LB 02.5 - Distinct Antibody Groups in Patients With Vaccine-Induced Immune Thrombotic Thrombocytopenia (VITT) And Their Clinical Implications

Background: VITT is a rare complication of adenoviral vector-based vaccines against the SARS-CoV-2 virus and caused by antibodies against platelet factor 4 (PF4). It is characterized by thrombocytopenia and thrombosis, including cerebral venous sinus thrombosis (CVST) without any clear pathological mechanism for this occurrence.

Aims: The aim of this study was to identify molecular and biochemical characteristics of the VITT anti-PF4 antibodies that correlate with the clinical presentation of CVST.

Methods: In vitro platelet activation assays performed using the PF4-SRA.
Binding kinetics of VITT antibodies using biolayer interferometry (BLI).
Alanine scanning mutagenesis (ASM) was used to identify the sites of VITT antibodies on PF4.

Results: Of the 39 VITT patients, 17 (43.6%) were classified uas PF4-dependent and 22 (56.4%) were PF4-independent. In the PF4-dependent cohort, 1/17 (5.9%) had CVST compared with 11/22 (50.0%) in the PF4-independent cohort (p < 0.05)
The binding response of antibodies from VITT patients in the PF4-independent cohort (n = 5) was significantly higher than the PF4-dependent cohort (n = 7) (Figure 1, p < 0.05).
Every VITT sample (n=14) tested in ASM from both the PF4-dependent (n = 7) and PF4-independent (n = 7) cohorts bound to the heparin binding region. In addition, anti-PF4 antibodies from the PF4-independent cohort also had another binding site on PF4 distant from the heparin binding region (Figure 2) and consistent with a binding region on PF4 important for the binding of HIT antibodies.

Conclusion(s): A distinct subset of VITT anti-PF4 antibodies induce platelet activation without the addition of exogenous PF4 in the SRA and bind to two unique regions on the PF4 tetramer and correlate with the presence f CVST in those patients.