title: Pathophysiology of heparin-induced thrombocytopenia. Clinical and diagnostic implications--a review.
abstract: OBJECTIVE
  This review of heparin-induced thrombocytopenia (HIT), the most frequent and dangerous side effect of heparin exposure, covers the epidemiology, pathophysiology, clinical presentation, diagnosis, and treatment of this disease syndrome.
  
  
  METHODS
  Current consensus of opinion is given based on literature reports, as well as new information where available. A comprehensive analysis of the reasons for discrepancies in incidence numbers is given. The currently known mechanism is that HIT is mediated by an antibody to the complex of heparin->platelet factor 4, which binds to the Fc receptor on platelets. New evidence suggests a functional heterogeneity in the anti-heparin-platelet factor 4 antibodies generated to heparin, and a "superactive" heparin-platelet factor 4 antibody that does not require the presence of heparin to promote platelet activation or aggregation has been identified. Up-regulation of cell adhesion molecules and inflammatory markers, as well as preactivation of platelets/endothelial cells/leukocytes, are also considered to be related to the pathophysiology of HIT. Issues related to the specificity of currently available and new laboratory assays that support a clinical diagnosis are addressed in relation to the serotonin-release assay. Past experience with various anticoagulant treatments is reviewed with a focus on the recent successes of thrombin inhibitors and platelet GPIIb/IIIa inhibitors to combat the platelet activation and severe thrombotic episodes associated with HIT.
  
  
  CONCLUSIONS
  The pathophysiology of HIT is multifactorial. However, the primary factor in the mediation of the cellular activation is due to the generation of an antibody to the heparin-platelet factor 4 complex. This review is written as a reference for HIT research.
authors.affiliation: Department of Medical and Surgical Sciences, University of Padua, Medical School, Padua, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Fabris
authors.forename: S
authors.initials: S
authors.lastname: Ahmad
authors.forename: G
authors.initials: G
authors.lastname: Cella
authors.forename: W P
authors.initials: WP
authors.lastname: Jeske
authors.forename: J M
authors.initials: JM
authors.lastname: Walenga
authors.forename: J
authors.initials: J
authors.lastname: Fareed
mesh_terms: D006493:Heparin / Q000009:adverse effects*; D006801:Humans; D008954:Models, Biological; D013921:Thrombocytopenia / Q000139:chemically induced / Q000503:physiopathology*
chemical_list: D006493:Heparin