Tyrosine Kinase Inhibitor Pazopanib Inhibits Platelet Procoagulant Activity in Renal Cell Carcinoma Patients

摘要: Pazopanib is an angiostatic tyrosine kinase inhibitor (TKI) presently used for cancer treatment, particularly in patients with renal cell carcinoma (RCC). This treatment can be accompanied by mild bleeding as adverse effect. Given the role of protein kinases platelet activation processes, we investigated whether and how pazopanib affect functions purified systems during advanced RCC patients. In isolated platelets from healthy volunteers, dose-dependently reduced collagen-induced integrin secretion, well aggregation. addition diminished glycoprotein (GP) VI-dependent phosphorylation multiple proteins, including Syk. Furthermore, inhibited GPVI-induced Ca2+ elevation, resulting exposure procoagulant phospholipid phosphatidylserine (PS). Upon perfusion control blood over a collagen surface, thrombus size PS exposure. Blood samples 10 were also analyzed before after 14 days monotherapy. caused overall lowering count, 3 out experiencing bleeding. Platelets pazopanib-treated showed significant upon activation. addition, activity was thrombi formed under flow conditions. Control experiments indicated that higher concentrations required to inhibit GPVI-mediated presence plasma. Together, these results suppresses responses way partly antagonized treated patients, effects confined reduction GPVI-dependent Together this may explain tendency observed