Immune pathogenesis of heparin-induced thrombocytopenia

Abstract

The immune response to heparin is one of the most common drug-induced allergies, and yet, atypical for a drug hypersensitivity reaction. Whereas most drug-induced allergies are rare, idiosyncratic and life-long, the allergic response to heparin is common, predictable in certain clinical settings and transient. Advances in the last decade with regards to structural characterisation of the PF4/heparin antigenic complex, contributions of innate immunity and development of animal models have provided insights into the distinctive features of the HIT immune response. Recent descriptions of the crystal structure of the PF4/heparin complex, alongside other biophysical studies, have clarified the structural requirements for immunogenicity and heparin-dependency of antibody formation. Studies of interactions of PF4 with bacterial cell walls as well as epidemiologic associations of anti-PF4/heparin antibody formation and infection suggest a role for immune priming and explain the rapid evolution of an isotype-switched immune response in sensitised patients. Murine models have greatly facilitated investigations of cellular basis of the HIT response and identified a major role for T-cells and marginal zone B-cells, but key findings have yet to be validated in human disease. This chapter will summarise recent investigations of the HIT immune response in the context of major pathways of immune activation and identify areas of uncertainty.

Keywords: Heparin-induced thrombocytopenia; heparin; murine models; platelet factor 4.

Figure 1. A cartoon summarizing a model of PF4/heparin ULC formation {adapted from Cai et. al (32)}

PF4 molecules (dark grey circles) exist in an equilibrium among monomers, dimers and tetramers. Upon binding to heparin (light grey circles), the configuration of the tetramer is stabilized. Binding of heparin to PF4 also stabilizes the heparin in a linear configuration allowing binding of additional PF4. The net result is the generation of stable ultralarge immune complexes. As a result, the open end of the PF4 tetramer is oriented, revealing neo-epitopes that are recognized by HIT-antibody KKO (black). Figure reproduced with permission from the authors.