Platelet-activating antibodies against platelet factor 4 (PF4) cause highly prothrombotic disorders with reduced platelet counts. In heparin-induced thrombocytopenia (HIT), these antibodies bind PF4-heparin complexes, causing heparin-dependent platelet activation. Less common autoimmune and spontaneous HIT variants that are triggered by heparin and nonpharmacologic polyanions, respectively, have atypical clinical features and antibodies with additional heparin-independent platelet-activating properties. Vaccine-induced immune thrombocytopenia and thrombosis (VITT) antibodies directly target PF4. Initially, VITT was linked to adenoviral vector-based coronavirus disease 2019 vaccines, but in rare cases, an immune thrombocytopenia and thrombosis disorder that is clinically nearly identical to VITT can be caused by infection resulting from natural exposure to viruses, especially adenovirus. In persons with the IGLV3-21*02/*03 gene, anti-adenovirus protein VII antibody specificity shifts to PF4 by way of a specific somatic hypermutation (K31E) that creates VITT antibodies. In VITT-like monoclonal gammopathy of thrombotic significance, monoclonal anti-PF4 antibodies cause chronic prothrombotic conditions. Accurate diagnosis relies on distinct assays for HIT and VITT antibodies. Beyond anticoagulation, inhibition of FcγIIa receptor-mediated platelet activation may be needed for anti-PF4 disorders with heparin-independent reactivity (e.g., high-dose immune globulin in acute disease manifestations and Bruton's tyrosine kinase inhibitors in chronic manifestations).