Differences in sex-specific presentations of autosomal inherited bleeding disorders

March 2021 Clinical practice Tobias Rawson

Historically, clinical studies have primarily focused on haemophilia A and B. However, other autosomal inherited bleeding disorders exist, such as von Willebrand disease (VWD), rare bleeding disorders (RBDs) and congenital platelet defects (CPDs). Given the nature of inheritance, these diseases should affect both men and women at equal rates, although discrepancies in gender-specific distribution have been reported. Furthermore, there is increasing awareness of the difference of clinical presentation between men and women, given the unique physiological haemostatic challenge for women, as well as menstruation. In an attempt to clarify this, a study recently published in The Lancet has investigated the sex-specific differences in phenotype, diagnosis and management with autosomal inherited bleeding disorders. The study used patients from the Willebrand in Netherlands (WiN) study (N=834), the Rare Bleeding Disorders in Netherlands (RBiN) study (N= 263) and the thrombocytopathy in the Netherlands (TiN) study (N= 62). Enrolled patients were required to fill out a questionnaire related to their condition and give blood samples for coagulation testing.

Statistical difference in diagnostic delay between men and women

In total, 1092 patients were enrolled into this study, with 60.9% of patients being female. Of the 1014 patients for which a referral reason was known, the most common reason was a positive family history (50.3%), followed by personal referral due to bleeding (43.5%). A further 6.2% were referred due to an abnormal coagulation screen (prolonged prothrombin time [PT], activated partial thromboplastin time [APTT]). Women were more often referred because of bleeding symptoms, compared to men (47.9% vs. 36.6%, P= 0.002). However, men were more frequently referred due to a positive family history. For the 399 patients of this study that had a severe bleeding disorder (defined as type 2 and type 3 VWD, RBDs with factor activity below 0.10 IU/mL, Glanzmann thrombasthenia and Bernard Soulier Syndrome), there was no significant difference in the rate of referral, between men and women (48.1% vs. 51.9%, P= 0.215), respectively. Interestingly, there was a numerical difference in the age of first bleeding, with men reporting their first bleed-event earlier at 8.9 ± 13.6 year, whilst women on average started later in life 10.6 ± 11.3 years in women (p = 0.075). There was however, a statistical difference in the age of diagnosis with men being diagnosed earlier than women (16.6 ± 19.6 vs. 22.5 ± 18.4, P <0.001). This translated into a diagnostic delay, which was statistically longer for women compared to men (11.6 ± 16.4 years vs 7.7 ± 16.6 years, P = 0.002).  This difference persisted after adjustment for type of disease and bleeding score, minus sex-specific bleeding with a difference of β=3.6 (1.1; 6.1) years. Finally, for women aged 12 or older, 77.1% had received treatment because of sex-specific bleeding. Bleeding score (BS), which gives an indication of the severity of bleeding over a patient’s life time, was lower in men when compared to women (9.7 ± 6.9 vs. 11.6 ± 7.2, P <0.001), although BS score was higher for men than women after exclusion of sex-specific bleeding (9.6 ± 6.8 vs 8.8 ± 6.0, P = 0.036).

Conclusion

This study demonstrated for women with autosomal inherited bleeding disorders are more often reffered for bleeding abnormalities, despite having a longer diagnostic delay. Furthermore, women require sex-specific management for bleeding for frequently than men.

Reference:

Atiq F et al., Major differences in clinical presentation, diagnosis and management of men and women with autosomal inherited bleeding disorders. E Clinical Medicine. 2021; 32(100726).

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