Heparin-induced thrombocytopenia is associated with a high risk of mortality in critical COVID-19 patients receiving heparin-involved treatment

  1. Xuan Liu
  2. Xiaopeng Zhang
  3. Yongjiu Xiao
  4. Ting Gao
  5. Guangfei Wang
  6. Zhongyi Wang
  7. Zhang Zhang
  8. Yong Hu
  9. Qincai Dong
  10. Songtao Zhao
  11. Li Yu
  12. Shuwei Zhang
  13. Hongzhen Li
  14. Kaitong Li
  15. Wei Chen
  16. Xiuwu Bian
  17. Qing Mao
  18. Cheng Cao

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Abstract

Background

Coronavirus infectious disease 2019 (COVID-19) has developed into a global pandemic. It is essential to investigate the clinical characteristics of COVID-19 and uncover potential risk factors for severe disease to reduce the overall mortality rate of COVID-19.

Methods

Sixty-one critical COVID-19 patients admitted to the intensive care unit (ICU) and 93 severe non-ICU patients at Huoshenshan Hospital (Wuhan, China) were included in this study. Medical records, including demographic, platelet counts, heparin-involved treatments, heparin-induced thrombocytopenia-(HIT) related laboratory tests, and fatal outcomes of COVID-19 patients were analyzed and compared between survivors and nonsurvivors.

Findings

Sixty-one critical COVID-19 patients treated in ICU included 15 survivors and 46 nonsurvivors. Forty-one percent of them (25/61) had severe thrombocytopenia, with a platelet count (PLT) less than 50×10 9 /L, of whom 76% (19/25) had a platelet decrease of >50% compared to baseline; 96% of these patients (24/25) had a fatal outcome. Among the 46 nonsurvivors, 52·2% (24/46) had severe thrombocytopenia, compared to 6·7% (1/15) among survivors. Moreover, continuous renal replacement therapy (CRRT) could induce a significant decrease in PLT in 81·3% of critical CRRT patients (13/16), resulting in a fatal outcome. In addition, a high level of anti-heparin-PF4 antibodies, a marker of HIT, was observed in most ICU patients. Surprisingly, HIT occurred not only in patients with heparin exposure, such as CRRT, but also in heparin-naïve patients, suggesting that spontaneous HIT may occur in COVID-19.

Interpretation

Anti-heparin-PF4 antibodies are induced in critical COVID-19 patients, resulting in a progressive platelet decrease. Exposure to a high dose of heparin may trigger further severe thrombocytopenia with a fatal outcome. An alternative anticoagulant other than heparin should be used to treat COVID-19 patients in critical condition.

Funding

This investigation was supported by grants 2016CB02400 and 2017YFC1201103 from the National Major Research and Development Program of China.

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  1. ScreenIT

    SciScore for 10.1101/2020.04.23.20076851: (What is this?)

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

    Table 1: Rigor

    Institutional Review Board StatementIRB: This study was approved by the Ethics Committee of Huoshenshan Hospital (Wuhan, China).
    RandomizationAnother 93 patients with severe COVID-19 who had never stayed in the ICU were randomly selected from the hospital (herein and after referred to as non-ICU patients).
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variablenot detected.

    Table 2: Resources

    Antibodies
    SentencesResources
    Anti-heparin-PF4 antibody assay (HIT assay): Human anti-heparin-PF4 complex antibodies (IgG) were detected using an antigen-sandwiched enzyme-linked immunosorbent assay (ELISA) kit produced by Jonln Biological Company (Cat JL12174).
    Anti-heparin-PF4
    suggested: None
    anti-heparin-PF4 complex antibodies (IgG
    suggested: None
    In the assay, the microplate well was coated with anti-C3a antibody (capturing antibody), and the presence of C3a in patient’s serum was quantified with an HRP-conjugated C3a antibody.
    anti-C3a
    suggested: None

    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: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.

    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 10.1101/2020.04.23.20076851v1 on medRxiv