Oxaliplatin is a third-generation platinum derivative that has been widely used in patients with gastrointestinal malignancies including colorectal cancer (CRC). The combination of 5-fluorouracil, leucovorin and oxaliplatin (FOLFOX) has been demonstrated in several studies to increase survival rate and reduce the risk of disease progression in patients with metastatic CRC and stage III colon cancer [1, 2]. Thrombocytopenia has been noted in more than 70% of patients receiving FOLFOX., and is usually self-limited and related to myelosuppression from oxaliplatin [2]. The isolated and acute decline in platelets after FOLFOX treatment is thought to be immune-mediated, and is referred as drug-induced immune thrombocytopenia (DIIT). Oxaliplatin-dependent antibody against platelet glycoprotein IIb/IIIa complex has been identified in patients with oxaliplatin-induced immune thrombocytopenia [3].

The hypersensitivity reaction associated with oxaliplatin typically consists of rigors, fever, rash, tachycardia, and dyspnea. The incidence in patients with CRC was reported as high as 15% and mainly occurred shortly after infusion in patients who had prior exposure to oxaliplatin [4, 5]. The mild hypersensitivity reaction (grade 1 or 2) usually responds to discontinuation of oxaliplatin and supportive treatment with antihistamine agents and steroid. Frequently, patients with mild hypersensitivity reaction can be re-treated with oxaliplatin by adding appropriate pre-medications such as antihistamine agents and steroid, and increasing infusion time with more diluted concentration [5, 6]. Severe and potentially fatal hypersensitivity reaction with symptomatic bronchospasm, angioedema, hypotension and anaphylaxis, occurred in about 2% of patients receiving oxaliplatin treatment [7, 8]. Although the manufacturer recommends not to re-treat with oxaliplatin after the incidence of severe hypersensitivity reaction, a desensitization protocol has been successfully implemented in patients with grade 3 hypersensitivity [9].

Here, we describe two cases of acute thrombocytopenia with concurrent oxaliplatin-induced hypersensitivity reaction in patients with metastatic CRC. Both patients had prior oxaliplatin treatment without occurrence of hypersensitivity, or acute thrombocytopenia and received oxaliplatin several years later due to disease progression with non-responsiveness to other chemotherapeutic regimens.

We describe two cases of immune-mediated thrombocytopenia immediately following the onset of the hypersensitivity reaction in patients with metastatic CRC receiving oxaliplatin treatment. To our knowledge, this is the first report demonstrating the association between de novo oxaliplatin-induced hypersensitivity reaction and immune-mediated thrombocytopenia from oxaliplatin. Both patients received FOLFOX chemotherapy several years prior without hypersensitivity symptoms or evidence of acute thrombocytopenia. However, both patients experienced hypersensitivity reaction on retreatment with oxaliplatin. In both cases, acute thrombocytopenia transpired immediately after the occurrence of hypersensitivity symptoms. Our first patient developed severe thrombocytopenia with mucocutaneous bleeding after completing the rest of oxaliplatin treatment, and was hospitalized for platelet transfusion and close observation. For our second patient, a Jehovah's Witness, oxaliplatin infusion was not resumed after the occurrence of hypersensitivity reaction with moderate thrombocytopenia. Both patients had oxaliplatin appended to their drug allergy list to prevent re-exposure.

In order to verify that the isolated, precipitous drop in platelet counts was due to oxaliplatin, serum samples from our two patients were collected and sent for drug-induced platelet antibody analyses to the BloodCenter of Wisconsin (Milwaukee, WI). Detection of oxaliplatin-dependent antibodies in patients' sera was performed via flow cytometry [3]. Normal group O platelets were incubated with test serum in the presence and absence of oxaliplatin and were washed twice in buffer containing oxaliplatin at the same concentration as in the primary incubation mixture. Platelet-associated immunoglobulins were then detected by flow cytometry using fluorescein isothiocyanate-tagged anti-human IgG (Fcg-specific) and phycoerythrin-tagged anti-human IgM (Fcm-specific). Sera from normal, healthy donors, and sera containing previously identified quinine-dependent platelet antibodies served as negative and positive controls, respectively. A positive reaction was defined as a mean platelet fluorescence intensity at least twice that of platelets processed identically except for the absence of oxaliplatin. As shown in Fig. 4, patients' sera were incubated with normal group O platelets in the absence and presence of oxaliplatin. Both patients were confirmed to have oxaliplatin-dependent IgG platelet antibodies. In patient 1, a weak non-drug-dependent antibody was also present, and the significance of which is uncertain.

Drug-induced immune-mediated thrombocytopenia (DIIT) is diagnosed by demonstrating an antibody in the patient's serum that reacts with normal platelets in the presence of soluble drug [10]. Fewer than 10 chemotherapeutic agents have been shown to cause DIIT [3]. In patients receiving chemotherapy, thrombocytopenia is usually due to myelosuppression; however, acute thrombocytopenia of unknown cause should prompt suspicion for this entity. For DIIT, discontinuation of the offending drug is the most important treatment. Platelet transfusion is frequently needed when severe thrombocytopenia occurs with consequent mucocutaneous bleeding as in Patient 1. Whether corticosteroids are helpful is uncertain. Both our patients developed DIIT despite receiving dexamethasone as part of antiemetic regimen prior to oxaliplatin treatment.

Immune-mediated thrombocytopenia has been recognized as a rare adverse outcome of oxaliplatin infusion and has been identified in approximately 7% of allergic-type reactions to oxaliplatin in a retrospective analysis [11]. We have summarized all published case reports related to oxaliplatin-induced acute thrombocytopenia in table S1 (see additional file 1) [3, 12–14] and table S2 (see additional file 2) [15–25], with table S2 reflecting reports without documentation of oxaliplatin-induced platelet antibodies. Each patient received prior oxaliplatin treatment, and all except one had metastatic CRC. Affected patients were predominately female. As shown in table S2 (additional file 2), acute thrombocytopenia with hemolysis (Evan's syndrome) has also been described in patients with hypersensitivity reaction from oxaliplatin. Furthermore, most patients with Evan's syndrome or hemolytic uremic syndrome likely from multiple exposures to oxaliplatin, presented with back pain during oxaliplatin infusion.

Taleghani et al. described oxaliplatin-induced immune pancytopenia four hours after the 15^th oxaliplatin treatment in a patient with advanced CRC [12]. They identified oxaliplatin-dependent antibodies to platelets, red blood cells and neutrophils. The patient developed significant pancytopenia upon re-treatment with oxaliplatin 30 minutes after infusion, with inception of hypersensitivity reaction. Curtis et al. reported two patients with metastatic CRC who developed acute thrombocytopenia one to two days after repeated (more than 10 times) oxaliplatin treatment [3]. Oxaliplatin-dependent antibodies specific for the platelet glycoprotein IIb/IIIa complex were identified in both patients' sera. As summarized in table S1 (additional file 1), primarily female patients were more likely to develop immune-mediated thrombocytopenia after repeated oxaliplatin treatment. Recovery from thrombocytopenia was observed in all cases after discontinuation of oxaliplatin. The majority of patients received platelet transfusion.

Moreover, as shown in tables S1 and S2 (additional files 1 and 2), some patients had received other chemotherapeutic agents such as irinotecan, cetuximab, bevacizumab and 5-FU after recovery from oxaliplatin-induced acute thrombocytopenia, and none of them had recurrent acute thrombocytopenia. This observation indicates that oxaliplatin-induced platelet antibodies do not cross-react with other chemotherapeutic agents. In our report, patient 1 resumed treatment three months later with 5-FU and LV, with later addition of bevacizumab. Patient 2 received bevacizumab and 5-FU, with addition of irinotecan. Neither patient experienced recurrent hypersensitivity reaction or recurrent episode of acute thrombocytopenia. Bozec et al. reported a case of a 53-year-old male with metastatic CRC, previously treated with FOLFOX, who presented with irinotecan-induced immune thrombocytopenia 18 hours after the onset of hypersensitivity reaction during the first irinotecan treatment [26]. The patient experienced another episode of hypersensitivity reaction followed by acute thrombocytopenia during the second irinotecan infusion. IgG platelet antibody in the presence of irinotecan was identified in the serum. Since the patient developed immune thrombocytopenia during the first irinotecan infusion, the authors speculated that this patient's drug-dependent platelet antibody could have been prompted by the previously administered chemotherapeutic agent which appeared to possess the ability to cross-react with irinotecan. It is likely that oxaliplatin might have been the culprit in their case; however, analysis for the presence of oxaliplatin-dependent platelet antibody was not performed to support this hypothesis.

Our report highlights the importance of promptly recognizing the association between oxaliplatin-induced hypersensitivity reaction and immune-mediated thrombocytopenia. Female patients with advanced CRC and prior oxaliplatin exposure are more likely to develop this consequence, although it may also occur in male patients. Therefore, it is imperative that patients should be thoroughly examined for signs and symptoms of bleeding, with concurrent CBC evaluation even after recovery from the hypersensitivity symptoms. Heightened vigilance and prompt testing may be helpful in recognizing development of antibody in patients with religious objections to transfusion before the onset of severe thrombocytopenia. Patients usually respond to discontinuation of oxaliplatin, with concurrent platelet transfusion if indicated. Additional tests such as peripheral blood smear examination and direct antiglobulin test are also helpful in assessing Evan's syndrome or hemolytic-uremic syndrome if worsening anemia or hemolysis is noted. Patients with documented oxaliplatin-induced acute thrombocytopenia should not be re-challenged with oxaliplatin and should have oxaliplatin listed as a drug allergy.

Written informed consent was obtained from each patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.