Oxaliplatin-Mediated Autoimmune Thrombocytopenia

Abstract

Drug-induced immune thrombocytopenia (DITP) has been associated with > 100 drugs, including chemotherapeutic agents. Platelet destruction in DITP is caused by immunoglobulins that recognize specific platelet membrane glycoproteins only in the presence of the sensitizing drug.1,2 The diagnosis of DITP is often delayed in patients with cancer who develop thrombocytopenia after the administration of chemotherapeutic agents and is most commonly attributable to myelosuppression by chemotherapy and/or marrow replacement by the tumor. We previously described a case of thrombocytopenia caused by oxaliplatin,3 and in this report, we describe another patient who developed severe thrombocytopenia and bleeding symptoms during treatment of metastatic colon cancer with oxaliplatin. A 57-year-old black woman with stage IV colon cancer was transferred from a local hospital with bleeding from her port in the setting of profound thrombocytopenia. Her past treatments included 6 cycles of systemic 5-fluorouracil (5-FU) and leucovorin per the Mayo Regimen that was subsequently changed to XELOX-B (oxaliplatin; 130 mg/m2 day 1 every 3 weeks, capecitabine 850 mg/m2 orally twice daily × 14 days, bevacizumab 7.5 mg/kg every 3 weeks) because of progressive disease. The patient received her 11 cycles of XELOX-B about 17 hours before the onset of bleeding. The hematologic profile before initiating the eleventh cycle showed the following: white blood cell count: 2.3/mm3 (absolute neutrophil count: 1.8/mm3); hematocrit (HCT): 40%; and platelet count: 89 × 109/L. On presentation, the patient was afebrile and hemodynamically stable. A slow but continuous bleeding was noted at the site of her porta-catheter on the right side of her chest with no local evidence for trauma or infection. Laboratory data demonstrated a platelet count of 17 × 109/L. The patient was transfused with 6 units of platelets and transferred to the university hospital for further management. After transfer, further laboratory work was obtained, which showed platelet count of 27 × 109/L. Disseminated intravascular coagulation (DIC) panel was negative for any abnormality, and HCT dropped to 29%. The patient was observed in the hospital, and her platelet count was checked every 12 hours as shown in Figure 1. Because of concern for oxaliplatin-mediated autoimmune thrombocytopenia, serum was collected on the third day of hospitalization and sent to the Blood Center of Southeastern Wisconsin, Inc. to detect drug-dependent antibodies. Drug-dependent platelet antibodies were detected in patient sera using flow cytometry as previously described.4-6 In brief, normal group O platelets were incubated with test serum in the presence and absence of drug and were washed twice in buffer containing drug at the same concentration as in the primary incubation mixture. Platelet-associated immunoglobulins were then detected by flow cytometry using fluorescein isothiocyanate (FITC)–tagged anti-human immunoglobulin (Ig) G (Fcγ-specific) and phycoerythrin (PE)-tagged anti-human IgM, (Fcμ-specific). Sera from normal, healthy donors and sera containing previously identified quinine-dependent platelet antibodies served as negative and positive controls, respectively. In selected studies, platelets were “coated” with oxaliplatin by incubating washed normal platelets with the drug at various concentrations followed by 5 washes in 1.5-mL volumes of acid citrate dextrose (ACD)/phosphate-buffered saline (PBS)/bovine serum albumin (BSA) to remove unbound drug. A positive reaction was defined as mean platelet fluorescence intensity (MFI) at least twice that of platelets processed identically except for the absence of drug. Reactions of this strength always exceeded