Anti-Platelet factor 4 immunothrombosis—not just heparin and vaccine triggers

Derailments at the tightly regulated interface of blood coagulation and innate inflammatory immune responses can lead to pathologic immunothrombosis. A special subset of immunothrombosis is caused by antibodies against platelet-factor 4 (PF4). Anti-PF4 antibodies triggered by heparin treatment in heparin-induced thrombocytopenia (HIT) are known for more than 50 years. Interest in anti-PF4 disorders rekindled when first cases of vaccine-induced immune thrombocytopenia and thrombosis (VITT) occurred during the worldwide COVID-19 vaccination campaign. During this time new diagnostic procedures were established to identify affected patients and to differentiate between different kinds of anti-PF4 antibodies. This review article gives an overview about the current knowledge of HIT and VITT with concepts of the underlying pathogenesis. In addition to heparin and vaccination as known triggers for HIT and VITT, concepts for other clinical cases with anti-PF4 antibodies are described in more detail. Anti-PF4 antibodies in atypical HIT-like syndromes could be triggered by presentation of various polyanions, eg, in settings of orthopedic surgery or bacterial infections. Anti-PF4 antibodies in acute VITT-like disorders can occur after viral infections. Chronic VITT-like anti-PF4 antibodies causing recurrent thrombosis and thrombocytopenia are often linked to monoclonal gammopathies. For all disorders with anti-PF4 antibodies, timely identification in patients with thrombocytopenia with or without thrombosis is crucial for successful therapy.