Increased risk of thrombosis in FcγRIIA 131RR patients with HIT due to defective control of platelet activation by plasma IgG2
Autor: | Rollin, Jérôme, Pouplard, Claire, Sung, Hsueh Cheng, Leroux, Dorothée, Saada, Armand, Gouilleux-Gruart, Valérie, Thibault, Gilles, Gruel, Yves, Cheng Sung, Hsueh |
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Přispěvatelé: | LAB'URBA (LAB'URBA), Université Paris-Est Marne-la-Vallée (UPEM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Génétique, immunothérapie, chimie et cancer (GICC), UMR 7292 CNRS [2012-2017] (GICC UMR 7292 CNRS), Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS), CHU Trousseau [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Université de Tours-Centre National de la Recherche Scientifique (CNRS) |
Jazyk: | angličtina |
Rok vydání: | 2015 |
Předmět: |
Genotype
medicine.drug_class [SDV]Life Sciences [q-bio] Immunology Monoclonal antibody Biochemistry Tissue factor medicine Humans Platelet Platelet activation Whole blood Polymorphism Genetic biology Heparin business.industry Receptors IgG Anticoagulants Thrombosis Cell Biology Hematology Platelet Activation Thrombocytopenia 3. Good health Immunoglobulin G biology.protein Antibody business Cell activation medicine.drug |
Zdroj: | Blood Blood, American Society of Hematology, 2015, 125 (15), pp.2397-2404. ⟨10.1182/blood-2014-09-594515⟩ |
ISSN: | 0006-4971 1528-0020 |
DOI: | 10.1182/blood-2014-09-594515⟩ |
Popis: | International audience; 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. |
Databáze: | OpenAIRE |
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