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REVIEW ARTICLE
Year : 2016  |  Volume : 12  |  Issue : 2  |  Page : 509-514

Oxaliplatin-induced acute thrombocytopenia


Department of Medical Oncology, Ankara Numune Training and Research Hospital, Altındağ/Ankara, Turkey

Date of Web Publication25-Jul-2016

Correspondence Address:
Gokmen Umut Erdem
Department of Medical Oncology, Ankara Numune Training and Research Hospital, Altındag-06100, Ankara
Turkey
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.154056

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 > Abstract 


Oxaliplatin (1, 2-diamminocyclohexaneoxalato-platinum) is a novel platin analog, which is widely used in gastrointestinal malignancies. Platinum analogs damage cellular deoxyribonucleic acid (DNA) by leading covalent bifunctional DNA adducts with cellular DNA. Major side effects of oxaliplatin are neurotoxicity (peripheral neuropathy), myelosuppression with moderate thrombocytopenia and gastrointestinal toxicity (diarrhea). Thrombocytopenia might be related to myelosuppression and/or drug-induced immune thrombocytopenia (DIIT). In here, oxaliplatin-induced thrombocytopenia is discussed with review of the literature.

Keywords: Drug-induced immune thrombocytopenia, oxaliplatin, thrombocytopenia


How to cite this article:
Erdem GU, Dogan M, Demirci NS, Zengin N. Oxaliplatin-induced acute thrombocytopenia. J Can Res Ther 2016;12:509-14

How to cite this URL:
Erdem GU, Dogan M, Demirci NS, Zengin N. Oxaliplatin-induced acute thrombocytopenia. J Can Res Ther [serial online] 2016 [cited 2019 Dec 5];12:509-14. Available from: http://www.cancerjournal.net/text.asp?2016/12/2/509/154056




 > Introduction Top


Oxaliplatin is a third-generation platinum analog, which is commonly used in gastrointestinal tract malignancies with 5-fluorouracil (5-FU)-based regimens, like FOLFOX (oxaliplatin: 85 mg/m 2 day 1, Leucovorin (LV): 400 mg/m 2 day 1, 5-FU: 400 mg/m 2 as an intravenous bolus on day 1, followed by 2,400 mg/m 2 on day 1 infused over 46 hours every two weeks). It increases both progression-free and overall survival rates.[1],[2]

Though neurotoxicity (peripheral neuropathy) is the dose-limiting side effect of oxaliplatin, myelosuppression with moderate thrombocytopenia is a prominent side effect with clinical significance.

Urticaria, pruritis, flushing, hypotension, extremity edema and possible facial-laryngeal angioedema might occur as a result of oxaliplatin-induced type 1 hypersensitivity reactions. Oxaliplatin-related hypersensitivity rate was determined as 10% and generally reported after five cycles of oxaliplatin-based chemotherapy.[3],[4] Antibody (IgM and/or IgG)-mediated type II hypersensitivity reactions contribute to cell lysis via activation of complement system and phagocytic cells. These type II reactions lead to thrombocytopenia, hemolytic anemia and/or leucopenia. They generally occur after long-term oxaliplatin usage.[4],[5],[6],[7],[8],[9] However, acute hemolytic anemia might occur just after platinum-based chemotherapy regimens rarely.[6],[10],[11],[12],[13]


 > The Mechanisms of Thrombocytopenia With Oxaliplatin Top


Thrombocytopenia was reported in three-fourth of the patients receiving FOLFOX regimen and generally attributed to the oxaliplatin-related myelosupression.[4],[14] Severe thrombocytopenia rate is 3–4% with oxaliplatin.[15] Sudden onset of isolated severe thrombocytopenia is the major characteristic of oxaliplatin-induced thrombocytopenia.

Myelosupression, splenic sequestration, non-immune microangiopathy and immune-mediated thrombocytopenia are major mechanisms of thrombocytopenia.[16] The most common one is myelosupression. Myelosupression-related thrombocytopenia is frequently accompanied by anemia and neutropenia that generally recover spontaneously. Splenic sequestration leads to thrombocytopenia due to portal hypertension related with sinusoidal damage with a rate of 24%.[17] Splenomegaly and portal hypertension should be documented. Microangiopathy may lead to hemolytic uremic syndrome. The last mechanism is immune-mediated thrombocytopenia (DIIT; drug-induced immune thrombocytopenia). It generally leads to acute isolated thrombocytopenia. Antibodies against specific platelet glycoproteins, such as glycoprotein IIb/IIIa (GPIIb/IIIa) complex proteins are supposed to have role in DIIT.[7],[18] Glycoprotein IIb/IIIa is the most common target for antibody production in oxaliplatin-induced immune thrombocytopenia (OIIT), but GPIb/IX or GPIa/IIa are also reported as potential targets.[18],[19] Hapten-associated antibody response, autoantibody and/or immune complex formation are among suspected mechanisms for OIIT.[7] Recurrent oxaliplatin infusions might lead to immune response in sensitized patients. The patients with DIIT were reported to have high cumulative oxaliplatin doses in the literature.[4]

To our knowledge, around 41 cases with OIIT were reported in PubMed screening with 'oxaliplatin',

'thrombocytopenia','oxaliplatin-induced thrombocytopenia' and 'oxaliplatin immune-mediated thrombocytopenia' keywords in September 2014 [Table 1],[Table 2],[Table 3]. Hemolytic anemia without thrombocytopenia was excluded. We consider that the absolute rate of oxaliplatin-induced acute thrombocytopenia is not so clear since interval hemogram screening in those without any symptoms is not part of daily routine. The patient characteristics of oxaliplatin-induced acute thrombocytopenia are summarized [Table 1],[Table 2],[Table 3]. The patients with documented antibody formation are listed in [Table 1],[7],[8],[9],[18],[19],[20],[21],[22],[23] while the others without documented antibody formation are shown in [Table 2].[15],[24],[25],[26],[27],[28],[29],[30],[31],[32],[33] Acute thrombocytopenia with hemolysis (Evan's syndrome),[10], 14, [34],[35],[36],[37],[38],[39] hemolytic uremic syndrome,[26],[40],[41],[42] and thrombotic thrombocytopenic purpura [43],[44],[45] (TTP) were also defined in some of the patients with oxaliplatin-induced hypersensitivity reactions as listed in [Table 3]. Thrombocytopenia occurred after 24 hours in four cases.[7],[23],[29],[39] Most (60%) of the patients were female with a median age of 60 years. Median chemotherapy cycle for thrombocytopenia was 15 (range = 2-34) and only four patients had thrombocytopenia with less than 10 cycles.[15],[34],[40],[41] In this analysis, female patients with increased oxaliplatin exposure seem to have higher risk.
Table 1: Oxaliplatin-induced immune-mediated thrombocytopenia

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Table 2: Other oxaliplatin-related acute thrombocytopenia reports

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Table 3: Other oxaliplatin-related acute thrombocytopenia reports

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 > Symptoms Top


The patients might present with chills, fever, rash, abdominal and/or back pain, nausea, fatigue, tachycardia and bronchospasm [Table 1],[Table 2],[Table 3]. Most of those with oxaliplatin-induced Evan's syndrome or hemolytic uremic syndrome present with back pain. Thrombocytopenia that leads to bleeding might occur in hours or days.[7],[23],[29],[39] It might mimic severe infection or acute TTP, so other causes should be ruled out.


 > Treatment Top


OIIT is generally a self-limiting process that frequently recovers within weeks with conventional treatment. Only 7% of the cases reported in the literature did not recover.[31],[38],[45] Research on desensitization mechanisms for OIIT is promising. However, drug hypersensitivity is a lifetime process and it might be difficult to keep away from drug re-exposure especially in those who has no more therapeutic choices. Thrombocytopenia recurrence with shorter onset was reported in the patients with OIIT. So, it is not suggested to use oxaliplatin in the patients with a history of OIIT, since it might trigger following thrombocytopenia attacks.[20],[40]

Thrombocytopenia recovery is generally expected after oxaliplatin cessation; however, the patients may need platelet transfusion for symptomatic severe thrombocytopenia. Steroids might be an option since immune-mediated thrombocytopenia is related to antibodies against some structures, like glycoprotein IIb/IIIa complex.[7],[18],[19] It is hypothesized that these antibodies are powered by extended oxaliplatin exposure leading to platelet damage and thrombocytopenia.[5]

Some of the cases summarized below were reported to have chemotherapy, including irinotecan, cetuximab, bevacizumab and 5-FU even after oxaliplatin-related acute thrombocytopenia occurred without any acute thrombocytopenia recurrence. It gives rise to thought of non-cross reaction between oxaliplatin-induced platelet antibodies and other chemotherapeutics.


 > Are We Really Aware of Oxaliplatin-Induced Thrombocytopenia? Top


A 55-year-old male admitted with a history of abdominal pain for a few weeks. He was diagnosed an ulcero-vegetative lesion on splenic flexura and the biopsy revealed adenocarcinoma. He had left hemicolectomy with lymph node dissection. He was given adjuvant FOLFOX for T3N1M0 colon adenocarcinoma. Unresectable liver and lung oligometastasis occurred after 10 months of follow-up in remission. Fortunately, metastasectomy could be applied for this metastasis after FOLFIRI and Bevacizumab. (Bevacizumab 5 mg/kg on day 1 plus irinotecan 180 mg/m 2 on day 1 plus leucovorin 400 mg/m 2 infusion to match duration of irinotecan infusion on day 1 plus 5-FU 400 mg/m 2 IV bolus on day 1, then 1,200 mg/m 2/day for 2 days (total 2,400 mg/m 2 over 46–48 h) continuous infusion; repeat every 2 weeks). However, he had additional liver metastasis besides intra-abdominal and mediastinal lymph node metastasis after 8 months. K-Ras analysis was not wild type and FOLFOX regimen was again preferred with bevacizumab as second-line palliative chemotherapy since he had disease-free survival for 10 months without any treatment-related toxicity, such as neuropathy or others. He had partial remission with FOLFOX and bevacizumab. However, he had epistaxis and gingival bleeding after 10 hours of chemotherapy cessation during the sixth cycle. The pre-treatment platelet level was 190,000/mm 3 whereas it was 5,000/mm 3 after chemotherapy. He needed platelet transfusion for symptomatic severe thrombocytopenia. The platelet level recovered (120,000/mm 3) after 2 days of follow-up. Twenty percent dose reduction for both oxaliplatin and bevacizumab was applied for toxicity. Epistaxis relapsed with severe thrombocytopenia (6,000/mm 3) despite dose reduction during the following cycle. He had thrombocyte transfusion. The platelet level again recovered (105,000/mm 3). Bevacizumab was stopped and bolus dose of 5-FU was 20% reduced during the next FOLFOX cycle. Unfortunately, he had again thrombocytopenia (2,000/mm 3) with gingival bleeding after 5 hours of follow-up. The platelet level recovered. The bone marrow aspiration and biopsy showed no infiltration. The chemotherapy was stopped for symptomatic severe thrombocytopenia despite clinical benefit. He had progression after four months of follow-up. Capecitabine was given for progressive disease and he tolerated it. So, the previous clinical situation was considered as OIIT.

The long-term oxaliplatin exposure with symptomatic acute severe thrombocytopenia just after oxaliplatin infusion was considered as OIIT despite no documentation of anti-platelet antibodies. It relapsed with additional infusions. It was in concordance to the literature with sudden onset and occurrence after repeating infusions. Four patients reported below had thrombocytopenia after 24 hours of exposure [Table 1],[Table 2],[Table 3].[7],[23],[29],[39] Our patient was male and 55 years old although most of the cases in the literature were female with a median age of 60. He had no splenomegaly, portal hypertension, myelosupression, abnormal disseminated intravascular coagulopathy or TTP parameters, which might give rise to thought of other etiologic factors. He had no fragmented erythrocytes/schistocytes on peripheral blood smear. He had also no abnormal LDH, reticulocyte count or BUN/creatinine levels or neurological symptoms excluding TTP/HUS. His Naranjo Probability Score [46] was +11, supporting the diagnosis of adverse drug reaction. So, he was considered as OIIT.


 > Conclusion Top


Both immune and non-immune oxaliplatin-induced thrombocytopenia (OIT) seems to be a significant problem for cancer patients. We consider that OIIT should be kept in mind, especially in those who have acute thrombocytopenia after oxaliplatin exposure. It might be difficult to look for specific antibodies in clinical practice, but the patients should be evaluated completely and other causes of thrombocytopenia should be ruled out. Early awareness of OIIT might save lives with easier interventions like platelet transfusion for symptomatic severe thrombocytopenia as mentioned in our case. Drug cessation is also recommended. Steroids, intravenous γ-globulin and plasma exchange might be also needed in severe symptomatic thrombocytopenia. We should also be alerted about thrombocytopenia after long-term exposure since the median exposure of oxaliplatin was reported as 10 cycles in the literature.

 
 > References Top

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