Longitudinal Laboratory and Clinical Outcomes in Vaccine-Induced Immune Thrombotic Thrombocytopenia after 3 Years

Introduction: Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a rare yet severe complication that occurs 5 - 30 days after adenoviral vector-based vaccines against SARS-CoV-2. Patients with VITT present with thrombocytopenia and venous or arterial thrombosis, in unusual locations such as cerebral venous sinus thrombosis (CVST). The pathophysiology of VITT involves the generation of antibodies against platelet factor 4 (PF4, CXCL4), forming immune complexes that activate platelets, thereby leading to thrombosis. VITT is similar to the immune-mediated drug reaction known as heparin-induced thrombocytopenia (HIT), which presents as thrombocytopenia with an increased risk of thrombosis in patients with recent heparin administration. It has been shown that anti-PF4/heparin antibodies in HIT patients typically persist for 50 to 85 days. Initial reports have shown that some patients with VITT have persistent anti-PF4 antibodies without ongoing or new clinical symptoms; however, a description of VITT antibodies and clinical symptoms after prolonged follow-up is currently lacking. In this study, we report VITT anti-PF4 antibody levels, their ability to activate platelets, and clinical outcomes from VITT patients in Canada after nearly 3 years. Methods: VITT patient follow-up samples were studied (n = 30) after a median of 23.8 months (4.2 - 35.5 months) post-vaccination with an adenoviral vector-based vaccine against SARS-CoV-2. VITT follow-up samples were tested for the presence of anti-PF4 IgG/A/M antibodies using a commercially available enzyme immunoassay [EIA; positive optical density (OD) 405nm ≥ 0.4] and tested for their functional ability to activate platelets using the PF4-serotonin release assay (SRA; positive ≥ 20% 14C-serotonin release) with increasing concentrations of exogenous human PF4. Self-reported clinical outcomes from VITT patients were also collected. Results: In our cohort of VITT patients, anti-PF4 IgG/A/M antibodies were detected in 22 out of 30 (73.3%) individuals at their most recent follow-up. Of the 22 VITT patients who tested positive for anti-PF4 antibodies, 14 (63.6%) had platelet-activating anti-PF4 antibodies. Clinical follow-up data were available for 8 out of the 14 (57.1%) patients with persistent platelet-activating antibodies. Among these patients, 7 out of 8 (87.5%) continued to receive anticoagulant therapy (Apixaban or Rivaroxaban; n = 5) or anti-platelet therapy (Aspirin; n = 2). There were no reported cases of recurrent thrombosis. Conclusion: The persistence of anti-PF4 antibodies in VITT contrasts with the transient nature of HIT antibodies, which typically become undetectable after 2 to 3 months following heparin administration. None of the VITT patients experienced thrombotic events despite having persistent pathogenic anti-PF4 antibodies, possibly due to continued treatment. Therefore, ongoing surveillance of VITT patients is imperative to fully understand persistent serological and clinical outcomes such as the risk of recurrent thrombosis over time.

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