Platelet Factor 4 Antibody Persistence and Long-term Pathogenicity in Vaccine-induced Immune Thrombotic Thrombocytopenia

Rarely, recipients of adenoviral vector-based vaccines experience a severe thrombotic thrombocytopenic condition referred to as vaccine-induced immune thrombotic thrombocytopenia (VITT). VITT is a transient prothrombotic process, although recent data suggests that VITT anti-platelet factor 4 (PF4) antibodies are more persistent than antibodies seen in heparin-induced thrombocytopenia. Whether anti-PF4 antibody persistence in VITT is related to the continued persistence of antibody clones from the acute phase or the development of novel antibodies is unclear. To study this, acute and follow-up samples were obtained from six Ad26.COV2.S-associated VITT patients, with a median time to follow-up of 244 days from acute presentation (Range, 114-664 days). Upon affinity-enrichment of antibodies, mono/oligoclonal PF4/heparin-reactive anti-PF4 antibodies were observed despite negative results in serum protein electrophoresis and the more sensitive "Mass-Fix" technique. This finding distinguishes VITT from monoclonal gammopathy of thrombotic significance where monoclonal antibodies are observed in native sera. Anti-PF4 antibody abundance decreased over time, with no evidence of novel anti-PF4 antibody production after acute presentation. Although previous studies indicate a stereotypical pairing of VITT antibodies with <i>lambda</i> light chains, one VITT patient produced anti-PF4 antibodies with a <i>kappa</i> light chain, suggesting immunological heterogeneity. While none of these six antibodies caused long-term thrombocytopenia or thrombosis, platelet-activating anti-PF4 antibodies were seen four years after the acute event in an additional ChAdOx1 nCoV-19-associated VITT patient. These antibodies continued to cause chronic low-grade thrombocytopenia, highlighting the potential for long-term sequelae in what is generally viewed as a transient thrombotic thrombocytopenic syndrome.