Contribution of the elevated thrombosis risk of males to the excess male mortality observed in COVID-19: an observational study

  1. Kenneth Roy Cohen
  2. David Anderson
  3. Sheng Ren
  4. David J Cook

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Abstract

The mortality rate of COVID-19 is elevated in males compared with females.

Objective

Determine the extent that the elevated thrombotic risk in males relative to females contributes to excess COVID-19 mortality in males.

Design

Observational study.

Setting

Data sourced from electronic medical records from over 200 US hospital systems.

Participants

60 877 patients aged 18 years and older hospitalised with COVID-19.

Exposure

Exposure variable: biological sex; key variable of interest: thrombosis.

Primary outcome measures

Primary outcome was COVID-19 mortality. We measured: (1) mortality rate of males relative to females, (2) rate of thrombotic diagnoses occurring during hospitalisation for COVID-19 in both sexes and (3) mortality rate when evidence of thrombosis was present.

Results

The COVID-19 mortality rate of males was 29.9% higher than that of females. Males had a 35.8% higher rate of receiving a thrombotic diagnosis compared with females. The mortality rate of all patients with a thrombotic diagnosis was 40.0%—over twice that of patients with COVID-19 without a thrombotic diagnosis (adjusted OR 2.50 (2.37 to 2.64), p<0.001). When defining thrombosis as either a documented thrombotic diagnosis or a D-dimer level ≥3.0 µg/mL, 16.4% of the excess mortality in male patients could be explained by increased thrombotic risk.

Conclusions

Our findings suggest the higher COVID-19 mortality rate in males may be significantly accounted for by the elevated risk of thrombosis among males. Understanding the mechanisms that underlie increased male thrombotic risk may allow for the advancement of effective anticoagulation strategies that reduce COVID-19 mortality in males.

Article activity feed

  1. Version published to 10.1136/bmjopen-2021-051624
  2. Version published to 10.21203/rs.3.rs-1097336/v1 on Research Square
  3. ScreenIT

    SciScore for 10.1101/2021.05.04.21256001: (What is this?)

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

    Table 1: Rigor

    Ethicsnot detected.
    Sex as a biological variableFor each of the groups, we compared the male and female incidence of receiving a thrombosis diagnosis code while hospitalized for Covid-19.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.

    Table 2: Resources

    No key resources detected.

    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:
    Strengths and weaknesses in relation to other studies: To our knowledge, this is the first study to specifically address the significantly elevated risk of thrombosis and its associated excess mortality in males with Covid-19 relative to females. Although mortality as a function of sex was not specifically addressed in the meta-analysis of the 42 studies noted in the introduction,5 that study also documented that thrombosis contributes to excess mortality in COVID-19. Moreover, among those 42 studies, 29 documented the sex of the patients. Of those 29 studies, 27 (93%) documented a higher percentage of thromboembolism in males relative to females. Of all cases of thromboembolism across those 29 studies, 70% occurred in males and 30% occurred in females. Studies of prophylactic treatment for thrombosis among Covid-19 patients also suggest that greater attention to thrombosis risk may be warranted. A recent systematic review and pooled analysis of 35 studies looked at anticoagulation strategies in 4,685 hospitalized patients with Covid-19.19 This review showed standard prophylactic doses of anticoagulation were associated with significant reductions in venous thromboembolism and arterial thrombosis events, with intermediate and therapeutic doses of anticoagulation providing no additional benefit. Data from these studies did not allow for an analysis of dose intensity by sex. Unanswered questions and future research: Because the known genetic risks for thrombophilia (factor V Le...

    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.
    • Thank you for including a protocol registration statement.

    Results from scite Reference Check: We found no unreliable references.

    About SciScore

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  4. Version published to 10.1101/2021.05.04.21256001 on medRxiv