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Role of SHP2 (PTPN11) in glycoprotein VI-dependent thrombus formation: Improved platelet responsiveness by the allosteric drug SHP099 in Noonan syndrome patients.
- Source :
-
Thrombosis research [Thromb Res] 2023 Aug; Vol. 228, pp. 105-116. Date of Electronic Publication: 2023 Jun 05. - Publication Year :
- 2023
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Abstract
- Introduction: The protein tyrosine phosphatase SHP2 (PTPN11) is a negative regulator of glycoprotein VI (GPVI)-induced platelet signal under certain conditions. Clinical trials with derivatives of the allosteric drug SHP099, inhibiting SHP2, are ongoing as potential therapy for solid cancers. Gain-of-function mutations of the PTPN11 gene are observed in part of the patients with the Noonan syndrome, associated with a mild bleeding disorder. Assessment of the effects of SHP2 inhibition in platelets from controls and Noonan syndrome patients.<br />Materials and Methods: Washed human platelets were incubated with SHP099 and stimulated with collagen-related peptide (CRP) for stirred aggregation and flow cytometric measurements. Whole-blood microfluidics assays using a dosed collagen and tissue factor coating were performed to assess shear-dependent thrombus and fibrin formation. Effects on clot formation were evaluated by thromboelastometry.<br />Results: Pharmacological inhibition of SHP2 did not alter GPVI-dependent platelet aggregation under stirring, but it enhanced integrin αIIbβ3 activation in response to CRP. Using whole-blood microfluidics, SHP099 increased the thrombus buildup on collagen surfaces. In the presence of tissue factor and coagulation, SHP099 increased thrombus size and reduced time to fibrin formation. Blood from PTPN11-mutated Noonan syndrome patients, with low platelet responsiveness, after ex vivo treatment with SHP099 showed a normalized platelet function. In thromboelastometry, SHP2 inhibition tended to increase tissue factor-induced blood clotting profiles with tranexamic acid, preventing fibrinolysis.<br />Conclusion: Pharmacological inhibition of SHP2 by the allosteric drug SHP099 enhances GPVI-induced platelet activation under shear conditions with a potential to improve platelet functions of Noonan syndrome patients.<br />Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.<br /> (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)
- Subjects :
- Humans
Blood Platelets metabolism
Thromboplastin metabolism
Platelet Glycoprotein GPIIb-IIIa Complex metabolism
Collagen metabolism
Fibrin metabolism
Platelet Membrane Glycoproteins
Protein Tyrosine Phosphatase, Non-Receptor Type 11 metabolism
Noonan Syndrome drug therapy
Noonan Syndrome genetics
Noonan Syndrome metabolism
Thrombosis
Subjects
Details
- Language :
- English
- ISSN :
- 1879-2472
- Volume :
- 228
- Database :
- MEDLINE
- Journal :
- Thrombosis research
- Publication Type :
- Academic Journal
- Accession number :
- 37302266
- Full Text :
- https://doi.org/10.1016/j.thromres.2023.06.001