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

Dofferhoff, Anton S M; Piscaer, Ianthe; Schurgers, Leon J.; Walk, Jona; Ouweland, Jody M.W. van den; Hackeng, Tilman M.; Jong, Pim A. de; Gosens, Reinoud; Lux, Petra; Daal, Henny van; Maassen, Cecile; Maassen, Esther G.A.; Kistemaker, Loes; Vermeer, Cees; Wouters, Emiel F.M.; Janssen, Rob

doi:10.20944/preprints202004.0457.v2

Cited by 36 publications

(53 citation statements)

References 47 publications

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“…High pulmonary concentrations of matrix metalloproteinases-9 or other proteases produced either by infiltrating or locally proliferating macrophages could be an explanation for this (51,52) . A significant correlation between dp-ucMGP and the rate of elastic fibre degradation was observed in Covid-19 patients (34) . We suspect that accelerated elastic fibre degradation due to enhanced proteolytic activity in SARS-CoV-2-infected lungs increases elastic fibre vulnerability to Ca, leading to an up-regulation of MGP synthesis and depletion of extrahepatic vitamin K stores.…”

Section: Vitamin K Insufficiency In the Pathogenesis Of Coronavirus Dmentioning

confidence: 84%

“…This shortage impairs MGP activation, presumably causing further elastic fibre damage, and elevation of circulating dp-ucMGP. The rate of elastic fibre degradation associates with poor outcome in patients with SARS-CoV-2 pneumonia (34) , as it does in other pulmonary diseases such as chronic obstructive pulmonary disease, cystic fibrosis and bronchiectasis (13,53,54) .…”

Section: Vitamin K Insufficiency In the Pathogenesis Of Coronavirus Dmentioning

confidence: 97%

“…Importantly, a specific subset of macrophages appears in the lungs of Covid-19 patients (51) , which has previously been demonstrated to produce matrix metalloproteinases-9 in patients with idiopathic pulmonary fibrosis (52) . Upon SARS-CoV-2 infection, elastic fibre breakdown accelerates compared with degradation rates in age-matched controls (34) . High pulmonary concentrations of matrix metalloproteinases-9 or other proteases produced either by infiltrating or locally proliferating macrophages could be an explanation for this (51,52) .…”

Section: Vitamin K Insufficiency In the Pathogenesis Of Coronavirus Dmentioning

confidence: 98%

“…Extrahepatic vitamin K status is severely reduced in Covid-19 patients, reflected by elevated dp-ucMGP levels (34) . Reasons for this could include premorbid low vitamin K status in combination with accelerated utilisation during infection.…”

Section: Vitamin K Metabolism In Coronavirus Disease 2019mentioning

confidence: 99%

“…Conditions associated with chronic elastic fibre pathology, including diabetes, hypertension and CVD, are also related to worse prognosis of SARS-CoV-2 infection. Recent data demonstrated that Covid-19 patients with poor outcomes had increased thoracic aortic and coronary artery calcification on computed tomography scan, though these analyses lost significance after correction for age and sex (34) . Nevertheless, pre-existing elastic fibre damage predisposes to enhanced proteolytic degradation during inflammation (42) , potentially explaining the increased severity of Covid-19 in those populations.…”

Section: Vitamin K Insufficiency In the Pathogenesis Of Coronavirus Dmentioning

confidence: 99%

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Vitamin K metabolism as the potential missing link between lung damage and thromboembolism in Coronavirus disease 2019

et al. 2020

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Coronavirus disease 2019 (Covid-19), caused by SARS-CoV-2, exerts far-reaching effects on public health and socioeconomic welfare. The majority of infected individuals have mild to moderate symptoms but a significant proportion develops respiratory failure due to pneumonia. Thrombosis is another frequent manifestation of Covid-19 that contributes to poor outcomes. Vitamin K plays a crucial role in activation of both pro- and anticlotting factors in the liver, and the activation of extrahepatically synthesised protein S which seems to be important in local thrombosis prevention. However, the role of vitamin K extends beyond coagulation. Matrix Gla protein (MGP) is a vitamin K-dependent inhibitor of soft tissue calcification and elastic fibre degradation. Severe extrahepatic vitamin K insufficiency was recently demonstrated in Covid-19 patients, with high inactive MGP levels correlating with elastic fibre degradation rates. This suggests that insufficient vitamin K-dependent MGP activation leaves elastic fibres unprotected against SARS-CoV-2 induced proteolysis. In contrast to MGP, Covid-19 patients have normal levels of activated factor II, in line with previous observations that vitamin K is preferentially transported to the liver for activation of procoagulant factors. We therefore expect that vitamin K-dependent endothelial protein S activation is also compromised, which would be compatible with enhanced thrombogenicity. Taking these data together, we propose a mechanism of pneumonia-induced vitamin K depletion, leading to a decrease in activated MGP and protein S, aggravating pulmonary damage and coagulopathy, respectively. Intervention trials should be conducted to assess whether vitamin K administration plays a role in prevention and treatment of severe Covid-19.

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Section: Vitamin K Insufficiency In the Pathogenesis Of Coronavirus Dmentioning

confidence: 84%

Section: Vitamin K Insufficiency In the Pathogenesis Of Coronavirus Dmentioning

confidence: 97%

Section: Vitamin K Insufficiency In the Pathogenesis Of Coronavirus Dmentioning

confidence: 98%

Section: Vitamin K Metabolism In Coronavirus Disease 2019mentioning

confidence: 99%

Section: Vitamin K Insufficiency In the Pathogenesis Of Coronavirus Dmentioning

confidence: 99%

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Vitamin K metabolism as the potential missing link between lung damage and thromboembolism in Coronavirus disease 2019

et al. 2020

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Stability of vitamin K antagonist anticoagulation after COVID‐19 diagnosis

Camilleri

Rein

Meer

et al. 2021

Research and Practice in Thrombosis and Haemostasis

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Background Coagulopathy has been reported in severely ill patients with coronavirus disease 2019 (COVID‐19). It is unclear whether outpatients with COVID‐19 who are treated with vitamin K antagonists (VKAs) have unstable anticoagulation. Objective To assess the stability of VKA therapy in patients with COVID‐19 through a case‐crossover study. Methods Between February and July 2020, we included patients who tested positive for COVID‐19 from two anticoagulant clinics in the Netherlands. We collected international normalized ratios (INRs) determined between 26 weeks before infection and 12 weeks after. Time in therapeutic range (TTR) and the variance growth rate (VGR) were calculated within patients. Results Fifty‐one patients with COVID‐19 (mean age, 84 years) were included, of whom 15 (29%) were men. Mean TTR in the 26 weeks before COVID‐19 was 80% (95% confidence interval [CI], 75‐85) compared to 59% (95% CI, 51‐68) in the 6 weeks after infection. Mean TTR difference was −23% (95% CI, −32 to −14) with a time above therapeutic range of 38% (95% CI, 30‐47) in the 6 weeks after infection. The TTR rose again to 79% (95% CI, 69‐89) between 6 and 12 weeks after infection. Also, VGR increased, with a mean increase of 4.8 (95% CI, 2.1‐7.5) in the 6 weeks after infection. In the 26 weeks before infection, we registered 19 of 641 (3%) of INR ≥5.0 compared with 35 of 247 (14%) in the 6 weeks after (risk ratio, 4.4; 95% CI, 2.7‐7.3). Conclusions COVID‐19 is associated with a strong decrease in TTR and in therapeutic stability in patients taking VKAs. Additional monitoring in these patients is advised to maximize therapeutic stability.

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The Role of Vitamin K in CKD-MBD

Fusaro

Tondolo

Gasperoni

et al. 2022

Curr Osteoporos Rep

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Purpose of Review We describe the mechanism of action of vitamin K, and its implication in cardiovascular disease, bone fractures, and inflammation to underline its protective role, especially in chronic kidney disease (CKD). Recent Findings Vitamin K acts as a coenzyme of y-glutamyl carboxylase, transforming undercarboxylated in carboxylated vitamin K-dependent proteins. Furthermore, through the binding of the nuclear steroid and xenobiotic receptor, it activates the expression of genes that encode proteins involved in the maintenance of bone quality and bone remodeling. There are three main types of K vitamers: phylloquinone, menaquinones, and menadione. Summary CKD patients, for several conditions typical of the disease, are characterized by lower levels of vitamin K than the general populations, with a resulting higher prevalence of bone fractures, vascular calcifications, and mortality. Therefore, the definition of vitamin K dosage is an important issue, potentially leading to reduced bone fractures and improved vascular calcifications in the general population and CKD patients.

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

Cited by 36 publications

References 47 publications

Vitamin K metabolism as the potential missing link between lung damage and thromboembolism in Coronavirus disease 2019

Vitamin K metabolism as the potential missing link between lung damage and thromboembolism in Coronavirus disease 2019

Stability of vitamin K antagonist anticoagulation after COVID‐19 diagnosis

The Role of Vitamin K in CKD-MBD

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