Acquired Glanzmann's thrombasthenia with optimal response to rituximab therapy
Authors: Melhem Solh, Craig Mescher, Anthony Klappa, Surbhi Shah, Nicole Zantek, Yvonne Datta
Journal: American Journal of Hematology (2011)

Acquired Glanzmann's thrombasthenia (GT) involves the development of autoantibodies that bind to platelet glycoprotein (GP) IIB and/or IIIa[1]. This rare acquired hemorrhagic disorder causes a reduction in platelet aggregation with collagen, adenosine diphosphate (ADP), epinephrine (EPI), and arachidonic acid while maintaining normal agglutination with ristocetin and normal coagulation studies. Currently, 21 cases have been reported, typically occurring in patients with lymphoproliferative or autoimmune conditions, and rarely in otherwise healthy individuals [2]. Focusing treatment on the underlying disease typically leads to the resolution of symptoms, although not always. Here, we report a case of acquired GT that had a complete response to rituximab therapy. This is a case of a 52-year-old woman who presented with a 2-year history of increased bruising with minimal trauma and an episode of epistaxis that lasted 3 days and required nasal packing. She had no excessive menstrual bleeding. She had undergone laparoscopic surgery and childbirth with no bleeding complications. There was no family history of excessive bleeding. Her past medical history was significant for hypothyroidism for 8 years controlled on levothyroxine, asthma, and diverticular disease. The physical exam was normal except for scattered ecchymoses. Her initial laboratory values showed a hemoglobin 13.3 mg/dL, white cell count 6.3 × 109/L (normal differential), and platelets 148 × 109/L. These values remained stable throughout her course of treatment. Platelet morphology was normal by light microscopy. Laboratory tests revealed normal activity for factor VIII (114%), ristocetin cofactor activity (112%), and von Willebrand antigen (100%). Prothrombin time (PT)/International normalized ratio (INR), partial thromboplastin time, fibrinogen activity, and thrombin time were normal. Serologic tests for HIV 1 and 2, Hepatitis B, and Hepatitis C were negative. Platelet function analyzer (PFA-100) values were greater than 300 sec for collagen/ADP (normal < 120 sec) and collagen/EPI (normal < 185 sec). Platelet aggregation testing revealed absent of aggregation to ADP (2.5 and 20 μM), EPI (5and 10 μM), collagen (2 μg/mL), arachidonic acid (0.50 mM), and low-dose ristocetin (0.50 mg/mL). Aggregation, followed by disaggregation, was present with intermediate (1.00 mg/mL) and high dose (1.25 mg/mL) of ristocetin (Table I). Based on this bleeding profile, a diagnosis of acquired or congenital GT was suggested. Further testing at the Blood Center of Wisconsin Platelet and Neutrophil Immunology Laboratory included evaluation for platelet autoantibodies and surface GP expression. There was normal binding of GPIb/IX monoclonal antibody to the patient's platelets, and this ruled out a diagnosis of Bernard Soulier syndrome. However, there were discrepant results for GPIIb/IIIa, in which the patient's platelets had normal reactivity to monoclonal antibodies to GPIIIa and GPIIb/IIIa but decreased reactivity to two different monoclonal antibodies against epitopes on GPIIb. Autoantibodies directed at platelet GPs were detected by washing the patient's platelets and preparing an eluate. This eluate was then tested against immobilized normal platelet GPs. The eluate from the patient's platelets was strongly reactive with purified GPIb/IX, GPIa/IIa, and GPIIb/IIIa. The patient's plasma also had antibodies directed against immobilized GPIIb/IIIa but not GPIb/IX and GPIa/IIa. The discrepant results in the GPIIb/IIIa binding assay may have been due to the patient's GPIIb/IIIa autoantibody blocking binding by one of the two monoclonal antibodies used in the assay. Platelet aggregation tests were repeated 3 months later with similar results. A platelet aggregation mixing study demonstrated inhibition of normal donor platelets with the patient's plasma; however, normal donor plasma could not fully restore platelet aggregation of the patient's plasma. These findings along with the absence of lifelong bleeding history were consistent with a diagnosis of acquired GT due to an autoantibody to GPIIb/IIIa. One month after the patient's initial visit, she was started on a trial of pulse dexamethasone (40 mg daily) for 4 days. The results of PFA-100 testing were not markedly changed during 5 days poststeroid therapy; however, after 14 days, the collagen/EPI and collagen/ADP were both normal. Disease relapse occurred 1 month as evidenced by abnormal PFA-100 results. She continued to have problems with bruising, but no major bleeding episodes. Transfusion of one unit of apheresis platelets had no effect on the prolonged PFA-100 results 1 hr after transfusion. The patient continued to do clinically well over the next 10 months with no major bleeding episodes. She then presented with recurrent episodes of diverticulitis and was recommended for surgical resection once her platelet disorder resolved. Rituximab therapy (375 mg/m2) was initiated on a weekly basis. After three doses of rituximab, her PFA-100 normalized to 108 sec with collagen/EPI and 78 sec with collagen/ADP. After the fourth dose, aggregation studies were repeated; these showed normal aggregation to ADP (10μM), EPI (10 μM), collagen (2 μg/mL), arachidonic acid (0.50 mg/mL), and ristocetin (1.00 and 1.25 mg/mL; Table I). Six months after the fourth dose of rituximab, the PFA-100 remained normal, and the patient did not have any further bleeding symptoms. Acquired GT is characterized by decreased or absent aggregation of platelets in the presence of an adequate number of GPIIb/IIIa receptors. This is likely due to autoantibodies generated secondary to various conditions such as non-Hodgkin's lymphoma, hairy cell leukemia, multiple myeloma, Castleman's disease, myelodysplastic syndrome, and iatrogenic immunosuppression for transplantation [3-5]. Patients with acquired GT usually do not have a history of bleeding diathesis early in life. When bleeding episodes start, they are characterized by severe bleeding at mucosal sites, such as epistaxis, gum bleeding, and bruising, as well as life-threatening hemorrhages secondary to menorrhagia and gastrointestinal losses. On laboratory evaluation, platelet count is usually within a normal range. Formal platelet aggregation testing reveals absent aggregation to ADP, EPI, arachidonic acid, and collagen but preserved aggregation to ristocetin [6]. Although the number of GPIIb/IIIa receptors may be normal to low normal on western blot analysis, elevated platelet associated IgM can be noted on flow cytometric analysis [2]. Treatment for acquired GT has included platelet transfusions, intravenous immunoglobulin [7], systemic steroids [8], splenectomy [9], and plasmapheresis [10]. Recently, anecdotal case reports of use of recombinant factor VIIa have been documented [11]. If the underlying process is a hematological malignancy, treatment of the underlying disease with chemotherapy has been associated with marked improvement in control of bleeding [5]. Another case report describing the use of rituximab in a cardiac transplant patient with acquired GT has proposed the use of this novel approach to treatment in such patients [12]. The use of rituximab in the treatment of refractory immune thrombocytopenic purpura (ITP) is well described in the literature with a sustained platelet response in the range of 25–35% of patients [13-15]. Rituximab has also been shown to improve response rates in untreated patients with ITP. In a study of 103 adult ITP patients, addition of rituximab to steroid therapy improved the sustained response rate (platelet count > 50 × 109/L for 6 months) from 36 to 63% (P = 0.04) [16]. In the above case report, our patient was unique in the sense that she did not have any underlying overt autoimmune disorder, hematological malignancy, or immunosuppressed state as described previously in literature; however, her clinical presentation along with the laboratory parameters was supportive of a diagnosis of acquired GT. She had a short-lived response to dexamethasone, but her platelet aggregation studies were abnormal 1 month later. Because of recurrent and progressive diverticulitis and her poor response to steroids, she was at a higher risk of perioperative mortality secondary to bleeding. She was successfully treated with rituximab, which supports the use of this agent as a possible treatment option for management of refractory cases. Unfortunately, rituximab use would not have optimal response in emergency situations, because platelet studies did not normalize until after the third weekly dose of rituximab. However, if used pre-emptively, this agent could prevent life-threatening bleeding catastrophes. Melhem Solh*, Craig Mescher*, Anthony Klappa*, Surbhi Shah*, Nicole Zantek , Yvonne Datta*, * Division of Hematology, Oncology, and Transplantation University of Minnesota, Minneapolis, Minnesota, Department of Laboratory Medicine and Pathology University of Minnesota, Minneapolis, Minnesota.