Mechanisms of induction of anti-PF4/polyanion antibodies. (A) Noncomplexed PF4 is not immunogenic. (B) However, when PF4 forms complexes with polyanions it undergoes a conformational change exposing epitopes to which PF4/heparin antibodies bind. These polyanions can be structures on bacterial surfaces or heparin bound to platelets. (C) The PF4/polyanion complexes induce antibody production of (most likely) MZ B cells (black antibodies, upper portion of panel C), which can induce platelet activation in the presence of heparin, that is, they are typically heparin-dependent. In delayed onset HIT and spontaneous HIT, the B cells produce antibodies which bind to, and potentially thereby cluster, PF4 and then activate platelets, typically in the absence of heparin (red antibodies, lower portion of panel C). It is unresolved which factors trigger these antibodies (D): potential candidates are PF4/bacteria clusters or PF4/nucleic acid clusters; it is also unclear whether heparin-independent platelet activation is a quantitative or a qualitative feature of these antibodies.