  Antibodies recognizing complexes of the chemokine platelet factor 4
(PF4-CXCL4) and polyanions (P) opsonize PF4-coated bacteria hereby mediating
bacterial host defense. A subset of these antibodies may activate platelets
after binding to PF4-heparin complexes, causing the prothrombotic adverse drug
reaction heparin-induced thrombocytopenia (HIT). In autoimmune-HIT,
anti-PF4-P-antibodies activate platelets in the absence of heparin. Here we
show that antibodies with binding forces of approximately 60-100 pN activate
platelets in the presence of polyanions, while a subset of antibodies from
autoimmune-HIT patients with binding forces greater than 100 pN binds to PF4
alone in the absence of polyanions. These antibodies with high binding forces
cluster PF4-molecules forming antigenic complexes which allow binding of
polyanion-dependent anti-PF4-P-antibodies. The resulting immunocomplexes induce
massive platelet activation in the absence of heparin. Antibody-mediated
changes in endogenous proteins that trigger binding of otherwise non-pathogenic
(or cofactor-dependent) antibodies may also be relevant in other
antibody-mediated autoimmune disorders.
