Evidence for secondary thrombotic microangiopathy in COVID-19

  1. Joseph M. Sweeney
  2. Mohammad Barouqa
  3. Gregory J. Krause
  4. Jesus D. Gonzalez-Lugo
  5. Shafia Rahman
  6. Morayma Reyes Gil

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Abstract

The causes of coagulopathy associated with COVID-19 disease are poorly understood. We aimed to investigate the relationship between markers of endothelial activation, intravascular hemolysis, coagulation, and organ damage in COVID-19 patients and study their association with disease severity and mortality. We conducted a retrospective study of 181 hospitalized COVID-19 patients randomly selected with equal distribution of survivors and non-survivors. Patients who died had significantly lower ADAMTS13 activity, significantly higher LDH, schistocytes and von Willebrand Factor levels compared to patients discharged alive. Only 30% of patients with an initial ADAMTS13 activity <43% survived vs. 60% with ADAMTS13 ≥43% who survived. In conclusion, COVID-19 may manifest as a TMA-like illness in a subset of hospitalized patients. Presence of schistocytes on admission may warrant a work-up for TMA. These findings indicate the need for future investigation to study the relationship between endothelial and coagulation activation and the efficacy of TMA treatments in COVID-19.

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  1. ScreenIT

    SciScore for 10.1101/2020.10.20.20215608: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    Institutional Review Board Statementnot detected.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variablenot detected.

    Table 2: Resources

    Antibodies
    SentencesResources
    Anti-rabbit IgG-alkaline phosphatase-conjugated antibody (Sigma A8025) was applied as the secondary antibody for 45 minutes at a concentration of 1.5 µg/mL diluted in 1.2% BSA.
    Anti-rabbit IgG-alkaline phosphatase-conjugated antibody
    suggested: None
    Anti-rabbit IgG-alkaline
    suggested: None
    ADAMTS13 Antibody Detection: The presence of human IgG autoantibodies against ADAMTS13 was determined using Technozym® ADAMTS-13 Inhibitor ELISA (cat# 5450451).
    ADAMTS13
    suggested: None
    Software and Algorithms
    SentencesResources
    The measure function in ImageJ was used to measure the raw integrated density of each size of the multimers.
    ImageJ
    suggested: (ImageJ, RRID:SCR_003070)

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:
    Like any other retrospective studies, limitations include intrinsic confounders and bias. Choosing samples from a limited repository bank could create bias. We tried to compensate by randomly selecting a balanced cohort with equal distribution of survivors and non-survivors and similar demographics. We could only demonstrate correlations but no causality. Major confounders include: a wide spectrum of disease severity at presentation, and over imposed sepsis. Thus, we cannot exclude the possibility that low ADAMTS13 is simple a passive biomarker and an indirect consequence of disease severity. Therefore, prospective randomized clinical studies are needed to determine the relationship and causality between ADAMTS13 levels, complement, endothelial, and coagulation activation and to study the efficacy of TMA treatments in treating COVID-19. In summary, we present the most comprehensive and largest study to date analyzing correlations of D-Dimer levels with VWF activity/antigen, size of VWF multimers, ADAMTS13 levels, markers of intravascular hemolysis and smear pathology in hospitalized COVID-19 patients. Low ADAMTS13 and increased schistocytes on admission correlated with mortality. Thus, in addition to D-Dimer, presence of schistocytes on admission may warrant a work up for TMA, including ADAMTS13 levels, since this group may require different/additional therapy.

    Results from TrialIdentifier: No clinical trial numbers were referenced.

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • No protocol registration statement was detected.

    About SciScore

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  2. Version published to 10.1101/2020.10.20.20215608v1 on medRxiv