Evolution of antiplatelet antibodies after HP infection. Platelets may be activated by binding of first-generation HP antibodies (1) to platelet FcγIIA or through an interaction between HP-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 recognize either bacterially derived factors that bind to platelets (3) or that cross-react 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-HP antibodies (early response), which may be followed by a decrease in bacterial antigen and reduction in the titer of cross-reacting antibody (late durable response). In patients with protracted disease unresponsive to antibiotic eradication, antibodies to HP 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. Antibodies (light chains, heavy chains, isotype switching, and somatic mutations) are drawn as in Figure 2. Modified and reprinted with permission. Professional illustration by Paulette Dennis and Kenneth Probst.