Shaping individualized care for women with hemophilia A Free

In this issue of Blood, Guillet et al¹ published the results of a very interesting study, which identified variables that might help clinicians choose the most effective therapeutic approach for women who are hemophilia A carriers. Using data from 361 female carriers from 14 French centers, the authors examined the role of factor 8 (FVIII) gene (F8) variant types and body weight in shaping the response to treatment.¹ These factors have either been overlooked or studied only in small samples in previous studies.

The study shows that the response to desmopressin in this patient group is strongly influenced by F8 variant type and body weight.¹ In fact, females carrying F8 null variants had a notably weaker response to desmopressin compared to those carrying non-null F8 variants including lower FVIII peak, smaller area under the curve, shorter time spent with FVIII levels above 0.8 IU/ml and, consequently, lower percentage of individuals with normalized FVIII activity in plasma.¹ Thus, in the presence of a null F8 mutation, desmopressin may not work as well or as long as in other individuals. Another important and novel finding was the influence of body weight on FVIII response to desmopressin. Patients who weighed heavier showed stronger and longer-lasting responses than those who were lighter (ie, <35 kg), which included children and adolescents because age was strongly correlated to body weight in individuals <18 years.¹ As suggested by the authors, this evidence could be used to reduce desmopressin dose in women who were overweight/obese and belonged to a family with mild hemophilia A (usually caused by F8 non-null mutations), to minimize drug-related side effects.¹ Blood type had no meaningful impact on desmopressin response; this finding challenges previous assumptions but simplifies the decision-making process for clinicians.

“Is hemophilia fe(male)?” This is the title of the advocacy campaign promoted by the European Hemophilia Consortium for the 2025 World Hemophilia Day to raise awareness on care in women and girls with hemophilia.² For decades this group of patients have been neglected and had no or limited access to care, whereas up to 30% of women and girls who carry F8 mutations have low FVIII levels and can bleed like their male peers,³ especially after trauma, surgery, or invasive procedures. Likewise, women and girls who carry F8 mutations, may experience abnormal uterine bleeding, which causes chronic anemia, iron depletion, and fatigue. Desmopressin has been extensively used to correct FVIII levels in women and girls with hemophilia and symptomatic hemophilia carriers,⁴ based on the experiences of males with mild hemophilia A. However, this has been done without properly exploring possible differences in safety and efficacy of the drug in females. It is well known that sex is a basic biological factor driving differences between individuals, however women and girls are often underrepresented in clinical trials, and, as a consequence, sex-specific analyses are often lacking.⁵ Studying drug responses in both sexes helps personalize treatment by improving outcomes and minimizing risks. The study by Guillet et al expands our understanding of the interindividual variability of the FVIII response to desmopressin in women and girls with hemophilia A and represents a substantial leap forward in personalized medicine for this population. In fact, this research has immediate clinical translation: for women and girls with non-null F8 variants and higher body weight, desmopressin may be reliably effective for both minor and certain major procedures, whereas for those with null variants or low body weight, clinicians might consider FVIII concentrates instead. This highlights that genetic testing for F8 variants in hemophilia A is not only important for genetic counseling or to predict inhibitor risk in affected males, it is also useful to predict FVIII response to desmopressin in women and girls with hemophilia A. And where genetic testing is unavailable, body weight and baseline von Willebrand factor (VWF) levels (ie, VWF:Ag > 0.70 IU/mL) can serve as practical predictors of response. This is a step toward more equitable personalized care.

Although the study does not uncover a new biological mechanism, it indirectly supports the idea that endogenous FVIII production and clearance (related to F8 mutation type and VWF levels) are key to FVIII response to desmopressin.

Future studies should aim for prospective, possibly multicenter and international, trials to validate these findings. Bayesian modeling, as suggested by the authors, could be developed into user-friendly clinical tools to individualize desmopressin dosing with minimal blood draws. Moreover, incorporating patients’ surgical outcomes or bleeding scores would correlate pharmacokinetic data with clinical end points, making the case even stronger for genotype-guided treatment.

Conflict-of-interest disclosure: The author declares no competing financial interests.