title: Increased risk of thrombosis in FcγRIIA 131RR patients with HIT due to defective control of platelet activation by plasma IgG2.
abstract: Thrombosis results in heparin-induced thrombocytopenia (HIT) from cellular activation involving Fc receptors. In this study, the FcγRIIA 131RR genotype was found to increase the risk of thrombosis in HIT patients (odds ratio: 5.9; 95% confidence interval: 1.7-20). When platelet aggregation tests (PATs) were performed with platelet-rich plasma (PRP), a shorter lag time was measured in 131RR donors compared to individuals with the HR and HH genotypes in response to HIT plasma or 5B9, a recently developed humanized monoclonal antibody to PF4/heparin. Importantly, this difference was no longer detectable when PATs were performed with washed platelets or immunoglobulin (Ig)G-depleted PRP. Moreover, polyclonal IgG or monoclonal IgG1 added to IgG-depleted PRP increased the lag time in response to 5B9. HH platelets were also sensitive to IgG2, which in contrast, failed to inhibit the response of 131RR platelets to 5B9. Finally, higher tissue factor messenger RNA levels were measured in the whole blood of 131RR donors after activation by HIT antibodies, with increased phospholipid procoagulant activity. These results demonstrate that HIT patients homozygous for the FcγRIIA 131R allele have a higher risk of thrombosis, probably due to increased cell activation by antibodies to PF4/heparin, with a lower inhibitory effect of endogenous IgG, especially from the IgG2 subclass.
authors: Unité Mixte de Recherche 7292, Centre National de la Recherche Scientifique, Université François Rabelais, Tours, France; Laboratoire d'Hématologie-Hémostase, and.
authors: Jérôme
authors: J
authors: Rollin
authors: Unité Mixte de Recherche 7292, Centre National de la Recherche Scientifique, Université François Rabelais, Tours, France; Laboratoire d'Hématologie-Hémostase, and.
authors: Claire
authors: C
authors: Pouplard
authors: Unité Mixte de Recherche 7292, Centre National de la Recherche Scientifique, Université François Rabelais, Tours, France;
authors: Hsueh Cheng
authors: HC
authors: Sung
authors: Unité Mixte de Recherche 7292, Centre National de la Recherche Scientifique, Université François Rabelais, Tours, France; Laboratoire d'Hématologie-Hémostase, and.
authors: Dorothée
authors: D
authors: Leroux
authors: Laboratoire d'Hématologie-Hémostase, and.
authors: Armand
authors: A
authors: Saada
authors: Unité Mixte de Recherche 7292, Centre National de la Recherche Scientifique, Université François Rabelais, Tours, France; Laboratoire d'Immunologie, Centre Régional Hospitalier Universitaire de Tours, Tours, France.
authors: Valérie
authors: V
authors: Gouilleux-Gruart
authors: Unité Mixte de Recherche 7292, Centre National de la Recherche Scientifique, Université François Rabelais, Tours, France; Laboratoire d'Immunologie, Centre Régional Hospitalier Universitaire de Tours, Tours, France.
authors: Gilles
authors: G
authors: Thibault
authors: Unité Mixte de Recherche 7292, Centre National de la Recherche Scientifique, Université François Rabelais, Tours, France; Laboratoire d'Hématologie-Hémostase, and.
authors: Yves
authors: Y
authors: Gruel
mesh_terms: D000925:Anticoagulants / Q000009:adverse effects*; D005838:Genotype; D006493:Heparin / Q000009:adverse effects*; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood / Q000276:immunology*; D015539:Platelet Activation; D011110:Polymorphism, Genetic; D017452:Receptors, IgG / Q000235:genetics / Q000276:immunology*; D013921:Thrombocytopenia / Q000097:blood / Q000139:chemically induced / Q000150:complications* / Q000276:immunology; D013927:Thrombosis / Q000097:blood / Q000209:etiology* / Q000235:genetics / Q000276:immunology
chemical_list: D000925:Anticoagulants; C080568:Fc gamma receptor IIA; D007074:Immunoglobulin G; D017452:Receptors, IgG; D006493:Heparin