Desmopressin revisited in mild hemophilia A

In this issue of Blood, Kumar et al¹ present the results of a randomized trial comparing the efficacy of induction of endogenous factor VIII (FVIII) by moderate-intensity aerobic exercise with intranasal (IN) DDAVP/desmopressin in adolescents with mild hemophilia A, to determine if the 2 approaches provide the same level of efficacy before more intense sports activity.

For patients with severe and nonsevere hemophilia, improved access to treatment and prophylaxis permits increased engagement in sports while maintaining adequate hemostatic levels of clotting factor activity. Studies have shown that factor levels of at least 20% may be required to prevent joint bleeding.² Thus, mild hemophilia may not be a benign disease after all and may present an increased bleeding risk with intense physical activities. IN desmopressin has been shown to increase levels of endogenous FVIII in nonsevere hemophilia.³ Kumar et al, in 2016, reported the hemostatic benefits of exercise in 13 adolescent males with mild and moderate hemophilia A and demonstrated a 2.3-fold increase in FVIII:C immediately following exercise. The FVIII:C remained elevated at 1.9-fold, 1 hour after exercise.⁴ In the current study, they expanded their observations and measured the changes induced by exercise and IN desmopressin, either independently or in combination. They demonstrated that IN desmopressin alone or in combination with exercise was associated with a sustained increase in FVIII:C compared with exercise alone. If confirmed to be clinically effective, this approach could be an option to prevent bleeding episodes before participation in sports/physical activity in patients with nonsevere hemophilia.

The National Hemophilia Foundation in the United States and the World Federation of Hemophilia have provided information on the risk of bleeding associated with different sports/physical activities. However, there is significant variability in individual physical abilities and joint health that influence the risk of bleeding. There are also differing opinions on what is an adequate protective level.^5,6 A single prospective study that assessed the factor levels and risk of bleeding by Broderick et al found that an FVIII:C of > 50% was associated with less bleeding than that during inactivity with no factor replacement.⁷ In the current study by Kumar et al, 67% (10/15) of participants randomized to receive IN desmopressin with exercise achieved >50% FVIII:C 75 minutes after the interventions that persisted in 60% (9/15) for an additional hour (135 minutes). Even monotherapy with IN desmopressin or exercise alone was associated with normal FVIII:C in 35% (6/17) and 24% (4/17) of participants at 75 and 135 minutes, respectively. Therefore, a trial of IN or intravenous desmopressin with assessment of FVIII:C at 90 or 135 minutes may identify the patients who may benefit from desmopressin stimulation alone, providing patients with a much less burdensome treatment option. Current desmopressin trials in patients with mild hemophilia only recommend assessment of FVIII:C 30 minutes after the administration. Obtaining additional levels at 3 to 4 hours would be more informative for sports participation lasting longer than 60 to 90 minutes.

The benefits of exercise and IN desmopressin may be extended to include women and girls (WG) with hemophilia, most of whom fall into the moderate and mild category. There is a growing understanding of the bleeding phenotype in this group of patients, although research in this population lags far behind that in males with mild hemophilia.⁸ Candy et al reported a lower response to desmopressin in females with mild hemophilia.⁹ It would therefore be important to determine the FVIII:C response to exercise in WG with mild hemophilia. The authors here indicate that they are currently studying the effect of exercise in WG and if successful in increasing the FVIII:C, this would again, provide a noninvasive management option that would be beneficial to promote general health while providing bleed protection.

Several challenges remain in the optimization of care of patients with mild hemophilia. Despite there being significant differences in the disease manifestations, most of the guidelines are derived from research on severe hemophilia. Diagnosis of mild disease is often delayed, as is early recognition of bleeding. Many studies have reported poor joint health in patients with mild hemophilia, usually from poor recognition of bleeds and delays in treatment.¹⁰ With most efforts of the scientific community focused on severe disease, it is encouraging to see research focused on mild hemophilia. It would be beneficial to develop guidelines for the management of patients with mild hemophilia, including WG, to expand research on the pathophysiology of inhibitor development, to develop immune tolerance induction regimens tailored for mild hemophilia patients, and to increase access to new diagnostic and therapeutic agents.