Anti-platelet factor 4/polyanion antibodies mediate a new mechanism of autoimmunity

TL;DR

This study uncovers a new autoimmune mechanism where high-affinity anti-PF4 antibodies form complexes that activate platelets without heparin, contributing to autoimmune thrombocytopenia.

Contribution

It reveals that high-binding force anti-PF4 antibodies can cluster PF4 molecules, forming complexes that induce platelet activation independently of heparin, a novel insight into autoimmune HIT.

Findings

High-binding force antibodies (>100 pN) activate platelets without heparin.

Antibody-induced PF4 clustering forms antigenic complexes.

Massive platelet activation occurs via immunocomplexes in autoimmune HIT.

Abstract

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.