Reduced Vitamin K Status as a Potentially Modifiable Risk Factor of Severe Coronavirus Disease 2019

Abstract

Background Respiratory failure and thromboembolism are frequent in SARS-CoV-2-infected patients. Vitamin K activates both hepatic coagulation factors and extrahepatic endothelial anticoagulant protein S, required for thrombosis prevention. In times of vitamin K insufficiency, hepatic procoagulant factors are preferentially activated over extrahepatic proteins. Vitamin K also activates matrix Gla protein (MGP), which protects against pulmonary and vascular elastic fiber damage. We hypothesized that vitamin K may be implicated in coronavirus disease 2019 (COVID-19), linking pulmonary and thromboembolic disease Methods 135 hospitalized COVID-19 patients were compared with 184 historical controls. Poor outcome was defined as invasive ventilation and/or death. Inactive vitamin K-dependent MGP (dp-ucMGP) and prothrombin (PIVKA-II) were measured, inversely related to extrahepatic and hepatic vitamin K status, respectively. Desmosine was measured to quantify the rate of elastic fiber degradation. Arterial calcification severity was assessed by computed tomography Results Dp-ucMGP was elevated in COVID-19 patients compared to controls (p<0.001), with even higher dp-ucMGP in patients with poor outcomes (p<0.001). PIVKA-II was normal in 82.1% of patients. Dp-ucMGP was correlated with desmosine (p<0.001), and coronary artery (p=0.002) and thoracic aortic (p<0.001) calcification scores Conclusions Dp-ucMGP was severely increased in COVID-19 patients, indicating extrahepatic vitamin K insufficiency, which was related to poor outcome while hepatic procoagulant factor II remained unaffected. These data suggest a mechanism of pneumonia-induced extrahepatic vitamin K depletion leading to accelerated elastic fiber damage and thrombosis in severe COVID-19 due to impaired activation of MGP and endothelial protein S, respectively. A clinical trial could assess whether vitamin K administration improves COVID-19 outcomes

Clinical characteristics and outcomes of venous thromboembolism in patients hospitalized for COVID-19: Systematic review and meta-analysis

“…Interestingly, the relationship between hypoalbuminemia and coagulopathy has been raised by Violi, et al, and further emphasized by Eloisio, et al Nonetheless, the cause-effect relationship between hypoalbuminemia and coagulopathy is currently unknown, and should be further explored with newer studies( 81 , 82 ). The association between prolonged prothrombin time (PT) and VTE incidence may be associated with extrahepatic vitamin K depletion induced by pneumonia, which is important in preventing thrombosis ( 83 ).…”

Low vitamin K status predicts mortality in a cohort of 138 hospitalized patients with COVID-19

“…This is supported by the earlier finding of a preserved intrahepatic prothrombotic effect, as reflected by normal levels of PIVKAII, in COVID-19 patients in spite of significantly increased levels of dp-ucMGP. 4 In addition, the decreased activation of the calcification inhibitory MGP may increase calcification and subsequent degradation of elastic fibres in the extracellular matrix of lung tissue leading to more severe lung damage in COVID-19 patients.…”

“…3 A recently published study found significantly higher levels of dp-ucMGP (reflecting lower vitamin K status) in hospitalized COVID-19 patients compared to controls suggesting a role of vitamin K in COVID-19. 4 Among the COVID-19 patients low vitamin K status was associated with a poor outcome of disease (need of invasive ventilation or death). Furthermore, low vitamin K status was associated with increased blood levels of desmosine, a biomarker of degradation of elastic fibres in the lung tissue, 5 suggesting that low vitamin K status could increase the rate of degradation of elastic fibres during severe COVID-19.…”

“…During a state of Vitamin K deficiency, e.g. increased vitamin K use during acute illness, vitamin K is primarily used for carboxylation of the prothrombotic coagulation factors in the liver and to a lesser extent for carboxylation of the extrahepatic vitamin K dependent proteins including MGP and the antithrombotic Protein S 4 . It has been hypothesised that this could induce a prothrombotic state with increased blood clotting in peripheral tissues as has been seen in COVID-19 patients.…”

Drug design and repurposing with DockThor-VS web server focusing on SARS-CoV-2 therapeutic targets and their non-synonym variants

“…Due to its inhibitory effect on IL-6 signalling, bazedoxifene has been proposed as a promising drug to prevent the cytokine storm, ARDS and mortality in severe COVID-19 patients [99][100][101] . Menaquinone (Vitamin K2) is one of the three types of Vitamin K, and a recent preliminary study suggested that patients with Vitamin K deficiency were related to poor prognostic 102 . However, there is no yet evidence if menaquinone administration helps to treat or prevent COVID-19 infection.…”