Successful Management of Endometriosis,In Vitro Fertilization,Pregnancy,and Postpartum Recovery in a Woman with Glanzmann's Thrombasthenia

Introduction

Glanzmann's thrombasthenia (GT) is an autosomal recessive bleeding disorder first described in 1918. The prevalence of the condition is estimated to be less than 1/1000,000 and it is more frequent in populations with a high degree of consanguinity. The underlying abnormality involves a deficiency or dysfunction of platelet-receptor GPIIIa/IIb, which is essential for platelet aggregation, although the platelet count remains normal. ¹ Successful pregnancies have already been reported in patients who have GT, with good maternal and neonatal outcomes. ² However, recently, there have been new insights into the association of endometriosis and GT.

We report on a patient with GT, complicated by infertility and endometriosis, who had a successful ovarian cystectomy with recombinant-factor VIIa (rFVIIa; NovoSeven,^® Novo Nordisk), used to help control bleeding, followed by a successful pregnancy by in-vitro fertilization (IVF).

Case

A 35-year-old Omani woman presented to the current authors' infertility clinic for evaluation and management. She had been diagnosed with GT since childhood with symptoms of occasional epistaxis, frequent minor nosebleeds, and heavy menstrual periods, for which she was on tranexamic acid. During her infertility workup, it was noted that she had a persistent left-ovarian cyst causing occasional episodes of pain in her abdomen. Magnetic resonance imaging of her pelvis revealed a left-ovarian cyst measuring 6 × 4 cm, suggestive of an endometrioma.

It was decided to remove this cyst surgically, as she was presenting with an acute episode of pain. The hospital's hematology team was involved and recombinant-activated factor VII (rFVIIa) was administered, using 90 μg/kg intravenously (IV), that was started at 30 minutes before surgery, followed by every 2 hours for 6 hours, and then every 6 hours for 24 hours.

The patient underwent laparotomy and ovarian cystectomy along with an intraperitoneal-drain insertion while she was under general anesthesia. In addition to the rFVIIa, this patient received 1 unit of packed red cells, 3 units of platelet transfusion, and 1 g of tranexamic acid every 6 hours. Nonsteroidal anti-inflammatory drugs and intramuscular injections were avoided. She had an uneventful recovery and was discharged on the sixth postoperative day. Histopathology testing confirmed the presence of endometriosis. Postsurgery, she received 3 doses of a gonadotropin-releasing hormone agonist subcutaneously.

Ovulation induction was commenced with intrauterine insemination for a few cycles with no resulting pregnancy. Hence, she was advised to undergo IVF, with a preimplantation diagnosis if possible. This patient was married to her first cousin, with a very strong family history of GT. They shared 3 first cousins and 7 second cousins with the condition. Reproductive genetic counseling was provided for her. Her husband had been was diagnosed as a carrier just after their marriage, but no known mutation was identified. Preimplantation diagnosis was not feasible and the patient underwent an IVF cycle. One hour prior to oocyte retrieval, she received 4 units of random donor platelets (RDP), followed by tranexamic acid (500 mg) and rFVIIa 15 minutes before retrieval. She conceived in this first cycle of IVF.

The pregnancy was uneventful until 34 weeks, when the fetus was diagnosed with symmetrical intrauterine growth restriction (IUGR). At 36 + weeks, this patient had induction of labor in view of the IUGR with oligohydramnios. While in active labor, she received 5 units of single-donor platelets and desmopressin (DDAVP^®) nasal spray. She received 1 g of tranexamic IV at full dilatation.

Results

This patient progressed to spontaneous vaginal delivery of a 2.215-kg baby girl, with a blood loss of 350 mL, and was discharged on the first postnatal day with tranexamic acid treatment for 1 week. Subsequently, she was readmitted with secondary postpartum hemorrhage after 2 weeks. Ultrasound showed that she had hematometra. This was managed conservatively with oral methyl ergometrine and blood products and the patient was discharged in stable condition after 48 hours.

Discussion

Patients with GT are typically diagnosed in infancy or early childhood. They commonly present with epistaxis, easy bruising, gingival bleeding, and heavy menstrual bleeding (HMB). Other rarer presentations might be gastrointestinal bleeding, hematuria, hemarthrosis, and intracranial hemorrhaging. ³

There has been recent interest in the evolving association of endometriosis and GT. Women with HMB are recognized to be at high risk of developing hemorrhagic ovarian cysts. According to a study by Kirtava et al., 30% of patients with von Willebrand's disease had endometriosis, compared to 13% in controls. ⁴ The prevalence of HMB in GT approaches 98%. The most-plausible theory of the pathogenesis of endometriosis in such women appears to be the retrograde menstruation theory by Sampson, ⁵ although there might be other contributing factors.

Alatas and his colleagues reported endometriosis in 2 sisters who were known to have GT. ⁶ One sister underwent laparotomy for a 3.5-cm endometrioma, and received platelet concentrate and whole blood during the surgery. The other sister had a 20 × 15–cm ovarian mass removed, which was confirmed to be endometriosis. In another report, Imperiale et al., from Italy, who reported endometriosis in 3 sisters—2 of them twins—suffering from endometriosis. ⁷ The researchers described the correlation of endometriosis with increased levels of vitronectin. Vitronectin is an adhesion protein that is a cofactor for plasminogen activator inhibitor–1. Patients with deficiency in GPIIIa/IIb have aberrant αVβ3-receptor expression leading to increased levels of vitronectin. This serves as a substrate that enhances both attachment and proliferation of ectopic endometrial cells.

Surgical intervention can be quite risky and life-threatening in patients with GT. Surgery for such patients requires a multidisciplinary approach, with both hematology and anesthesia teams, to achieve a good outcome. Platelet transfusions have been the standard method of prophylaxis for surgical procedures. However, there are risks associated with these transfusions—including anaphylaxis, bloodborne-pathogen transmission, and alloimmunization—leading to refractoriness in the future. Hence, single-donor platelets, which are human leukocyte antigen–matched, are preferred in these patients but availability of such platelets can be a problem. ⁸

rFVIIa has been used very effectively in patients with congenital bleeding disorders to treat nonsurgical bleeding. This product was licensed 2009 in the European Union for patients with GT who have platelet refractoriness owing to antiplatelet antibodies. High-dose rFVIIa binds to the negatively charged phospholipid surfaces of the activated platelets, leading to an enhanced thrombin burst that enhances hemostasis.^8–10 The product also decreases permeability of clots and tightens the fibrin network. According to data from the International Observational Glanzmann Thrombasthenia Registry, rFVIIa was used off-label for surgical and nonsurgical bleeding episodes with equal effectiveness.^11,12 The current patient received 24 hours of NovoSeven, supplemented with platelet transfusion and antifibrinolytics, as she never had antiplatelet antibodies. No thromboembolic complications were observed in this patient. This product can also be used prior to oocyte retrieval to avoid the complication of late intraovarian bleeding.

The possibility of endometriosis should be recognized early in the reproductive life of a patient with GT. Antifibrinolytics play a major role in the control of HMB, decreasing the possibility of endometriosis to a certain extent. Combined pills, such as dienogest (a progestin medication) or the levonorgestrel-releasing intrauterine system (Mirena^®) are options for patients who do not desire fertility.

Conclusion

Although surgical intervention is risky in patients with GT, sometimes, surgery is unavoidable. It can still be undertaken safely with adequate support of blood products, rFVIIa, and antifibrinolytics. The current patient is the one of very few women (she might actually be the first case reported in English-language literature) who was treated successfully with rFVIIa for endometriosis surgery and oocyte retrieval, as well as in her postpartum period.