Severe, prolonged thrombocytopenia in a patient sensitive to exenatide
Authors: Yazhini Vallatharasu, Yacki Hayashi‐Tanner, Peter J. Polewski, Wayne A. Bottner, Lori J. Rosenstein, Dipesh Uprety, Amir Bista, John P. Farnen, Richard Aster
Journal: American Journal of Hematology (2018)

Drug-induced immune thrombocytopenia (DITP), characterized by an acute, often severe drop in platelet levels following exposure to a sensitizing medication, has a complex pathogenesis, involving multiple mechanisms1 and can be triggered by more than 100 different drugs.1 Here, we report the first case of DITP caused by sensitivity to Exenatide extended-release (ExER, Bydureon BCise), an agonist for the glucagon-like peptide-1 receptor that is administered subcutaneously for management of type 2 diabetes mellitus (T2DM). Most cases of DITP are caused by drug-induced antibodies that bind to platelets only when drug is present.1 Therefore, when the implicated drug is discontinued, platelet levels return to normal within a few days despite the continued presence of antibody. As ExER consists of biodegradable microspheres, however, detectable levels of drug remain in the circulation for up to 10 weeks after the last exposure.2 In the patient described here, this led to persistence of profound thrombocytopenia for almost 2 months, leading to an erroneous diagnosis of autoimmune thrombocytopenia (ITP). A 55-year-old man (Figure 1) presented with acute onset of hemorrhagic bullae in the buccal mucosa and a worsening petechial rash on his lower extremities. He had observed intermittent "red spots" on his extremities and spontaneous, mild bruising several weeks prior to the day of presentation. Past medical history was significant for T2DM inadequately controlled by four oral agents, including dapagliflozin, metformin, glimepiride, sitagliptin and exenatide ER (injectable administered weekly). Exenatide ER and sitagliptin had been started 11 weeks prior to the day of hospital admission. He had received a total of 11 injections of ExER with the last dose being given 1 week prior to admission. Upon hospital admission, a blood count showed WBC 11 370/μL, hemoglobin 16.6 g/dL, and platelets 1000/μL, a marked drop from the last documented platelet count 3 years earlier (165 000/μL). Blood cell morphology, coagulation testing and blood chemistries were normal and testing for HIV, hepatitis B and C, Helicobacter pylori, and Anaplasma was negative. All anti-hyperglycemic agents, including ExER, were discontinued and dexamethasone 40 mg was given daily for 4 days with no effect on the platelet count. IVIg 20 g given daily for 5 days because of a suspicion of ITP was similarly ineffective. Due to continued bleeding complications, including a hemorrhagic renal cyst, a laparoscopic splenectomy was performed on hospital day 10. Spleen pathology was reported normal. Platelets levels improved transiently post-splenectomy but dropped back to pre-splenectomy levels in a few days. At this time, a serum sample obtained the day after admission was found to contain a drug-dependent, platelet-reactive IgG antibody (DDAb) specific for ExER on both initial and confirmatory testing done by the Platelet and Neutrophil Immunology Laboratory, BloodCenter of Wisconsin utilizing a flow cytometric assay that demonstrated significant binding of IgG in patient serum to normal platelets in the presence, but not in the absence of exenatide.3 Controls in which normal serum was similarly tested were repeatedly negative. DDAb testing for sitagliptin, the only other new drug to which the patient had been exposed in the past year, was negative. After 2 weeks, the patient remained severely thrombocytopenic and had epistaxis and upper gastrointestinal bleeding requiring interventional embolization. Additional IVIg infusions, dexamethasone, platelet transfusions, weekly rituximab and romiplostim failed to improve platelet levels. Nuclear liver/spleen scan was negative for accessory spleen. Bone marrow examination identified only moderate megakaryocytic hyperplasia. On hospital day 39, the patient was discharged with a platelet count of 32 000/μL and he was re-started on each of the anti-hyperglycemic agents he had been taking except for ExER. Approximately, 8 weeks after the last dose of ExER, when drug levels would be expected to be less than 5% of the initial value, platelet count was 325 000/μL and has remained normal since that time. Confirming a diagnosis of DITP can be challenging because many different drugs can cause this condition and serologic testing for DDAbs is complex and available only through a few reference laboratories. George et al. describe four criteria to assess the likelihood that thrombocytopenia was caused by drug sensitivity including (i) thrombocytopenia occurred after exposure to drug and resolved after discontinuation, (ii) the culprit drug was the only drug used before the onset of thrombocytopenia or other drugs were resumed after stopping the offending agent, (iii) other causes of thrombocytopenia were ruled out, and (iv) culprit drug challenge led to a recurrence of thrombocytopenia.4 On this basis, the diagnosis of DITP in our patient would be "probable," but not "definite," since re-exposure to ExER was felt to be unjustified. Detection of an IgG antibody that reacted with normal platelets only when exenatide was present, together with recovery of a normal platelet count at about the time exenatide would be expected to be essentially cleared provided convincing evidence that an exenatide-specific antibody was the cause of thrombocytopenia in this case.1, 3, 5 As noted, in DITP platelet recovery usually occurs within 1 week of stopping the implicated medication.1, 5 When the sensitizing drug is cleared mainly by the kidney, however, drug levels and thrombocytopenia, can persist much longer when there is renal insufficiency.6, 7 Although exenatide clearance is largely renal, our patient did not have impaired renal function so prolonged thrombocytopenia cannot be explained on this basis. ExER releases drug slowly into the circulation so that it is cleared with a half time of about 2 weeks.2 In the patient described here, prolonged, severe thrombocytopenia likely resulted from persistence of drug at levels sufficient to permit binding of the patient's DDAb to platelets for more than 6 weeks after discontinuing treatment. ExER differs from other drugs known to cause DITP in being a 39-amino acid peptide of molecular mass about 4300 and it is not possible to say whether it caused thrombocytopenia by one of the mechanisms demonstrated for drugs that have a much lower molecular weight.1 Unfortunately, this patient's DDAb became undetectable at the end of his course, possibly the result of having been consumed by participating in platelet destruction for a lengthy period of time, and this precluded further studies to address this question. Ordinarily, symptomatic thrombocytopenia occurs about 6-8 days after starting a sensitizing drug, the length of time required to initiate antibody production following exposure to a new medication (1, 5). The exact time between first exposure to ExER and the onset of thrombocytopenia in this patient is uncertain because he recalled having intermittent skin lesions that may have represented petechial hemorrhages for 2-3 weeks prior to presentation but it is likely that the lag time between starting drug and onset of thrombocytopenia was at least 2 months, during which time ExER must have been continuously present in the circulation. We have no explanation for why drug sensitization was delayed in this case but from experience with DITP caused by certain other drugs such as rifampin, we can say that a delay of several months is not unprecedented (RH Aster, unpublished observations). This case highlights the importance of considering DITP in the differential diagnosis of patients presenting with acute thrombocytopenia, especially when new medications have been started and/or platelets fail to improve with typical ITP treatments. Unfortunately, despite having considered DITP on the first day of admission, serologic test results did not become available until the patient had several bleeding events and had undergone splenectomy. Experience with this case illustrates the importance of considering DITP in any patient who presents with acute, severe thrombocytopenia of uncertain etiology, even when the timing relative to the first drug exposure is atypical. Nothing to report.