Background: The prototypic anti-platelet factor 4 (PF4) disorder-heparin-induced thrombocytopenia and thrombosis (HITT)-features immunoglobulin G (IgG) class antibodies that activate platelets, monocytes, and neutrophils in a mainly heparin-dependent fashion via Fcγ receptor-dependent cellular activation. The identification in 2021 of an ultrarare HITT-mimicking disorder, vaccine-induced immune thrombocytopenia and thrombosis (VITT)-triggered by two different adenoviral vector vaccines-abruptly broadened the spectrum of recognized anti-PF4 disorders.

Objective: To classify platelet-activating anti-PF4 disorders, both HITT/HITT-like and VITT/VITT-like.

Methods: Literature was reviewed from the perspective of a researcher-clinician involved in identifying novel anti-PF4 disorders.

Results: Atypical presentations of HITT with proximate heparin triggers but which evince heparin-independent platelet-activating properties ("autoimmune HITT") have been recognized since 2001; heparin-independent platelet-activating properties also characterize HITT-mimicking disorders with undefined non-heparin triggers (e.g., post-knee replacement "spontaneous HITT"). Antibodies identical to those of (vaccine-induced) VITT can rarely be triggered by natural adenovirus infection. HITT and VITT antibodies recognize different epitopes on PF4. All the aforementioned anti-PF4 disorders are acute, transient, and self-limited. Recently, however, chronic anti-PF4 disorders featuring potent VITT-like properties of monoclonal proteins (M-proteins) have been identified: this oftentimes treatment-refractory entity, named "VITT-like monoclonal gammopathy of thrombotic significance" (VITT-like MGTS), dramatically expands the clinical spectrum of recognized anti-PF4 disorders. Anti-PF4 disorders with heparin-independent platelet-activating antibodies, whether HITT or VITT, may require management strategies beyond anticoagulation alone, including high-dose intravenous immunoglobulin (IVIG) or (for VITT-like MGTS) the Bruton's tyrosine kinase inhibitor, ibrutinib.

Conclusions: Clinicians and laboratorians require knowledge of the rapidly broadening spectrum of recognized acute and chronic anti-PF4 disorders.