In this issue of Blood, Emilia and coworkers report durable responses in a high proportion of patients with immune thrombocytopenic purpura (ITP) who are treated for infection with Helicobacter pylori. They propose that differences in expression of the cagA gene and other bacterial virulence factors contribute to the considerable variation in the effectiveness of bacterial eradication among similar studies of ITP patients drawn from different countries.

The relationship between H pylori infection and ITP as defined in the American and British guidelines has been affirmed by many groups, primarily in patients from Italy and Japan. However, treatment was far less effective in studies emanating from the United States, France, and Spain, which has been attributed to the lower prevalence of H pylori infection and a high proportion of patients with severe, long-standing disease in these countries who were studied.1,2  Although the severity and duration of ITP did not influence outcome in the study by Emilia and colleagues, some platelet responses may have been maintained with prednisone, and relatively few patients with severe disease were studied (see Table 3 in Emilia et al).

Dissecting the host response to H pylori provides a remarkable opportunity to study the evolution of autoantibodies and the development and progression of ITP. Molecular mimicry between the immune response to cagA or Lewis antigen and platelets may sustain the production of self-reactive antibodies during persistent infection in susceptible individuals.3,4  Comparing the T- and B-cell repertoire in patients with durable complete responses before and after antibiotic treatment with those who relapse and those who do not respond may reveal the emergence of H pylori–independent antiplatelet autoantibodies (see figure) reminiscent of the response of mucosa-associated lymphoid tissue (MALT) lymphomas. It will also be of interest to profile the virulence factors expressed by H pylori isolated from ITP patients in the United States, where response rates are low.

Evolution of antiplatelet antibodies after H pylori infection. Platelets may be activated by binding of first-generation H pylori antibodies (1) to platelet FcγRIIA or through an interaction between H pylori–bound von Willebrand factor (VWF) and platelet glycoprotein IB (gpIB). Activation may promote platelet clearance and antigen presentation, which augments production of antibacterial antibodies. Somatic mutation may lead to the development of second-generation antibodies (2) that either recognize bacterially derived factors that bind to platelets (3) or crossreact with platelet antigens (4). Improved mucosal permeability or bacterial eradication with proton-pump inhibitors and antibiotics may initiate the clinical response in patients with anti–H pylori antibodies (early response), which may be followed by a decrease in bacterial antigen and reduction in the titer of crossreacting antibody (late durable response). In patients with protracted disease unresponsive to antibiotic eradication, antibodies to H pylori may have undergone additional somatic mutations (third-generation antibodies; [5]) that lose their reactivity with the inciting antigen, but retain platelet reactivity (6) leading to early relapse or no response. APC indicates antigen-presenting cell. Professional illustration by Kenneth Xavier Probst.

Evolution of antiplatelet antibodies after H pylori infection. Platelets may be activated by binding of first-generation H pylori antibodies (1) to platelet FcγRIIA or through an interaction between H pylori–bound von Willebrand factor (VWF) and platelet glycoprotein IB (gpIB). Activation may promote platelet clearance and antigen presentation, which augments production of antibacterial antibodies. Somatic mutation may lead to the development of second-generation antibodies (2) that either recognize bacterially derived factors that bind to platelets (3) or crossreact with platelet antigens (4). Improved mucosal permeability or bacterial eradication with proton-pump inhibitors and antibiotics may initiate the clinical response in patients with anti–H pylori antibodies (early response), which may be followed by a decrease in bacterial antigen and reduction in the titer of crossreacting antibody (late durable response). In patients with protracted disease unresponsive to antibiotic eradication, antibodies to H pylori may have undergone additional somatic mutations (third-generation antibodies; [5]) that lose their reactivity with the inciting antigen, but retain platelet reactivity (6) leading to early relapse or no response. APC indicates antigen-presenting cell. Professional illustration by Kenneth Xavier Probst.

Any hypothesis related to treatment outcome must account for the observation that responses (including to proton-pump inhibitors as the sole treatment modality5 ) may begin within 1 to 3 weeks of initiation of antibiotics,6  before antibody synthesis by plasma cells is affected. Of note, it has been reported that some H pylori strains bind von Willebrand factor7 ; that bacterial homogenates promote platelet activation in vitro; that platelet-platelet and platelet-leukocyte aggregates bind to murine gastric venules in animal models; and that circulating platelet aggregates have been found in infected patients.8  Eliminating the production and transfer of bacteria-derived products that accelerate platelet activation and clearance may precede the effect of depleting inciting antigens, and may contribute to a brief response in patients with bacteria-independent autoantibodies (see Figure 1 in the article).

The study by Emilia and colleagues is well designed, with careful attention paid to the diagnosis of chronic ITP, documentation of tissue infection, inclusion of some patients with severe disease, and meaningful follow-up. H pylori, like HIV and hepatitis C, appears to predispose susceptible individuals to the development of idiopathic thrombocytopenia. Has the time come to screen all ITP patients and those with mild thrombocytopenia at risk to develop clinically relevant ITP9  for H pylori at diagnosis, before the autoantibody repertoire no longer depends on persistence of bacterial antigens—and should an attempt to eradicate the bacterium precede nonemergent ITP-directed therapies in infected individuals, as the authors suggest?

Conflict-of-interest disclosure: The author declares no competing financial interests. ■

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