Friday, April 19, 2024
4/19/2024
ABSTRACT Despite decades of research into the immunopathology of heparin-induced thrombocytopenia (HIT), an unpredictable, life-threatening, immune-mediated adverse reaction to heparin treatment, a fundamental knowledge gap regarding the cause of HIT remains. The inability to predict HIT represents a considerable liability associated with heparin, which is given to 12 million individuals or one third of all hospitalized patients every year. Because the exact cellular and molecular mechanisms underlying HIT have yet to be identified, including intrinsic immune cell roles and the difference between pathogenic and non-pathogenic antibodies, there is an essential need to apply alternative approaches to understand the biological basis for HIT and to identify clinically implementable biomarkers. The PI’s central hypothesis is that immunogenomic variation impacts HIT pathogenesis and can be used to differentiate non-pathogenic and pathogenic PF4/heparin antibodies, which are produced by immune cell populations intrinsic to HIT. Based on strong preliminary data that constitute the largest genome-wide association study (GWAS) for HIT, the working hypothesis is that the presence of the HLA-DRB3*01:01 allele combined with proliferating Vß 5.1 family T-Cell receptor (TCR) clonotypes in Th2 cells predisposes patients to pathogenic PF4/heparin antibody production, and these antibodies result in high HIT risk in patients with the ABO O blood group. We will pursue three Specific Aims (SAs) to test the central hypothesis: (SA1) Determine the role of ABO variation in HIT; (SA2) Determine the influence of genomic variation on PF4/heparin antibody production; and (SA3) Identify intrinsic immune cell involvement in HIT. In SA #1, deep ABO sequencing data will be utilized in our large cohort of functional assay-confirmed HIT patients to elucidate the role of ABO variability in HIT. In SA #2, we will perform several GWAS to determine genetic influences of PF4/heparin antibody production, including diverse populations, and differentiate genetic influences on pathogenic versus non-pathogenic antibodies. In SA#3, we will sample paired cell populations during the acute phase of HIT and after HIT resolution and conduct focused single cell (sc) studies to determine proliferation of TCR clonotypes and activated cell populations using sc-RNA-TCR-CITE-seq. Our studies overcome major limitations of previous genomic studies of HIT by incorporating large, diverse cohorts, a PF4/heparin antibody- positive case group, and functional assay confirmation of HIT cases. This work is technically and conceptually innovative as it leverages a sc-RNA-TCR-CITE-seq approach, utilizes large, unique HIT cohorts, and advances an original model of HIT immunopathogenesis. We expect to provide mechanistic insights into HIT pathology and advance a framework for clinical translation of HIT biomarkers with direct application to other adverse drug reactions. The proposed studies leverage large-scale biological data to distinguish patients pre-disposed to HIT, potentially shifting clinical practice from treatment to prevention through biomarker-guided heparin treatment.
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