Sex differences in D-dimer and critical illness in patients with COVID-19: A systematic review and meta-analysis

Abstract

Background: Observed sex differences in COVID-19 outcomes suggest that men are more likely to experience critical illness and mortality. Thrombosis is common in severe COVID-19, and D-dimer is a significant marker for COVID-19 severity and mortality. It is unclear whether D-dimer levels differ between men and women, and the effect of D-dimer levels on disease outcomes remains under investigation.

Objectives: We aimed to evaluate the sex difference in the D-dimer level among hospitalized patients with COVID-19 and the effect of sex and D-dimer level on disease outcomes.

Methods: We meta-analyzed articles reporting D-dimer levels in men and women hospitalized for COVID-19, until October 2021, using random effects. Primary outcomes were mortality, critical illness, and thrombotic complications.

Results: In total, 11,682 patients from 10 studies were analyzed (N = 5606 men (55.7%), N = 5176 women (44.3%)). Men had significantly higher odds of experiencing mortality (odds ratios (OR) = 1.41, 95% CI: [1.25, 1.59], P ≤ .001, I² = 0%) and critical illness (OR = 1.76, 95% CI: [1.43, 2.18], P ≤ .001, I² = 61%). The mean D-dimer level was not significantly different between men and women (MD = 0.08, 95% CI: [-0.23, 0.40], P = .61, I² = 52%). In the subgroup analysis, men had significantly higher odds of experiencing critical illness compared with women in both the "higher" (P = .006) and "lower" (P = .001) D-dimer subgroups.

Conclusion: Men have significantly increased odds of experiencing poor COVID-19 outcomes compared with women. No sex difference was found in the D-dimer level between men and women with COVID-19. The diversity in D-dimer reporting impacts data interpretation and requires further attention.

Keywords: COVID-19; D-dimer; critical illness; sex differences; thrombosis.

Figure 1

PRISMA flow chart of the systematic literature search.

Figure 2

Forest plot of (A) difference in odds of critical illness between males and females, (B) difference in odds of mortality between males and females, (C) mean difference in male and female D-dimer concentration (mg/L, FEU). ‘Events’ is the number of males/females that experienced mortality/critical illness. ‘Total’ is the total number of males/females in the study. Blue/green squares represent the OR or MD. Horizontal lines represent the 95% CI of each study. Black diamond represents the overall OR or MD and 95% CI.