This case showed that RT recipients could develop ITP after CMV infection and, in such cases, TPO-RAs may be an attractive option as a second-line therapy.
Patients with ITP often present with unpredictable bleeding events. Additionally, severe mucosal bleeding could occur, causing epistaxis, gastrointestinal bleeding, haematuria, and, rarely, intracranial haemorrhage. However, even patients may develop severe thrombocytopenia but do not exhibit bleeding beyond bruising and petechiae [1].
Mortality in adults with ITP is 1.3-2 times higher than that in the general population due to cardiac disease, infection, and bleeding[11]. There is no gold standard for the diagnosis of ITP, which is diagnosed by excluding other causes of thrombocytopenia. ITP typically manifests with isolated thrombocytopenia. Further examination is recommended in the presence of cytopenia in other cell lineages [1]. The incidence of H. pylori-associated ITP is higher in Japan than in other countries[2]. Thrombocytopenia after RT is developed in up to 30% of RT recipients and often accompanied by cytopenia in other cell lineages. Thrombocytopenia is often observed in the first year after RT and has a wide variety of causes, including blood disorders (such as haemophagocytic syndrome and thrombotic microangiopathy), viral infections (such as CMV and EBV), immunosuppressants (such as MMF and mTOR inhibitors), and antiviral agents (such as GCV and VGCV) [12]. mTOR inhibitor-induced thrombocytopenia often occurs simultaneously with leukopenia, and usually resolves spontaneously [13]. In our case, thrombocytopenia was isolated, and conversion from EVR to low-dose MMF did not lead to complete recovery from thrombocytopenia. VGVC was discontinued after CMV antigenaemia turned negative. However, VGVC discontinuation did not resolve the thrombocytopenia. No EBV was detected in his blood, and his serum tested positive for H. pylori IgG antibody. The patient was finally diagnosed with ITP.
There have been several case reports on CMV-associated thrombocytopenia [3–8] and two common hypotheses regarding its pathogenesis [2][8][14]. The first hypothesis is that direct CMV infection of megakaryocytes induces thrombocytopenia, which develops with acute CMV infection (CMV-induced thrombocytopenia). In this case, treatment of CMV infection, including intravenous GCV, may be more effective in increasing platelet counts compared with treatment of thrombocytopenia, including corticosteroids [2][8]. On the other hand, the second hypothesis postulating that thrombocytopenia is developed by antiviral antibodies cross-reacting with platelets, is based on molecular mimicry (CMV-related ITP) [2][8][14]. In cases of suspected CMV-related ITP, treatment of the CMV infection may not always be necessary [8]. Considering that (1) there was a period of approximately 1 month between the initiation of treatment for primary CMV infection and the development of thrombocytopenia, (2) treatment of CMV infection alone did not improve his platelet count, and (3) IPF was elevated, we speculate that one of the mechanisms of thrombocytopenia in this case is the production of anti-platelet autoantibodies associated with molecular mimicry (CMV-related ITP).
In the treatment of ITP, corticosteroids (PSL, 0.5-2.0 mg/kg/day or dexamethasone, 40 mg/day for 4 days) are recommended as first-line therapy, if a platelet count is below 3.0 × 104 /µL and patient is asymptomatic or has minor mucocutaneous bleeding. Eradication therapy is recommended for H. pylori-associated ITP. Second-line therapeutic options include TPO-RAs (eltrombopag or romiplostim), rituximab, and splenectomy [1]. TPO-RAs bind to TPO receptors expressed on megakaryocytes and haematopoietic stem cells, promoting the differentiation and proliferation of megakaryocytes, leading to increased platelet counts [15]. Due to this mechanism of action, TPO-RA is the only non-immunosuppressive therapy among the three options. In our case, PSL and H. pylori eradication were partially effective. However, second-line therapy was required to taper off the PSL dose. Since the patient was an RT recipient and administered immunosuppressive therapy, we opted for TPO-RAs.
Our case has a limitation for diagnosis of ITP due to lack of bone marrow examination findings (it is not essential to diagnosis), but this diagnosis is supported by the partial efficacy of PSL and H. pylori eradication therapy for thrombocytopenia.
In summary, we encountered a rare case of ITP secondary to primary CMV infection (probably CMV-related ITP) following RT. TPO-RAs were successful as second-line treatments with few adverse events. Our findings suggest that TPO-RAs might be effective with fewer adverse effects in this situation.