| First Author | Zhou Y | Year | 2016 |
| Journal | Arterioscler Thromb Vasc Biol | Volume | 36 |
| Issue | 12 | Pages | 2315-2323 |
| PubMed ID | 27765766 | Mgi Jnum | J:248701 |
| Mgi Id | MGI:6094478 | Doi | 10.1161/ATVBAHA.116.307979 |
| Citation | Zhou Y, et al. (2016) TULA-2 (T-Cell Ubiquitin Ligand-2) Inhibits the Platelet Fc Receptor for IgG IIA (FcgammaRIIA) Signaling Pathway and Heparin-Induced Thrombocytopenia in Mice. Arterioscler Thromb Vasc Biol 36(12):2315-2323 |
| abstractText | OBJECTIVE: The objective of this study is to investigate the role of T-cell ubiquitin ligand-2 (TULA-2) in the platelet Fc receptor for IgG IIA (FcgammaRIIA) pathway and in the pathogenesis of heparin-induced thrombocytopenia (HIT). APPROACH AND RESULTS: HIT is a life-threatening thrombotic disease in which IgG antibodies against the heparin-platelet factor 4 complex activate platelets via FcgammaRIIA. We reported previously differential expression of TULA-2 in human population was linked to FcgammaRIIA responsiveness. In this study, we investigated the role of TULA-2, a protein phosphatase, in the FcgammaRIIA pathway and HIT pathogenesis by crossing TULA-2(-)(/-) mice with transgenic FcgammaRIIA (+/+) mice. Ablation of TULA-2 resulted in hyperphosphorylation of spleen tyrosine kinase, linker for the activation of T cells, and phospholipase Cgamma2 in platelets via FcgammaRIIA activation. Platelet integrin activation, granule secretion, phosphatidylserine exposure, and aggregation were also enhanced in TULA-2(-)(/-) murine platelets. Compared with wild-type mice, TULA-2(-)(/-) mice showed aggravated antibody-mediated thrombocytopenia, augmented thrombin generation, and shortened tail bleeding time. In contrast, there was no significant difference between TULA-2(-)(/-) and TULA-2(+/+) platelets in platelet spreading and clot retraction. Of note, heterozygous TULA-2(+/-) mice, whose platelets contained 50% as much protein as the TULA-2(+/+) platelets, showed significantly increased platelet reactivity and more severe thrombocytopenia in vivo compared with TULA-2(+/+) mice. CONCLUSIONS: Together, the data demonstrate that not only the absence of TULA-2 but also the relative level of TULA-2 expression modulates FcgammaRIIA-mediated platelet reactivity and HIT in vivo. TULA-2 expression could be a valuable marker for HIT and inhibiting TULA-2 may serve as a potential therapy to reverse the bleeding adverse effect of anticoagulants. |
