Acquired platelet antagonism: off‐target antiplatelet effects of malignancy treatment with tyrosine kinase inhibitors

Abstract

Platelets can contribute to tumor progression and metastasis. Cancer patients are at increased risk of thrombosis, and advanced stages of cancer are associated with thrombocytosis or increased platelet reactivity. Tyrosine kinase inhibitors (TKIs) are widely used as a targeted strategy for cancer treatment, with the aim of prolonging progression-free survival of the patients. Because of their broad kinase target spectrum, most TKIs inevitably have off-target effects. Platelets rely on tyrosine kinase activity for their activation. Frequently observed side effects are lowering of platelet count and inhibition of platelet functions, whether or not accompanied by an increased bleeding risk. In this review, we aim to give insights into: (i) 38 TKIs that are currently used for the treatment of different types of cancer, either on the market or in clinical trials; (ii) how distinct TKIs can inhibit activation mechanisms in platelets; and (iii) the clinical consequences of the antiplatelet effects of TKI treatment. For several TKIs, the knowledge on affinity for their targets does not align with the published effects on platelets and reported bleeding events. This review should raise awareness of the potential antiplatelet effects of several TKIs, which will be enhanced in the presence of antithrombotic drugs.

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

“…Also in the latter case, the patients' platelets were less responsive to collagen stimulation, resulting in decreased thrombus formation ( 57 ). To take this further, we recently reviewed how distinct TKIs inhibit platelet activation mechanisms, as well as the clinical consequences of antiplatelet effects due to TKI treatment ( 58 ). Comparison of affinity profiles of TKIs for platelet targets, as well as literature regarding effects on platelet count, platelet function and bleeding, enabled us to distinguish three categories of TKIs.…”

Tyrosine Kinase Inhibitor Sunitinib Delays Platelet-Induced Coagulation: Additive Effects of Aspirin

“…Hence, roles of different platelet receptors, such as GPVI, CLEC-2, GPIb, and integrin α 6 β 1 and α IIb β 3 , were investigated as described before. [20][21][22] Captured microscopic images were analyzed (►Supplementary Fig. S2, available in the online version), and a heatmap was generated for a more systematic analysis of the seven thrombus parameters, which were averaged and scaled per parameter (►Fig.…”

Anticoagulation of cancer patients with non‐valvular atrial fibrillation receiving chemotherapy: Guidance from the SSC of the ISTH

“…Second, chemotherapy regimens may independently increase the risk of bleeding, especially those that induce thrombocytopenia . The increasing use of targeted anticancer therapies such as tyrosine kinase inhibitors and monoclonal antibodies targeting vascular endothelial growth factor (VEGF) can be associated with an increased risk of bleeding due to off‐target kinase inhibition resulting in platelet dysfunction or the inhibition of angiogenesis pathways. Finally, all anticoagulants that are licensed for NVAF have potential to interact with some chemotherapy and supportive care drugs, increasing the risk of bleeding or stroke depending on their metabolic pathways.…”