Polymorphisms of protein tyrosine phosphatase CD148 influence FcγRIIA-dependent platelet activation and the risk of heparin-induced thrombocytopenia.

Abstract

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.

• Authors: Jérôme Rollin, Claire Pouplard, Marie-Pierre Gratacap, Dorothée Leroux, Marc-Antoine May, Michel Aupart, Valérie Gouilleux-Gruart, Bernard Payrastre, Yves Gruel
• Journal: Blood (Blood) Vol. 120 Issue 6 Pg. 1309-16 (Aug 09 2012) ISSN: 1528-0020 [Electronic] United States
• PMID: 22677127 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• FCGR2A protein, human
• Receptors, IgG
• Platelet Factor 4
• Heparin
• PTPRJ protein, human
• Protein Tyrosine Phosphatases
• Receptor-Like Protein Tyrosine Phosphatases, Class 3

Topics

• Case-Control Studies
• Female
• Genetic Predisposition to Disease
• Genotype
• Heparin (adverse effects, immunology, metabolism)
• Humans
• Male
• Platelet Activation (genetics)
• Platelet Factor 4 (immunology, metabolism)
• Polymorphism, Single Nucleotide (physiology)
• Protein Tyrosine Phosphatases (genetics)
• Receptor-Like Protein Tyrosine Phosphatases, Class 3 (genetics, physiology)
• Receptors, IgG (genetics, metabolism, physiology)
• Risk Factors
• Thrombocytopenia (blood, etiology, genetics)