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

2020 ◽  
Author(s):  
Anton S.M. Dofferhoff ◽  
Ianthe Piscaer ◽  
Leon J. Schurgers ◽  
Jona Walk ◽  
Jody M.W. van den Ouweland ◽  
...  
Keyword(s):  
Vitamin K ◽  
Vitamin K Antagonists ◽  
Elastic Fiber ◽  
Significant Proportion ◽  
Protein S ◽  
Matrix Gla Protein ◽  
Prothrombin Activity ◽  
Pneumonia Severity ◽  
Fiber Degradation ◽  
Thoracic Aortic Calcification

Background: A significant proportion of SARS-CoV-2-infected patients develops respiratory failure. Thromboembolism is also prevalent in coronavirus disease 2019 (Covid-19). Vitamin K plays a role in coagulation and possibly also in lung diseases. We therefore hypothesized that vitamin K is implicated in Covid-19 pathogenesis. Methods: 134 Covid-19 patients and 184 controls were included. Inactive vitamin K-dependent matrix Gla protein (i.e.dp-ucMGP) and prothrombin (i.e. PIVKA-II) were measured, which are inversely related to respectively extrahepatic and hepatic vitamin K status. Desmosine was measured to quantify elastic fiber degradation. Lung involvement and arterial calcifications severity were assessed by computed tomography. Results Dp-ucMGP was elevated in Covid-19 patients compared to controls (P=0.001). Higher dp-ucMGP was found in Covid-19 patients with poor compared to better outcomes (P=0.002). PIVKA-II was normal in 81.8%, mildly elevated in 14.0% and moderately elevated in 4.1% of Covid-19 patients not using vitamin K antagonists. Dp-ucMGP in Covid-19 patients was correlated with desmosine (P<0.001), thoracic aortic calcification (P<0.001) but not with pneumonia severity. Conclusions: Extrahepatic vitamin K status was severely reduced in Covid-19 patients, as reflected by elevated inactive MGP, and related to poor outcome. Procoagulant prothrombin activity remained preserved in the majority of Covid-19 patients, which is compatible with the increased thrombogenicity that is frequently observed in severe Covid-19. Impaired MGP activation was linked to accelerated elastic fiber degradation and premorbid vascular calcifications. A trial should assess whether increasing MGP and protein S activity by vitamin K administration improves Covid-19 outcomes.

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

2020 ◽  
Author(s):  
Anton S M Dofferhoff ◽  
Ianthe Piscaer ◽  
Leon J Schurgers ◽  
Margot P J Visser ◽  
Jody M W van den Ouweland ◽  
...  
Keyword(s):  
Vitamin K ◽  
Elastic Fiber ◽  
Protein S ◽  
Coagulation Factors ◽  
Matrix Gla Protein ◽  
Arterial Calcification ◽  
Fiber Damage ◽  
Fiber Degradation ◽  
Factor Ii ◽  
Poor Outcomes

Abstract Background Respiratory failure and thromboembolism are frequent in severe acute respiratory syndrome coronavirus 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 A total of 135 hospitalized COVID-19 patients were compared with 184 historic controls. Inactive vitamin K–dependent MGP (desphospho-uncarboxylated [dp-uc] MGP) 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 using computed tomography. Results dp-ucMGP was elevated in COVID-19 patients compared with controls (P < .001), with even higher dp-ucMGP in patients with poor outcomes (P < .001). PIVKA-II was normal in 82.1% of patients. dp-ucMGP was correlated with desmosine (P < .001) and with coronary artery (P = .002) and thoracic aortic (P < .001) calcification scores. Conclusions dp-ucMGP was severely increased in COVID-19 patients, indicating extrahepatic vitamin K insufficiency, which was related to poor outcome; hepatic procoagulant factor II remained unaffected. These data suggest 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.

scholarly journals Effects of Vitamin D and K on Interleukin-6 in COVID-19

2022 ◽  
Vol 8 ◽  
Author(s):  
Margot P. J. Visser ◽  
Anton S. M. Dofferhoff ◽  
Jody M. W. van den Ouweland ◽  
Henny van Daal ◽  
Cornelis Kramers ◽  
...  
Keyword(s):  
Vitamin D ◽  
Inflammatory Response ◽  
Vitamin K ◽  
Elastic Fiber ◽  
Matrix Gla Protein ◽  
Central Component ◽  
Hydroxyvitamin D ◽  
Fiber Degradation ◽  
Inflammatory Processes ◽  
25 Hydroxyvitamin D

BackgroundPathology during COVID-19 infection arises partly from an excessive inflammatory response with a key role for interleukin (IL)-6. Both vitamin D and K have been proposed as potential modulators of this process.MethodsWe assessed vitamin D and K status by measuring circulating 25-hydroxyvitamin D (25(OH)D) and desphospho-uncarboxylated Matrix Gla-Protein (dp-ucMGP), respectively in 135 hospitalized COVID-19 patients in relation to inflammatory response, elastic fiber degradation and clinical outcomes.ResultsComparing good and poor disease outcomes of COVID-19 patients, vitamin 25(OH)D levels were not significantly different. IL-6 levels, however, were significantly higher in patients with poor outcome, compared to patients with good outcome (30.3 vs. 153.0 pg/mL; p < 0.0001). Dp-ucMGP levels as biomarker of extrahepatic vitamin K status was associated with IL-6 levels (r = 0.35; p < 0.0001). In contrast, 25(OH)D levels were only borderline statistically significant correlated with IL-6 (r = −0.14; p <0.050). A significant association was also found between IL-6 and elastic fiber degradation. Contrary to vitamin K status, 25(OH)D did not correlate with elastic fiber degradation.ConclusionsDp-ucMGP associates with IL-6 as a central component of the destructive inflammatory processes in COVID-19. An intervention trial may provide insight whether vitamin K administration, either or not in combination with vitamin D, improves clinical outcome of COVID-19.

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

2020 ◽  
pp. 1-8 ◽  
Author(s):  
Rob Janssen ◽  
Margot P. J. Visser ◽  
Anton S. M. Dofferhoff ◽  
Cees Vermeer ◽  
Wim Janssens ◽  
...  
Keyword(s):  
Vitamin K ◽  
Significant Proportion ◽  
Protein S ◽  
Elastic Fibre ◽  
Matrix Gla Protein ◽  
Lung Damage ◽  
Degradation Rates ◽  
Fibre Degradation ◽  
Poor Outcomes ◽  
Intervention Trials

Abstract Coronavirus disease 2019 (Covid-19), caused by severe acute respiratory syndrome coronavirus (SARS-CoV)-2, exerts far-reaching effects on public health and socio-economic 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 the 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 the prevention and treatment of severe Covid-19.

Relation of circulating matrix Gla-protein and anticoagulation status in patients with aortic valve calcification

2009 ◽  
Vol 101 (04) ◽  
pp. 706-713 ◽  
Author(s):  
Thilo Krueger ◽  
Ralf Westenfeld ◽  
Harald Peter Kühl ◽  
Vincent Brandenburg ◽  
Andreas Horst Mahnken ◽  
...  
Keyword(s):  
Aortic Valve ◽  
Vitamin K ◽  
Vitamin K Antagonists ◽  
Reference Population ◽  
Matrix Gla Protein ◽  
Control Group ◽  
Adverse Side Effect ◽  
Dependent Protein ◽  
Local Expression

SummaryMatrix-Gla Protein (MGP) is a vitamin K-dependent protein acting as a local inhibitor of vascular calcification. Vitamin K-antagonists (oral anticoagulant; OAC) inhibit the activation of MGP by blocking vitamin K-metabolism. The aim of this study was to investigate the effect of long-term OAC treatment on circulating MGP levels in humans and on MGP expression in mice. Additionally, we tested the association between circulating inactive MGP (ucMGP) levels and the presence and severity of AVC in patients with aortic valve disease (AVD). We analysed circulating ucMGP levels in 191 consecutive patients with echocardiographically proven calcific AVD and 35 control subjects. The extent of AVC in the patients was assessed by multislice spiral computed tomography. Circulating ucMGP levels were significantly lower in patients with AVD (348.6 ± 123.1 nM) compared to the control group (571.6 ± 153.9 nM, p < 0.001). Testing the effect of coumarin in mice revealed that also the mRNA expression of MGP in the aorta was downregulated. Multifactorial analysis revealed a significant effect of glomerular filtration rate and long-term OAC therapy on circulating ucMGP levels in the patient group. Subsequently, patients on long-term OAC had significantly increased AVC scores. In conclusion, patients with calcific AVD had significantly lower levels of circulating ucMGP as compared to a reference population, free of coronary and valvular calcifications. In addition, our data suggest that OAC treatment may decrease local expression of MGP, resulting in decreased circulating MGP levels and subsequently increased aortic valve calcifications as an adverse side effect.

Characterisation and potential diagnostic value of circulating matrix Gla protein (MGP) species

2010 ◽  
Vol 104 (10) ◽  
pp. 811-822 ◽  
Author(s):  
Ellen Cranenburg ◽  
Ralf Koos ◽  
Leon Schurgers ◽  
Elke Magdeleyns ◽  
Thea Schoonbrood ◽  
...  
Keyword(s):  
Vitamin K ◽  
Vitamin K Antagonists ◽  
Diagnostic Value ◽  
Serine Phosphorylation ◽  
Matrix Gla Protein ◽  
Antibody Assay ◽  
Post Translational Modifications ◽  
Stage Renal Disease ◽  
End Stage ◽  
Sandwich Assays

SummaryMatrix γ-carboxyglutamate (Gla) protein (MGP) is an important local inhibitor of vascular calcification, which can undergo two post-translational modifications: vitamin K-dependent γ-glutamate carboxylation and serine phosphorylation. While carboxylation is thought to have effects upon binding of calcium-ions, phosphorylation is supposed to affect the cellular release of MGP. Since both modifications can be exerted incompletely, various MGP species can be detected in the circulation. MGP levels were measured with two commercially available competitive and two novel sandwich assays in healthy controls, in patients with rheumatic disease, aortic valve disease, and end-stage renal disease, as well as in volunteers after vitamin K supplementation (VKS) and treatment with vitamin K antagonists (VKA). Major differences were found between the MGP assays, including significantly different behaviour with regard to vascular disease and the response to VKA and VKS. The dual-antibody assay measuring non-phosphorylated, non-carboxylated MGP (dp-ucMGP) was particularly sensitive for these changes and would be suited to assess the vascular vitamin K status. We conclude that the different assays for particular circulating MGP species allows the assessment of various aspects of the MGP system.

scholarly journals Effect of 6-Month Vitamin D Supplementation on Plasma Matrix Gla Protein in Older Adults

Nutrients ◽  
2019 ◽  
Vol 11 (2) ◽  
pp. 231 ◽  
Author(s):  
Adriana van Ballegooijen ◽  
Joline Beulens ◽  
Leon Schurgers ◽  
Elisa de Koning ◽  
Paul Lips ◽  
...  
Keyword(s):  
Vitamin D ◽  
Vitamin K ◽  
Controlled Trial ◽  
Vitamin K Antagonists ◽  
Functional Limitation ◽  
Vitamin D Supplementation ◽  
Vitamin K Antagonist ◽  
Matrix Gla Protein ◽  
Double Blind

Vitamin D supplementation has been widely promoted to restore 25-hydroxyvitamin D concentrations; however, experimental evidence suggests a nutrient interaction with vitamin K. We assessed the effects of 1200 IU vitamin D3 per day versus placebo for six months on vitamin K status in a randomized, double-blind, placebo-controlled trial with participants aged 60–80 years with depressive symptoms and ≥1 functional limitation for a secondary analysis. Stored baseline and six-month follow-up blood samples were available for 131 participants (n = 65 placebo vs. n = 66 vitamin D supplementation). We measured dephosphorylated uncarboxylated matrix gla protein (MGP) (dp-ucMGP) concentrations—a marker of vitamin K deficiency. Mean age was 68 years, and 89 participants (68%) were women. Vitamin K antagonists were used by 16 participants and multivitamin supplements by 50 participants. No differences in change between intervention and placebo were found (−38.5 ± 389 vs. 4.5 ± 127 (pmol/L), p = 0.562). When excluding vitamin K antagonist users and multivitamin users, dp-ucMGP at follow-up was significantly higher in the vitamin D group (n = 40) compared to placebo (n = 30), with a difference of 92.8 (5.7, 180) pmol/L, adjusting for baseline dp-ucMGP and sex. In conclusion, vitamin D supplementation for six months did not affect vitamin K status; however, among participants without vitamin K antagonist or multivitamin use, vitamin D supplementation influenced dp-ucMGP concentrations.

scholarly journals Vitamin K-Dependent Proteins in Skeletal Development and Disease

2021 ◽  
Vol 22 (17) ◽  
pp. 9328
Author(s):  
Michael Stock ◽  
Georg Schett
Keyword(s):  
Vitamin K ◽  
Skeletal Development ◽  
Bone Matrix ◽  
Growth Arrest ◽  
Protein S ◽  
Matrix Gla Protein ◽  
The Other ◽  
Skeletal Biology ◽  
Other Hand ◽  
And Cartilage

Vitamin K and Vitamin K-dependent proteins (VKDPs) are best known for their pivotal role in blood coagulation. Of the 14 VKPDs identified in humans to date, 6 play also important roles in skeletal biology and disease. Thus, osteocalcin, also termed bone Gla-protein, is the most abundant non-collagenous protein in bone. Matrix Gla protein and Ucma/GRP on the other hand are highly abundant in cartilage. Furthermore, periostin, protein S, and growth arrest specific 6 protein (GAS 6) are expressed in skeletal tissues. The roles for these VKDPs are diverse but include the control of calcification and turnover of bone and cartilage. Vitamin K plays an important role in osteoporosis and serum osteocalcin levels are recognized as a promising marker for osteoporosis. On the other hand, matrix Gla protein and Ucma/GRP are associated with osteoarthritis. This review focuses on the roles of these three VKDPs, osteocalcin, matrix Gla protein and Ucma/GRP, in skeletal development and disease but will also summarize the roles the other skeletal VKDPs (periostin, protein S and GAS6) in skeletal biology.

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

2020 ◽  
Author(s):  
Anton S.M. Dofferhoff ◽  
Ianthe Piscaer ◽  
Leon J. Schurgers ◽  
Jona Walk ◽  
Jody M.W. van den Ouweland ◽  
...  
Keyword(s):  
Risk Factor ◽  
Respiratory Failure ◽  
Severe Acute Respiratory Syndrome ◽  
Vitamin K ◽  
Poor Prognosis ◽  
Severe Disease ◽  
Significant Proportion ◽  
Matrix Gla Protein ◽  
Intervention Trial ◽  
Elastin Degradation

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 (1,673&Aring;}1,584 pmol/L) compared to controls (536&plusmn;291 pmol/L; p&lt;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&lt;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.

Duration of Oral Anticoagulant Treatment in Patients with Venous Thromboembolism and a Deficiency of Antithrombin, Protein C or Protein S - A Decision Analysis

2000 ◽  
Vol 84 (11) ◽  
pp. 758-763 ◽  
Author(s):  
Angelique van den Belt ◽  
Barbara Hutten ◽  
Patrick Bossuyt ◽  
Martin Prins
Keyword(s):  
Pulmonary Embolism ◽  
Venous Thromboembolism ◽  
Decision Analysis ◽  
Vitamin K ◽  
Protein C ◽  
Thromboembolic Event ◽  
Vitamin K Antagonists ◽  
Protein S ◽  
Oral Anticoagulant Treatment ◽  
Increased Risk

SummaryPatients with a first venous thromboembolic event and a deficiency of the coagulation inhibitors antithrombin, protein C or protein S have an increased risk of recurrent venous thromboembolism compared to patients without such a deficiency. A decision analysis was performed to assess the effect of continuing treatment with vitamin K antagonists on mortality by a reduction in fatal recurrent pulmonary embolism and an induction of fatal haemorrhages associated with their use. The treatment decision involves continuation or discontinuation of vitamin K antagonists in patients with a first spontaneous or secondary venous thromboembolism and an antithrombin, protein C or S deficiency. Although the efficiency of oral anticoagulation is high in all age groups early after the first thromboembolic event, it decreases over time. Our analysis indicates that the optimal treatment duration will vary, depending on the type of the initial event (spontaneous or secondary; deep venous thrombosis or pulmonary embolism), age, and time passed since the initial thromboembolic episode. Moreover, life-long duration of the prophylaxis seems not warranted in all patients.

scholarly journals Vitamin D – contrary to vitamin K – does not associate with clinical outcome in hospitalized COVID-19 patients

2020 ◽  
Author(s):  
Jona Walk ◽  
Anton S.M. Dofferhoff ◽  
Jody M.W. van den Ouweland ◽  
Henny van Daal ◽  
Rob Janssen
Keyword(s):  
Vitamin D ◽  
Clinical Outcome ◽  
Vitamin K ◽  
Elastic Fiber ◽  
Vitamin D Status ◽  
Vitamin K Deficiency ◽  
Fiber Degradation ◽  
K Deficiency ◽  
Mild Deficiency ◽  
Asymptomatic Individuals

AbstractSARS-CoV-2 causes remarkably variable disease from asymptomatic individuals to respiratory insufficiency and coagulopathy. Vitamin K deficiency was recently found to associate with clinical outcome in a cohort of COVID-19 patients. Vitamin D has been hypothesized to reduce disease susceptibility by modulating inflammation, yet little is known about its role in disease severity. Considering the critical interaction between vitamin K and vitamin D in calcium and elastic fiber metabolism, we determined vitamin D status in the same cohort of 135 hospitalized COVID-19 patients by measuring blood 25(OH)D levels. We found no difference in vitamin D status between those with good and poor outcome (defined as intubation and/or death). Instead, we found vitamin D sufficient persons (25(OH)D >50 nmol/L) had accelerated elastic fiber degradation compared to those with mild deficiency (25(OH)D 25-50 nmol/L). Based on these findings, we hypothesize that vitamin D might have both favorable anti-inflammatory and unfavorable pro-calcification effects during COVID-19 and that vitamin K might compensate for the latter.

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