Antibodies to Heparin–Platelet Factor 4 Complex: Pathogenesis, Epidemiology, and Management of Heparin-Induced Thrombocytopenia in Hemodialysis  Andrew Davenport, MD  American Journal of Kidney Diseases  Volume 54, Issue 2, Pages 361-374 (August 2009) DOI: 10.1053/j.ajkd.2009.03.012 Copyright © 2009 National Kidney Foundation, Inc. Terms and Conditions

Figure 1 Change in peripheral platelet count in the index patient, who was started on prophylactic subcutaneous heparin from the day of admission. American Journal of Kidney Diseases 2009 54, 361-374DOI: (10.1053/j.ajkd.2009.03.012) Copyright © 2009 National Kidney Foundation, Inc. Terms and Conditions

Figure 2 Computed tomographic (CT) chest scan of a patient in whom the dialyzer circuit clotted, who then collapsed when reconnected after a second bolus of low-molecular-weight heparin. The scan shows intra-alveolar edema, typical of pseudo-pulmonary embolus syndrome. American Journal of Kidney Diseases 2009 54, 361-374DOI: (10.1053/j.ajkd.2009.03.012) Copyright © 2009 National Kidney Foundation, Inc. Terms and Conditions

Figure 3 Iceberg model of heparin-induced thrombocytopenia (HIT). Incidence data from Greinacher.5 American Journal of Kidney Diseases 2009 54, 361-374DOI: (10.1053/j.ajkd.2009.03.012) Copyright © 2009 National Kidney Foundation, Inc. Terms and Conditions

Figure 4 Schematic representation of the development of heparin-induced thrombocytopenia (HIT). Heparin binds to the platelet surface and leads to release of platelet factor 4 (PF4). If a critical stoichiometric ratio of heparin to PF4 is achieved, the heparin-PF4 complex undergoes a conformational change that exposes novel epitopes, leading to antibody (Ab) formation. The heparin-PF4 complex–bound antibody then binds to platelets, leading to activation and microparticle release, which activates the contact coagulation cascade to produce thrombin and further platelet activation. The antibody complex also binds endothelial cells through heparin sulfate and activates endothelial cells, leading to local thrombus and endothelial permeability, which causes the pseudo-pulmonary embolus syndrome. Abbreviation: ADP, adenosine diphosphate. American Journal of Kidney Diseases 2009 54, 361-374DOI: (10.1053/j.ajkd.2009.03.012) Copyright © 2009 National Kidney Foundation, Inc. Terms and Conditions

Figure 5 Schematic representation of nonlinear relationship between activated partial thromboplastin time (aPTT) and plasma hirudin concentration compared with ecarin clotting time. American Journal of Kidney Diseases 2009 54, 361-374DOI: (10.1053/j.ajkd.2009.03.012) Copyright © 2009 National Kidney Foundation, Inc. Terms and Conditions

Figure 6 Schematic representation of relationship between plasma concentration of 2 direct reversible thrombin inhibitors, argatroban and bivalirudin, and ecarin clotting time. American Journal of Kidney Diseases 2009 54, 361-374DOI: (10.1053/j.ajkd.2009.03.012) Copyright © 2009 National Kidney Foundation, Inc. Terms and Conditions