Background: D-dimer is generally considered positive above 0.5 mg/L irrespective of gender. However, women have been shown to be more likely to have a positive D-dimer after controlling for other factors. Thus, differences may exist between males and females for using D-dimer as a marker of venous thromboembolism (VTE). We hypothesized the accuracy of D-dimer tests may be enhanced by using appropriate cut-off values that reflect gender-related differences in D-dimer levels.
Methods: This research is a secondary analysis of a multi-center, international, prospective, observational study of adult (18+ years) patients suspected of VTE, with low-to-intermediate pre-test probability based on Wells criteria ≤ 6 for PE and ≤ 2 for DVT. VTE diagnoses were based on computed tomography, ventilation perfusion scanning or venous ultrasound. D-dimer levels were tested for statistical difference across groups stratified by gender and diagnosis. Multivariable regression was used to investigate sex as a predictor of diagnosis. Gender-specific optimal D-dimer thresholds for PE and DVT were calculated from ROC analyses. A Youden threshold (D-dimer level coinciding with the maximum of sensitivity plus specificity) and a cut-off corresponding to 95%-sensitivity was calculated. Statistical difference for cut-offs was tested from 2000 bootstrapped samples.
Results: We enrolled 3856 subjects, 61% were female, 63% were white, 27% Black/African American, and 6% Hispanic. 6% in the PE cohort were diagnosed with PE. In the DVT cohort, 11% were diagnosed with DVT. D-dimer levels were significantly higher in males for PE negative, PE positive, and DVT negative groups. Regression models show male gender as a significant positive predictor of DVT diagnosis, controlling for D-dimer levels. The Youden threshold for PE patients were 0.97 mg/L (95%CI 0.64-1.79) and 1.45 (95%CI 1.36-1.95) for females and males, respectively; 95%-sensitivity cut-offs for this group were 0.64 (95%CI 0.2-0.89) and 0.55 (95%CI 0.29-1.61). For DVT, the Youden thresholds were 0.80 mg/L (95%CI 0.84-1.56) for females and 1.25 (95%CI 0.65-3.33) for males and 95%-sensitivity cut-offs were 0.33 (95%CI 0.2-0.61) and 0.32 (95%CI 0.18-0.7), respectively.
Conclusion: Differences in D-dimer between males and females are diagnosis specific, however cut-off values for excluding PE and DVT were not significantly different.