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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
Proposed sequential pathologic steps linking SARS-CoV-2 pneumonia to vitamin K insufficiency and accelerated elastic fiber degradation. (1) SARS-CoV-2 enters AT2 cell. (2) The infected AT2 cell responds by upregulating synthesis of proinflammatory cytokines. (3) This leads to an increase in the number and activation of pulmonary macrophages. (4) These infiltrating macrophages produce MMPs (5), which leads to accelerated degradation of elastic fibers (5a) and thereby the release of desmosine from these fibers (5b), leading to elevated desmosine levels in lungs and blood. (6) The increased polarity of partially degraded elastic fibers (7) enhances their affinity for calcium and, consequently, leads to increased elastic fiber calcium content. (7a) MMP synthesis is upregulated in parallel with the calcium content, which further accelerates elastic fiber degradation in a self-propagating vicious circle. (8) MGP synthesis is upregulated in an attempt to protect elastic fibers from calcification and degradation, (8a) which means that need for vitamin K to activate additional MGP increases. (8b) This increased use of vitamin K may induce vitamin K insufficiency, (9) in which case increased production of MGP in a state of vitamin K insufficiency leads to increased dp-ucMGP in lungs and blood. Abbreviations: AT2, alveolar type II; dp-uc, desphospho-uncarboxylated; MGP, matrix Gla protein; MMP, matrix metalloproteinase; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2 Downloaded from https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciaa1258/5898121 by guest on 29 October 2020
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MAJOR ARTICLE
Severe Vitamin K Insufficiency in COVID-19 • CID 2020:XX (XX XXXX) • 1
Clinical Infectious Diseases
Received 26 June 2020; editorial decision 19 August 2020; accepted 25 August 2020; published
online August 27, 2020.
aA. S.M. D., I.P., L.J. S., and M.P. J.V.contributed equally to this work.
bJ. W.and R.J.contributed equally to this work.
Correspondence: J.Walk, Department of Internal Medicine, Canisius-Wilhelmina Hospital,
Weg door Jonkerbos 100, 6532 SZ Nijmegen, The Netherlands (jona.walk@cwz.nl).
Clinical Infectious Diseases® 2020;XX(XX):1–8
© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society
of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.
DOI: 10.1093/cid/ciaa1258
Reduced Vitamin K Status as a Potentially Modiable Risk
Factor of Severe Coronavirus Disease2019
AntonS.M. Dofferhoff,1,a Ianthe Piscaer,2,a LeonJ. Schurgers,3,a MargotP.J. Visser,4,a JodyM.W. vandenOuweland,5 PimA. deJong,6 Reinoud Gosens,7
TilmanM. Hackeng,3 Henny vanDaal,5 Petra Lux,3 Cecile Maassen,3 EstherG.A. Karssemeijer,1 Cees Vermeer,3 EmielF.M. Wouters,2,8
LoesE.M. Kistemaker,9 Jona Walk,1,b, and Rob Janssen4,b
1Department of Internal Medicine, Canisius-Wilhelmina Hospital, Nijmegen, The Netherlands, 2Department of Respiratory Medicine, Maastricht University Medical Center, Maastricht, The
Netherlands, 3Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands, 4Department of Pulmonary Medicine, Canisius-
Wilhelmina Hospital, Nijmegen, The Netherlands, 5Department of Clinical Chemistry, Canisius-Wilhelmina Hospital, Nijmegen, The Netherlands, 6Department of Radiology, University Medical
Center Utrecht and Utrecht University, The Netherlands, 7Department of Molecular Pharmacology, University of Groningen, Groningen, The Netherlands, 8Ludwig Boltzmann Institute for Lung
Health, Vienna, Austria, and 9Aquilo BV, Groningen, The Netherlands
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, re-
quired for thrombosis prevention. In times of vitamin K insuciency, hepatic procoagulant factors are preferentially activated over
extrahepatic proteins. Vitamin K also activates matrix Gla protein (MGP), which protects against pulmonary and vascular elastic
ber 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–de-
pendent 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 ber degradation.
Arterial calcication 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) calcication scores.
Conclusions. dp-ucMGP was severely increased in COVID-19 patients, indicating extrahepatic vitamin K insuciency,
which was related to poor outcome; hepatic procoagulant factor II remained unaected. ese data suggest pneumonia-induced
extrahepatic vitamin K depletion leading to accelerated elastic ber damage and thrombosis in severe COVID-19 due to impaired
activation of MGP and endothelial protein S, respectively.
Keywords. COVID-19; elastic bers; factor II; matrix Gla protein; vitamin K.
Coronavirus disease 2019 (COVID-19) is caused by severe
acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [1].
The majority of individuals who contract SARS-CoV-2 have
mild symptoms; however, a significant proportion develop res-
piratory failure due to pneumonia [1]. COVID-19 may also
have extrapulmonary manifestations, including coagulopathy
and venous thromboembolism, which are associated with de-
creased survival [2]. The mechanisms that activate coagulation
in COVID-19 remain incompletely understood.
Coagulation is an intricate balance between clot promoting
and dissolving processes in which vitamin K plays a well-
known role. Procoagulant factor II (FII; ie, prothrombin) re-
quires vitamin K–dependent carboxylation to fulll its primary
function. Vitamin K is also a cofactor of anticoagulant pro-
tein S.In contrast to FII, a signicant proportion of protein S
is extrahepatically synthesized in endothelial cells, which play
a local suppressive role against thrombosis [3]. Vitamin K de-
ciency results in more severely compromised carboxylation
of extrahepatic than of hepatic vitamin K–dependent pro-
teins (Figure 1) [4]. is can paradoxically lead to enhanced
thrombogenicity in a state of low vitamin K [5].
Matrix Gla protein (MGP) is also vitamin K–dependent
but not involved in coagulation [6]. MGP is well known as a
calcication inhibitor in arterial walls [7], and MGP’s role in
the pulmonary compartment seems to be comparable [8, 9].
Elastic bers are essential matrix components in lungs and
have high calcium anity [10]. Degradation and mineraliza-
tion of elastic bers are interrelated processes [11, 12]. Matrix
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2 • CID 2020:XX (XX XXXX) • Doerho etal
metalloproteinase (MMP) synthesis increases parallel with
elastic ber calcication [13], and partially degraded elastic
bers become prone to mineralization [10]. Recent data show
that a subset of MMP-producing macrophages is increased in
severe SARS-CoV-2 pneumonia [14]. COVID-19 may theoret-
ically be linked to both vitamin K deciency and elastic ber
metabolism through a series of sequential pathologic steps
(Figure2).
Individuals with severe SARS-CoV-2 infections oen have
comorbidities that are associated with reduced vitamin K status,
such as hypertension, diabetes, and cardiovascular diseases [1,
7]. e body uses vitamin K very eciently, and storage ca-
pacity is low [15]. ere are reasons to suspect that there is in-
creased use of vitamin K for carboxylation of pulmonary MGP
and coagulant factors during COVID-19 [16]. Vitamin K de-
pletion may have devastating consequences in the lungs [17].
Our aim in this study was to determine whether a reduced
vitamin K status plays a role in the pathogenesis of COVID-19
by interacting with both elastic ber metabolism and the coag-
ulation cascade, thereby linking pulmonary and coagulopathic
disease manifestations.
METHODS
Patients
A total of 135 patients hospitalized with COVID-19 at the
Canisius-Wilhelmina Hospital between 12 March 2020 and
15 April 2020 were included. SARS-CoV-2 infection was con-
firmed using real-time polymerase chain reaction testing.
Patient data were extracted from hospital records, and vitamin
K antagonist (VKA) usage was determined from pharmacy
and anticoagulant clinic records. The United Medical Research
Ethics Committees of Canisius-Wilhelmina Hospital approved
the study and waived the need for written informed consent.
Patients could opt out after they were informed about thestudy.
A total of 186 controls from a previously published chronic
obstructive pulmonary disease (COPD) study were also in-
cluded [18]. Two control patients for whom the use of VKA was
unknown were excluded from the analysis.
Patients were followed up until discharge from the hospital,
intubation and mechanical ventilation, or death. e outcome
of COVID-19 patients was categorized as “good” if they were
discharged from the hospital without the need for invasive
ventilation and “poor” if they required either intubation and
mechanical ventilation or died. During admission, blood was
sampled 3 times per week and EDTA plasma and serum were
frozen at −80°C for retrospective analysis.
Desphospho-UncarboxylatedMGP
Direct quantification of blood vitamin K is not appropriate
to assess vitamin K status due to differences in bioavailability
and half-life time between the 2 naturally occurring forms
(vitamin K1 and K2). Additionally, the intake of vitamin K2
Figure 1. Distribution of vitamin K1 in the body. (1) After absorption, vitamin K1 is preferentially transported to the liver via the portal circulation, where it is used for
carboxylation of hepatic coagulation factors. This implies that during periods of vitamin K insufficiency, (2) the grade of carboxylation is usually higher for hepatic factor II (3)
than for endothelial protein S in veins and pulmonary MGP. Abbreviation: MGP, matrix Gla protein.
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Severe Vitamin K Insufficiency in COVID-19 • CID 2020:XX (XX XXXX) • 3
is too low to measure accurately. Measuring inactive levels of
vitamin K–dependent protein in the circulation is a valuable
method to quantify the combined deficit of vitamin K1 and
K2. Desphospho-uncarboxylated (dp-uc) MGP (inactive MGP)
is an appropriate indirect marker of extrahepatic vitamin K
status [19, 20]. Individuals with high dp-ucMGP levels have low
extrahepatic vitamin K status and viceversa.
Circulating dp-ucMGP levels were determined in EDTA
plasma using the commercially available IVD chemiluminescent
InaKif MGP assay on the IDS-iSYS system (IDS, Boldon, United
Kingdom) as previously described [21]. e within-run and total
precision of this assay were .8%–6.2% and 3.0%–8.2%, respectively.
e assay measuring range is between 200 and 12000 pmol/L
and was found to be linear up to 11651 pmol/L. dp-ucMGP
values <300 pmol/L are in the normal healthy range and values
>500 pmol/L reect vitamin K deciency [22].
Protein Induced by Vitamin K Absence-II
Protein induced by vitamin K absence (PIVKA)-II was used to
assess hepatic vitamin K status. Individuals with high PIVKA-II
levels have low hepatic vitamin K status and vice versa.
Circulating PIVKA-II levels were measured in serum using a
conformation-specific monoclonal antibody in an enzyme-
linked immunosorbent assay as previously described [23]. The
detection limit as well as upper limit of normal was .15 AU/mL
[23].
Desmosine
Plasma (p) desmosine and isodesmosine (DES) levels were used
as a marker for the rate of elastic fiber degradation [24]. DES are
formed during the cross-linking of tropo-elastin polymers and are
released in the bloodstream after degradation of elastic fibers [24].
pDES directly reflects the rate of systemic elastic fiber degradation.
DES fractions were measured using liquid chromatography-
tandem mass spectrometry as previously described [18, 24].
Coecients of variation of intra- and interassay imprecision
were <8.2%, the lower limit of quantication was 140ng/L, and
assay linearity was up to 210000ng/L.
Computed Tomography Assessment
Thin-slice computed tomography (CT) scans were acquired
using a Philips Ingenuity multidetector row scanner (Philips
Figure 2. Proposed sequential pathologic steps linking SARS-CoV-2 pneumonia to vitamin K insufficiency and accelerated elastic fiber degradation. (1) SARS-CoV-2 enters
AT2 cell. (2) The infected AT2 cell responds by upregulating synthesis of proinflammatory cytokines. (3) This leads to an increase in the number and activation of pulmonary
macrophages. (4) These infiltrating macrophages produce MMPs (5), which leads to accelerated degradation of elastic fibers (5a) and thereby the release of desmosine from
these fibers (5b), leading to elevated desmosine levels in lungs and blood. (6) The increased polarity of partially degraded elastic fibers (7) enhances their affinity for calcium
and, consequently, leads to increased elastic fiber calcium content. (7a) MMP synthesis is upregulated in parallel with the calcium content, which further accelerates elastic
fiber degradation in a self-propagating vicious circle. (8) MGP synthesis is upregulated in an attempt to protect elastic fibers from calcification and degradation, (8a) which
means that need for vitamin K to activate additional MGP increases. (8b) This increased use of vitamin K may induce vitamin K insufficiency, (9) in which case increased pro-
duction of MGP in a state of vitamin K insufficiency leads to increased dp-ucMGP in lungs and blood. Abbreviations: AT2, alveolar type II; dp-uc, desphospho-uncarboxylated;
MGP, matrix Gla protein; MMP, matrix metalloproteinase; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2
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4 • CID 2020:XX (XX XXXX) • Doerho etal
Healthcare). CT images of 1-mm thickness were reconstructed
using iterative model-based reconstruction in the axialplane.
Quantitative measurements of the volume of ground glass
and consolidation were undertaken using the Intellispace Portal
(COPD package, Intellispace version 10, Philips Healthcare).
In the soware, rst the lungs were segmented from the chest
wall and major vessels and main bronchi. Manual adjustments
were made where required by a board-certied chest radiol-
ogist. Subsequently, the lung voxels were counted to derive a
total lung volume in milliliters. Diseased lung tissue was de-
ned as those voxels with an attenuation of Hounseld units
(HU) greater than −700 as previously dened. e abnormal
voxels were expressed as a percentage diseased lung of the total
volume. An HU value at the 85th percentile was used [25, 26].
Coronary aortic calcication (CAC) and thoracic aortic cal-
cication (TAC) were also quantied in the Intellispace Portal
(Heartbeat CS package). Calcications were dened as areas
with an HU of 130 and higher. e calcications were visually
localized up to the arterial wall by a board-certied chest radi-
ologist and semiautomatically segmented. e volume was used
as a measure of calcication burden.
Statistical Analyses
Statistical analyses were performed using SPSS (version 24,
IBM, Chicago, IL). Analysis of variance was used to compare
dp-ucMGP, pDES, and radiological scores between groups.
Analysis of covariance was used to perform the aforementioned
analyses: dp-ucMGP, CAC, and TAC adjusted for age, sex, and
use of VKA and pDES adjusted forage.
For each pDES measurement in a COVID-19 patient, vir-
tual age-matched pDES values were calculated using pub-
lished pDES equations for never and (ex-) smokers [24].
pDES is strongly dialyzed (R. Janssen, unpublished data),
and patients receiving dialysis at baseline were excluded
from pDES analyses.
e Spearman correlation coecient was used to test the as-
sociation of closest time-matched dp-ucMGP with pDES and
radiologicalscores.
For PIVKA-II, patients were categorized as follows: normal
<.15 AU/mL, mildly elevated .15–.5 AU/mL, moderately ele-
vated .5–2.0 AU/mL, and severely elevated >2.0AU/mL.
dp-ucMGP, pDES, and radiological scores had a log-normal
distribution and were therefore natural log-transformed prior
to analyses. Since CAC and TAC scores included values equal
to zero, these values were transformed using Ln(CAC + 1)
and Ln(TAC + 1), respectively. e mean dierence and
95% condence interval (CI) of log-transformed values was
backtransformed to the mean fold change. Normally distrib-
uted continuous variables are presented as mean ± standard
deviation, whereas continuous variables with a natural-log
distribution are presented as backtransformed mean and 95%
CI. AP value of < .05 was used as the threshold for statistical
signicance.
RESULTS
The mean age of COVID-19 patients was 68 ± 12 years, 93
(69%) were male, and 12 (8.9%) used VKA. Of the historical
controls, 85 (46%) were male, 3 (1.6%) were taking VKA, and
the mean age was 61 ± 6.5years. Patient and control character-
istics are shown in Table1.
dp-ucMGP
dp-ucMGP was measured in all available samples. Maximum
dp-ucMGP levels were significantly higher in COVID-19 pa-
tients (1476 pmol/L; 95% CI, 1341 to 1625) compared with
healthy controls (471 pmol/L; 95% CI, 434 to 511; mean fold
change, 3.14; 95% CI, 2.76 to 3.56; P < .001; Figure3A), which
remained significant after adjustment for age, sex, and use of
VKAs (P < .001). dp-ucMGP levels were significantly higher in
Table 1. Baseline Characteristics of Coronavirus Disease 2019 Patient and Healthy Control Cohorts
Characteristic
Coronavirus Disease 2019 Controls
Good Outcome, n (%) Poor Outcome, n (%) All, N (%)
Patients 75 60 135 184
Age, y 64 ± 13 72 ± 10 68 ± 12 61 ± 6.5
Male (%) 46 (61) 47 (78) 93 (69) 85 (46)
Vitamin K antagonist use (%) 5 (6.7) 7 (12) 12 (8.9) 3 (1·6)
Hypertension (%) 28 (37) 21 (35) 49 (36) 41 (22)
Diabetes mellitus (%) 15 (20) 15 (25) 30 (22) 14 (7.6)
Cardiac or cardiovascular disease (%) 17 (23) 21 (35) 38 (28) 12 (6.5)
Asthma/Chronic obstructive pulmonary disease (%) 13 (17) 12 (20) 25 (19) 7 (3.8)
Other respiratory disease (%) 5 (6.7) 10 (17) 15 (11) 3 (1.6)
Immunocompromised (%) 4 (5.3) 2 (3.3) 6 (4.4) 0 (0)
Dialysis dependent (%)a1 (1.3) 2 (3.3) 3 (2.2) 0 (0)
Active malignancy (%) 6 (8.0) 6 (10) 12 (8.9) 0 (0)
aAt admission.
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Severe Vitamin K Insufficiency in COVID-19 • CID 2020:XX (XX XXXX) • 5
COVID-19 patients with poor outcome (1998 pmol/L; 95% CI,
1737 to 2296)compared with those with good outcome (1157
pmol/L; 95% CI, 1022 to 1312; mean fold change, 1.73; 95% CI,
1.43 to 2.08; P < .001; Figure 3A), and significance was main-
tained after adjustments (P < .001).
PIVKA-II
PIVKA-II was measured in the first available sample after ad-
mission. Levels were normal in 82.1%, mildly elevated in 13.0%,
moderately elevated in 4.1%, and severely elevated in .8% of
COVID-19 patients not using VKA (Figure3B). PIVKA-II dis-
tribution was comparable between patients with good (78.6%,
15.7%, 4.3%, and 1.4%, respectively) and poor outcomes
(86.8%, 9.4%, 3.8%, and 0%, respectively). PIVKA-II levels were
severely elevated in 100% of COVID-19 patients using VKA.
Desmosine
Sufficient plasma for pDES measurements was available for 127
patients and measured in the first available sample after admis-
sion. Three dialysis-dependent patients were excluded from the
analysis. pDES levels were significantly higher in COVID-19
patients (380ng/L; 95% CI, 355 to 405) compared with age-
dependent reference values of never-smokers (243ng/L; 95%
CI, 228 to 260; mean fold change, 1.56; 95% CI, 1.42 to 1.71;
P < .001) and former or current smokers (278ng/L; 95% CI, 260
to 296; mean fold change, 1.37; 95% CI, 1.25 to 1.50; P < .001;
Figure 4A) [24]. pDES levels, corrected for age, were signifi-
cantly higher in COVID-19 patients with poor (430ng/L; 95%
CI, 384 to 481)compared with good outcomes (342ng/L; 95%
CI, 310 to 379; mean fold change, 1.25; 95% CI, 1.07 to 1.47;
P = .004). dp-ucMGP levels significantly correlated with pDES
(n = 124; r = .47; P < .001; Figure4B).
CT Assessment
CT scans were available for 109 patients, and CAC and TAC
scores were successfully determined for 107 of these patients.
TAC and CAC scores were significantly higher in COVID-19
patients with poor outcome compared with those with good
outcome; however, both lost significance after adjustments
(Supplementary Materials). The association between pulmo-
nary involvement on CT and time-matched dp-ucMGP levels
was not significant (n = 109; r = .18; P = .06). dp-ucMGP was
significantly associated with TAC scores (n = 107; r = .36;
P < .001) and CAC scores (n = 107; r = .30; P = .002).
DISCUSSION
dp-ucMGP, which indirectly indicates extrahepatic vitamin K
insufficiency, was severely elevated in hospitalized COVID-19
patients. Impaired MGP activation was associated with poor
outcome and accelerated elastic fiber degradation. In contrast,
procoagulant FII activity remained preserved.
dp-ucMGP, as a measure of extrahepatic vitamin K status,
is a relevant parameter given its close association with mor-
tality [22]. Low dietary vitamin K intake and VKA use are
evident causes of elevated dp-ucMGP [15, 22]. Pathological
processes leading to upregulation of vitamin K–dependent pro-
tein production and resulting in accelerated use of vitamin K
Figure 3. Circulating dp-ucMGP and PIVKA-II in COVID-19 patients. A, dp-ucMGP was measured in plasma of COVID-19 patients with a good outcome (discharge without
invasive ventilation, n = 75; orange) or poor outcome (invasive ventilation and/or death, n = 60; red) compared with a cohort of controls. Patients with high dp-ucMGP have
low extrahepatic vitamin K status and vice versa. The maximum dp-ucMGP measured during the study is shown, with open circles representing those patients using vitamin
K antagonist (VKA) at admission. B, PIVKA-II was measured in plasma at baseline in those patients not using VKA (n = 122). The detection threshold and normal range for
healthy controls is shown in gray. Asingle patient not using VKAs had a severely elevated PIVKA-II outside the detection range and is not shown in the figure. Abbreviations:
COVID-19, coronavirus disease 2019; dp-ucMGP, desphospho-uncarboxylated matrix Gla protein; PIVKA-II, protein induced by vitamin K absence. ***P < .001.
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6 • CID 2020:XX (XX XXXX) • Doerho etal
for carboxylation may be another important reason for severe
extrahepatic vitamin K insuciency in COVID-19. Vitamin
K supplementation reduced dp-ucMGP in various cohorts
[22, 27], with favorable eects on clinically relevant outcome
measurements [27]. It is reasonable to assume that vitamin K
administration reduces dp-ucMGP in COVID-19. Whether
improving dp-ucMGP results in a better outcome of COVID-
19 remains to be evaluated.
Intriguingly, many comorbid conditions related to poor
COVID-19 clinical outcomes are associated with compromised
vitamin K status [1, 7, 18]. e same holds true for ageing [1].
Elastic ber calcication and degradation are closely related
processes [11, 12]. ere seems to be an association between
vascular mineralization and lung pathologies [28–30]. We
demonstrated accelerated elastic ber degradation and arterial
calcication correlating with dp-ucMGP, suggesting interrela-
tionships between vitamin K shortage, insucient MGP car-
boxylation, and elastic ber pathologies in COVID-19.
Although signicance was lost aer adjustment for age, sex,
and VKA use, we found enhanced TAC and CAC in patients
with poor prognosis. Hypertension, diabetes, cardiovascular di-
sease, and older age are associated with remodeling of elastic
tissues [7]. ese damaged and calcied elastic bers are more
prone to further degradation than intact bers [11]. We specu-
late that this preexisting elastic ber dysfunction renders them
more susceptible to degradation following enhanced proteolytic
activity during COVID-19 [14].
We did not nd a signicant correlation between dp-ucMGP
and pneumonia severity. It is possible that the correlation is
confounded by the fact that those with preexisting conditions
are predisposed to both higher dp-ucMGP and the develop-
ment of respiratory failure with less pulmonary involvement.
Furthermore, CT severity is a dynamic process that may change
rapidly [31]. Aclinical trial in which change of both vitamin
K status and CT severity are simultaneously assessed before
and aer vitamin K supplementation would be a more suitable
analysis.
Vitamin K1, the main source of vitamin K in the
Netherlands, is preferentially transported to the liver,
implying that the grade of carboxylation is usually higher
for hepatic than extrahepatic vitamin K–dependent proteins
(Figure1) [3, 4, 32]. is likely explains why dp-ucMGP was
severely elevated while PIVKA-II was normal in the majority
of patients. Similar to MGP, the activation of endothelial pro-
tein S is disproportionally impacted in times of vitamin K
deciency. eoretically, these observations could be com-
patible with enhanced thrombogenicity in COVID-19 [2],
where autopsies revealed bilateral deep venous leg throm-
bosis in all thromboembolic cases and thrombosis of the
prostatic venous plexus in the majority of men who died [33].
Future research should investigate this; however, there is
currently no readily available assay to measure carboxylated
(active) vs uncarboxylated (inactive) protein S. Enhanced
thrombosis in a state of vitamin K deciency has previously
been described in calciphylaxis [5]. Calciphylaxis is charac-
terized by cutaneous blood vessel occlusion due to calcica-
tion, leading to ischemic skin infarction [5]. Increased levels
of inactive MGP are found in skin tissues and the circulation
of calciphylaxis patients [5]. It may be speculated that, anal-
ogous to calciphylaxis, impaired local anticoagulant activity
due to vitamin K insuciency is responsible for microvessel
thrombosis in COVID-19 [34].
e major strength of our study is the use of robust bio-
markers and quantitative CT assessment. Our ndings are
Figure 4. Correlation between dp-ucMGP and desmosine. A, Scatterplot
showing circulating desmosine levels in those patients aged >40years (n = 121)
by age. The black line represents the deduced equation for coronavirus disease
2019 (COVID-19) patients. The green and blue lines represent Huang etal’s [24]
calculated equations for nonsmoking and smoking controls, respectively. B, For
all COVID-19 patients who were not dialysis-dependent at admission with a good
outcome (discharge without invasive ventilation, n = 69; orange) or poor outcome
(invasive ventilation and/or death, n = 58; red) log-transformed baseline dp-ucMGP
and desmosine values are shown, with open circles representing vitamin K antag-
onist users. The black line represents a linear regression analysis. Abbreviation:
dp-ucMGP, desphospho-uncarboxylated matrix Gla protein.
Downloaded from https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciaa1258/5898121 by guest on 29 October 2020
Severe Vitamin K Insufficiency in COVID-19 • CID 2020:XX (XX XXXX) • 7
limited by the fact that it is impossible to determine which
proportion of circulating dp-ucMGP and DES levels origin-
ated from the lungs, as both biomarkers are not tissue-specic.
erefore, there is an urgent need for experimental data to
better link vitamin K insuciency specically with COVID-
19–related lung pathologies.
As low vitamin K levels are found in comorbidities that
are related to poor outcome of COVID-19 [1, 7], we were
unable to formally determine whether vitamin K insu-
ciency truly predisposes patients to the development of se-
vere COVID-19 or whether it is merely an epiphenomenon.
However, the latter seems highly unlikely given the extreme
elevation of dp-ucMGP levels in COVID-19 patients, which
was much more pronounced than in hypertensive, dia-
betic, cardiovascular, and COPD patients without COVID-
19 (Supplementary Table 1). e strong correlation that we
found between vitamin K status and the rate of elastic ber
degradation also suggests causality.
We had to make use of a historical control group due to the
implementation of quarantines and social distancing practices
to contain SARS-CoV-2. We do not consider this to be a signif-
icant problem, however, as dp-ucMGP levels of our historical
controls were higher than previously reported in large groups
of controls (Supplementary Table 2). Furthermore, dierences
in dp-ucMGP levels between COVID-19 patients and controls
were of such a magnitude that loss of signicance when com-
paring to a matched control group would be highly unlikely.
In conclusion, dp-ucMGP was strongly elevated in hos-
pitalized COVID-19 patients, which indirectly indicates
extrahepatic vitamin K insuciency. Impaired MGP activation
was associated with poor outcomes. COVID-19 patients with
premorbid elastic ber pathologies appeared, in particular, to
be at increased risk of a complicated disease course. Despite
extrahepatic vitamin K deciency, hepatic prothrombin acti-
vation remained preserved. Taken together, these data suggest
a mechanism of pneumonia-induced extrahepatic vitamin K
depletion leading to accelerated elastic ber degradation and
thrombosis formation. An intervention trial is now needed to
assess whether vitamin K administration improves outcomes
in patients with COVID-19 by increasing pulmonary MGP and
endothelial protein S activation.
SupplementaryData
Supplementary materials are available at Clinical Infectious Diseases online.
Consisting of data provided by the authors to benet the reader, the posted
materials are not copyedited and are the sole responsibility of the authors, so
questions or comments should be addressed to the correspondingauthor.
Notes
Author contributions. R.J.developed the theory. A.S. M. D., R.J., and
L.J. S.designed the study. L.J. S., P.L., and C.M.were responsible for the
desphospho-uncarboxylated matrix Gla protein and protein induced by vi-
tamin K absence-II measurements. J.M. W.O.and H.D.were responsible
for the (iso)desmosine measurements. P. A. J. performed the computed
tomography analyses. H.D., E.G. A.K., C.V., M.P. J.V., and J.W.analyzed
the data. I.P.performed the statistical analyses. I.P., J.W., and R.J.wrote the
rst dra of the manuscript. A.S. M.D., L.J. S., J.M. W.O., P.A. J., T.M. H.,
R.G., L.E. M.K., and E.F. M.W.critically revised the manuscript.
Acknowledgments. e authors thank Twan Beijers, Manon Bindels,
Monique Bruns, Edwin van Harn, Karin Hoppenbrouwers, Britt Hulsen,
Wim Kools, Maarten Paul, Anne Rikken-Krijnen, Franz Roos, Rotraut
Schoop, Leon Tax, Dirk Traufelder, and Yannick van Til, and the Departments
of Internal Medicine, Pulmonary Medicine, Microbiology, and Radiology of
the Canisius-Wilhelmina Hospital for their support. Upon publication, the
full deidentied patient dataset will be provided as a supplementary le.
Potential conicts of interest. L. J. S. reports a consultancy fee from
Immunodiagnostic Systems and grants from NattoPharma. J.M. W.O.and
R.J.are owners of Desmosine.com. R.J.is owner of Emphysema Solutions
BV and discloses application of a patent on vitamin K in coronavirus 2019
for prognostic and therapeutic purposes. All other authors report no poten-
tial conicts. All authors have submitted the ICMJE Form for Disclosure of
Potential Conicts of Interest. Conicts that the editors consider relevant to
the content of the manuscript have been disclosed.
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... These studies displayed discordant results, some suggesting an impact on the incidence of infection and/or the duration of symptoms while others showed no effect [6][7][8][9][10][11][12][13]. Studies in the context of COVID-19 have mostly been ecological [14], or conducted on patients in already infected patients, focusing on the prognosis of the COVID-19 disease, in a context of tertiary prevention [15][16][17][18][19]. These studies provide crucial insights for disease management but they are not appropriate to investigate the potential influence of dietary habits on the risk of being infected by SARS-CoV-2, in a context of primary prevention. ...
... See legend on next page.)[17,39]. Our data suggest that it could also help prevent the infection by SARS-CoV-2.The potential effect of dietary fibers on the risk of SARS-CoV-2 infection is likely resulting from their interaction with the gut microbiota, producing shortchain fatty acids (SCFA) and promoting a diverse and balanced community. ...
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... There have been recent studies demonstrating the importance of combination therapy in individuals who have been diagnosed with comorbidity along with COVID, such as hypertension, kidney disease, or obesity. This is because individuals, who may have comorbidities, may also be vitamin K deficient [12]. Vitamin D and vitamin K combination therapy may also be beneficial because an increase of vitamin D through supplemental intake may increase calcium permeability of elastic fibers and stimulate degradation of these fibers. ...
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... In a study, it was reported that vitamin K decreased in COVID-19 patients and this decrease was related to poor prognosis. This study states that new studies are required to determine the effect of vitamin K administration on patients with COVID-19 [40]. In another study, it is reported that small intestine involvement and/or decreased dietary intake due to COVID-19 may be among the causes of decreased vitamin K status in COVID-19 patients. ...
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... [463][464][465] Third, studies have found that vascular endothelial cells activation and dysfunction mediate inflammation and abnormal coagulation in COVID-19 patients. 106,107 In addition, some other factors can also play a role by influencing the above three systems, such as RAS, 466 complement and coagulation cascade signaling, 125,467,468 mineralocorticoid receptor (MR) and its downstream target galectin-3 (Gal-3), 469 IL-6, 124 extrahepatic vitamin K insufficiency, 470 etc. These molecules and pathways form a complex network leading to the complexity of the disease and the difficulty of the treatment. ...
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Although COVID-19 is most well known for causing substantial respiratory pathology, it can also result in several extrapulmonary manifestations. These conditions include thrombotic complications, myocardial dysfunction and arrhythmia, acute coronary syndromes, acute kidney injury, gastrointestinal symptoms, hepatocellular injury, hyperglycemia and ketosis, neurologic illnesses, ocular symptoms, and dermatologic complications. Given that ACE2, the entry receptor for the causative coronavirus SARS-CoV-2, is expressed in multiple extrapulmonary tissues, direct viral tissue damage is a plausible mechanism of injury. In addition, endothelial damage and thromboinflammation, dysregulation of immune responses, and maladaptation of ACE2-related pathways might all contribute to these extrapulmonary manifestations of COVID-19. Here we review the extrapulmonary organ-specific pathophysiology, presentations and management considerations for patients with COVID-19 to aid clinicians and scientists in recognizing and monitoring the spectrum of manifestations, and in developing research priorities and therapeutic strategies for all organ systems involved.
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Respiratory immune characteristics associated with Coronavirus Disease 2019 (COVID-19) severity are currently unclear. We characterized bronchoalveolar lavage fluid immune cells from patients with varying severity of COVID-19 and from healthy people by using single-cell RNA sequencing. Proinflammatory monocyte-derived macrophages were abundant in the bronchoalveolar lavage fluid from patients with severe COVID-9. Moderate cases were characterized by the presence of highly clonally expanded CD8⁺ T cells. This atlas of the bronchoalveolar immune microenvironment suggests potential mechanisms underlying pathogenesis and recovery in COVID-19.
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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19), with a clinical outcome ranging from mild to severe, including death. To date, it is unclear why some patients develop severe symptoms. Many authors have suggested the involvement of vitamin D in reducing the risk of infections; thus, we retrospectively investigated the 25-hydroxyvitamin D (25(OH)D) concentrations in plasma obtained from a cohort of patients from Switzerland. In this cohort, significantly lower 25(OH)D levels (p = 0.004) were found in PCR-positive for SARS-CoV-2 (median value 11.1 ng/mL) patients compared with negative patients (24.6 ng/mL); this was also confirmed by stratifying patients according to age >70 years. On the basis of this preliminary observation, vitamin D supplementation might be a useful measure to reduce the risk of infection. Randomized controlled trials and large population studies should be conducted to evaluate these recommendations and to confirm our preliminary observation.
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Background and aims COVID-19 and low levels of vitamin D appear to disproportionately affect black and minority ethnic individuals. We aimed to establish whether blood 25-hydroxyvitamin D (25(OH)D) concentration was associated with COVID-19 risk, and whether it explained the higher incidence of COVID-19 in black and South Asian people. Methods UK Biobank recruited 502,624 participants aged 37–73 years between 2006 and 2010. Baseline exposure data, including 25(OH)D concentration and ethnicity, were linked to COVID-19 test results. Univariable and multivariable logistic regression analyses were performed for the association between 25(OH)D and confirmed COVID-19, and the association between ethnicity and both 25(OH)D and COVID-19. Results Complete data were available for 348,598 UK Biobank participants. Of these, 449 had confirmed COVID-19 infection. Vitamin D was associated with COVID-19 infection univariably (OR = 0.99; 95% CI 0.99–0.999; p = 0.013), but not after adjustment for confounders (OR = 1.00; 95% CI = 0.998–1.01; p = 0.208). Ethnicity was associated with COVID-19 infection univariably (blacks versus whites OR = 5.32, 95% CI = 3.68–7.70, p-value<0.001; South Asians versus whites OR = 2.65, 95% CI = 1.65–4.25, p-value<0.001). Adjustment for 25(OH)D concentration made little difference to the magnitude of the association. Conclusions Our findings do not support a potential link between vitamin D concentrations and risk of COVID-19 infection, nor that vitamin D concentration may explain ethnic differences in COVID-19 infection.
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