Heparin-induced thrombocytopenia and other immune thrombocytopenias: lessons from mouse models.
The prototype immune thrombocytopenia is (auto)immune thrombocytopenic purpura, ITP. The major issues in the pathophysiology, diagnosis, and therapy of ITP are presented. Mouse models of the pathophysiology of ITP have allowed greater understanding of the role of antiplatelet antibodies and of antibody effector mechanisms. In addition, there has been a substantial increase in interest in the use of mouse models to understand the mechanisms of action of therapeutics for ITP, with notable progress for intravenous immunoglobulin (IVIG) and anti-red blood cell therapies. The immune-mediated thrombocytopenia and thrombosis syndromes are a common cause of morbidity and mortality; the prototype is heparin-induced thrombocytopenia and thrombosis (HITT). There has been substantial progress in understanding the pathophysiology, diagnosis, and therapy of HITT in the last decade, but there remain major questions. The four necessary and sufficient elements for HITT in vivo were established in our mouse model (namely platelet factor 4 [PF4], heparin, antibody to the heparin/PF4 complex, and platelet Fc receptor for immunoglobulin G [FcgammaRIIa]). Currently, our HITT mouse models are being used to address a number of questions. For example, what are the roles of antibody titer, isotype, and epitope targets? Are there genetic determinants of platelet activation, such as the platelet FcgammaRIIa receptor density, operable in HITT? What are the roles of tissue factor/factor VIIa (TF/VIIa), monocytes, and blood cell-derived microparticles? What is the contribution of pre-existing endothelial cell (EC) dysfunction, and/or induced EC dysfunction? As in many human disorders, preclinical mouse models will continue to be important in the immune thrombocytopenia syndromes to achieve translation into improved patient care.
McKenzie
Steven E
SE
Cardeza Foundation for Hematologic Research, Division of Hematology, Department of Medicine, Thomas Jefferson University, Philadelphia, PA 19107, USA. steven.mckenzie@mail.tju.edu
Reilly
Michael P
MP
D000818:Animals; D000906:Antibodies / Q000737:chemistry; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000166:cytology; D006493:Heparin / Q000494:pharmacology*; D006801:Humans; D016756:Immunoglobulins, Intravenous / Q000627:therapeutic use; D051379:Mice; D008954:Models, Biological; D013921:Thrombocytopenia / Q000139:chemically induced* / Q000175:diagnosis / Q000276:immunology*
D000906:Antibodies; D016756:Immunoglobulins, Intravenous; D006493:Heparin