DISCUSSION:
Treatment of acute blood loss anemia in GT patients has been well-studied in the literature. Platelet transfusion remains the standard therapy for non-surgical episodes of bleeding (epistaxis, gastrointestinal bleeding, etc.) in GT patients. Transfusion of platelets, especially multiple transfusions, is not without risk.
Platelet immunization or refractoriness is a potential risk and is the most concerning life-long complication for GT patients receiving platelet transfusions. Approximately 17% of GT patients receiving leukoreduced platelet transfusions will develop antibodies against HLAs and has been associated with developing alloimmunization to future platelet transfusions. This poses a dilemma as many patients will require multiple transfusions in their life-time, propagating further refractoriness to increasing number of transfusions [4]. Up to 98.2% of GT patients will report clinical symptoms of HMB according to Poon et. al., and thus we cannot rely solely on multiple blood product transfusions for bleeding control. [4, 14]. Due to the rarity of the disease, there is no standardized approach to managing this high prevalence of HMB among adolescents with GT. Thus, we rely on case reports to help guide management.
In our patient’s case, she did not receive a premenarchial Pediatric Gynecology consultation which may have proved useful in preparation for menarche and potentially reduced the morbidity associated with her first menses. She had failed routine hormonal therapy and required a novel approach of leuprolide acetate-induced suppression of the immature HPO axis with concomitant hormonal therapy to regulate her HMB and achieve amenorrhea. The use of leuprolide acetate is not currently FDA-approved for the treatment of HMB in adolescents with bleeding disorders, though its benefits of producing a hypoestrogenic state proved beneficial to our patient’s HMB refractory to hormonal therapy. The mechanism of action of gonadotropin releasing hormone agonist (GNRH-a) involves an initial increase in endogenous estrogen that is then followed by a hypoestrogenic state. In our patient the temporary increase in estrogen was the presumed cause of the thickened endometrial stripe found on ultrasound. Norethindrone was utilized to mitigate any additional bleeding cause by this effect. In the long term use of GNRH-a, caution should be exercised to avoid the additional risk of bone mineral density (BMD) loss with greater than 6 months treatment. The use of norethindrone additionally also provides “add-back” therapy, to prevent the deleterious effect of GnRH-a on BMD [6].
Other methods have been described in the literature to achieve initial cessation of HMB in this patient population ranging from uterotonics such as methylergonovine maleate to uterine packing with tampons [9]. Lu et al found success with the Levonorgestrel-releasing intrauterine system (LNG-IUS) in two 14-year-old patients with a history of HMB since menarche [7]. Due to higher rate of expulsion in women with bleeding disorders, Rimmer et al recommend acute management of HMB prior to placement of the LNG-IUS [8]. Both cases required that the patient achieve lighter periods with hormonal therapy prior to insertion of the LNG-IUS. As was the case with this patient, she was initially a poor candidate for an intrauterine system as she had significant heavy bleeding at the time. After in-depth counseling with the patient and parents, they did not desire to pursue and intrauterine system. In the future, as her bleeding continues to be controlled, the use of the LNG-IUS should be revisited as a reasonable long-term option in the prevention of her HMB.
In the reproductive age woman, treatment of HMB with rFVIIa has been shown to be successful in several case studies. However, in the adolescent patient with HMB, rFVIIa is not sufficient in the treating the underlying mechanism of anovulatory bleeding in the setting of an immature HPO axis[5]. To date, the only curative treatment is allogenic hematopoietic stem cell transplant (HSTC). However, only limited cases have been reported in the literature with varying degrees of success [10]. Due to the complexity of this disease in a high-risk population, we provide a unique case of successful use of GNRH-a with transition to oral hormonal therapy to treat and prevent acute blood loss anemia in an adolescent with GT-related HMB.