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.