Platelet-activating anti-PF4 disorders: An overview

Platelet factor 4 (PF4) is a highly cationic tetrameric protein that can be targeted by platelet-activating anti-PF4 antibodies of immunoglobulin G (IgG) class. Certain features of PF4, including its multivalent nature (duplicate antigen sites per tetramer), the ability of many PF4 tetramers to undergo close approximation through charge neutralization, and the dimeric binding of IgG molecules, results in formation of IgG-containing immune complexes in situ on platelets, neutrophils, and monocytes, resulting in Fcγ receptor-mediated pancellular activation that also activates hemostasis (potential for disseminated intravascular coagulation). This review discusses 4 anti-PF4 disorders: classic heparin-induced thrombocytopenia ([HIT]; triggered by heparin and certain other polyanionic pharmaceuticals, featuring predominantly heparin-dependent antibodies), autoimmune HIT (aHIT; severe subtype of HIT that features both heparin-dependent and heparin-independent platelet-activating antibodies), and spontaneous HIT (non-heparin triggers such as knee replacement surgery and infection; predominantly heparin-independent platelet-activating antibodies). Most recently, a novel fourth anti-PF4 disorder, vaccine-induced immune thrombotic thrombocytopenia (VITT), was identified as an ultrarare complication of adenovirus vector vaccines. VITT is characterized by thrombocytopenia, disseminated intravascular coagulation, a high frequency of thrombosis—including in unusual sites (cerebral veins, splanchnic veins)—and highly pathogenic anti-PF4 antibodies with heparin-independent platelet-activating properties.