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Prognostic value of von Willebrand factor and ADAMTS13 in patients with COVID-19: A systematic review and meta-analysis

  • Author Footnotes
    1 These authors contributed equally to this work.
    Xin Xu
    Correspondence
    Corresponding authors at: Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, 45 Changchun Street, Beijing 100053, China.
    Footnotes
    1 These authors contributed equally to this work.
    Affiliations
    Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, 45 Changchun Street, Beijing, China

    China International Neuroscience Institute (China-INI), 45 Changchun Street, Beijing, China
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  • Author Footnotes
    1 These authors contributed equally to this work.
    Yao Feng
    Footnotes
    1 These authors contributed equally to this work.
    Affiliations
    Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, 45 Changchun Street, Beijing, China

    China International Neuroscience Institute (China-INI), 45 Changchun Street, Beijing, China
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  • Yitong Jia
    Affiliations
    Department of Anesthesiology, Xuanwu Hospital, Capital Medical University, 45 Changchun Street, Beijing, China
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  • Xiao Zhang
    Affiliations
    Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, 45 Changchun Street, Beijing, China

    China International Neuroscience Institute (China-INI), 45 Changchun Street, Beijing, China
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  • Long Li
    Affiliations
    Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, 45 Changchun Street, Beijing, China

    China International Neuroscience Institute (China-INI), 45 Changchun Street, Beijing, China
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  • Xuesong Bai
    Affiliations
    Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, 45 Changchun Street, Beijing, China

    China International Neuroscience Institute (China-INI), 45 Changchun Street, Beijing, China
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  • Liqun Jiao
    Correspondence
    Corresponding authors at: Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, 45 Changchun Street, Beijing 100053, China.
    Affiliations
    Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, 45 Changchun Street, Beijing, China

    China International Neuroscience Institute (China-INI), 45 Changchun Street, Beijing, China

    Department of Interventional Neuroradiology, Xuanwu Hospital, Capital Medical University, 45 Changchun Street, Beijing, China.
    Search for articles by this author
  • Author Footnotes
    1 These authors contributed equally to this work.

      Highlights

      • Endotheliopathy and coagulopathy are key pathogenic mechanisms in COVID-19.
      • Plasma VWF-related variables are associated with poor outcomes of COVID-19 patient.
      • Imbalanced VWF-ADAMTS13 axis is involved in pathophysiological process of COVID-19.

      Abstract

      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.

      Keywords

      1. Introduction

      The global pandemic of coronavirus disease 2019 (COVID-19) caused by novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has affected tens of millions of people with the number of deaths growing exponentially [
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      ]. These distinct features suggest that CAC differs mechanistically from coagulopathy arising after other acute infections and common DIC. Several lines of evidence suggest the vascular events in COVID-19 patients appear to be mostly caused by in situ platelet-fibrin thrombus formation rather than embolic thrombi [
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      ] demonstrated that endotheliopathy defined by the shedding of syndecan-1 is associated with respiratory failure, liver injury, multi-organ failure, and death of patients with COVID-19. von Willebrand factor (VWF) and its cleaving protease ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) play important roles in primary and secondary thrombotic, and inflammatory response to vascular injury [
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      ]. This imbalance has also been increasingly recognized for the development of complications of COVID-19 with increasing plasma VWF antigen and activity, and a generally reduction (or occasionally normal) of ADAMTS-13 activity [
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      ], it is far less known regarding roles of other factors closely related to VWF biology, such as VWF release defined by VWF propeptide (VWFpp), adhesive activity (VWF ristocetin cofactor; VWF:Rco), multimer distribution, association with coagulation factor VIII (FVIII), and ADAMTS13 activity (ADAMTS13:Ac), in the development of COVID-19 complications. We therefore conducted a literature review and meta-analysis for information related to the association between VWF-related variables and outcomes in patients with COVID-19.

      2. Methods

      This systematic review and meta-analysis was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement guidelines [
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      ]. The pre-specified protocol for this meta-analysis has registered in the International Prospective Register of Systematic Reviews (PROSPERO; registration number: CRD42021287385).

      2.1 Search strategy and study selection

      A comprehensive literature search was performed using MEDLINE (via PubMed), Cochrane Library, Web of Science, and the EMBASE databases from inception to March 4th, 2022. We searched for studies that investigated the plasma levels of VWF-related variables in patients with COVID-19 according to clinical outcomes using predefined keywords: (“SARS-CoV-2” OR “COVID-19” OR “2019-nCoV” OR “Coronavirus disease 19”) AND (“von Willebrand Factor” OR “VWF” OR “von Willebrand” OR “Willebrand Protein”) AND (“ADAMTS13” OR “von Willebrand Factor cleaving proteinase”) AND (“Factor VIII” OR “FVIII”). The references listed in the retrieved articles were also reviewed to identify additional studies. Duplicate articles were removed after the initial search. Two reviewers (YJ and XZ) independently screened the title and abstract of the articles. The full-text of those that had passed the initial screening were assessed according to the eligibility criteria. Discrepancies were resolved by consensus between the two reviewers or by a third reviewer (XB) when a consensus could not be achieved.

      2.2 Eligibility criteria

      The inclusion criteria were as follows: 1) clinical trial or observational prospective/retrospective studies on COVID-19 with clinical outcomes for mortality (survivor vs. non-survivor), need for intensive care unit (ICU) admission (non-ICU vs. ICU), and severity (non-severe vs. severe); 2) reporting data on plasma levels of VWF:Ag, VWF:Rco, VWFpp, VWF multimer distribution, ADAMTS13:Ac, VWF:Ag/ADAMTS13:Ac ratio, and FVIII; 3) results were presented as or could be converted/digitized to standardized mean difference (SMD). The following types of articles were excluded from the analysis: case reports/series, brief reports, communications, correspondence, or letters that involved less than ten patients, review articles, commentaries, non-English language articles, research articles on the pediatric population, animal or in-vitro studies, unpublished studies, and studies with irrelevant or non-extractable results.

      2.3 Data extraction

      Two reviewers (YJ and XZ) extracted data from eligible studies independently using a predefined spreadsheet containing authors, country, publication date, study design, sample size, patient demographics, including age and gender, criteria used for clinical outcome classification, VWF related variable. The raw data were compared and pooled by the third investigator (XB) to eliminate extraction errors. The pooled effect estimates were SMD in terms of these variable between patients with and without poor clinical outcomes. When the data were expressed in median and quantiles, we derived and estimated the mean and standard deviation with accepted methods [
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      2.4 Quality assessment

      Two reviewers (YJ and XZ) also independently assessed the risk of bias (methodological quality) for each included study based on the principle of the eight-item Newcastle-Ottawa Scale (NOS; for case-control study) [
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      2.5 Data synthesis and statistical analysis

      The meta-analysis was conducted using the Review Manager software (RevMan5.3, Cochrane Collaboration, Oxford, UK). Continuous outcome variables were presented as SMD with 95 % confidence interval (CI). I-square (I2) statistics was used to evaluate the data heterogeneity. Outcomes with I2 > 50 % were regarded as having a high heterogeneity. The random-effects model was used to analyze outcomes for included studies when I2 > 50 %. Otherwise, a fixed-effect model was used. A p value of <0.05 was considered statistically significant in the test for overall effect. Publication bias was assessed by visualization of funnel plots.

      3. Results

      3.1 Study selection and characteristics

      A total of 1211 potentially relevant studies were included in the combined electronic and paper reference search. After removing 446 duplicates, 602 studies were excluded by title and abstract screening (reviews or not relevant). The final full-text review included 163 reports, from which 123 studies did not meet the inclusion criteria and were excluded. A total of 40 studies comprising of 3764 patients met the including criteria and were included in this systematic review and meta-analysis [
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      ,
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      ,
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      ,
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      • et al.
      Oxidative stress-induced endothelial dysfunction and decreased vascular nitric oxide in COVID-19 patients.
      ,
      • Nougier C.
      • Benoit R.
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      • Marcotte G.
      • Argaud L.
      • et al.
      Hypofibrinolytic state and high thrombin generation may play a major role in SARS-COV2 associated thrombosis.
      ,
      • Pascreau T.
      • Zia-Chahabi S.
      • Zuber B.
      • Tcherakian C.
      • Farfour E.
      • Vasse M.
      ADAMTS 13 deficiency is associated with abnormal distribution of von Willebrand factor multimers in patients with COVID-19.
      ,
      • Philippe A.
      • Chocron R.
      • Gendron N.
      • Bory O.
      • Beauvais A.
      • Peron N.
      • et al.
      Circulating Von Willebrand factor and high molecular weight multimers as markers of endothelial injury predict COVID-19 in-hospital mortality.
      ,
      • Philippe A.
      • Gendron N.
      • Bory O.
      • Beauvais A.
      • Mirault T.
      • Planquette B.
      • et al.
      Von Willebrand factor collagen-binding capacity predicts in-hospital mortality in COVID-19 patients: insight from VWF/ADAMTS13 ratio imbalance.
      ,
      • Rauch A.
      • Labreuche J.
      • Lassalle F.
      • Goutay J.
      • Caplan M.
      • Charbonnier L.
      • et al.
      Coagulation biomarkers are independent predictors of increased oxygen requirements in COVID-19.
      ,
      • Rodriguez Rodriguez M.
      • Castro Quismondo N.
      • Zafra Torres D.
      • Gil Alos D.
      • Ayala R.
      • Martinez-Lopez J.
      Increased von Willebrand factor antigen and low ADAMTS13 activity are related to poor prognosis in COVID-19 patients.
      ,
      • Sinkovits G.
      • Reti M.
      • Muller V.
      • Ivanyi Z.
      • Gal J.
      • Gopcsa L.
      • et al.
      Associations between the von Willebrand factor-ADAMTS13 axis, complement activation, and COVID-19 severity and mortality.
      ,
      • Sweeney J.M.
      • Barouqa M.
      • Krause G.J.
      • Gonzalez-Lugo J.D.
      • Rahman S.
      • Gil M.R.
      Low ADAMTS13 activity correlates with increased mortality in COVID-19 patients.
      ,
      • Thangaraju K.
      • Katneni U.
      • Akpan I.J.
      • Tanaka K.
      • Thomas T.
      • Setua S.
      • et al.
      The impact of age and BMI on the VWF/ADAMTS13 axis and simultaneous thrombin and plasmin generation in hospitalized COVID-19 patients.
      ,
      • Thomas V.V.
      • Kumar S.E.
      • Alexander V.
      • Nadaraj A.
      • Vijayalekshmi B.
      • Prabhu S.
      • et al.
      Plasma von Willebrand factor levels predict survival in COVID-19 patients across the entire Spectrum of disease severity.
      ,
      • Tiscia G.
      • Favuzzi G.
      • De Laurenzo A.
      • Cappucci F.
      • Fischetti L.
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      • et al.
      The prognostic value of ADAMTS-13 and von Willebrand factor in COVID-19 patients: prospective evaluation by care setting.
      ,
      • Torres-Ruiz J.
      • Perez-Fragoso A.
      • Maravillas-Montero J.L.
      • Llorente L.
      • Mejia-Dominguez N.R.
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      • et al.
      Redefining COVID-19 severity and prognosis: the role of clinical and immunobiotypes.
      ,
      • Vassiliou A.G.
      • Keskinidou C.
      • Jahaj E.
      • Gallos P.
      • Dimopoulou I.
      • Kotanidou A.
      • et al.
      ICU admission levels of endothelial biomarkers as predictors of mortality in critically ill COVID-19 patients.
      ,
      • von Meijenfeldt F.A.
      • Havervall S.
      • Adelmeijer J.
      • Lundstrom A.
      • Rudberg A.S.
      • Magnusson M.
      • et al.
      Prothrombotic changes in patients with COVID-19 are associated with disease severity and mortality.
      ]. Fig. 1 shows the flow diagram of study selection. Table 1 presents study characteristics and patient demographics.
      Fig. 1
      Fig. 1Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram.
      Table 1Characteristics of the included studies.
      TotalFavorable clinical outcomesUnfavorable clinical outcomes
      StudyCountryDesignPeriodSizeAge

      (year)
      Gender, n

      (Female/Male)
      EndpointsSizeAge

      (year)
      Gender, n

      (Female/Male)
      SizeAge

      (year)
      Gender, n (Female/Male)VWF-related variablesQuality

      (NOS)
      Bauer et al.GermanyProspective; Single centerMarch 2020–June 20201770.1 (IQR, 55.6–72.0)11/6ICU admission1063.7 (IQR, 52.5–71.0)6/4771.9 (IQR, 57.5–76.8)5/2VWF: Ag; VWF: Rco8
      Bazzan et al.ItalyRetrospective; Single centerN/A88N/AN/AMortality7959.37 ± 12.725/54971.89 ± 7.13/6VWF: Ag;

      ADAMTS13: Ac
      7
      Blasi et al.SpainProspective; Single centerApril 20202364 (IQR, 53–74)9/14ICU admission1158 (IQR, 42–74)3/81269 (IQR, 57–76)6/6VWF: Ag; ADAMTS13: Ac; FVIII7
      Cugno et al.ItalyProspective; Single centerMarch 1, 2020-

      April 15, 2020
      104N/AN/ASeverity58N/AN/A46N/AN/AVWF: Ag7
      De Jongh et al.NetherlandsCross-sectional; Single centerN/A16N/AN/AMortality1162.5 ± 13.7N/A578.0 ± 6.4N/AVWF: Ag; ADAMTS13: Ac; FVIII5
      Delrue et al.FranceProspective; Single centerMarch 17, 2020-

      11 April 2020
      13365 (IQR, 56–75)97/26Mortality110N/AN/A23N/AN/AADAMTS13: Ac5
      Doevelaar et al.GermanyProspective; Single centerN/A7566 ± 1638/37Mortality62N/AN/A13N/AN/AVWF: Ag/ADAMTS13 ratio; ADAMTS13: Ac6
      Dupont et al.FranceProspective; Single centerMarch 21, 2020-

      April 16, 2020
      8260 ± 1418/64Mortality60N/AN/A22N/AN/AVWF: Ag9
      Dushianthan et al.GBRRetrospective; Single centerMarch 2020-

      March 2021
      65N/AN/AMortality54N/AN/A11N/AN/AVWF: Ag; ADAMTS13: Ac; VWF: Ag/ADAMTS13 ratio; FVIII7
      Fan et al.SingaporeProspective; Multi-centerJune 2020–January 20212060 (IQR, 49.5–64.5)4/16Severity1060 (IQR,

      50–65)
      2/81060 (IQR, 49–64)2/8VWF: Ag; FVIII8
      Fernández et al.SpainProspective; single centerMay 1, 2020–May 31, 202034N/AN/ASeverity2453 (IQR,

      43–71)
      10/141066 (IQR, 52–75)3/7VWF: Ag;

      ADAMTS13: Ac
      7
      Francischetti et al.United StatesCross-sectional; Single centerApril 2020–October 202066N/A33/33Severity4047 (IQR,

      22–65.2)
      21/192666 (IQR, 34–78)12/14VWF: Ag; VWF: Ac; ADAMTS13: Ac7
      Goshua et al.United StatesCross-sectional; Single centerApril 13, 2020–April 24, 20206862 ± 1627/41ICU admission2058 ± 1515/334864 ± 1612/8VWF: Ag; FVIII7
      Helin et al.FinlandRetrospective; Single centerApril 2020-

      May 2020
      7856 (Range, 16–87)34/44ICU admission44N/A23/2134N/A11/23FVIII5
      Henry et al.United StatesProspective; Single centerApril 2020-

      May 2020
      5251 (IQR, 39–66)22/30Severity36N/AN/A16N/AN/AVWF: Ag; ADAMTS13: Ac; VWF: Ag/ADAMTS13 ratio6
      Herr et al.GermanyProspective; Multi-centerMarch 2020–July 20203563.86 ± 3.189/26Mortality2461.96 ± 4.3N/A1168.27 ± 3.72)N/AVWF: Ag7
      Joly et al.FranceProspective; Single centerMarch 18, 2020–May 9, 20205359 (IQR, 53–66)14/39Mortality3860 (IQR,

      50–64)
      12/261558 (IQR, 56–67)2/13VWF: Ag; ADAMTS13: Ac; VWF: Ag/ADAMTS13 ratio7
      Jothimani et alIndiaProspective; Single centerJuly 1, 2020-

      July 12, 2020
      3550 (IQR, 44.5–55.7)13/22ICU admission27N/AN/A8N/AN/AVWF: Ag6
      Lichter et al.IsraelRetrospective; Single centerMarch 10, 2020-

      April 26, 2020

      January 5, 2021-

      February 4, 2021
      39N/AN/AICU admission5N/AN/A3457 (Range, 22–76)10/24FVIII7
      Lopez-Castaneda et al.MexicoProspective; Single centerJuly 2020-

      September 2020
      55N/AN/ASeverity3744.52 ± 12.711/261863.77 ± 13.89/9VWF: Ag8
      Mancini et al.ItalyRetrospective; Single centerMarch 2020-mid-April 202033N/AN/ASeverity1458 (Range, 27–85)7/71959 (Range, 40–71)6/13VWF: Ag; VWF: Ac; ADAMTS13: Ac;

      VWF: Ag/ADAMTS13 ratio
      7
      Marchetti et al.ItalyProspective; Single centerMarch 23, 2020-

      May 30, 2020
      6362 (Range 35–88)18/45Mortality50N/AN/A13N/AN/AVWF: Ag; VWF: Rco7
      Marco et al.SpainProspective; single centerApril 2020-

      May 2020
      152N/AN/AMortality143N/AN/A9N/AN/AVWF: Ag; ADAMTS13: Ac; VWF: Ag/ADAMTS13 ratio6
      5068.39 (IQR, 61.43–79.05)16/34ICU admission28N/AN/A22N/AN/A
      Martıín-Rojas et al.SpainRetrospective; Single centerApril 20206261.8 ± 15.210/43Mortality5161.2 ± 15.416/351164.7 ± 14.93/8VWF: Ag; ADAMTS13: Ac; FVIII8
      Martıín-Rojas et al.SpainRetrospective; Single centerApril 3, 2020–May 3, 202020663.6 ± 13.475/131Mortality18862.4 ± 12.968/1201876.0 ± 12.37/11FVIII7
      ICU admission18064.22 ± 13.8467/1132659.9 ± 9.558/18
      Montiel et al.BelgiumProspective; Single centerApril 27, 2020–November 3, 202060N/A13/47ICU admission3052.1 ± 13.58/223061.3 ± 8.75/25VWF: Ag; VWF: Rco; ADAMTS13: Ac; VWF: Ag/ADAMTS13 ratio8
      Nougier et al.FranceProspective; Single centerN/A7860.2 ± 14.427/51ICU admission3060.2 ± 14.6N/A4862.8 ± 13.1N/AFVIII8
      Pascreau et al.FranceProspective; Single centerN/A70N/AN/AMortality55N/AN/A15N/AN/AVWF: Ag6
      66ICU admission44N/AN/A22N/AN/A
      Philippe et al.FranceProspective; Multi-centerMarch 13, 2020-

      June 26, 2020
      185N/AN/ASeverity9665.5 (IQR, 55.0–76.0)41/558962.0 (IQR, 51.0–71.0)24/65VWF: Ag; VWF: Rco8
      Philippe et al.FranceCross-sectional; Single centerN/A77N/AN/ASeverity3763 (IQR,

      52–72)
      12/254062 (IQR, 53–72)7/33ADAMTS13: Ac; VWF: Ag/ADAMTS13 ratio7
      Rauch et al.FranceProspective; Single centerMarch 20, 2020-

      April 17, 2020
      24363.9 ± 16.288/155Mortality211N/AN/A32N/AN/AVWF: Ag; FVIII8
      Rodríguez et al.FranceRetrospective; Single centerMarch 15, 2020-

      April 1, 2020
      10060.530/70Mortality81N/AN/A19N/AN/AVWF: Ag; ADAMTS13: Ac7
      Severity50N/AN/A50N/AN/A
      Sinkovits et al.HungaryProspective; Single centerApril 20, 2020-

      July 2, 2020
      10267 (IQR, 56–76)46/56Mortality77N/AN/A25N/AN/AVWF: Ag; ADAMTS13: Ac; VWF: Ag/ADAMTS13 ratio7
      Severity60N/AN/A42N/AN/A
      Sweeney et al.United StatesRetrospective; Single centerMarch 26, 2020-

      May 5, 2020
      181N/AN/AMortality9162.0 (IQR, 50.5–70.0)45/469072.5 (IQR, 63.3–79.8]30/60VWF: Ag; VWF: Rco; ADAMTS13: Ac; FVIII8
      Thangaraju et al.United StatesRetrospective; Single centerApril 14, 2020-

      May 312,020
      54363 (Range, 3.0–99)N/AMortality433N/AN/A110N/AN/AVWF: Ag; ADAMTS13: Ac; VWF: Ag/ADAMTS13 ratio; FVIII6
      Thomas et al.IndiaProspective; Single centerJuly 22, 2020–August 3, 202071N/AN/ASeverity3435.5 (IQR, 29–49)12/223757 (IQR, 49–62)3/34VWF: Ag6
      Tiscia et al.ItalyProspective; Single centerMarch 12,020–September 30, 20207468.0 (IQR, 22.0)43ICU admission5269.0 (IQR,19.7)26/262263.0 (IQR,15.2)5/17VWF: Ag; VWF: Rco; ADAMTS13: Ac; VWF: Ag/ADAMTS13 ratio; FVIII7
      Torres-Ruiz et al.MexicoProspective; Single centerMarch 2020-

      August 2020
      70N/AN/ASeverity3434.00 (IQR, 27.25–43.00)15/193654.50 (IQR, 46.75–60.75)6/30VWF: Ag7
      Vassiliou et al.GreeceProspective; Single centerMarch 22, 2020-

      October 25, 2020
      3863 ± 117/31Mortality2862 ± 115/231068 ± 102/8VWF: Ag9
      von Meijenfeldt et al.SwedenProspective; Single centerApril 9, 2020-

      June 8, 2020
      102N/AN/AMortality92N/AN/A10N/AN/AVWF: Ag; ADAMTS13: Ac; FVIII7
      Abbreviations: ADAMTS13: Ac, a disintegrin and metalloprotease with thrombospondin type I repeats, member 13: Activity; CI, confidence interval; FVIII, factor VIII; ICU, intense care unit; IQR, interquartile range; NOS, Newcastle-Ottawa Scale; VWF, von Willebrand factor; VWF: Ag, VWF antigen; VWF: Rco, VWF ristocetin cofactor.

      3.2 Meta-analysis of VWF-ADAMTS13 axis

      We analyzed reported plasma levels of VWF:Ag, VWF:Rco, ADAMTS13:Ac, VWF:Ag/ADAMTS13:Ac ratio, and FVIII in patients with COVID-19. Since there were 2 studies that met the inclusion criteria having plasma VWFpp values [
      • De Jongh R.
      • Ninivaggi M.
      • Mesotten D.
      • Bai C.
      • Marcus B.
      • Huskens D.
      • et al.
      Vascular activation is a strong predictor of mortality in coronavirus disease 2019 patients on the ICU.
      ,
      • Mancini I.
      • Baronciani L.
      • Artoni A.
      • Colpani P.
      • Biganzoli M.
      • Cozzi G.
      • et al.
      The ADAMTS13-von Willebrand factor axis in COVID-19 patients.
      ] and 2 studies measured VWF multimeric pattern [
      • Mancini I.
      • Baronciani L.
      • Artoni A.
      • Colpani P.
      • Biganzoli M.
      • Cozzi G.
      • et al.
      The ADAMTS13-von Willebrand factor axis in COVID-19 patients.
      ,
      • Philippe A.
      • Chocron R.
      • Gendron N.
      • Bory O.
      • Beauvais A.
      • Peron N.
      • et al.
      Circulating Von Willebrand factor and high molecular weight multimers as markers of endothelial injury predict COVID-19 in-hospital mortality.
      ], these variables were not included in this meta-analysis.

      3.2.1 VWF:Ag

      A total of 33 studies comprising of 3377 patients were included. Plasma VWF:Ag levels were significantly higher in unfavorable outcomes than those with favorable outcomes (SMD = −0.95 95%CI [−1.15, −0.75], p < 0.00001; I2 = 81 %; Fig. 2). Further analyses showed that COVID-19 patients with non-survivor status (SMD = −0.79 95%CI [−1.05, −0.52], p < 0.00001; I2 = 77 %), ICU need (SMD = −0.96 95%CI [−1.30, −0.62], p < 0.00001; I2 = 61 %) or high severity (SMD = −1.18 95%CI [−1.59, −0.77], p < 0.00001; I2 = 86 %) had higher plasma levels of VWF:Ag when compared to those with survivor status, non-ICU status, or low severity (Table 2 and Fig. S1).
      Fig. 2
      Fig. 2Forest plot of the association between VWF:Ag and composite clinical outcomes.
      Table 2Summary of stratified subgroup analysis of VWF-ADAMTS13 axis-related parameters between unfavorable and favorable clinical outcomes.
      VWF: Ag
      EndpointsNumber of studies includedFavorable clinical outcomes

      (total patients, n)
      Unfavorable clinical outcomes

      (total patients, n)
      Total patients, nStandard mean difference, 95%CIP valueI2
      Mortality1715384571995−0.79 [−1.05, −0.52]p < 0.0000177 %
      ICU admission9253202455−0.96 [−1.30, −0.62]p < 0.0000161 %
      Severity13518409927−1.18 [−1.59, −0.77]p < 0.0000186 %
      VWF: Rco
      ICU admission39259151−0.85 [−1.20, −0.50]p < 0.0000121 %
      Severity3150134284−1.29 [−2.30, −0.29]p = 0.00191 %
      ADAMTS13: Ac
      Mortality13132235016720.78 [0.57, 1.00]p < 0.0000155 %
      ICU admission51521172690.72 [0.31, 1.13]p = 0.000660 %
      Severity72612034640.76 [0.34, 1.19]p = 0.000477 %
      VWF: Ag/ADAMTS13: Ac Ratio
      Mortality5664174838−0.85 [−1.36, −0.33]p = 0.00182 %
      ICU admission311074184−0.96 [−1.27, −0.64]p < 0.000010 %
      Severity4147117264−1.06 [−1.61, −0.52]p = 0.000174 %
      FVIII
      Mortality810672551322−0.62 [−1.27, −0.04]p = 0.0693 %
      ICU admission8373255628−0.81 [−1.15, −0.47]p < 0.0000167 %
      Abbreviations: ADAMTS13: Ac, a disintegrin and metalloprotease with thrombospondin type I repeats, member 13: Activity; CI, confidence interval; FVIII, factor VIII; ICU, intense care unit; VWF, von Willebrand factor; VWF: Ag, VWF antigen; VWF: Rco, VWF ristocetin cofactor.

      3.2.2 VWF:Rco

      A total of 8 studies comprising of 679 patients were included. The plasma levels of VWF:Rco, which measures the ability of VWF to agglutinate platelets, were significantly higher in patients with unfavorable outcomes than those with favorable outcomes (SMD = −0.83 95%CI [−1.33, −0.34], p < 0.00001; I2 = 87 %; Fig. 3). They were also significantly higher in ICU-patients (SMD = −0.85 95%CI [−1.20, −0.50], p < 0.00001; I2 = 21 %) and severe patients (SMD = −1.29 95%CI [−2.30, −0.29], p = 0.001; I2 = 91 %) when compared to non-ICU-patients or non-severe patients (Table 2 and Fig. S2).
      Fig. 3
      Fig. 3Forest plot of the association between VWF:Rco and composite clinical outcomes.

      3.2.3 ADAMTS13:Ac

      A total of 21 studies comprising of 2405 patients were included. Plasma levels of ADAMTS13:Ac was significantly lower in patients with unfavorable outcomes than those with favorable outcomes (SMD = 0.78 95%CI [0.60, 0.95], p < 0.00001; I2 = 63 %; Fig. 4). The subgroup analyses (Table 2 and Fig. S3) further showed statistically significant differences between survivors and non-survivors (SMD = 0.78 95%CI [0.57, 1.00], p < 0.00001; I2 = 55 %), ICU admission and non-ICU admission (SMD = 0.72 95%CI [0.31, 1.13], p = 0.0006; I2 = 60 %), and severe status and non-severe status (SMD = 0.76 95%CI [0.34, 1.19], p = 0.0004; I2 = 77 %).
      Fig. 4
      Fig. 4Forest plot of the association between ADAMTS13:Ac and composite clinical outcomes.

      3.2.4 VWF:Ag/ADAMTS13:Ac ratio

      A total of 11 studies comprising of 1286 patients were included. The ratio of VWF:Ag to ADAMTS13:Ac was significantly higher in patients with unfavorable outcomes than those with favorable outcomes (SMD = −0.94 95%CI [−1.24, −0.65], p < 0.00001; I2 = 76 %; Fig. 5). A higher VWF:Ag/ADAMTS13:Ac ratio was also associated to the non-survivor status (SMD = −0.85 95%CI [−1.36, −0.33], p = 0.001; I2 = 82 %), ICU admission (SMD = −0.96 95%CI [−1.27, −0.64], p < 0.00001; I2 = 0 %), and severe disease (SMD = −1.06 95%CI [−1.61, −0.52], p = 0.0001; I2 = 74 %) (Table 2 and Fig. S4).
      Fig. 5
      Fig. 5Forest plot of the association between VWF:Ag/ADAMTS13:Ac ratio and composite clinical outcomes.

      3.2.5 FVIII

      A total of 15 studies comprising of 1970 patients were included. The plasma levels of FVIII were significantly higher in patients with unfavorable outcomes than those with favorable outcomes (SMD = −0.69 95%CI [−1.05, −0.33], p = 0.0002; I2 = 88 %; Fig. 6). Subgroup analyses (Table 2 and Fig. S5) further showed that plasma FVIII levels were significantly higher in COVID-19 patients who were admitted to ICU (SMD = −0.81 95%CI [−1.15, −0.47], p < 0.00001; I2 = 67 %), while there was no significant difference between non-survivors and survivors (SMD = −0.62 95%CI [−1.27, 0.04], p = 0.06; I2 = 93 %).
      Fig. 6
      Fig. 6Forest plot of the association between FVIII and composite clinical outcomes.

      3.3 Publication bias

      All included studies were assessed with 5 to 9 points (Table 1). The funnel plot was used to assess the publication bias for endpoint measures which pooled more than ten studies. No apparent publication bias was found in all the eligible endpoints. The funnel plots were listed in the supplement Fig. S6.

      4. Discussion

      This meta-analysis found a significant association between imbalanced VWF-related variables (massive quantitative and qualitative increases of VWF with relative deficiency of ADAMTS13) and outcomes in patients with COVID-19. However, the question remains as whether these VWF-related variables should be considered as an independent entity or part of CAC.

      4.1 COVID-19-associated endotheliopathy and coagulopathy

      CAC was first described by Tang et al. in a single-center study in Wuhan, China [
      • Tang N.
      • Li D.
      • Wang X.
      • Sun Z.
      Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia.
      ]. Autopsy results from COVID-19 deaths have consistently highlighted the marked endotheliopathy, which is characterized with EC desquamation, cytoplasmic vacuolization, swelling, tight junction disruption, and loss of contact with the basilar membrane in the lung, heart, brain, mesentery, and kidney [
      • Wichmann D.
      • Sperhake J.P.
      • Lutgehetmann M.
      • Steurer S.
      • Edler C.
      • Heinemann A.
      • et al.
      Autopsy findings and venous thromboembolism in patients with COVID-19: a prospective cohort study.
      ,
      • Ackermann M.
      • Verleden S.E.
      • Kuehnel M.
      • Haverich A.
      • Welte T.
      • Laenger F.
      • et al.
      Pulmonary vascular endothelialitis, thrombosis, and angiogenesis in COVID-19.
      ]. Recent evidence suggests that endotheliopathy contributes to hyperinflammatory and hypercoagulable states that predispose COVID-19 patients to thrombosis and microvascular events [
      • Libby P.
      • Luscher T.
      COVID-19 is, in the end, an endothelial disease.
      ,
      • Dupont A.
      • Rauch A.
      • Staessens S.
      • Moussa M.
      • Rosa M.
      • Corseaux D.
      • et al.
      Vascular endothelial damage in the pathogenesis of organ injury in severe COVID-19.
      ,
      • Bonaventura A.
      • Vecchie A.
      • Dagna L.
      • Martinod K.
      • Dixon D.L.
      • Van Tassell B.W.
      • et al.
      Endothelial dysfunction and immunothrombosis as key pathogenic mechanisms in COVID-19.
      ]. Won et al. [
      • Won T.
      • Wood M.K.
      • Hughes D.M.
      • Talor M.V.
      • Ma Z.
      • Schneider J.
      • et al.
      Endothelial thrombomodulin downregulation caused by hypoxia contributes to severe infiltration and coagulopathy in COVID-19 patient lungs.
      ] reported the upregulated pro-coagulants, downregulated anti-coagulants and severe thrombosis, and infiltration of activated macrophages, monocytes, and T cells within autopsy lungs of COVID-19 patients. Ranucci et al. [
      • Ranucci M.
      • Ballotta A.
      • Di Dedda U.
      • Baryshnikova E.
      • Dei Poli M.
      • Resta M.
      • et al.
      The procoagulant pattern of patients with COVID-19 acute respiratory distress syndrome.
      ] demonstrated a closely correlation between interleukin (IL)-6 and fibrinogen in patients with COVID-19. A correlation between inflammatory cytokines and VWF was also reported by Dupont and colleagues [
      • Dupont A.
      • Rauch A.
      • Staessens S.
      • Moussa M.
      • Rosa M.
      • Corseaux D.
      • et al.
      Vascular endothelial damage in the pathogenesis of organ injury in severe COVID-19.
      ]. The coordinated activation of the inflammatory and thrombotic responses is now termed immunothrombosis (or thromboinflammation), whereby COVID-19 induces endothelial injury, immune dysregulation, and inflammation, with resultant thrombosis and further propagation of inflammation [
      • Cacciola R.
      • Gentilini Cacciola E.
      • Vecchio V.
      • Cacciola E.
      Cellular and molecular mechanisms in COVID-19 coagulopathy: role of inflammation and endotheliopathy.
      ,
      • Jose R.J.
      • Manuel A.
      COVID-19 cytokine storm: the interplay between inflammation and coagulation.
      ]. Ciceri et al. [
      • Ciceri F.
      • Beretta L.
      • Scandroglio A.M.
      • Colombo S.
      • Landoni G.
      • Ruggeri A.
      • et al.
      Microvascular COVID-19 lung vessels obstructive thromboinflammatory syndrome (MicroCLOTS): an atypical acute respiratory distress syndrome working hypothesis.
      ] thus recommended the use of MicroCLOTS (microvascular COVID-19 lung vessels obstructive thromboinflammatory syndrome) to define thromboinflammatory response to COVID-19. A prevalent view holds that SARS-CoV-2 enters ECs directly by binding to the transmembrane angiotensin-converting enzyme 2 (ACE2) receptor [
      • Ackermann M.
      • Verleden S.E.
      • Kuehnel M.
      • Haverich A.
      • Welte T.
      • Laenger F.
      • et al.
      Pulmonary vascular endothelialitis, thrombosis, and angiogenesis in COVID-19.
      ,
      • Hamming I.
      • Timens W.
      • Bulthuis M.L.
      • Lely A.T.
      • Navis G.
      • van Goor H.
      Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis.
      ,
      • Monteil V.
      • Kwon H.
      • Prado P.
      • Hagelkruys A.
      • Wimmer R.A.
      • Stahl M.
      • et al.
      Inhibition of SARS-CoV-2 infections in engineered human tissues using clinical-grade soluble human ACE2.
      ]. But more recent studies have disputed the expression of ACE2 on ECs in postmortem COVID-19 tissues and in cultured ECs, and they suggest that the endotheliopathy is induced by pro-inflammatory cytokine milieu, complement activation, or tissue hypoxia [
      • Won T.
      • Wood M.K.
      • Hughes D.M.
      • Talor M.V.
      • Ma Z.
      • Schneider J.
      • et al.
      Endothelial thrombomodulin downregulation caused by hypoxia contributes to severe infiltration and coagulopathy in COVID-19 patient lungs.
      ,
      • McCracken I.R.
      • Saginc G.
      • He L.
      • Huseynov A.
      • Daniels A.
      • Fletcher S.
      • et al.
      Lack of evidence of angiotensin-converting enzyme 2 expression and replicative infection by SARS-CoV-2 in human endothelial cells.
      ,
      • Deinhardt-Emmer S.
      • Bottcher S.
      • Haring C.
      • Giebeler L.
      • Henke A.
      • Zell R.
      • et al.
      SARS-CoV-2 causes severe epithelial inflammation and barrier dysfunction.
      ,
      • Nascimento Conde J.
      • Schutt W.R.
      • Gorbunova E.E.
      • Mackow E.R.
      Recombinant ACE2 expression is required for SARS-CoV-2 to infect primary human endothelial cells and induce inflammatory and procoagulative responses.
      ]. Ma et al. [
      • Ma Z.
      • Yang K.Y.
      • Huang Y.
      • Lui K.O.
      Endothelial contribution to COVID-19: an update on mechanisms and therapeutic implications.
      ] recently reviewed and summarized that ROS, VEGFA/VEGFR2, and HMGB1/RAGE/TLR4 are potential signaling pathways that involved in the COVID-19-associated endotheliopathy. These findings explain why patients with conditions of systemic endotheliopathy, such as cardiovascular disease, diabetes mellitus, chronic kidney disease, and cancer, are at a higher risk for severe COVID-19. It is therefore also not surprisingly that endotheliopathy and resultant CAC are more severe in the elderly with preexisting comorbidities [
      • Chen N.
      • Zhou M.
      • Dong X.
      • Qu J.
      • Gong F.
      • Han Y.
      • et al.
      Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study.
      ,
      • Richardson S.
      • Hirsch J.S.
      • Narasimhan M.
      • Crawford J.M.
      • McGinn T.
      • Davidson K.W.
      • et al.
      Presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with COVID-19 in the New York City area.
      ,
      • Williamson E.J.
      • Walker A.J.
      • Bhaskaran K.
      • Bacon S.
      • Bates C.
      • Morton C.E.
      • et al.
      Factors associated with COVID-19-related death using OpenSAFELY.
      ,
      • Yin J.
      • Wang S.
      • Liu Y.
      • Chen J.
      • Li D.
      • Xu T.
      Coronary microvascular dysfunction pathophysiology in COVID-19.
      ,
      • Inciardi R.M.
      • Lupi L.
      • Zaccone G.
      • Italia L.
      • Raffo M.
      • Tomasoni D.
      • et al.
      Cardiac involvement in a patient with coronavirus disease 2019 (COVID-19).
      ]. An interesting question is as whether individuals on anti-platelet or anti-coagulant regimens for other conditions are less vulnerable for more severe COVID-19. Although D-dimer and fibrinogen are recognized to be related to thrombotic risk in COVID-19 early during the pandemic [
      • Thachil J.
      • Tang N.
      • Gando S.
      • Falanga A.
      • Cattaneo M.
      • Levi M.
      • et al.
      ISTH interim guidance on recognition and management of coagulopathy in COVID-19.
      ]. Circulating soluble biomarkers associated with endotheliopathy, including syndecan-1, VWF, selectins P and E, and intercellular adhesion molecule-1 (ICAM-1) have emerged as more clinically relevant biomarkers of CAC, multi-organ failure, and disease severity [
      • Andrianto
      • Al-Farabi M.J.
      • Nugraha R.A.
      • Marsudi B.A.
      • Azmi Y.
      Biomarkers of endothelial dysfunction and outcomes in coronavirus disease 2019 (COVID-19) patients: a systematic review and meta-analysis.
      ,
      • Vassiliou A.G.
      • Keskinidou C.
      • Jahaj E.
      • Gallos P.
      • Dimopoulou I.
      • Kotanidou A.
      • et al.
      ICU admission levels of endothelial biomarkers as predictors of mortality in critically ill COVID-19 patients.
      ,
      • Gorog D.A.
      • Storey R.F.
      • Gurbel P.A.
      • Tantry U.S.
      • Berger J.S.
      • Chan M.Y.
      • et al.
      Current and novel biomarkers of thrombotic risk in COVID-19: a consensus statement from the international COVID-19 thrombosis biomarkers colloquium.
      ,
      • Lampsas S.
      • Tsaplaris P.
      • Pantelidis P.
      • Oikonomou E.
      • Marinos G.
      • Charalambous G.
      • et al.
      The role of endothelial related circulating biomarkers in COVID-19. A systematic review and meta-analysis.
      ]. However, whether these variables can be used for prospective clinical assessments may require further studies [
      • Gorog D.A.
      • Storey R.F.
      • Gurbel P.A.
      • Tantry U.S.
      • Berger J.S.
      • Chan M.Y.
      • et al.
      Current and novel biomarkers of thrombotic risk in COVID-19: a consensus statement from the international COVID-19 thrombosis biomarkers colloquium.
      ].

      4.2 VWF-ADAMTS13 axis in COVID-19-associated endotheliopathy and coagulopathy

      VWF is a large multimeric glycoprotein encoded by the VWF gene on the short arm of chromosome 12, and is synthesized primarily in ECs and megakaryocytes [
      • Haberichter S.L.
      von Willebrand factor propeptide: biology and clinical utility.
      ,
      • Lenting P.J.
      • Christophe O.D.
      • Denis C.V.
      von Willebrand factor biosynthesis, secretion, and clearance: connecting the far ends.
      ]. The architecture of pro-VWF composes four types of domains that are constructed as repeats in the following order: D1-D2-D′-D3-A1-A2-A3-D4-C1-C2-C3-C4-C5-C6-CK. The D1-D2 domains represent VWFpp that is cleaved off by furin, and the D′-CK represents mature VWF monomer. Mature VWF and VWFpp are secreted in equimolar amounts from ECs into plasma [
      • Zhou Y.F.
      • Eng E.T.
      • Zhu J.
      • Lu C.
      • Walz T.
      • Springer T.A.
      Sequence and structure relationships within von Willebrand factor.
      ]. Upon synthesis, VWF is either secreted constitutively as smaller multimers (basal secretion), or stored in Weibel-Palade bodies (WPBs) of ECs and α-granules of platelets where multimerization continues [large and ultra-large VWF (ULVWF)] and release occurs upon various pathological stimuli (regulated release) [
      • Lenting P.J.
      • Christophe O.D.
      • Denis C.V.
      von Willebrand factor biosynthesis, secretion, and clearance: connecting the far ends.
      ,
      • Sporn L.A.
      • Marder V.J.
      • Wagner D.D.
      Inducible secretion of large, biologically potent von Willebrand factor multimers.
      ]. The majority of circulating VWF (80–90 %) in blood is derived from ECs, and it is therefore frequently used as a biomarker for endothelial activation or injury [
      • Chen J.
      • Chung D.W.
      Inflammation, von Willebrand factor, and ADAMTS13.
      ,
      • Lenting P.J.
      • Christophe O.D.
      • Denis C.V.
      von Willebrand factor biosynthesis, secretion, and clearance: connecting the far ends.
      ]. Autopsy results reveal that VWF expression was increased in ECs of the lung, heart, and kidney from COVID-19 patients [
      • Won T.
      • Wood M.K.
      • Hughes D.M.
      • Talor M.V.
      • Ma Z.
      • Schneider J.
      • et al.
      Endothelial thrombomodulin downregulation caused by hypoxia contributes to severe infiltration and coagulopathy in COVID-19 patient lungs.
      ]. Babkina et.al [
      • Babkina A.S.
      • Ostrova I.V.
      • Yadgarov M.Y.
      • Kuzovlev A.N.
      • Grechko A.V.
      • Volkov A.V.
      • et al.
      The role of von Willebrand factor in the pathogenesis of pulmonary vascular thrombosis in COVID-19.
      ] found more intensive VWF immunostaining in pulmonary ECs of COVID-19 patients with thrombotic complications than those without thrombotic complications. Moreover, platelet-VWF plug formation was present within the pulmonary microcirculation of patients with COVID-19 [
      • Fox S.E.
      • Akmatbekov A.
      • Harbert J.L.
      • Li G.
      • Quincy Brown J.
      • Vander Heide R.S.
      Pulmonary and cardiac pathology in African American patients with COVID-19: an autopsy series from New Orleans.
      ,
      • Dupont A.
      • Rauch A.
      • Staessens S.
      • Moussa M.
      • Rosa M.
      • Corseaux D.
      • et al.
      Vascular endothelial damage in the pathogenesis of organ injury in severe COVID-19.
      ]. Several studies have reported elevated plasma levels of VWF:Ag in patients with COVID-19 compared with healthy controls, which confirmed a severe inflammatory state and fulminant endotheliopathy [
      • Blasi A.
      • von Meijenfeldt F.A.
      • Adelmeijer J.
      • Calvo A.
      • Ibanez C.
      • Perdomo J.
      • et al.
      In vitro hypercoagulability and ongoing in vivo activation of coagulation and fibrinolysis in COVID-19 patients on anticoagulation.
      ,
      • Cugno M.
      • Meroni P.L.
      • Gualtierotti R.
      • Griffini S.
      • Grovetti E.
      • Torri A.
      • et al.
      Complement activation and endothelial perturbation parallel COVID-19 severity and activity.
      ,
      • Doevelaar A.A.N.
      • Bachmann M.
      • Holzer B.
      • Seibert F.S.
      • Rohn B.J.
      • Bauer F.
      • et al.
      von Willebrand factor multimer formation contributes to immunothrombosis in coronavirus disease 2019.
      ,
      • Francischetti I.M.B.
      • Toomer K.
      • Zhang Y.
      • Jani J.
      • Siddiqui Z.
      • Brotman D.J.
      • et al.
      Upregulation of pulmonary tissue factor, loss of thrombomodulin and immunothrombosis in SARS-CoV-2 infection.
      ,
      • Herr C.
      • Mang S.
      • Mozafari B.
      • Guenther K.
      • Speer T.
      • Seibert M.
      • et al.
      Distinct patterns of blood cytokines beyond a cytokine storm predict mortality in COVID-19.
      ,
      • Lopez-Castaneda S.
      • Garcia-Larragoiti N.
      • Cano-Mendez A.
      • Blancas-Ayala K.
      • Damian-Vazquez G.
      • Perez-Medina A.I.
      • et al.
      Inflammatory and prothrombotic biomarkers associated with the severity of COVID-19 infection.
      ,
      • Marco A.
      • Marco P.
      Von Willebrand factor and ADAMTS13 activity as clinical severity markers in patients with COVID-19.
      ,
      • Pascreau T.
      • Zia-Chahabi S.
      • Zuber B.
      • Tcherakian C.
      • Farfour E.
      • Vasse M.
      ADAMTS 13 deficiency is associated with abnormal distribution of von Willebrand factor multimers in patients with COVID-19.
      ,
      • von Meijenfeldt F.A.
      • Havervall S.
      • Adelmeijer J.
      • Lundstrom A.
      • Rudberg A.S.
      • Magnusson M.
      • et al.
      Prothrombotic changes in patients with COVID-19 are associated with disease severity and mortality.
      ,
      • Taus F.
      • Salvagno G.
      • Cane S.
      • Fava C.
      • Mazzaferri F.
      • Carrara E.
      • et al.
      Platelets promote thromboinflammation in SARS-CoV-2 pneumonia.
      ]. In addition, several studies found increased levels of VWFpp in patients with COVID-19, however, this increase was less pronounced than that of VWF:Ag. They assumed that the decreased ratio of VWFpp to VWF:Ag indicated a diminished clearance of VWF. Although the mechanism is unclear, this may further contribute to the markedly increased VWF:Ag [
      • De Jongh R.
      • Ninivaggi M.
      • Mesotten D.
      • Bai C.
      • Marcus B.
      • Huskens D.
      • et al.
      Vascular activation is a strong predictor of mortality in coronavirus disease 2019 patients on the ICU.
      ,
      • Mancini I.
      • Baronciani L.
      • Artoni A.
      • Colpani P.
      • Biganzoli M.
      • Cozzi G.
      • et al.
      The ADAMTS13-von Willebrand factor axis in COVID-19 patients.
      ,
      • Ward S.E.
      • Curley G.F.
      • Lavin M.
      • Fogarty H.
      • Karampini E.
      • McEvoy N.L.
      • et al.
      Von Willebrand factor propeptide in severe coronavirus disease 2019 (COVID-19): evidence of acute and sustained endothelial cell activation.
      ,
      • Fogarty H.
      • Townsend L.
      • Morrin H.
      • Ahmad A.
      • Comerford C.
      • Karampini E.
      • et al.
      Persistent endotheliopathy in the pathogenesis of long COVID syndrome.
      ]. However, whether the increase in VWF is the result of increased production, WPB exocytosis, or decreased clearance remains to be determined. Here, we indicated that levels of VWF:Ag were higher in patients with poor prognosis, consistent with those of two previous meta-analyses that included 10 studies/996 patients and 7 studies/695 patients, respectively [
      • Andrianto
      • Al-Farabi M.J.
      • Nugraha R.A.
      • Marsudi B.A.
      • Azmi Y.
      Biomarkers of endothelial dysfunction and outcomes in coronavirus disease 2019 (COVID-19) patients: a systematic review and meta-analysis.
      ,
      • Wibowo A.
      • Pranata R.
      • Lim M.A.
      • Akbar M.R.
      • Martha J.W.
      Endotheliopathy marked by high von Willebrand factor (vWF) antigen in COVID-19 is associated with poor outcome: a systematic review and meta-analysis.
      ]. Notably, Ward et al. [
      • Ward S.E.
      • Curley G.F.
      • Lavin M.
      • Fogarty H.
      • Karampini E.
      • McEvoy N.L.
      • et al.
      Von Willebrand factor propeptide in severe coronavirus disease 2019 (COVID-19): evidence of acute and sustained endothelial cell activation.
      ] reported that elevated VWF:Ag was persisted during 3-week ICU stay, suggesting the sustained synthesis and release of VWF. The “post-acute COVID-19 syndrome”, which is defined as having dyspnea, fatigue, sleep disorder, and exercise intolerance following acute COVID-19 resolution, has also been attributed to persistent endotheliopathy [
      • Fogarty H.
      • Townsend L.
      • Morrin H.
      • Ahmad A.
      • Comerford C.
      • Karampini E.
      • et al.
      Persistent endotheliopathy in the pathogenesis of long COVID syndrome.
      ,
      • Alkodaymi M.S.
      • Omrani O.A.
      • Fawzy N.A.
      • Shaar B.A.
      • Almamlouk R.
      • Riaz M.
      • et al.
      Prevalence of post-acute COVID-19 syndrome symptoms at different follow-up periods: a systematic review and meta-analysis.
      ]. Levels of plasma VWF:Ag and VWFpp remained persistently high in some convalescent COVID-19 patients [
      • Fogarty H.
      • Townsend L.
      • Morrin H.
      • Ahmad A.
      • Comerford C.
      • Karampini E.
      • et al.
      Persistent endotheliopathy in the pathogenesis of long COVID syndrome.
      ,
      • von Meijenfeldt F.A.
      • Havervall S.
      • Adelmeijer J.
      • Lundstrom A.
      • Magnusson M.
      • Mackman N.
      • et al.
      Sustained prothrombotic changes in COVID-19 patients 4 months after hospital discharge.
      ], and were correlated with elevated D-dimer levels [
      • Fogarty H.
      • Townsend L.
      • Morrin H.
      • Ahmad A.
      • Comerford C.
      • Karampini E.
      • et al.
      Persistent endotheliopathy in the pathogenesis of long COVID syndrome.
      ]. The mechanisms underlying these persistent endotheliopathy after recovery from COVID-19 remain poorly understood. It is worth noting that ECs of pulmonary small vessels and microvessels express 5–50 times higher concentrations of VWF mRNA than similar sized vessels in the kidney and liver [
      • Yamamoto K.
      • de Waard V.
      • Fearns C.
      • Loskutoff D.J.
      Tissue distribution and regulation of murine von Willebrand factor gene expression in vivo.
      ]. Another interesting observation is that a greater absolute increase in VWF:Ag than FVIII (mainly synthesized in hepatocytes [
      • Wion K.L.
      • Kelly D.
      • Summerfield J.A.
      • Tuddenham E.G.
      • Lawn R.M.
      Distribution of factor VIII mRNA and antigen in human liver and other tissues.
      ]) in COVID-19 patients [
      • Rauch A.
      • Labreuche J.
      • Lassalle F.
      • Goutay J.
      • Caplan M.
      • Charbonnier L.
      • et al.
      Coagulation biomarkers are independent predictors of increased oxygen requirements in COVID-19.
      ,
      • Ward S.E.
      • Curley G.F.
      • Lavin M.
      • Fogarty H.
      • Karampini E.
      • McEvoy N.L.
      • et al.
      Von Willebrand factor propeptide in severe coronavirus disease 2019 (COVID-19): evidence of acute and sustained endothelial cell activation.
      ]. These may highlight the predominantly pulmonary-centric nature of COVID-19 and the critical roles of VWF in the pathophysiology of COVID-19.
      Upon vascular injury, VWF undergo conformational changes that expose the functional A1 domain, which is hidden in a globular structure by forming a complex with the adjacent A2 domain, facilitating 1) binding of platelets to subendothelium under blood flow through its interactions with platelet receptor glycoprotein (GP)Ibα (via A1 domain) and subendothelial collagen (via A3 domain); 2) platelet-platelet interaction (platelet aggregation) by binding to platelet receptor GPIIb/IIIa, thereby inducing hemostatic plug formation (primary haemostasis) [
      • Mojzisch A.
      • Brehm M.A.
      The manifold cellular functions of von Willebrand factor.
      ,
      • Shahidi M.
      Thrombosis and von Willebrand factor.
      ]. VWF also serves as chaperone for FVIII (via D′-D3 domain), 1) protecting FVIII from enzymatic degradation and extending its half-life in blood; more importantly; 2) directing its localization to the site of vascular injury and promoting coagulation cascades (secondary haemostasis) [
      • Mojzisch A.
      • Brehm M.A.
      The manifold cellular functions of von Willebrand factor.
      ,
      • Shahidi M.
      Thrombosis and von Willebrand factor.
      ]. The ULVWF freshly released from activated ECs, either circulating in plasma or locating on endothelial surface, are intrinsically active and hyperadhesive because the functional A1 domain are continuously exposed [
      • Denorme F.
      • Vanhoorelbeke K.
      • De Meyer S.F.
      von Willebrand factor and platelet glycoprotein Ib: a thromboinflammatory axis in stroke.
      ,
      • Xu X.
      • Wang C.
      • Wu Y.
      • Houck K.
      • Hilton T.
      • Zhou A.
      • et al.
      Conformation-dependent blockage of activated VWF improves outcomes of traumatic brain injury in mice.
      ]. Activated VWF and freshly released ULVWF can also mediate leukocyte recruitment to facilitate inflammatory endotheliopathy at the site of injury and elsewhere either directly or indirectly after binding platelets [
      • Petri B.
      • Broermann A.
      • Li H.
      • Khandoga A.G.
      • Zarbock A.
      • Krombach F.
      • et al.
      von Willebrand factor promotes leukocyte extravasation.
      ,
      • Denorme F.
      • Martinod K.
      • Vandenbulcke A.
      • Denis C.V.
      • Lenting P.J.
      • Deckmyn H.
      • et al.
      The von Willebrand factor A1 domain mediates thromboinflammation, aggravating ischemic stroke outcome in mice.
      ]. Consistent with this notion, neutrophil activation and the formation of neutrophil extracellular traps (NETs) have been found to be involved in thromboinflammatory response to COVID-19 [
      • Kinnare N.
      • Hook J.S.
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      Neutrophil extracellular trap formation potential correlates with lung disease severity in COVID-19 patients.
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      Circulating markers of neutrophil extracellular traps are of prognostic value in patients with COVID-19.
      ,
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      Neutrophil extracellular traps infiltrate the lung airway, interstitial, and vascular compartments in severe COVID-19.
      ]. VWF interacts with NETs to provide a scaffold for platelet/leukocyte adhesion thus promoting thrombus formation and inflammation [
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      ,
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      Patients with COVID-19: in the dark-NETs of neutrophils.
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      ,
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      Fibrin to von Willebrand factor ratio in arterial thrombi is associated with plasma levels of inflammatory biomarkers and local abundance of extracellular DNA.
      ]. In addition, Ackermann et.al [
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      Pulmonary vascular endothelialitis, thrombosis, and angiogenesis in COVID-19.
      ] reported an unexpected new vessel growth within lungs of COVID-19 patients through a mechanism of intussusceptive angiogenesis, and speculated that it is because of endothelialitis and thrombosis in the lungs. Similarly, we have recently shown that VWF served as a coupling factor that tethered platelet-derived extracellular vesicles (EVs) to ECs, thus locally concentrating vascular endothelial growth factor (VEGF) for aberrant angiogenesis in patients with left ventricular assist device implantation [
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      Hyperadhesive von Willebrand factor promotes extracellular vesicle-induced angiogenesis: implication for LVAD-induced bleeding.
      ]. We also found that hyperadhesive VWF released during acute traumatic brain injury mediated EVs to active ECs and platelets, thus responsible for consumptive coagulopathy and vascular leakage in the brain and the lung [
      • Xu X.
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      ,
      • Wu Y.
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      von Willebrand factor enhances microvesicle-induced vascular leakage and coagulopathy in mice with traumatic brain injury.
      ]. Increased circulating EVs, containing procoagulant, proinflammatory, and prothrombotic factors in their cargo, have been reported to be predictive biomarkers and likely to enhance immunothrombosis in patients with COVID-19 [
      • Campello E.
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      ,
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      ,
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      ,
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      Extracellular vesicle associated miRNAs regulate signaling pathways involved in COVID-19 pneumonia and the progression to severe acute respiratory corona virus-2 syndrome.
      ,
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      Circulating extracellular vesicles are endowed with enhanced procoagulant activity in SARS-CoV-2 infection.
      ,
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      Dissemination of extreme levels of extracellular vesicles: tissue factor activity in patients with severe COVID-19.
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      Patients with COVID-19 have elevated levels of circulating extracellular vesicle tissue factor activity that is associated with severity and mortality-brief report.
      ]. Hence, VWF tethered EVs (VWF+EVs) may also be involved in COVID-19-associated endotheliopathy and coagulopathy, and a promising diagnostic or prognostic marker.
      A key determinant of VWF functional capacity is that larger VWF size is more active due to more monomeric subunits and higher sensitivity for shear forces [
      • Furlan M.
      Von Willebrand factor: molecular size and functional activity.
      ,
      • Crawley J.T.
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      Unraveling the scissile bond: how ADAMTS13 recognizes and cleaves von Willebrand factor.
      ]. ADAMTS13, mainly synthesized in hepatic stellate cells, is primarily responsible for specifically cleaving the ULVWF (>10,000 kDa; Tyr1605-Met1606 peptide bond within A2 domain) to smaller and less active multimers (<10,000 kDa), thus preventing the spontaneous intravascular platelet aggregation and resultant thromboembolism, as is seen in patients with thrombotic thrombocytopenic purpura (TTP), while maintaining the basic hemostatic activity of VWF [
      • Crawley J.T.
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      ,
      • Fujikawa K.
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      Purification of human von Willebrand factor-cleaving protease and its identification as a new member of the metalloproteinase family.
      ]. Roh et al. [
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      Plasma proteomics of COVID-19-associated cardiovascular complications: implications for pathophysiology and therapeutics.
      ] recently performed a case-control plasma proteomics study, and demonstrated that, of the 4996 protein analytes assessed, ADAMTS13 was the most significantly decreased in severe COVID-19, and displayed the strongest inverse association with myocardial injury. Abnormalities in plasma VWF multimeric pattern have been reported in patients with COVID-19. Several groups reported a relative decreased high molecular weight multimer (HMWM) of VWF in COVID-19 patients [
      • Doevelaar A.A.N.
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      von Willebrand factor multimer formation contributes to immunothrombosis in coronavirus disease 2019.
      ,
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      The ADAMTS13-von Willebrand factor axis in COVID-19 patients.
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      ADAMTS13 regulation of VWF multimer distribution in severe COVID-19.
      ], which could be explained by an early increase in VWF proteolysis by ADAMTS13. This may also be attributable in part to the formation of ULVWF-platelet aggregates and the corresponding VWF and platelet consumption. However, thrombocytopenia is relatively rare in COVID-19 patients [
      • Tang N.
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      Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia.
      ,
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      ]. But other studies of severe COVID-19 have observed evidence of increased HMWM [
      • Philippe A.
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      Circulating Von Willebrand factor and high molecular weight multimers as markers of endothelial injury predict COVID-19 in-hospital mortality.
      ,
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      Low ADAMTS13 activity correlates with increased mortality in COVID-19 patients.
      ]. The differences likely due to the study cohort recruitment, time of sample collection, and the methodologies of VWF multimer distribution [
      • Ward S.E.
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      • Lavin M.
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      • et al.
      ADAMTS13 regulation of VWF multimer distribution in severe COVID-19.
      ]. The exact dynamic changes of VWF multimeric pattern after COVID-19 still need further study. The majority of studies reported normal or mildly to moderately decreased ADAMTS13:Ac levels [
      • Blasi A.
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      In vitro hypercoagulability and ongoing in vivo activation of coagulation and fibrinolysis in COVID-19 patients on anticoagulation.
      ,
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      • Lippi G.
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      ADAMTS13 activity to von Willebrand factor antigen ratio predicts acute kidney injury in patients with COVID-19: evidence of SARS-CoV-2 induced secondary thrombotic microangiopathy.
      ,
      • Marco A.
      • Marco P.
      Von Willebrand factor and ADAMTS13 activity as clinical severity markers in patients with COVID-19.
      ,
      • Martin-Rojas R.M.
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      A mild deficiency of ADAMTS13 is associated with severity in COVID-19: comparison of the coagulation profile in critically and noncritically ill patients.
      ,
      • Sinkovits G.
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      • Gal J.
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      Associations between the von Willebrand factor-ADAMTS13 axis, complement activation, and COVID-19 severity and mortality.
      ,
      • von Meijenfeldt F.A.
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      Prothrombotic changes in patients with COVID-19 are associated with disease severity and mortality.
      ], and a strongly elevated VWF:Ag/ADAMTS13:Ac ratio in patients with COVID-19 when compared to healthy controls, especially in those with worse illness or in non-survivors [
      • Doevelaar A.A.N.
      • Bachmann M.
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      • Bauer F.
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      von Willebrand factor multimer formation contributes to immunothrombosis in coronavirus disease 2019.
      ,
      • Marco A.
      • Marco P.
      Von Willebrand factor and ADAMTS13 activity as clinical severity markers in patients with COVID-19.
      ,
      • Sinkovits G.
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      • Gal J.
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      Associations between the von Willebrand factor-ADAMTS13 axis, complement activation, and COVID-19 severity and mortality.
      ]. We confirmed that lower levels of ADAMTS13:Ac and higher VWF:Ag/ADAMTS13:Ac ratio and VWF:Rco were related to poor clinical outcomes. Several lines of evidence indicated that this is because massive increase of VWF with relative deficiency of ADAMTS13: 1) inflammatory cytokines and/or tissue hypoxia induce massively increased WPB exocytosis of VWF multimers by activating ECs [
      • Montiel V.
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      Oxidative stress-induced endothelial dysfunction and decreased vascular nitric oxide in COVID-19 patients.
      ,
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      Endothelial cells of different organs exhibit heterogeneity in von Willebrand factor expression in response to hypoxia.
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      Hypoxia results in upregulation and de novo activation of von Willebrand factor expression in lung endothelial cells.
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      Effects of inflammatory cytokines on the release and cleavage of the endothelial cell-derived ultralarge von Willebrand factor multimers under flow.
      ]; 2) there is no alteration in ADAMTS13 gene expression after stimulation of liver cells with pro-inflammatory stimuli [
      • Claus R.A.
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      Transcriptional regulation of ADAMTS13.
      ]; 3) there is no intracellular storage pool of ADAMTS13 [
      • Uemura M.
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      Localization of ADAMTS13 to the stellate cells of human liver.
      ]. The latter two suggest AMAMTS13 may not increase as rapidly after COVID-19 as VWF does. Other possible mechanisms contributing this imbalanced VWF-ADAMTS13 axis include: 1) inflammatory (including complement and NET products) [
      • Bernardo A.
      • Ball C.
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      Effects of inflammatory cytokines on the release and cleavage of the endothelial cell-derived ultralarge von Willebrand factor multimers under flow.
      ,
      • Fujimura Y.
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      COVID-19 microthrombosis: unusually large VWF multimers are a platform for activation of the alternative complement pathway under cytokine storm.
      ] and oxidative [
      • Fu X.
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      • Lopez J.A.
      Shear stress-induced unfolding of VWF accelerates oxidation of key methionine residues in the A1A2A3 region.
      ,
      • Chen J.
      • Fu X.
      • Wang Y.
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      • Kulman J.
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      Oxidative modification of von Willebrand factor by neutrophil oxidants inhibits its cleavage by ADAMTS13.
      ] mediators enhance VWF self-association to increase VWF reactivity, make VWF resistant to cleavage, and reduce ADAMTS13 activity in cleaving VWF; 2) reduced ADAMTS13 synthesis because of COVID-19-induced pathologies of the liver [
      • Uemura M.
      • Tatsumi K.
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      Localization of ADAMTS13 to the stellate cells of human liver.
      ,
      • Baiges A.
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      Liver injury and elevated levels of interleukins, Interleukin-2 receptor, and Interleukin-6 predict the severity in patients with COVID-19.
      ]; 3) Considering high-density lipoprotein (HDL) prevents VWF self-association, while low-density lipoprotein (LDL) has the opposite effect [
      • Chen J.
      • Chung D.W.
      Inflammation, von Willebrand factor, and ADAMTS13.
      ]. HDL reduction and LDL elevation observed in patients with COVID-19 may also contribute to the imbalanced VWF-ADAMTS13 axis [
      • Henry B.M.
      • Benoit S.W.
      • de Oliveira M.H.S.
      • Lippi G.
      • Favaloro E.J.
      • Benoit J.L.
      ADAMTS13 activity to von Willebrand factor antigen ratio predicts acute kidney injury in patients with COVID-19: evidence of SARS-CoV-2 induced secondary thrombotic microangiopathy.
      ,
      • Wang G.
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      ].
      Although several case reports showed SARS-CoV-2 infection trigger acute TTP [
      • Beaulieu M.C.
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      ], and therapeutic plasma exchange, a mainstay treatment for TTP, has shown to reduce immunothrombosis while improve respiratory parameters and clinical outcomes in critically ill patients with COVID-19 [
      • Arulkumaran N.
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      • Dhingra G.
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      COVID 19 infection associated with thrombotic thrombocytopenic purpura.
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      • Seibert F.S.
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      Effect of plasma exchange on COVID-19 associated excess of von Willebrand factor and inflammation in critically ill patients.
      ]. CAC do not resemble a classic TTP since there is lack of severe ADAMTS13 deficiency (activity levels <10 %), major thrombocytopenia, or hemolytic anemia [
      • Scully M.
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      • de la Rubia J.
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      ,
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      von Willebrand factor/ADAMTS13 axis and venous thromboembolism in moderate-to-severe COVID-19 patients.
      ,
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      Imbalance of von Willebrand factor and ADAMTS13 axis is rather a biomarker of strong inflammation and endothelial damage than a cause of thrombotic process in critically ill COVID-19 patients.
      ,
      • Mancini I.
      • Baronciani L.
      • Artoni A.
      • Colpani P.
      • Biganzoli M.
      • Cozzi G.
      • et al.
      The ADAMTS13-von Willebrand factor axis in COVID-19 patients.
      ,
      • Marco A.
      • Marco P.
      Von Willebrand factor and ADAMTS13 activity as clinical severity markers in patients with COVID-19.
      ,
      • Sinkovits G.
      • Reti M.
      • Muller V.
      • Ivanyi Z.
      • Gal J.
      • Gopcsa L.
      • et al.
      Associations between the von Willebrand factor-ADAMTS13 axis, complement activation, and COVID-19 severity and mortality.
      ,
      • Sweeney J.M.
      • Barouqa M.
      • Krause G.J.
      • Gonzalez-Lugo J.D.
      • Rahman S.
      • Gil M.R.
      Low ADAMTS13 activity correlates with increased mortality in COVID-19 patients.
      ]. However, the imbalanced VWF-ADAMTS13 axis combined with clinical and pathologic findings of widespread microvascular thrombi in multi-organs may suggest a secondary TMA-like phenomenon [
      • Henry B.M.
      • Benoit S.W.
      • de Oliveira M.H.S.
      • Lippi G.
      • Favaloro E.J.
      • Benoit J.L.
      ADAMTS13 activity to von Willebrand factor antigen ratio predicts acute kidney injury in patients with COVID-19: evidence of SARS-CoV-2 induced secondary thrombotic microangiopathy.
      ], which can also be seen in other forms of TMA (drug, cancer, or hematopoietic stem cell transplant induced TMA [
      • Masias C.
      • Vasu S.
      • Cataland S.R.
      None of the above: thrombotic microangiopathy beyond TTP and HUS.
      ]) and thrombotic disorders (e.g., severe sepsis, malaria, trauma, and preeclampsia) [
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      ,
      • Plautz W.E.
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      Reduced cleavage of von Willebrand factor by ADAMTS13 is associated with microangiopathic acute kidney injury following trauma.
      ,
      • Xu X.
      • Wang C.
      • Wu Y.
      • Houck K.
      • Hilton T.
      • Zhou A.
      • et al.
      Conformation-dependent blockage of activated VWF improves outcomes of traumatic brain injury in mice.
      ,
      • Wu Y.
      • Liu W.
      • Zhou Y.
      • Hilton T.
      • Zhao Z.
      • Liu W.
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      von Willebrand factor enhances microvesicle-induced vascular leakage and coagulopathy in mice with traumatic brain injury.
      ,
      • Peetermans M.
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      Von Willebrand factor and ADAMTS13 impact on the outcome of Staphylococcus aureus sepsis.
      ,
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      The role of ADAMTS-13 in the coagulopathy of sepsis.
      ,
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      ,
      • Chen Y.
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      Association of placenta-derived extracellular vesicles with pre-eclampsia and associated hypercoagulability: a clinical observational study.
      ,
      • Stepanian A.
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      Von Willebrand factor and ADAMTS13: a candidate couple for preeclampsia pathophysiology.
      ,
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      Low ADAMTS13 activity is associated with an increased risk of ischemic stroke.
      ,
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      • et al.
      High VWF, low ADAMTS13, and oral contraceptives increase the risk of ischemic stroke and myocardial infarction in young women.
      ]. Here, we speculate the mechanisms that link VWF-ADAMTS13 axis, endotheliopathy, and CAC: SARS-CoV-2 direct invasion and/or indirect pathophysiologic conditions induce endotheliopathy and subsequent overwhelming ULVWF release. Multiple mechanisms, including pro-inflammatory and oxidative mediator milieu, reduced hepatic ADAMTS13 synthesis due to liver injury, or imbalanced HDL/LDL levels, induce reduced cleavage of ADAMTS13 and dysregulation of VWF proteolysis. This imbalanced VWF-ADAMTS13 axis ultimately trigger immunothrombosis and lead to CAC, first localized to lung, then eventually spreading systematically and leading to multi-organ damage. Further vigorous experimental and prospective clinical studies are warranted to elucidate the exact role of VWF-ADAMTS13 axis in the pathophysiological process of COVID-19 as well as the mechanisms by which it becomes imbalanced. Also, in addition to aforementioned ultima ratio therapy of plasma exchange (remove VWF and replenish ADAMTS13) [
      • Seibert F.S.
      • Blazquez-Navarro A.
      • Holzer B.
      • Doevelaar A.A.N.
      • Nusshag C.
      • Merle U.
      • et al.
      Effect of plasma exchange on COVID-19 associated excess of von Willebrand factor and inflammation in critically ill patients.
      ], strategies that specifically balance VWF-ADAMTS13 axis may have therapeutic effects on COVID-19. A recent study from a cross-sectional cohort of 36 severe COVID-19 patients indicated that incubation of patient plasma samples with recombinant ADAMTS13 resulted in a time- and concentration-dependent reduction in abnormally high VWF activity and VWF multimer size, suggesting a potential therapeutic role in treating COVID-19 [
      • Turecek P.L.
      • Peck R.C.
      • Rangarajan S.
      • Reilly-Stitt C.
      • Laffan M.A.
      • Kazmi R.
      • et al.
      Recombinant ADAMTS13 reduces abnormally up-regulated von Willebrand factor in plasma from patients with severe COVID-19.
      ]. Caplacizumab is a humanized immunoglobulin specifically targeting the VWF A1 domain, blocking its interaction with platelet receptor GPIbα and thereby preventing platelet aggregation. It is the first nanobody drug approved by the US Food and Drug Administration (FDA) to treat adult acquired TTP, which is caused by the development of anti-ADAMTS13 autoantibodies and subsequent accumulation ULVWF [
      • Scully M.
      • Cataland S.R.
      • Peyvandi F.
      • Coppo P.
      • Knobl P.
      • Kremer Hovinga J.A.
      • et al.
      Caplacizumab treatment for acquired thrombotic thrombocytopenic purpura.
      ,
      • Peyvandi F.
      • Cataland S.
      • Scully M.
      • Coppo P.
      • Knoebl P.
      • Kremer Hovinga J.A.
      • et al.
      Caplacizumab prevents refractoriness and mortality in acquired thrombotic thrombocytopenic purpura: integrated analysis.
      ]. We thus propose to consider caplacizumab as a new treatment option. In this regard, anti-VWF A1 aptamers, such as ARC1779 [
      • Cataland S.R.
      • Peyvandi F.
      • Mannucci P.M.
      • Lammle B.
      • Kremer Hovinga J.A.
      • Machin S.J.
      • et al.
      Initial experience from a double-blind, placebo-controlled, clinical outcome study of ARC1779 in patients with thrombotic thrombocytopenic purpura.
      ], TAGX-0004 [
      • Sakai K.
      • Someya T.
      • Harada K.
      • Yagi H.
      • Matsui T.
      • Matsumoto M.
      Novel aptamer to von Willebrand factor A1 domain (TAGX-0004) shows total inhibition of thrombus formation superior to ARC1779 and comparable to caplacizumab.
      ], and BT200 [
      • Zhu S.
      • Gilbert J.C.
      • Hatala P.
      • Harvey W.
      • Liang Z.
      • Gao S.
      • et al.
      The development and characterization of a long acting anti-thrombotic von Willebrand factor (VWF) aptamer.
      ], may also be novel therapies. Similarly, we recently demonstrated that recombinant VWF A2 domain prevented traumatic brain injury-induced coagulopathy by selectively blocking the exposed A1 domain of the hyperadhesive VWF [
      • Xu X.
      • Wang C.
      • Wu Y.
      • Houck K.
      • Hilton T.
      • Zhou A.
      • et al.
      Conformation-dependent blockage of activated VWF improves outcomes of traumatic brain injury in mice.
      ]. We also found that A2 specifically bound activated VWF in the plasma of a TTP patient [
      • Xu X.
      • Wang C.
      • Wu Y.
      • Houck K.
      • Hilton T.
      • Zhou A.
      • et al.
      Conformation-dependent blockage of activated VWF improves outcomes of traumatic brain injury in mice.
      ]. In addition, N-acetylcysteine (NAC) is a FDA-approved pleiotropic drug with anti-oxidant and anti-inflammatory mechanisms, primarily for the treatment of pulmonary diseases. NAC can also reduce VWF multimers and inhibit VWF-dependent platelet aggregation and collagen binding [
      • Chen J.
      • Reheman A.
      • Gushiken F.C.
      • Nolasco L.
      • Fu X.
      • Moake J.L.
      • et al.
      N-acetylcysteine reduces the size and activity of von Willebrand factor in human plasma and mice.
      ]. Many studies have shown that NAC reduced disease severity in the treatment of COVID-19 patients [
      • Izquierdo J.L.
      • Soriano J.B.
      • Gonzalez Y.
      • Lumbreras S.
      • Ancochea J.
      • Echeverry C.
      • et al.
      Use of N-acetylcysteine at high doses as an oral treatment for patients hospitalized with COVID-19.
      ,
      • De Flora S.
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      Rationale for the use of N-acetylcysteine in both prevention and adjuvant therapy of COVID-19.
      ,
      • Di Marco F.
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      Where are we with the use of N-acetylcysteine as a preventive and adjuvant treatment for COVID-19?.
      ]. Of interest, several clinical trials using NAC in COVID-19 have been registered and implemented (e.g., NCT04374461, NCT04419025, and NCT05074121), and these results will clarify its safety and efficacy [
      • Di Marco F.
      • Foti G.
      • Corsico A.G.
      Where are we with the use of N-acetylcysteine as a preventive and adjuvant treatment for COVID-19?.
      ].

      4.3 Limitation

      First, most of the included studies are observational retrospective with small sample size, and the study results are high heterogeneous. Second, there is no standardized method to measure VWF-related variables. These were either in-house assays or from different commercial manufacturers, and thus might lead to different values. Third, the time of sample collection varied and could attribute to different outcome measures. Fourth, due to the lack of individual patient data, multivariable regression analyses could not be performed to adjust for potential confounding influences (e.g., blood type, age, sex, body mass index, diabetes, hypertension, and medication usage) [
      • Thangaraju K.
      • Katneni U.
      • Akpan I.J.
      • Tanaka K.
      • Thomas T.
      • Setua S.
      • et al.
      The impact of age and BMI on the VWF/ADAMTS13 axis and simultaneous thrombin and plasmin generation in hospitalized COVID-19 patients.
      ,
      • Ward S.E.
      • O'Sullivan J.M.
      • O'Donnell J.S.
      The relationship between ABO blood group, von Willebrand factor, and primary hemostasis.
      ]. Despite these limitations, this study represents a large systematic reviews and meta-analysis to investigate the association between changes in VWF-related variables and clinical outcomes in the COVID-19 population.

      5. Conclusion

      Increased plasma levels of VWF:Ag, VWF:Rco, VWF:Ag/ADAMTS13:Ac ratio, and FVIII, and decreased ADAMTS13:Ac are associated with unfavorable outcomes of patients with COVID-19. However, there are currently insufficient data available to recommend VWF-related variables as routine clinical assessments.

      Abbreviations

      ACE2
      angiotensin-converting enzyme 2
      ADAMTS13
      a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13
      ADAMTS13
      Ac: ADAMTS13 activity
      ARDS
      acute respiratory distress syndrome
      COVID-19
      coronavirus disease 2019
      CAC
      COVID-19-associated coagulopathy
      CI
      confidence interval
      DIC
      diffuse intravascular coagulopathy
      EC
      endothelial cell
      EV
      extracellular vesicles
      FDA
      Food and Drug Administration
      FVIII
      factor VIII
      GP
      glycoprotein
      HDL
      high-density lipoprotein
      ICAM-1
      intercellular adhesion molecule-1
      ICU
      intensive care unit
      IL
      interleukin
      LDL
      low-density lipoprotein
      NAC
      N-acetylcysteine
      NETs
      neutrophil extracellular traps
      NOS
      Newcastle-Ottawa Scale
      PT
      prothrombin time
      PRISMA
      Preferred Reporting Items for Systematic Reviews and Meta-Analyses
      PROSPERO
      Prospective Register of Systematic Reviews
      SARS-CoV-2
      severe acute respiratory syndrome coronavirus 2
      SMD
      standardized mean difference
      TMA
      thrombotic microangiopathy
      TTP
      thrombotic thrombocytopenic purpura
      VEGF
      vascular endothelial growth factor
      VWF
      von Willebrand factor
      VWF:Ag
      VWF antigen
      VWF:Rco
      VWF ristocetin cofactor
      VWFpp
      VWF propeptide
      ULVWF
      ultra-large VWF
      WPB
      weibel-palade bodie

      Ethics approval and consent to participate

      Not applicable.

      Consent for publication.

      Not applicable

      Availability of data and materials

      The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

      Funding

      This research was supported by grants from the National Natural Science Foundation of China (grant 82001317 and 82171303 ).

      Authors' contributions

      XX and YF designed the study. YJ, XZ, and XB performed the literature search, assessed the quality of the literature, and extracted the data independently. YF and LL did the statistical analysis. XX, YF, and LL interpreted the results and drafted the manuscript. LJ and XX reviewed and revised the manuscript and supervised the study. All authors read and approved the final manuscript.

      Declaration of competing interest

      The authors declare no competing interest in this work.

      Acknowledgements

      The authors thank the researchers of the included studies in the present meta-analysis, and Professor Jing-fei Dong (Bloodworks Research Institute, 1551 Eastlake Avenue East, Seattle, WA, USA; Division of Hematology, Department of Medicine, University of Washington, School of Medicine, Seattle, WA, USA) for reviewing the manuscript and providing comments.

      Appendix A. Supplementary data

      • Figure S1. Forest plot of the association between VWF:Ag and mortality (A), intensive care unit (ICU) admission (B), or severity (C).

        Figure S2. Forest plot of the association between VWF:Ac and ICU admission (A) or severity (B).

        Figure S3. Forest plot of the association between ADAMTS13:Ac and mortality (A), intensive care unit (ICU) admission (B), or severity (C).

        Figure S4. Forest plot of the association between the ratio of VWF:Ag/ADAMTS13:Ac and mortality (A), ICU admission (B), or severity (C).

        Figure S5. Forest plot of the association between FVIII and mortality (A) or ICU admission (B).

        Figure S6. Funnel plot of the included studies. (A) VWF:Ag; (B) VWF:Rco; (C) ADAMTS13:Ac; (D) VWF:Ag/ADAMTS13:Ac ratio; (E) FVIII.

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