Role of SHP2 (PTPN11) in glycoprotein VI-dependent thrombus formation: Improved platelet responsiveness by the allosteric drug SHP099 in Noonan syndrome patients

• Published in: Thrombosis research 2023-08, Vol.228, p.105-116
• Main Authors: Fernández, Delia I., Diender, Marije, Hermida-Nogueira, Lidia, Huang, Jingnan, Veiras, Sonia, Henskens, Yvonne M.C., te Loo, Maroeska W.M., Heemskerk, Johan W.M., Kuijpers, Marijke J.E., García, Ángel
• Format: Article
• Language: English
• Subjects: Blood Platelets - metabolism; Collagen - metabolism; Fibrin - metabolism; Glycoprotein VI; Humans; Noonan syndrome; Noonan Syndrome - drug therapy; Noonan Syndrome - genetics; Noonan Syndrome - metabolism; Platelet; Platelet Glycoprotein GPIIb-IIIa Complex - metabolism; Platelet Membrane Glycoproteins; Protein Tyrosine Phosphatase, Non-Receptor Type 11 - metabolism; PTPN11; SHP099; SHP2; Thromboplastin - metabolism; Thrombosis
• ISSN: 0049-3848; 1879-2472
• DOI: 10.1016/j.thromres.2023.06.001

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. 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. 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. 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. [Display omitted] •The PTPN11 inhibitor SHP099 was used to study effects in platelets.•SHP099 increased collagen-induced thrombus build-up in whole blood microfluidics.•SHP099 enhanced platelet- and shear-dependent coagulation.•SHP099 restored thrombus formation in Noonan syndrome patients with mutated PTPN11.