Polymorphisms of protein tyrosine phosphatase CD148 influence FcγRIIA-dependent platelet activation and the risk of heparin-induced thrombocytopenia.
Heparin-induced thrombocytopenia (HIT) is due primarily to IgG antibodies specific to platelet factor 4/heparin complexes (PF4/Hs) that activate platelets via FcγRIIA. CD148 is a protein tyrosine phosphatase that regulates Src kinases and collagen-induced platelet activation. Three polymorphisms affecting CD148 (Q276P, R326Q, and D872E) were studied in HIT patients and 2 control groups, with or without antibodies to PF4/Hs. Heterozygote status for CD148 276P or 326Q alleles was less frequent in HIT patients, suggesting a protective effect of these polymorphisms. Aggregation tests performed with collagen, HIT plasma, and monoclonal antibodies cross-linking FcγRIIA showed consistent hyporesponsiveness of platelets expressing the 276P/326Q alleles. In addition, platelets expressing the 276P/326Q alleles exhibited a greater sensitivity to the Src family kinases inhibitor dasatinib in response to collagen or ALB6 cross-linking FcγRIIA receptors. Moreover, the activatory phosphorylation of Src family kinases was considerably delayed as well as the phosphorylation of Linker for activation of T cells and phospholipase Cγ2, 2 major signaling proteins downstream from FcγRIIA. In conclusion, this study shows that CD148 polymorphisms affect platelet activation and probably exert a protective effect on the risk of HIT in patients with antibodies to PF4/Hs.
Unité Mixte de Recherche Centre National de la Recherche Scientifique 7292 and Université François Rabelais, Tours, France.
Jérôme
J
Rollin
Claire
C
Pouplard
Marie-Pierre
MP
Gratacap
Dorothée
D
Leroux
Marc-Antoine
MA
May
Michel
M
Aupart
Valérie
V
Gouilleux-Gruart
Bernard
B
Payrastre
Yves
Y
Gruel
D016022:Case-Control Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006493:Heparin / Q000009:adverse effects* / Q000276:immunology / Q000378:metabolism; D006801:Humans; D008297:Male; D015539:Platelet Activation / Q000235:genetics*; D010978:Platelet Factor 4 / Q000276:immunology / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide / Q000502:physiology; D017027:Protein Tyrosine Phosphatases / Q000235:genetics; D054631:Receptor-Like Protein Tyrosine Phosphatases, Class 3 / Q000235:genetics / Q000502:physiology; D017452:Receptors, IgG / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D012307:Risk Factors; D013921:Thrombocytopenia / Q000097:blood / Q000209:etiology / Q000235:genetics*
C445323:FCGR2A protein, human; D017452:Receptors, IgG; D010978:Platelet Factor 4; D006493:Heparin; C486288:PTPRJ protein, human; D017027:Protein Tyrosine Phosphatases; D054631:Receptor-Like Protein Tyrosine Phosphatases, Class 3