Multiparameter Evaluation of the Platelet-Inhibitory Effects of Tyrosine Kinase Inhibitors Used for Cancer Treatment

Abstract

Current antiplatelet drugs for the treatment of arterial thrombosis often coincide with increased bleeding risk. Several tyrosine kinase inhibitors (TKIs) for cancer treatment inhibit platelet function, with minor reported bleeding symptoms. The aim of this study was to compare the antiplatelet properties of eight TKIs to explore their possible repurposing as antiplatelet drugs. Samples of whole blood, platelet-rich plasma (PRP), or isolated platelets from healthy donors were treated with TKI or the vehicle. Measurements of platelet aggregation, activation, intracellular calcium mobilization, and whole-blood thrombus formation under flow were performed. Dasatinib and sunitinib dose-dependently reduced collagen-induced aggregation in PRP and washed platelets; pazopanib, cabozantinib, and vatalanib inhibited this response in washed platelets only; and fostamatinib, axitinib, and lapatinib showed no/limited effects. Fostamatinib reduced thrombus formation by approximately 50% on collagen and other substrates. Pazopanib, sunitinib, dasatinib, axitinib, and vatalanib mildly reduced thrombus formation on collagen by 10–50%. Intracellular calcium responses in isolated platelets were inhibited by dasatinib (>90%), fostamatinib (57%), sunitinib (77%), and pazopanib (82%). Upon glycoprotein-VI receptor stimulation, fostamatinib, cabozantinib, and vatalanib decreased highly activated platelet populations by approximately 15%, while increasing resting populations by 39%. In conclusion, the TKIs with the highest affinities for platelet-expressed molecular targets most strongly inhibited platelet functions. Dasatinib, fostamatinib, sunitinib, and pazopanib interfered in early collagen receptor-induced molecular-signaling compared with cabozantinib and vatalanib. Fostamatinib, sunitinib, pazopanib, and vatalanib may be promising for future evaluation as antiplatelet drugs.

Differential Regulation of GPVI-Induced Btk and Syk Activation by PKC, PKA and PP2A in Human Platelets

“…In a Btk-deficient murine model (Btk xid animals), platelet functions in response to GPIb-V-IX (GPIb) were reduced [17]. Recent attention shifted to platelet Btk as a potential therapeutic target in platelet-related thrombotic diseases [18][19][20][21][22][23], but clinically used Btk inhibitors affecting platelet functions may also cause bleeding events [22,24]. While the principal mechanism of Btk activation is well-defined in platelets (membrane recruitment combined with tyrosine phosphorylation of the critical sites Y223 and Y551) [1,25], there are still important open questions concerning Btk activation and steady-state regulation by other protein kinases.…”

Modelling arterial thrombus formation in vitro

“…A potential limitation of this model is priming of platelets as they flow over one spot, therefore affecting responses to downstream spots, however control experiments demonstrated no differences in thrombus formation based on the order of coated proteins [ 37 ]. The flexibility of this model has resulted in its extensive use over the past few years in a diverse range of experiments including assessment of variations in thrombus formation between healthy individuals [ 39 ], assessment of coagulation under flow [ 41 , 42 ], phenotyping patients with platelet disorders [ 40 , 43 ▪ ], assessment of pharmacological GPVI and integrin α2β1 inhibitors [ 44 ], characterization of calcium entry pathways in platelets [ 45 ] and assessment of the platelet inhibitory effects of different cancer treatments [ 46 ].…”

Patients Undergoing Systemic Anti-Cancer Therapy Who Require Surgical Intervention: What Surgeons Need to Know

“…However, those of specific relevance to patients with cancer undergoing surgical intervention relate to platelet function. Tyrosine kinase inhibitors are heterogeneous in terms of affinity for platelet TKs, and the mechanism by which TKIs disrupt platelet function is, therefore, varied [49]. Molecules including axitinib, sorafenib and sunitinib have been associated with reduced platelet count [50], and it has been demonstrated that sunitinib delays fibrin formation and inhibits thrombus formation [51].…”