Methylprednisolone‐induced immune thrombocytopenia
Authors: Marie Dubert, Emilie Le Toriellec, Laure Croisille, Laure Thomas, Michel Ducreux, Antoine Froissart, Raoul Herbrecht, Bénédicte Lebrun‐Vignes, Jean‐Pierre Marolleau, Jean‐Baptiste Méric, Matthieu Mahevas, Marc Michel, Philippe Bierling
Journal: American Journal of Hematology (2019)

Drug-induced immune thrombocytopenia (DITP) is a rare but severe drug side effect caused by antibodies that bind platelets only in the presence of a drug. Drug-dependent antibodies (DDabs) usually target platelet-specific glycoproteins (Gp), such as GpIIb/IIIa or GpIb/IX.1, 2 About a 100 different drugs have been linked to DITP.3 Immune severe thrombocytopenia occurs quickly after the administration of the drug, following an extended period of well-tolerated drug administration, and resolves within 1 to 10 days after drug withdrawal. We describe six patients who experienced severe thrombocytopenia due to methylprednisolone (MP) DITP. We retrospectively analyzed the medical records of six patients for whom blood samples were sent to the Platelet Immunology Laboratory of the EFS (Henri Mondor Hospital, Creteil, France) for suspected MP-induced thrombocytopenia. Anti-platelet antibodies were searched with the monoclonal antibody-specific immobilization of platelet antigen (MAIPA) assay (ApDia, Turnhout, Belgium),4 in the presence and absence of the drug (see supplemental data). Sera were tested against immobilized GpIIb/IIIa, GpIb/IX and GpIa/IIa. No anti-platelets antibodies were detected in the 6 patient's serum in the absence of drugs, when DDabs targeting GpIIb/IIIa were identified in the presence of drugs (see below). No DDAbs directed against GpIb/IX or GpIa/IIa were detected in presence or absence of drugs (Table 1). The three first patients were treated with MP, one for a multiple sclerosis (yet reported5) and two for premedication for chemotherapy (FOLFOX$) for the treatment of cancer. They all presented acute and severe thrombocytopenia immediately after administration of MP, that resolved in 6 to 48 hours. For all, the readministration of the MP link to recurrence of thrombocytopenia that did not reappear after the eviction of MP. One of them (patient number 2) needed to be transferred to the intensive care unit because of massive hematuria. Serum samples from the patients were tested with several suspected drugs, and only GpIIb/IIIa DDAbs in the presence of MP were detected (Table S1). The fourth patient was a 64-year-old man with colorectal cancer previously treated from 2003 to 2010, with intermittent FOLFOX chemotherapy without complication. From June 2010 to August 2012, he presented eight episodes of acute thrombocytopenia. Six were attributed to one drug (MP (n = 3), oxaliplatin (n = 2) or leucovorin (n = 1)) and two were attributed to oxaliplatin and/or either MP or leucovorin. A blood sample collected following the first episode of DITP contains GpIIb/IIIa-specific DDabs in the presence of MP and oxaliplatin (Table S2). Unfortunately, no blood sample collected at the moment of leucovirin DITP was available to search leucovirin DDAbs. The fifth patient was a 75-year-old man with cystadenocarcinoma treated with intermittent fortnightly infusions of fluorouracil (FU), leucovorin and oxaliplatin with premedication based on MP and ondansetron (FOLFOX) without complication from 2014 to 2017. From July 2017 to November 2017, he presented seven episodes of acute thrombocytopenia that resolved spontaneously in less than a week after drug withdrawal. Four episodes occurred after MP (one with oxaliplatin), and three after leucovorin administration (one with oxaliplatin). Blood samples contained GpIIb/IIIa DDabs in the presence of MP and leucovorin (Table S3). One serum was adsorbed into platelets in the presence of MP and leucovorin separately. Both eluates and adsorbed serum were then tested by MAIPA in the presence or absence of the drugs. Only antibodies specific for the drug used in the adsorption procedure were detected in the eluates, indicating the presence of different DDabs rather than a single antibody cross-reacting with multiple drugs (Table S4). The sixth patient was a 49-year-old woman with colon cancer diagnosed in January 2010 and treated with 26 cycles of FOLFOX without complication. The first episode of DITP occurred in February 2011, after the administration of oxaliplatin following premedication with MP and ondansetron. Oxaliplatin was then replaced with irinotecan with MP as premedication, but the patient's platelet count fell again (1 × 109 G/L) after the first administration. Eight other episodes of DITP occurred between June 2011 and October 2015. Each administration of oxaliplatin resulted in thrombocytopenia. The other DITPs appeared after the administration of either MP or leucovorin. However some treatments with MP (2012) or leucovorin (2015) had no effect on platelet count. Blood samples from March 2011 and November 2011 contained GpIIb/IIIa-specific DDabs in the presence of MP, oxaliplatin and leucovorin (Table S5). Finally, sera of six other patients receiving FOLFOX with MP premedication but without thrombocytopenia were tested as controls. No DDAbs in the presence of MP, dexamethasone (DXM), oxaliplatin, ondansetron or leucovorin were found. Then, our series contained six patients presenting DITP due to MP. All patients had anti-GpIIb/IIIa DDabs only highlighted in the presence of MP, and these antibodies did not cross-react with DXM. Three patients also presented DITP linked to leucovorin and/or oxaliplatin, with different and specific DDabs detected in the presence of these drugs. Five of the six patients were treated with platinum-based chemotherapy for gastrointestinal or urinary tract cancer, and all had a prolonged event-free period of prior exposure to MP. All patients experienced immunoallergy-like symptoms (chills and/or fever) during the drug administration, that lead to severe thrombocytopenia. In all episodes, platelet count recovered spontaneously within a few days after drug withdrawal. In five of the six patients (the exception being patient six), the episodes of sudden thrombocytopenia and the presence of DDabs were perfectly correlated, providing evidence for the specificity of the reaction. Oxaliplatin-induced DITP have been widely described6 and considered as often responsible for DITP and other autoimmune cytopenia in cancer. Curtis et al. reported two patients treated for cancer with platinum-based chemotherapy with premedication based on DXM (more widely used than MP in USA) that presented oxaliplatin associated DDabs.7 However since DXM, leucovorin and irinotecan DDabs were also detected, both cases could also be attributed to DXM induced DITP. Furthermore only four of our patients had been treated with oxaliplatin before the first episode of DITP, and only two of these patients presented DDabs in the presence of oxaliplatin. We described the first serie of DITP related to MP. Physicians should be aware that in patients with cancer, drugs other than oxaliplatin, such as MP may induce DITP, sometimes with the simultaneous production of multiple DDabs. Addendum: during the writing of this article, a seventh case of MP-induced thrombocytopenia was referred to our laboratory, with DDAbs associated with MP, oxaliplatin and leucovorin. Dr Camille Jung, Dr Isabelle Cojean-Zelek and Dr Sandrine Lacour, Dr Hassina Mimoune, Dr Nouara Arab. None of the authors declared conflict of interest. M.D. designed research, monitored the database, analyzed data, and wrote the manuscript, E.LT. perfomed biological analysis, and contributed to the writing of the manuscript, L.C. supervised biological analysis, analyzed data and contributed to the writing of the manuscript, L.T. analyzed the data and contributed to the writing of the manuscript, M.D. included a patient and approved the manuscript, A.F. included a patient and approved the manuscript, R.H. included a patient and approved the manuscript, B.LV. included a patient and approved the manuscript, J.P.M. included a patient and approved the manuscript, J.B.M included a patient and approved the manuscript, M.M. verified and analyzed the data, contributed to the writing of the manuscript, M.M. verified and analyzed the data and contributed to the writing of the manuscript, P.B. designed research, verified and analyzed the data, supervised biological analysis and the writing of the manuscript. Table S1 Medical history of the first three patients described above Table S2: Chronology of multiple drug administrations and DITP episodes (patient #4) Table S3: Chronology of multiple drug administrations and DITP episodes (patient #5) Table S4: Adsorption-elution analysis in patient #5 Table S5: Chronology of multiple drug administrations and DITP episodes (patient #6) Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.