Platelet factor 4 antibody persistence and long-term pathogenicity in vaccine-induced immune thrombotic thrombocytopenia

Background Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a transient prothrombotic process, although recent data suggests that VITT anti-platelet factor 4 (PF4) antibodies are more persistent than those in heparin-induced thrombocytopenia. Objectives We sought to interrogate whether anti-PF4 antibody persistence in VITT is related to the continued persistence of antibody clones from the acute phase or to the development of novel anti-PF4 antibodies due to epitope spreading. Patients/Methods Samples 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) were studied in antigenic/functional assays and by mass spectrometry. One ChAdOx1 nCoV-19-associated VITT patient was tested >4 years after acute presentation. Results Upon affinity-enrichment of anti-PF4 antibodies, mono/oligoclonal anti-PF4 antibodies were observed despite negative results in serum protein electrophoresis/"Mass-Fix" testing of 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 lambda light chains, one VITT patient produced antibodies with a kappa light chain. Long-term thrombocytopenia/thrombosis was not seen in any of these six patients, however, platelet-activating anti-PF4 antibodies were seen four years after the acute event in an additional ChAdOx1 nCoV-19-associated VITT patient with chronic low-grade thrombocytopenia. Conclusions VITT, unlike monoclonal gammopathy of thrombotic significance, appears to be an MGUS-negative state, but needs confirmation in larger studies. VITT antibodies can be comprised of lambda or kappa light chains, and some VITT patients exhibit persistent thrombocytopenia many years after the acute event.