VEGFR signalling and hemoptysis: mechanisms, critical appraisal of the evidence, and the double-edged role of VEGFR-2 inhibition — a narrative review

Abstract

Abstract Hemoptysis is a potentially life-threatening manifestation of pulmonary disease, including lung cancer, bronchiectasis and pulmonary tuberculosis. Critically, in approximately 90% of cases the bleeding arises from the high-pressure bronchial (systemic) arterial circulation rather than from the low-pressure pulmonary circulation, and the dominant mechanisms — bronchial artery hypertrophy and systemic neovascularisation, cavitary wall erosion, Rasmussen aneurysm and direct tumour invasion of vessels — are not primarily driven by vascular endothelial growth factor receptor (VEGFR) signalling. VEGFR signalling nevertheless regulates angiogenesis and vascular permeability, is upregulated in lung cancer and in infective and inflammatory lung disease, and is the target of agents that are increasingly used in patients who bleed. This narrative review therefore asks a deliberately restricted question: what can, and what cannot, VEGFR biology explain about hemoptysis? We describe the review methodology, separate neoplastic from infective and inflammatory aetiologies rather than treating VEGFR as a common driver, and grade the supporting evidence explicitly. We find that the evidence for VEGFR-2 inhibitors (apatinib, anlotinib) as a treatment for hemoptysis is confined to case reports, small retrospective series, and oncology trials in which bleeding was recorded as an adverse event rather than an efficacy endpoint; no controlled trial has evaluated a VEGFR inhibitor for the treatment of hemoptysis, and pivotal trials systematically excluded patients with major vascular invasion or significant hemoptysis. We give particular attention to the central paradox of the field: VEGFR-2 inhibition may reduce bleeding through vascular normalisation, yet in centrally located, cavitating or vessel-abutting tumours the same on-target activity precipitates tumour necrosis and fatal pulmonary haemorrhage. We propose an explicit phenotype-based framework separating patients in whom normalisation plausibly dominates from those in whom necrosis dominates. VEGFR-targeted therapy is not an alternative to airway stabilisation, CT angiography, bronchoscopy, bronchial artery embolisation, surgery and treatment of the underlying disease, and should be positioned only as a disease-directed adjunct in carefully selected patients. Taken together, current evidence supports a biologically plausible but clinically unproven role for VEGFR-targeted therapy in carefully selected patients, which requires prospective validation.