Does the elevated (thrombosis risk of males relative to females help account for the excess male mortality observed in Covid-19? An observational study

Objectives

We sought to determine whether underlying thrombophilia helps account for excess Covid-19 mortality rates in males relative to females. Specifically, we asked: What is the contribution of thrombophilia to the excess Covid-19 mortality risk among malesã

Design

Cross-sectional observational study.

Setting

Data were sourced from electronic medical records (EMRs) drawn from over 200 US hospital systems.

Participants

16,576 patients hospitalized with Covid-19, aged 40 and above.

Main outcome measures

The primary study outcome was Covid-19 mortality. We measured: 1) the mortality rate of male patients relative to female patients, 2) the rate of thrombotic diagnoses occurring during hospitalization for Covid-19 in male and female patients, and 3) the mortality rate when evidence of thrombosis was present. We used hospital EMR data to determine the rates of a thrombotic diagnosis by sex, and D-dimer levels to help identify undiagnosed thrombosis.

Results

The Covid-19 mortality rate of males was higher than that of females by 16.1%. Males with Covid-19 also had a 25.4% higher rate of receiving a thrombotic diagnosis compared to females with Covid-19. The mortality rate of all patients with a thrombotic diagnosis was 42.4%—a rate over twice that of Covid-19 patients without a thrombotic diagnosis (adjusted OR 2.4 (2.17 to 2.65), p-value < .001). When defining thrombosis as either a documented thrombotic diagnosis or markedly elevated D-dimer levels, over half of the excess mortality in male patients could be explained by thrombophilia.

Conclusions

Our findings suggest the higher Covid-19 mortality rate in males may be significantly accounted for by the increased propensity for thrombophilia among males. This thrombotic tendency is additive to the thrombotic risk associated with Covid-19. Understanding the mechanisms that underlie male thrombophilia may allow for the advancement of effective anticoagulation strategies that reduce Covid-19 mortality.

Strengths and limitations of this study

• To our knowledge, this population study is the first to provide evidence of a sex-based clinical association that may help explain the excess Covid-19 mortality in males compared to females.

• This was an observational study using diagnosis codes and natural language processing (NLP) extractions of detailed electronic health record (EHR) data for 16,576 hospitalized patients with Covid-19.

• We evaluated underlying thrombosis based on both an inpatient thrombotic diagnosis as well as a markedly elevated D-dimer level relative to CRP level.

• A limitation of this study was that a portion of the estimated excess male mortality was based on the analysis of a subset of 3,442 patients that had serial D-dimer and CRP levels measured in the hospital, and that a potential undercount of these patients was possible due to the use of NLP.