Abstract
Heparin-induced thrombocytopenia (HIT) is an unpredictable, complex, immune-mediated adverse drug reaction associated with a high mortality. Despite decades of research into HIT, fundamental knowledge gaps persist regarding HIT likely due to the complex and unusual nature of the HIT immune response. Such knowledge gaps include the identity of a HIT immunogen, the intrinsic roles of various cell types and their interactions, and the molecular basis that distinguishes pathogenic and non-pathogenic PF4/heparin antibodies. While a key feature of HIT, thrombocytopenia, implicates platelets as a seminal cell fragment in HIT pathogenesis, strong evidence exists for critical roles of multiple cell types. The rise in omic technologies over the last decade has resulted in a number of agnostic, whole system approaches for biological research that may be especially informative for complex phenotypes. Applying multi-omics techniques to HIT has the potential to bring new insights into HIT pathophysiology and identify biomarkers with clinical utility. In this review, we review the clinical, immunological, and molecular features of HIT with emphasis on key cell types and their roles. We then address the applicability of several omic techniques underutilized in HIT, which have the potential to fill knowledge gaps related to HIT biology.
Highlights
Heparin is a widely used anticoagulant indicated for a broad range of diseases and procedures
heparin-induced thrombocytopenia (HIT) occurs in 0.2–2.7% of patients exposed to heparin anticoagulants and this risk increases in patients undergoing cardiac surgery (Warkentin et al, 1995; Warkentin et al, 2000; Girolami et al, 2003; Martel et al, 2005; Smythe et al, 2007)
An individual’s neutrophil response to ultra-large complexes (ULCs) remained fixed over a longitudinal 1-year period (Duarte et al, 2019), suggesting that susceptibility to neutrophil activation by ULCs is specific to the host and may be genetic in nature
Summary
Heparin is a widely used anticoagulant indicated for a broad range of diseases and procedures. An individual’s neutrophil response to ULCs remained fixed over a longitudinal 1-year period (Duarte et al, 2019), suggesting that susceptibility to neutrophil activation by ULCs is specific to the host and may be genetic in nature These studies indicate that NETosis is a driver of thrombosis in HIT, but inter-individual variability in neutrophil count and heterogeneity, including polymorphism in cell surface receptors, are potential modifiers of HITT risk. EC indicates endothelial cells; FcγRIIa, low affinity immunoglobulin gamma Fc region receptor II-a; GAG, glycosaminoglycans; ICAM-1, intracellular adhesion molecule 1; NET, neutrophil extracellular traps; PF4-VWF-IgG, platelet factor 4–von Willebrand factor–immunoglobulin G complexes; TULA-2, T-Cell Ubiquitin Ligand-2; TF, tissue factor; ULC, ultra-large complexes; VCAM, vascular cell adhesion molecule; VWF, von Willebrand factor sequencing is a cost-effective solution to surveying the communities of a bacterial microbiome via a single gene, the 16S ribosomal gene. As this theory of a misguided immune response in HIT has yet to identify specific classes or even phyla of bacteria, sequencing the microbiome may provide powerful insights into HIT pathogenesis
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