Introduction

          Megathrombocytes, or giant platelets, are young platelets recently released from the bone marrow and usually observed in patients with Bernard-Soulier syndrome, May-Hegglin anomaly, and idiopathic thrombocytopenic purpura (ITP) [1]. Apart from these hematologic disorders, patients with diabetic retinopathy and rheumatic diseases, as well as some after surgery, were also reported to show increases in megathrombocytes [1]. The appearance of megathrombocytes is associated with thrombocytopenia and the tendency to bleed [2].

         Helicobacter pylori (H. pylori) is well-known to induce thrombocytopenia in ITP patients. Although the precise mechanism of this phenomenon is not fully understood, successful eradication of the bacterium results in remission and even cure of thrombocytopenia in ITP [3,4]. Antibodies against surface glycoproteins expressed on the megakaryocyte lineages are presumed to participate in the pathoetiology of thrombocytopenia [5-8].

          We present a unique case in which the regression of megathrombocytes was confirmed after H. pylori eradication.

Case Report

          A 61-year-old man visited Tsurumi University Hospital in July 2016. He had undergone a medical examination in May 2016, and the results suggested the presence of H. pylori infection. We rechecked the data for H. pylori infection on August 25, 2016, and the titer of anti-H. pylori IgG antibody was 81.0 U/mL (a titer greater than 10.0 is considered to indicate H. pylori infection). Values of pepsinogen I (PG I), PG II, and the PG I/PG II ratio were 51.6 ng/mL, 18.2 ng/mL, and 2.83, respectively, also indicating H. pylori infection (Table 1). The patient opted for H. pylori eradication therapy and, after undergoing a gastrofiberscopic examination to confirm the diagnosis of H. pylori-induced atrophic gastritis according to the guidelines of the Ministry of Health, Labor, and Welfare of Japan, the triple-therapy regimen of amoxicillin, clarithromycin, and lansoprazole was initiated.

          Before starting treatment, we also performed laboratory tests to evaluate the effects of H. pylori infection on hematologic, immunologic, and allergic parameters after receiving written informed consent from the patient. The peripheral blood smear showed the presence of approximately 5% megathrombocytes (Figure 1). He had no history of hematologic, rheumatic, or diabetic disorders and had not undergone recent surgery.

Figure 1

Figure 2

The initial therapy regimen failed to eradicate H. pylori, and anti-H. pylori IgG antibody, PG I, PG II, and the PG I/PG II ratio showed no marked changes (Table 1). A second treatment regimen consisting of amoxicillin 1500 mg/day, clarithromycin 400 mg/day, metronidazole 750 mg/day, and vonoprazan 40 mg/day for 1 week was initiated on February 7, 2017. Eradication was successful, and the titer of anti-H. pylori IgG antibody decreased from 81.0 U/mL to 44.0 U/mL, finally reaching 22.0 U/mL. The changes in serum levels of PG I and PG II and in fasting serum gastrin also indicated successful eradication. The presence of megathrombocytes was observed after the initial therapy. However, their presence could not be confirmed 3 months after the successful eradication. At the same time, platelet configurations decreased. We also confirmed the absence of antinuclear antibody, antiplatelet antibody, and PAIgG in September 2017.

Discussion

          The detailed process by which thrombocytopenia is induced in H. pylori-infected patients with ITP remains to be resolved, although it appears that immunologic mechanisms are involved [9-11].        

          It was reported that H. pylori binds von Willebrand factor and interacts with glycoprotein Ib (GPIb) [5]. Satoh et al. reported that the vacuolating cytotoxin (VacA) of H. pylori binds to multimerin 1 on human platelets [7]. In addition, Kuwana et al. found that peripheral B cells from primary ITP patients produce anti-GPIb autoantibodies [8]. From those results, it appears that H. pylori aggregates platelets in infected individuals through binding to GPIb or multimerin.

          Because the regression of megathrombocytes was observed only after successful eradication, the occurrence of H. pylori infection may affect normal proliferation or differentiation of the megakaryocytic lineage.

          With few reports on the presence of megathrombocytes in healthy individuals, it is difficult to determine whether the detection of megathrombocytes was unique to the current patient. However, Deb Roy et al. reported the presence of giant platelets in voluntary platelet donors in India [12]. Thirty of 45 “healthy” donors were found to have giant platelets and low platelet counts without showing a tendency to bleed. Those 30 donors had Harris platelet syndrome, which is unique to the Indian subcontinent [13]. That is not relevant to our patient, however, who was ethnically Japanese with normal platelet counts.

          Although we cannot rule out the possibility that the patient was in the process of developing ITP at the time of the first visit to Tsurumi University Hospital, the presence of megathrombocytes was clearly/closely associated with H. pylori infection, since their regression was observed only after H. pylori eradication. In accordance with the phenomenon, platelet parameters such as plateletcrit, mean platelet volume, and platelet distribution width were decreased only after the eradication. We therefore believe that the megathrombocytes were induced by H. pylori infection in our patient.

          To the best of our knowledge, increases in megathrombocytes in individuals without immunohematologic disorders have rarely been reported, except in diabetic patients with retinopathy and patients who have undergone recent surgery [2]. Because the current patient had neither ITP nor diabetes mellitus, this phenomenon seems to be uniquely induced by H. pylori infection.

          It remains difficult to understand how H. pylori eradication improves thrombocytopenia in some ITP patients. As in the current case, megakaryocytic proliferation/differentiation could be affected in some patients by H. pylori itself or by its products such as anti-GPIb antibody and VacA. Such patients may respond well to eradication therapy. ITP appears to develop via three distinct mechanisms: induction by H. pylori itself; induction by H. pylori products; and by a mechanism unrelated to H. pylori. If the status of megakaryocytic differentiation could be evaluated, it might be possible to predict the efficacy of H. pylori eradication for some ITP patients.

To clarify the mechanism of megathrombocytes induction in H. pylori-infected patients, further follow-up with careful evaluation of hematologic characteristics in those with and without ITP will be crucial. Elucidation of the pathoetiologic roles of H. pylori infection in ITP patients will require the collection and comparative analysis of additional cases in whom eradication were both successful and unsuccessful.

Conclusion

          Why H. pylori eradication improves thrombocytopenia in some ITP patients remains unresolved. As in the current case, some ITP patients could have hindered megakaryocytic proliferation/differentiation induced by H. pylori, and such patients may respond well to eradication therapy.

Acknowledgment

          We thank Dr. Yumi Ito, Division of Diagnostic Pathology, Tsurumi University School of Dental Medicine, for technical assistance in the analysis of this case study.

Authors’ contributions

HY, HT, and YM planned the case report concept and design, collected data, and prepared the manuscript. YF, TH, and KM assembled study data and offered useful criticism of the manuscript. All authors read and approved the final manuscript.

Conflicts of interest

          Dr. Yoshihiro Matsukawa received honoraria for lectures from Astra-Zeneca and Takeda Pharmaceutical.

          Dr. Hideto Tamura received honoraria for lectures from Bristol-Myers Squibb, Celegene, Ono Pharmaceutical, and Takeda Pharmaceutical; advisory fees from Ono Pharmaceutical; and a research grant from Celegene. 

          Drs. Hiroyuki Yamanaka, Yuri Fukui, Tohru Hayakawa, and Katsuhiro Miura have no conflicts of interest to report.

We declare that the patient’s written informed consent for the publication of this case report was obtained on December 1, 2018.