-CoV-2. Given that the virus has major actions on blood coagulation, inflammation, elastic fiber degradation and endothelial damage all intersections of the actions of Vitamin K2, and knowing that levels of Vitamin K2 are depleted in COVID19 patients, then the conversation transforms from being maybe a good idea to one that is more like an imperative.
What is lacking is affirmation that raising blood levels of Vitamin K2 with supplementation has desirable outcomes on survival, reduced rates of hospitalization, length of stay in hospitals/ICUs and reduced incidence and severity of COVID19 symptoms. These would be generated from solid, well designed Randomized Controlled clinical trials. That missing information is a big void. Until that evidence is available and the hypothesis is proven to have validity then there is an element for conjecture.
Nevertheless, independent of SARS-CoV-2, on a personal level my age suggests that any well supported nutritional approach that can reduce arterial and cardiac stiffness, and inflammation would be a good thing. Hence, I will continue to supplement my diet with high quality MK7. Personally, I use VitaMK7.