Surasak WichaiyoSaovaros SvastiWasu SupharattanasitthiNoppawan Phumala MoralesMahidol UniversityInstitute of Molecular Biosciences, Mahidol University2022-08-042022-08-042021-12-01Journal of Thrombosis and Haemostasis. Vol.19, No.12 (2021), 3154-316715387836153879332-s2.0-85113680041https://repository.li.mahidol.ac.th/handle/20.500.14594/77544Background: Inflammatory bleeding due to depletion of platelet glycoprotein VI (GPVI) and C-type lectin-like receptor 2 (CLEC-2) has been proposed as a potential novel mechanism to promote skin wound healing. Dasatinib inhibits a broad range of tyrosine kinases, including Src and Syk, the signaling molecules downstream of GPVI and CLEC-2. Objectives: To investigate whether dasatinib affects skin wound healing. Methods: A single (4-mm diameter) full-thickness excisional skin wound was generated in mice. Dasatinib (5 or 10 mg/kg) or dimethyl sulfoxide (DMSO) vehicle was intraperitoneally injected daily during the first 4 days. The wound was monitored over 9 days post injury. Results: Dasatinib induced loss of vascular integrity during the inflammatory phase of wound repair (day 1 to day 3 post injury), which was associated with the inhibition of platelet function stimulated by collagen and rhodocytin, the ligands for GPVI and CLEC-2, respectively. Dasatinib-treated mice, particularly at 5 mg/kg, exhibited accelerated wound closure compared to DMSO-treated controls. Transient bleeding into the wound during the inflammatory phase in dasatinib-treated mice allowed for extravasation of fibrinogen. The increased deposition of fibrinogen and fibrin in the wound on day 3 post injury was associated with the augmented progression of re-epithelialization and angiogenesis, attenuated infiltration of neutrophils and macrophages, and decreased levels of tumor necrosis factor-α (TNF-α). Conclusions: Our data show that dasatinib promotes skin wound healing, and the mechanisms include blocking GPVI- and CLEC-2-mediated platelet activation, leading to self-limited inflammatory bleeding and fibrinogen/fibrin deposition, in association with reduced inflammation, increased re-epithelialization, and enhanced angiogenesis.Mahidol UniversityMedicineArticleSCOPUS10.1111/jth.15499