Microvascular dysfunction in COVID-19: the MYSTIC study.
Angiogenesis. 2021 Feb;24(1):145-157. doi: 10.1007/s10456-020-09753-7. Epub 2020 Oct 14.
PMID: 33058027
Free PMC article.
METHODS: Hospitalized adult patients with moderate-to-severe or critical COVID-19
(n = 23) were enrolled non-consecutively in this prospective,
observational, cross-sectional, multi-center study. ...CONCLUSIONS: Our
data clearly show severe alterations …
Prognostic value of von Willebrand factor and ADAMTS13 in patients with COVID-19: A systematic review and meta-analysis.
Thromb Res. 2022 Oct;218:83-98. doi: 10.1016/j.thromres.2022.08.017. Epub 2022 Aug 18.
PMID: 36027630
Free PMC article.
Review.
The estimated pooled means indicated increased plasma levels of VWF:Ag, VWF:Rco, and VWF:Ag/ADAMTS13:Ac ratio, and decreased plasma levels of ADAMTS13:Ac in COVID-19 patients with unfavorable outcomes when compared to those with favorable outcomes (com …
Background:
Endotheliopathy and coagulopathy appear to be the main causes for
critical illness and death in patients with coronavirus disease 2019
(COVID-19). The adhesive ligand von Willebrand factor (VWF) has been
involved in immunothrombosis responding to endothelial injury. Here, we
reviewed the current literature and performed meta-analyses on the
relationship between both VWF and its cleaving protease ADAMTS13 (a
disintegrin and metalloproteinase with thrombospondin type 1 motif,
member 13) with the prognosis of COVID-19. Methods:
We searched MEDLINE, Cochrane Library, Web of Science, and EMBASE
databases from inception to 4 March 2022 for studies analyzing the
relationship between VWF-related variables and composite clinical
outcomes of patients with COVID-19. The VWF-related variables analyzed
included VWF antigen (VWF:Ag), VWF ristocetin cofactor (VWF:Rco),
ADAMTS13 activity (ADAMTS13:Ac), the ratio of VWF:Ag to ADAMTS13:Ac, and
coagulation factor VIII (FVIII). The unfavorable outcomes were defined
as mortality, intensive care unit (ICU) admission, and severe disease
course. We used random or fixed effects models to create summary
estimates of risk. Risk of bias was assessed based on the principle of
the Newcastle-Ottawa Scale. Results:
A total of 3764 patients from 40 studies were included. The
estimated pooled means indicated increased plasma levels of VWF:Ag,
VWF:Rco, and VWF:Ag/ADAMTS13:Ac ratio, and decreased plasma levels of
ADAMTS13:Ac in COVID-19 patients with unfavorable outcomes when compared
to those with favorable outcomes (composite outcomes or subgroup
analyses of non-survivor versus survivor, ICU versus non-ICU, and severe
versus non-severe). In addition, FVIII were higher in COVID-19 patients
with unfavorable outcomes. Subgroup analyses indicated that FVIII was
higher in patients admitting to ICU, while there was no significant
difference between non-survivors and survivors. Conclusions:
The imbalance of the VWF-ADAMTS13 axis (massive quantitative and
qualitative increases of VWF with relative deficiency of ADAMTS13) is
associated with poor prognosis of patients with COVID-19.
Increased VWF and Decreased ADAMTS-13 in COVID-19: Creating a Milieu for (Micro)Thrombosis.
Semin Thromb Hemost. 2021 Jun;47(4):400-418. doi: 10.1055/s-0041-1727282. Epub 2021 Apr 23.
PMID: 33893632
Review.
However, ADAMTS-13 deficiency may result from other
pathological processes. Of relevance is the recent finding that COVID-19 (coronavirus disease 2019) is associated with both increased levels and activity of VWF as well as generally decreased (or
occasionally normal) activity levels of ADAMTS-13. Thus, in COVID-19
there is an alteration in the VWF/ADAMTS-13 axis, most often described
by increased VWF/ADAMTS-13 ratio (or reduced ADAMTS-13/VWF ratio).
COVID-19 is also associated with high prothrombotic risk. Thus, the
imbalance of VWF and ADAMTS-13 in COVID-19 may be providing a milieu
that promotes (micro)thrombosis, in a clinical picture resembling a
secondary thrombotic microangiopathy in some patients. This review
therefore assesses the literature on VWF, ADAMTS-13, and COVID-19.
Whenever reported in COVID-19, VWF has always been identified as raised
(compared with normal reference ranges or control populations). Reports
have included VWF level (i.e., VWF antigen) and in some cases one or
more VWF "activity" (e.g., collagen binding; platelet glycoprotein Ib
[GPIb] binding, using ristocetin cofactor or more modern versions
including VWF:GPIbR [recombinant] and VWF:GPIbM [mutant]). Whenever
reported, ADAMTS-13 has been reported as "normal" or reduced; however,
it should be recognized that "normal" levels may still identify a
relative reduction in individual cases. Some reports also discuss the
raised VWF/ADAMTS-13 (or reduced ADAMTS-13/VWF) ratio, but very few
provide actual numerical data.
The ADAMTS13-von Willebrand factor axis in COVID-19 patients.
J Thromb Haemost. 2021 Feb;19(2):513-521. doi: 10.1111/jth.15191. Epub 2020 Dec 18.
PMID: 33230904
Free PMC article.
BACKGROUND: Severe coronavirus disease 2019 (COVID-19)
is characterized by an increased risk of thromboembolic events, with
evidence of microthrombosis in the lungs of deceased patients.
...CONCLUSIONS: We found a significant alteration of the V …
ADAMTS13 regulation of VWF multimer distribution in severe COVID-19.
J Thromb Haemost. 2021 Aug;19(8):1914-1921. doi: 10.1111/jth.15409. Epub 2021 Jun 20.
PMID: 34053187
Free PMC article.
OBJECTIVES: This study investigated the hypothesis that
ADAMTS-13 regulation of VWF multimer distribution may be impaired in severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection contributing to the o …
We observed markedly increased VWF collagen-binding activity in
patients with severe COVID-19 compared to controls (median 509.1 versus
94.3 IU/dl). Conversely, plasma ADAMTS-13 activity was significantly
reduced (median 68.2 IU/dl). In keeping with an increase in
VWF:ADAMTS-13 ratio, abnormalities in VWF multimer distribution were
common in patients with COVID-19, with reductions in high molecular
weight VWF multimers. Terminal sialylation regulates VWF susceptibility
to proteolysis by ADAMTS-13 and other proteases. We observed that both
N- and O-linked sialylation were altered in severe COVID-19.
Furthermore, plasma levels of the ADAMTS-13 inhibitors interleukin-6,
thrombospondin-1, and platelet factor 4 were significantly elevated.
Distinctive Biomarker Features in the Endotheliopathy of COVID-19 and Septic Syndromes.
Shock. 2022 Jan 1;57(1):95-105. doi: 10.1097/SHK.0000000000001823.
PMID: 34172614
Free PMC article.
Biomarkers distinguishing different COVID-19 phenotypes from sepsis syndrome remain poorly understood. ...METHODS: Patients with COVID-19 pneumonia (n = 49) were classified into moderate, severe, or critical (life-threatening) disease. Plasma samples were
collected within 48 to 72 h of hospitalization to analyze endothelial
activation markers, including soluble Vascular Cell Adhesion Molecule-1
(sVCAM-1), von Willebrand Factor (VWF), A disintegrin-like and
metalloprotease with thrombospondin type 1 motif no. 13 (ADAMTS-13)
activity, thrombomodulin (TM), and soluble TNF receptor I (sTNFRI);
heparan sulfate (HS) for endothelial glycocalyx degradation; C5b9
deposits on endothelial cells in culture and soluble C5b9 for complement
activation; circulating dsDNA for neutrophil extracellular traps (NETs)
presence, and α2-antiplasmin and PAI-1 as parameters of fibrinolysis.
We compared the level of each biomarker in all three COVID-19 groups and
healthy donors as controls (n = 45). Results in critically ill COVID-19
patients were compared with other intensive care unit (ICU) patients
with septic shock (SS, n = 14), sepsis (S, n = 7), and noninfectious
systemic inflammatory response syndrome (NI-SIRS, n = 7).
…
All analyzed biomarkers were increased in COVID-19 patients versus
controls (P < 0.001), except for ADAMTS-13 activity that was normal
in both groups. The increased expression of sVCAM-1, VWF, sTNFRI, and HS
was related to COVID-19 disease severity (P < 0.05). Several
differences in these parameters were found between ICU groups: SS
patients showed significantly higher levels of VWF, TM, sTNFRI, and NETS
compared with critical COVID-19 patients and ADAMTS-13 activity was
significantly lover in SS, S, and NI-SIRS versus critical COVID-19 (P
< 0.001). Furthermore, α2-antiplasmin activity was higher in critical
COVID-19 versus NI-SIRS (P < 0.01) and SS (P < 0.001), whereas
PAI-1 levels were significantly lower in COVID-19 patients compared with
NI-SIRS, S, and SS patients (P < 0.01).
Conclusions:
COVID-19 patients present with increased circulating endothelial
stress products, complement activation, and fibrinolytic dysregulation,
associated with disease severity. COVID-19 endotheliopathy differs from
SS, in which endothelial damage is also a critical feature of
pathobiology. These biomarkers could help to stratify the severity of
COVID-19 disease and may also provide information to guide specific
therapeutic strategies to mitigate endotheliopathy progression.
Low ADAMTS13 Activity Correlates with Increased Mortality in COVID-19 Patients.
TH Open. 2021 Mar 9;5(1):e89-e103. doi: 10.1055/s-0041-1723784. eCollection 2021 Jan.
PMID: 33709050
Free PMC article.
The causes of coagulopathy associated with coronavirus disease 2019 (COVID-19)
are poorly understood. We aimed to investigate the relationship between
von Willebrand factor (VWF) biomarkers, intravascular hemolysis,
coagulation, and organ damage in …
COVID-19 associated coagulopathy: Mechanisms and host-directed treatment.
Am J Med Sci. 2022 Jun;363(6):465-475. doi: 10.1016/j.amjms.2021.10.012. Epub 2021 Nov 6.
PMID: 34752741
Free PMC article.
Review.
Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) is associated with specific coagulopathy that frequently occurs during the different phases of coronavirus disease 2019 (COVID-19 …
Impaired exercise capacity in post-COVID-19 syndrome: the role of VWF-ADAMTS13 axis.
Blood Adv. 2022 Jul 12;6(13):4041-4048. doi: 10.1182/bloodadvances.2021006944.
PMID: 35543533
Free PMC article.
Post-COVID syndrome (PCS), or long COVID, is an increasingly recognized complication of acute SARS-CoV-2
infection, characterized by persistent fatigue, reduced exercise
tolerance, chest pain, shortness of breath, and cognitive slowing. Acute COVID-19 is strongly linked with an
increased risk of thrombosis, which is a prothrombotic state quantified
by an elevated von Willebrand factor (VWF) antigen (Ag)/ADAMTS13 ratio
that is associated with severity of acute COVID-19 infection. We
investigated whether patients with PCS also had evidence of a
prothrombotic state associated with symptom severity. In a large cohort
of patients referred to a dedicated post-COVID-19 clinic, thrombotic
risk, including VWF(Ag)/ADAMTS13 ratio, was investigated. An elevated
VWF(Ag)/ADAMTS13 ratio (≥1.5) was present in nearly one-third of the
cohort and was 4 times more likely to be present in patients with
impaired exercise capacity, as evidenced by desaturation ≥3% and/or an
increase in lactate level >1 from baseline on a 1-minute sit-to-stand
test and/or a 6-minute walk test (P < .0001). Of 276 patients, 56
(20%) had impaired exercise capacity, of which 55% (31/56) had a
VWF(Ag)/ADAMTS13 ratio ≥1.5 (P < .0001). Factor VIII and VWF(Ag) were
elevated in 26% and 18%, respectively, and support a hypercoagulable
state in some patients with PCS. These findings suggest possible ongoing
microvascular/endothelial dysfunction in the pathogenesis of PCS and
suggest a role for antithrombotic therapy in the treatment of these
patients.
Clin Hemorheol Microcirc. 2022;82(2):193-198. doi: 10.3233/CH-221514.
PMID: 35754264
BACKGROUND: The assessment of ADAMTS13 factor activity and inhibitor levels was conducted in severe COVID-19 patients as an observational study. ..Results:
A total of 14 patients were included and the average ADAMTS13
activity level at the time of admission was 28.54±30.74% (range
1.83-86.67%) which was reduced compared to controls (88.09±14.77). Nine
patients had reduced ADAMTS13 factor activity (<40%) and 77.7% among
them had severe deficiency (<10% activity). ADAMTS13 inhibitor was
positive (>15 IU/mL) only in two patients and an overall mean value
was 8.15±5.8. Elevated D-Dimer and length of hospital stay had
significant correlation with ADAMTS13 activity (-0.247 and 0.306
respectively). No features of thrombotic microangiopathy were observed
and hence no plasma exchange was performed. Conclusion:
Reduced ADAMTS13 factor activity without inhibitor development may give a clue to the disease progress in COVID-19.
…
