SLE is a systemic autoimmune disease that causes a variety of clinical manifestations and resultant multi-organ damage. In SLE, genetic factors and environmental triggers, such as ultraviolet exposure, together contribute to induction of autoimmunity against various self-antigens, resulting in the production of high-affinity pathogenic autoantibodies, including anti-double-stranded DNA antibodies. These autoantibodies typically form immune complexes, which accumulate in the kidneys, blood vessel walls, and many other organs, and trigger complement activation and inflammation. Anti-double-stranded DNA antibodies are not only a diagnostic marker but also are involved in disease progression and reflect disease activity [4, 5]. Thrombocytopenia is one of the major complications in patients with SLE, with a prevalence ranging from 10 to 30% [6]. The pathogenic processes of thrombocytopenia in SLE patients are heterogeneous and include ITP, thrombotic microangiopathy (i.e., thrombotic thrombocytopenic purpura and atypical hemolytic uremic syndrome), disseminated intravascular coagulation, and amegakaryocytic thrombocytopenia, while the most common mechanism is ITP, which is mediated through anti-GPIIb/IIIa and anti-GPIb/IX antibodies, as observed in patients with primary ITP [7, 8]. On the other hand, we have identified new autoantibodies reactive with thrombopoietin (TPO) receptor in patients with SLE [9]. Anti-TPO receptor antibodies often coexist with anti-GPIIb/IIIa antibodies and are associated with megakaryocytic hypoplasia and poor treatment response to corticosteroids or intravenous immunoglobulin (IVIG) [7]. SLE patients with anti-TPO receptor antibody often represent an extremely high level of circulating TPO. A rare manifestation of amegakaryocytic thrombocytopenia can occur in the presence of anti-TPO receptor antibodies. In fact, anti-TPO receptor antibodies are capable of inhibiting megakaryogenesis in vitro [9].

APS is characterized by recurrent arterial and/or venous thrombosis as well as adverse pregnancy outcomes in association with antiphospholipid (aPL) autoantibodies. According to the revised Sapporo criteria, clinically meaningful aPL positivity is defined by moderate levels of IgG/IgA/IgM anti-cardiolipin antibodies, IgG/IgA/IgM anti-β2GPI antibodies, or lupus anticoagulant, which are confirmed to be positive in two occasions apart from >12 weeks [10]. APS is divided into primary and secondary APS, based on the presence or absence of an underlying autoimmune condition; SLE is the commonest. Thrombocytopenia has been reported in ~40% of patients with primary APS and usually presents mildly without apparent bleeding symptoms [11, 12]. Severe thrombocytopenia in primary APS patients is correlated more closely with the presence of antiplatelet autoantibodies to GPIIb/IIIa and GPIb/IX [13, 14]. However, rare cases of APS patients who develop severe thrombocytopenia concomitant with repeated episodes of thrombosis have been reported. In these cases, thrombocytopenia is mediated by enhanced platelet consumption in association with accelerated coagulation pathways, and platelet count is fully recovered by treatment with warfarin [15]. aPL is occasionally found in patients with primary ITP without any thrombotic episodes. However, the presence of aPL in patients with primary ITP is a risk factor for future development of APS [16].

Several lines of evidence have indicated that platelet recovery occurs in a subset of ITP patients infected with H. pylori, a gram-negative bacterium that establishes chronic infection in the gastric mucosa, after the successful eradication of H. pylori [19]. Potential mechanisms for the role of H. pylori infection in ITP pathogenesis include molecular mimicry between H. pylori components and platelet antigens and modulation of the host’s immune system by H. pylori infection [20]. Another intriguing mechanism has also been proposed; H. pylori infection could modulate the Fcγ receptor balance of monocytes/macrophages toward inhibitory FcγRIIB, thereby enhancing phagocytosis and antigen presentation [21]. This activated monocyte phenotype was suppressed after H. pylori was successfully eradicated. It has been now accepted that ITP that recovered after H. pylori eradication is categorized as secondary ITP (H. pylori-associated ITP) [22]. Interestingly, platelet recovery after H. pylori eradication was observed in nearly half of the patients in cohorts from Japan and Italy, but only in <15% of the patients in cohorts from Spain and the United States [23]. This apparent ethnic difference suggests a potential role for host genetic factors in the development of ITP in H. pylori-infected individuals. In addition, single nucleotide polymorphisms within the genes for tumor necrosis factor-β and FcγRIIB were found to be useful for predicting the response to H. pylori eradication treatment [24, 25]. In the majority of ITP patients responding to H. pylori eradication therapy, antiplatelet autoantibody response is completely resolved with no relapse for more than 7 years, suggesting that the disease is cured. Therefore, in the H. pylori epidemic area, adult patients with ITP should be examined for H. pylori infection, and eradication therapy is recommended before any immunosuppressive therapy if the infection is present.

H. pylori infection is occasionally found in patients with other forms of secondary ITP, but platelet recovery was rarely observed in patients with SLE-associated or liver cirrhosis-associated ITP [19]. This finding clearly indicates that H. pylori eradication fails to improve the pathogenic process of other forms of secondary ITP. Thus, the efficacy of H. pylori eradication therapy is likely to be restricted to patients in a subgroup of H. pylori-associated ITP.

It has been reported that the prevalence of HCV infection in adult patients with ITP ranged from 10 to 36% [26, 27]. Infection with HCV is known to modulate host immune response and prone to elicit autoimmunity. The pathogenesis of HCV-associated ITP is not understood in detail, but it may involve polyclonal activation of B cells and the production of antibodies cross-reactive with HCV components and GPIIIa [28]. A higher frequency of circulating anti-GPIIb/IIIa antibody-producing B cells in HCV-infected patients with liver cirrhosis than in liver cirrhosis patients with other etiologies might be a consequence of enhanced immune activation in association with HCV infection [29]. Other causes of thrombocytopenia in HCV-infected patients may be related to impairment in hepatic function, such as hypersplenism due to portal hypertension and decreased TPO production from the liver [30]. Successful eradication of HCV by antiviral treatment such as type I interferon has resulted in an improved platelet count in some patients with HCV-associated ITP, supporting a direct role for HCV infection in the pathogenic process of ITP [31, 32]. Thus, anti-HCV treatment should be considered before introduction of any immunosuppressive treatment, including corticosteroids. In case of high risk for fatal bleeding, IVIG is reported to be efficacious.

Before wide availability of highly active antiretroviral therapy (HAART), HIV-associated ITP was observed in 5–25% of HIV-1-infected individuals [27]. HIV targets CD4⁺ T cells irrespective of their effector or regulatory subsets. Therefore, acquired immune system is dysregulated in HIV-infected individuals, resulting in increased risk for infection and cancer and, paradoxically, in increased risk for autoimmunity [33]. In addition, it has been shown that IgG anti-GPIIb/IIIa antibodies in patients with HIV-related ITP are able to cross-react with HIV-associated gp120 [34]. These potentially cross-reactive antibodies may trigger harmful autoimmune responses to platelets, resulting in the continuous production of IgG antiplatelet autoantibodies. On the other hand, it has been found that megakaryocytes express CD4 and co-receptors necessary for HIV infection [35]. Therefore, HIV infection to megakaryocytes directly leads to ineffective platelet production and may contribute to thrombocytopenia [36, 37]. Since recovery of platelet counts was reported in association with decreased HIV copies by HAART [38], anti-HIV treatment should be the first-line treatment in patients with HIV-associated ITP.

The diagnosis of primary ITP is based principally on the exclusion of the causes of secondary ITP. Table 2 lists the clinical and laboratory characteristics of selected secondary ITP that distinguish them from primary ITP. It is imperative to consider the risk factors for developing disorders potentially cause secondary ITP: i.e., SLE for young women; APS for episode of thrombosis and/or repeated fetal losses; H. pylori infection for elderly in the epidemic countries, such as in East Asia and Italy; and HIV infection for homosexuals and drug abusers. Clinical evaluations should be aimed at symptoms and physical findings other than bleeding manifestations, which are commonly found in patients with primary and secondary ITP. Constitutional symptoms, such as fever, joint pain, rashes, malaise, Raynaud phenomenon, weight loss, hepatomegaly, and lymphadenopathy, indicate the presence of underlying disorders, such as SLE, LPD, and infection with HCV or HIV. It is necessary to perform serum tests for antinuclear antibody (ANA) and aPL as well as blood tests for infectious agents (HCV and HIV), according to clinical suspicion based on risk factors and clinical signs [39]. In case of high titer of ANA, specific antibody assays should be further conducted to identify anti-double-stranded DNA, anti-Sm, anti-U1RNP, anti-SSA, and anti-SSB antibodies. Increased counts of small lymphocytes or lymphocytes with granular inclusions in peripheral blood smears suggest a diagnosis of CLL, but flow cytometry may be particularly helpful in identifying patients with CLL [40]. H. pylori infection can be detected by urea breath test and/or the stool antigen test, although stomach biopsy under endoscopy should be avoided because of the risk for massive mucosal bleeding after invasive procedure. Anti-H. pylori antibody testing is less sensitive or specific and does not prove active infection, and a false-positive result can occur after IVIG therapy. H. pylori screening is certainly worthwhile in East Asian countries, South and Middle American countries, and Italy, which are areas with a high background prevalence of the infection. In contrast, in the United States and European countries except Italy, testing for H. pylori infection remains controversial.