Dasatinib Inhibits Procoagulant and Clot Retracting Activities of Human Platelets

• Published in: International journal of molecular sciences Vol. 20; no. 21; p. 5430
• Main Authors: Beke Debreceni, Ildikó, Mezei, Gabriella, Batár, Péter, Illés, Árpád, Kappelmayer, János
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 31.10.2019; MDPI
• Subjects: Abl protein; BCR protein; Binding sites; bleeding; Blood Coagulation - drug effects; Blood Platelets - drug effects; Blood Platelets - metabolism; Chronic myeloid leukemia; Clot Retraction - drug effects; Collagen; Crotalid Venoms - pharmacology; Dasatinib - pharmacology; dasatinib therapy; Experiments; Fusion protein; glycoprotein vi; Humans; Kinases; Lectins, C-Type; Leukemia; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - blood; Myeloid leukemia; Phosphatidylserine; Phosphatidylserines - metabolism; Phosphorylation; Phosphorylation - drug effects; Plasmas (physics); platelet activation; Platelet Activation - drug effects; Protein Kinase Inhibitors - pharmacology; Protein-tyrosine kinase; Pyrimidines - pharmacology; Sarcoma; Signal transduction; src-Family Kinases - metabolism; Thrombin; Thrombin - metabolism; thrombin formation; Tyrosine; dasatinib therapy; thrombin formation; bleeding; platelet activation; glycoprotein VI
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms20215430

Tyrosine kinase inhibitors (TKI) such as the BCR-ABL inhibitor dasatinib and nilotinib are highly effective therapies for chronic myeloid leukemia (CML). However, several lines of evidence suggest that dasatinib can induce bleeding which may be due to impaired collagen-induced platelet adhesion, aggregation, and secretion. Sarcoma family kinases (SFK) play central role in the GPVI-induced signaling pathway. We aimed to investigate whether and how dasatinib can modulate SFK-mediated platelet procoagulant activity in a purified system and in dasatinib/nilotinib treated CML patients. In platelet rich plasmas of healthy volunteers, dasatinib dose-dependently reduced convulxin-induced phosphatidylserine exposure and attenuated thrombin formation. Similarly to these changes, integrin activation and clot retraction were also significantly inhibited by 100 nM dasatinib. Platelets isolated from dasatinib treated patients showed a significantly lower phosphatidylserine expression upon convulxin activation compared to premedication levels. In these samples, thrombin generation was significantly slower, and the quantity of formed thrombin was less compared to the trough sample. Western blot analyses showed decreased phosphorylation levels of the C-terminal tail and the activation loop of SFKs upon dasatinib administration. Taken together, these results suggest that dasatinib inhibits the formation of procoagulant platelets via the GPVI receptor by inhibiting phosphorylation of SFKs.