Immune thrombocytopenia (ITP) is an autoimmune disease mediated by antiplatelet autoantibodies that bind to circulating platelets and megakaryocytes, resulting in platelet destruction by the reticuloendothelial system as well as suppressed platelet production [1, 2]. T-cell-mediated destruction also participates in reducing the numbers of platelets and megakaryocytes [3].

Corticosteroids, intravenous immunoglobulin, and splenectomy have been employed in order to suppress platelet destruction mechanisms. In 1998, Gasbarrini et al. reported that the eradication of Helicobacter pylori in ITP patients increased platelet counts [4]. The eradication of H. pylori in ITP patients has since been attracting attention because the eradication treatment is basically a single course therapy that is cost effective and tolerable. Previous studies that reported the efficacy of H. pylori eradication therapy in ITP patients are reviewed herein, and the mechanisms of ITP related to H. pylori infection are discussed.

H. pylori is a gram-negative bacillus that colonizes the mucous layer of the human stomach. The persistent presence of H. pylori in the gastric mucosa induces gastrointestinal disorders including atrophic gastritis, peptic ulcers, and gastric cancer [5]. H. pylori has also been shown to activate the host immune system with cytokine signaling and the stimulation of various immune cells including macrophages and lymphocytes. The continuous stimulation of the immune system may induce mucosa-associated lymphoid tissue (MALT) lymphoma and various autoimmune disorders such as chronic thyroiditis, Sjögren disease, systemic sclerosis, rheumatoid arthritis, and ITP [6–8].

Triple therapy with a proton pump inhibitor (PPI), clarithromycin, and either amoxicillin or metronidazole for 1 or 2 weeks has been used as the standard eradication regimen for H. pylori therapy in the most countries worldwide [9]. However, H. pylori infection is becoming more difficult to treat because of the increasing failure of therapy. New first-line strategies including non-bismuth quadruple therapy (PPI + amoxicillin + metronidazole + clarithromycin) and bismuth quadruple therapy (PPI + bismuth + metronidazole + tetracycline) are now being recommended as the Toronto Consensus [10]. Another new regimen using a novel potassium-competitive acid blocker (PCAB) in combination with antibiotics has been tested in Japan [11] and may represent an effective option.

In 1998, Gasbarrini et al. reported increases in platelet counts after eradication therapy in most H. pylori-positive ITP patients [4]. Many studies have since been published on the effects of eradication therapy on platelet responses in H. pylori-positive ITP cases. In Italy and Japan, platelet counts were found to increase after H. pylori eradication in most (50–80%) H. pylori-positive ITP patients [12–23]. However, the effectiveness of eradication was very limited in Spain, France, and the United States [24–27]. Studies performed in Serbia, Turkey, and Iran also reported relatively low response rates [28–30]. The reasons for this discrepancy have not yet been established, but may be attributed to the high proportion of patients with severe and persistent ITP in these countries, differences in immunological backgrounds between populations, or differences in antigenicity [25, 26].

In Japan, a nationwide retrospective study was performed in order to assess the prevalence of H. pylori infection, the effects of the eradication of H. pylori on platelet counts, and the characteristic clinical features of chronic ITP with H. pylori infection [21]. A total of 435 ITP patients were enrolled in this study and H. pylori infection was detected in 300 patients. H. pylori-positive patients were significantly older, and hyperplastic megakaryocytes in bone marrow were also more frequently detected than in patients without H. pylori infection. A total of 207 H. pylori-positive ITP patients received H. pylori eradication therapy, and platelet counts increased in 63% of eradication-successful patients. Among most responders, the platelet count response started 1 month after eradication therapy, and increases in platelet counts continued without the ITP treatment for more than 12 months. Although most early studies excluded patients with severe thrombocytopenia, this study also reported the efficacy of eradicating H. pylori in severe patients with refractory ITP, even after splenectomy. In this study, increases in platelet counts were maintained without additional treatments for more than 12 months. Long-term follow-up studies confirmed that the platelet response after eradication therapy lasted 7 years or longer with very few cases of relapse [31, 32].

The first systematic review with a meta-analysis by Francini et al. reviewed 788 ITP patients including 494 H. pylori-positive patients [33]. Platelet counts were significantly higher in H. pylori-infected patients after successful H. pylori eradication than in the following groups: untreated H. pylori-infected patients, H. pylori-infected patients who failed eradication, and H. pylori-uninfected patients. Stasi et al. performed another systematic review involving 1555 patients and reported similar findings [34]. Therefore, H. pylori eradication is strongly related to platelet recovery in ITP patients. In another systematic review, Arnold et al. evaluated the efficacy of eradication therapy in ITP patients by comparing platelet responses in patients with or without H. pylori infection [35]. A total of 205 H. pylori-positive and 77 H. pylori-negative patients received eradication therapy. The odds of platelet counts increasing with eradication therapy were 14.5-fold higher in H. pylori-positive patients than in H. pylori-negative patients. This finding indicated a clear relationship between increased platelet counts and the successful eradication of H. pylori and also strongly suggested that H. pylori infection plays a direct role in the pathogenesis of ITP.

Although H. pylori eradication therapy is still only one of the treatment options available for patients with refractory ITP or those with ITP and less severe thrombocytopenia in the United States and European countries (other than Italy) [36–39], in a reference guide for managing adult ITP in Japan, H. pylori eradication is recommended as an initial strategy for managing ITP in adult patients [40].

In ITP, a pathogenic loop has generally been suggested to be established, and platelets and megakaryocytes are continuously impaired by macrophages and lymphocytes [2, 41]. The establishment of this loop may be initiated through the capture of opsonized platelets by the Fcγ receptors of macrophages in the reticuloendothelial system. Macrophages present antigenic peptides derived from platelet-specific glycoproteins including GPIb-IX-V and GPIIb/IIIa, and CD4+ T cells are activated by these autoantigens. These autoreactive T cells activate B cells to produce antiplatelet autoantibodies, which then bind to and destroy platelets and megakaryocytes.

In 2009, an international working group standardized terminologies and definitions for ITP [51]. The acronym ITP was proposed to stand for immune thrombocytopenia, and ITP was classified into “primary” and “secondary” ITP. The term “primary” indicates the absence of any obvious cause. The term “secondary” indicates that there is an underlying disease or drug exposure, and “secondary ITP” may broadly include all forms of immune thrombocytopenia, except for primary ITP. The panel proposed the diagnosis of improvements in thrombocytopenia after the successful eradication of H. pylori as “secondary ITP (H. pylori associated).” There are some refractory ITP patients who do not respond to eradication therapy. These refractory cases may be regarded as primary ITP and a coincidental H. pylori infection [41].