EXPERIMENTAL AND CLINICAL TRANSPLANTATION

Glanzmann thrombasthenia is an inherited auto-somal recessive disorder characterized by normal platelet count but lack of platelet aggregation due to absence of platelet glycoprotein IIb/IIIa. The disease usually is associated with mild bleeding, but severe fatal hemorrhage may occur. Allogeneic stem cell transplant is the only curative method of treatment. A literature search showed 18 previously reported cases of Glanzmann thrombasthenia treated with allogeneic hematopoietic stem cell transplant. We report an 18-year-old woman with severe Glanzmann thrombasthenia who was treated with allogeneic hematopoietic stem cell transplant from her sister. After 24-month follow-up, the patient was well, had no bleeding tendency, and had mild chronic skin graft-versus-host disease.

Key words : Graft-versus-host disease, Transplant, Inherited, Glanzmann

Glanzmann thrombasthenia is a rare inherited autosomal recessive disorder characterized by normal platelet count but lack of platelet aggregation due to absence of platelet glycoprotein IIb/IIIa. The clinical course of the disease usually can be mild but sometimes, may be severe and may be characterized by repeated life-threatening hemorrhage, with severity varying between patients.¹ The clinical course may be unpredictable.²

Therapy is based on supportive care including hemostatic procedures, antifibrinolytic agents, desmo-pressin for minor hemorrhage, and transfusion with packed red blood cells or platelet concentrates for major hemorrhage.^3-5 The main complication of platelet concentrate transfusion is the occurrence of alloimmunization against human leukocyte antigens (HLAs) and the glycoprotein IIb/IIIa complex. In this condition, patients become refractory to platelet transfusions and have a poor prognosis.

Allogeneic hematopoietic stem cell transplant for severe Glanzmann thrombasthenia was initially reported in 1985.⁶ Since then, hematopoietic stem cell transplant has been reported sporadically.^7-11 A literature search showed 18 cases of Glanzmann thrombasthenia treated with allogeneic hematopoietic stem cell transplant.¹²

We report an 18-year-old woman who presented with severe, repeated bleeding. She was treated successfully with allogeneic hematopoietic stem cell transplant in our center from her HLA-matched sister. At 2-year posttransplant follow-up, the patient was well, asymptomatic, and had mild chronic skin graft-versus-host disease (GVHD).

An 18-year-old woman was diagnosed at age 1 year, after gum bleeding, with Glanzmann thrombasthenia. She was referred to our center due to refractory bleeding and frequent hospitalization because of bleeding. She had a history of gastrointestinal bleeding at age 11 years that required blood transfusion for the first time. Since then, she had frequent epistaxis leading to severe anemia and requiring blood and platelet transfusion. During the past several years, she continued to need frequent platelet and blood transfusions, and recently required recombinant factor VII to stop severe and uncontrolled bleeding events. Her bleeding became frequent, and she required many hospitalizations during the preceding 6 months. She received > 100 platelet and 30 red blood cell transfusion bags during this time. She became refractory to platelets due to alloimmunization before transplant.

She had an HLA-matched healthy sister, and an allogeneic stem cell transplant from her sister was the best treatment option (Table 1). The conditioning chemotherapy regimen was busulfan-based myelo-ablative conditioning including 16 mg/kg busulfan in 4 days and 120 mg/kg cyclophosphamide in 3 days. Prophylaxis against GVHD included cyclosporine and short-term methotrexate. The patient received 4.2 ×10⁸/kg body weight nonmanipulated peripheral blood mononuclear cells (5.8 ×10⁶/kg CD34+ cells). The patient was treated in a room that had a high-efficiency particulate air filter, and she remained isolated in the room until engraftment.

Prophylactic antibiotics, antifungal drugs, and an antiviral agent (acyclovir) were administered during the neutropenic period. For prevention of damage to ovaries during conditioning chemotherapy, we used prophylactic gonadotropin-releasing hormone agonist injection subcutaneously before and after transplant. After transplant, the patient received granulocyte-colony stimulating factor 5 μg/kg/d until her absolute neutrophil count was > 0.5 ×10⁹/L for 3 consecutive days. All blood products, including packed red blood cells and platelets, were irradiated with gamma rays to prevent posttransfusion GVHD. Granulocyte engraftment (absolute neutrophil count > 500/mm³ for 2 consecutive days) was achieved by posttransplant day 11, and platelet engraftment (> 20 × 10⁹/L) was achieved on posttransplant day 23. On posttransplant day 12, the patient developed symptoms of skin GVHD grade 2. Severe hemorrhagic cystitis occurred 23 days after transplant that was treated with vigorous hydration, diuretics, conjugated estrogen, recombinant factor VII, platelet transfusion, and bladder irrigation.

She was discharged on posttransplant day 44. At 5 months after transplant, chronic GVHD was diagnosed in the patient. The patient had mild elevation of liver enzymes and extensive oral lichenlike lesions that improved with corticosteroids and mycophenolate mofetil. At 24 months after hematopoietic stem cell transplant, the patient was well and had mild to moderate skin GVHD.

We reported this patient with Glanzmann throm-basthenia from Iran who underwent hematopoietic stem cell transplant. This is the first case report of Glanzmann thrombasthenia treated with transplant reported from Iran, to our knowledge, and this patient was older than previously reported patients.

Hematopoietic stem cell transplant is a rapidly developing treatment, and use has expanded during the past 3 decades. It is considered the treatment of choice for many patients who have severe malignant or nonmalignant, acquired, or congenital disorders of the hematopoietic system. Recently, with improved hematopoietic stem cell transplant methods, there is more consideration for transplant in nonmalignant disease. In our center, we have long-term experience in transplant of inherited nonmalignant hematologic dis-orders with > 250 transplants for thalassemia, Fanconi anemia, and other congenital diseases during the past 20 years,^13-15 but this is the first experience with trans-plant for Glanzmann thrombasthenia at our center.

The role of hematopoietic stem cell transplant in Glanzmann thrombasthenia is controversial. However, allogeneic hematopoietic stem cell transplant is the only curative treatment for Glanzmann throm-basthenia. Because of the benign nature of disease, and the risks and complications associated with hematopoietic stem cell transplant, there has been controversy about the indications and benefits of transplant for these patients. A literature search showed only 19 successful hematopoietic stem cell transplants in 18 previously reported patients.¹² The most recent cases were reported in 2011.¹²

Our case was an 18-year-old woman and was older than previously reported cases except for 1 patient. The mean age in the 18 reported cases with transplant was 5 years. Most cases received sibling bone marrow transplant with busulfan and cyclophosphamide myeloablative conditioning. We used the peripheral blood of a fully HLA-matched donor. Reduced conditioning is less toxic and was used for stem cell transplant for children with peripheral blood cells from an unrelated donor.⁷ The incidence of GVHD was within usual range in that report, and our patient developed mild acute and extensive chronic GVHD that responded and was controlled with our treatment.

Data from the literature suggests that hema-topoietic stem cell transplant from a full HLA-matched sibling is a good option in patients with severe, persistent, and life-threatening hemorrhage, and may improve long-term quality of life. There is no prospective randomized clinical trial available to answer the question about treatment between transplant or other methods. Our experience showed that allogeneic hematopoietic stem cell transplant is a potentially curative option for severe Glanzmann thrombasthenia associated with severe bleeding, even in an adult patient, but careful evaluation of risks and benefits for individual cases is mandatory.

Volume: 14 Issue: 6 December 2016

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