Scholarlink

<p>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..</p> Graphical Abstract <p>Mechanisms and management of tyrosine kinase inhibitor-associated thrombosis and bleeding. Tyrosine kinase inhibitor (TKI) therapy can target multiple oncogenic pathways. Despite their therapeutic efficacy, TKIs exert dual haemostatic off-target effects on vascular and platelet homeostasis, predisposing patients to both thrombosis and bleeding. This figure presents proposed mechanisms and management strategies for both complications.&#xa0;VEGFR, Vascular endothelial growth factor receptor; BCR-ABL, Breakpoint cluster region-Abelson; ALK, Anaplastic lymphoma kinase; FLT3, Fms-like tyrosine kinase 3; PDGFR, Platelet-derived growth factor receptor; EGFR, Epidermal growth factor receptor; JAK, Janus kinase; BTK, Bruton’s tyrosine kinase; NO, Nitrous oxide; PAI-1, Plasminogen activator inhibitor-1; IL-1β, Interleukin 1β; ROS, Reactive oxygen species; vWF, von Willebrand factor; GPVI, Platelet glycoprotein VI; NETs, Neutrophil extracellular traps; pMCS, Percutaneous mechanical circulatory support; FGFR, Fibroblast growth factor receptor; GP1b, Glycoprotein 1b; SSRIs, Selective serotonin reuptake inhibitors; CV, Cardiovascular; ECG, Electrocardiogram; BP; Blood pressure; DM, Diabetes mellitus; HTN, Hypertension; DOACs, Direct oral anticoagulants; MDT, Multidisciplinary team; GI, Gastrointestinal; NSAID, Non-steroidal anti-inflammatory drug (<b>Fig a)</b><Emphasis Type="BoldUnderline">.</Emphasis></p> <p></p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

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

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年9月15日

查看全文
  • Lloyd E. Butel-Simoes,
  • Ammar Albayati,
  • Jie Yu,
  • Thomas Quirk,
  • Shanathan Sritharan,
  • Matthew French,
  • Joshua D. Bennetts,
  • Doan T. M. Ngo,
  • Aaron L. Sverdlov

摘要

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..

Graphical Abstract

Mechanisms and management of tyrosine kinase inhibitor-associated thrombosis and bleeding. Tyrosine kinase inhibitor (TKI) therapy can target multiple oncogenic pathways. Despite their therapeutic efficacy, TKIs exert dual haemostatic off-target effects on vascular and platelet homeostasis, predisposing patients to both thrombosis and bleeding. This figure presents proposed mechanisms and management strategies for both complications. VEGFR, Vascular endothelial growth factor receptor; BCR-ABL, Breakpoint cluster region-Abelson; ALK, Anaplastic lymphoma kinase; FLT3, Fms-like tyrosine kinase 3; PDGFR, Platelet-derived growth factor receptor; EGFR, Epidermal growth factor receptor; JAK, Janus kinase; BTK, Bruton’s tyrosine kinase; NO, Nitrous oxide; PAI-1, Plasminogen activator inhibitor-1; IL-1β, Interleukin 1β; ROS, Reactive oxygen species; vWF, von Willebrand factor; GPVI, Platelet glycoprotein VI; NETs, Neutrophil extracellular traps; pMCS, Percutaneous mechanical circulatory support; FGFR, Fibroblast growth factor receptor; GP1b, Glycoprotein 1b; SSRIs, Selective serotonin reuptake inhibitors; CV, Cardiovascular; ECG, Electrocardiogram; BP; Blood pressure; DM, Diabetes mellitus; HTN, Hypertension; DOACs, Direct oral anticoagulants; MDT, Multidisciplinary team; GI, Gastrointestinal; NSAID, Non-steroidal anti-inflammatory drug (Fig a).