Tyrosine kinase inhibitors - balancing the haemostatic scales: a review of associated thrombosis and bleeding.

Abstract

Tyrosine kinase inhibitors (TKIs) have revolutionised cancer therapy, significantly impacting survival and outcomes by targeting specific signalling pathways that are necessary for tumour survival. Despite their clinical efficacy, TKIs exhibit a complex toxicity profile. Many of the signalling pathways that are targeted by TKIs are shared with normal homeostatic processes, including those responsible for modulating thrombosis and bleeding. The risk profile of thrombosis and bleeding associated with TKIs varies considerably across agents. Multi-kinase inhibitors, particularly those targeting the breakpoint cluster regio-abelson murine leukaemia 1 gene mutation (BCR-ABL) (i.e., nilotinib and ponatinib), significantly elevate arterial thrombotic events. This thrombosis risk is driven by endothelial dysfunction, accelerated atherosclerosis, platelet hyper-reactivity, and impaired fibrinolysis. Similarly, vascular endothelial growth factor (VEGF) pathway inhibition contributes markedly to thrombotic vascular complications by reducing vasodilators like nitric oxide and promoting pro-thrombotic endothelial environments. TKIs targeting the VEGF receptor (VEGFR-TKIs) (i.e., sunitinib and regorafenib) and brutons tyrosine kinase (BTK) inhibitors (i.e., ibrutinib), increase bleeding risk through platelet dysfunction, thrombocytopenia, and interactions affecting coagulation pathways. Optimal management of these medications encompasses careful baseline cardiovascular and bleeding risk assessments, proactive modification of modifiable risk factors, and vigilant patient monitoring. Prophylactic antithrombotic therapy necessitates cautious individualised evaluation and comprehensive patient monitoring strategies. TKIs exemplify the advancements in precision oncology but necessitate nuanced management of their complex vascular toxicities. A multidisciplinary cardio-oncology approach involving detailed patient education, robust risk stratification, and collaborative clinical management is essential. Future research should aim to clarify TKI-specific haemostatic mechanisms and develop predictive biomarkers, enabling tailored therapeutic strategies to optimise clinical outcomes and reduce adverse events..