Heparin-induced thrombocytopenia: research and clinical updates

Abstract

Heparin-induced thrombocytopenia (HIT) remains an important diagnosis to consider in hospitalized patients developing thrombocytopenia. HIT is an immune-mediated prothrombotic disorder caused by antibodies to platelet factor 4 (PF4) and heparin. Recent basic scientific studies have advanced our understanding of disease pathogenesis through studies of the PF4/heparin structure, immune mechanisms, and cellular basis of thrombosis. Clinical advances have also occurred in areas of HIT prevention, description of disease variants, and diagnostic strategies. Emerging anticoagulants with the potential to change HIT treatment are evolving, although with limited data. This review will provide a current perspective on HIT pathogenesis, disease features, diagnostic strategies, and role of emerging therapies for the management of HIT.

Figure 1.

Crystal structure of the PF4/heparin complex and formation of ultralarge complexes. (A) Overall structure of the PF4/fondaparinux complex. Fondaparinux makes contact with a single PF4 tetramer in the groove among the monomers on one side of the asymmetric tetramer. Monomers A, B, C, and D in one PF4 tetramer are colored in green, cyan, magenta, and yellow, respectively. (B) Analysis of crystal lattice reveals a molecular pathway for the formation of antigenic complexes. A fragment of heparin first binds within the groove of one PF4 tetramer (limon, left); binding of the first PF4 tetramer imparts a local linearized structure on heparin, which enhances the binding of a second tetramer (pale green, middle); and progression of this process eventuates in the formation of ultralarge antigenic complexes (right). Reprinted from Cai et al with permission.

Figure 2.

Visualization of thrombus formation by a HIT-like monoclonal antibody. Confocal microscopy images of fixed thrombi formed in human whole blood perfused with a control antibody (RTO) or a HIT-like antibody (KKO), and PF4. Platelet aggregates are shown in green, fibrin fibers visualized by adding of Alexa 647-labeled fibrinogen are purple, and white blood cells are shown in cyan (overlap of blue nuclear dye is Hoechst and green is calcein AM). The attachment points of fibrin to platelets are white because of the superposition of purple and green colors. Reprinted from Tutweiler et al with permission.