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Review
. 2025 Jul 14;26(14):6733.
doi: 10.3390/ijms26146733.

Pulmonary Embolism in Acute Ischaemic Stroke: Evolving Evidence, Diagnostic Challenges, and a Novel Thromboinflammatory Axis Hypothesis

Darryl Chen  1   2 , Sonu M M Bhaskar  1   3   4   5   6
Affiliations
Review

Pulmonary Embolism in Acute Ischaemic Stroke: Evolving Evidence, Diagnostic Challenges, and a Novel Thromboinflammatory Axis Hypothesis

Darryl Chen et al. Int J Mol Sci. .

Abstract

Pulmonary embolism (PE) is an under-recognised yet serious complication in patients with acute ischaemic stroke (AIS), contributing significantly to morbidity and mortality. The interplay of traditional risk factors-such as immobility, endothelial dysfunction, and hypercoagulability-with AIS-specific conditions, including atrial fibrillation, malignancy, and reperfusion therapies, complicates both diagnosis and management. Despite available prophylactic strategies, including low-molecular-weight heparin and intermittent pneumatic compression, their use remains limited by bleeding concerns and a lack of tailored guidelines. This review synthesises the current evidence on the incidence, risk factors, pathophysiology, diagnostic approaches, and preventive strategies for PE in AIS, identifying critical gaps in risk stratification and clinical decision-making. We propose a novel mechanistic framework-the Brain-Lung Thromboinflammatory Axis Hypothesis-which posits that stroke-induced systemic inflammation, neutrophil extracellular trap (NET) formation, and pulmonary endothelial activation may drive in situ pulmonary thrombosis independent of deep vein thrombosis. This conceptual model highlights new diagnostic and therapeutic targets and underscores the need for stroke-specific VTE risk calculators, biomarker-guided prophylaxis, and prospective trials to optimise prevention and outcomes in this vulnerable population.

Keywords: anticoagulation; prophylaxis; pulmonary embolism; risk stratification; stroke.

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Conflict of interest statement

S.M.M.B. reports leadership or a fiduciary role in another board, society, committee, or advocacy group, paid or unpaid, with the National Cerebral and Cardiovascular Center (Osaka, Japan) as the Visiting Director (2023–2025); Rotary District 9675 (Sydney, Australia) as the District Chair for Diversity, Equity, and Inclusion; the Global Health and Migration Hub Community, Global Health Hub Germany (Berlin, Germany) as the Chair, Founding Member, and Manager; and editorial board memberships at PLoS ONE, BMC Neurology, Frontiers in Neurology, Frontiers in Stroke, Frontiers in Public Health, Journal of Aging Research, Neurology International, Diagnostics, and BMC Medical Research Methodology. Additionally, S.M.M.B. serves as a Member of the College of Reviewers for the Canadian Institutes of Health Research (CIHR), Government of Canada; Director of Research for the World Headache Society (Bengaluru, India); a member of the Scientific Review Committee at Cardiff University Biobank (Cardiff, UK); Chair of the Rotary Reconciliation Action Plan (RAP), Rotary District 9675 (NSW, Australia), Healthcare and Medical Adviser for the Japan Connect (Osaka, Japan), and as an Expert Adviser/Reviewer for the Cariplo Foundation (Milan, Italy). These roles are unrelated to the submitted work. Other authors (D.C.) report no conflicts of interest. The funding body has no role in the study design, data collection, analysis, interpretation of findings, and manuscript preparation. The content is solely the responsibility of the authors and does not necessarily represent the official views of the affiliated/funding organization/s.

Figures

Figure 1
Figure 1
Risk factors and pathophysiology of PE. Abbreviations: CRP, C-reactive protein; CTEPH, chronic thromboembolic pulmonary hypertension; IL-6, interleukin-6; LV, left ventricle; MP, microparticles; NET, neutrophil extracellular trap; RV, right ventricle; V/Q, ventilation/perfusion. This figure was created using BioRender.
Figure 2
Figure 2
Pathophysiology of hypercoagulability in acute ischemic stroke. Abbreviations: FVIII, clotting factor VIII; IL-6, interleukin-6; TF, tissue factor; TNF-α, tumour necrosis factor alpha; tPA, tissue plasminogen activator; PAI-1, plasminogen activator inhibitor-1; and MP, microparticles. This figure was created with BioRender.
Figure 3
Figure 3
Thrombus formation in hypercoagulability. Abbreviations: TNF-α, Tumour Necrosis Factor Alpha; WPB, Weibel Palade Bodies. This figure was created with BioRender.
Figure 4
Figure 4
A diagnostic and prophylactic algorithm for suspected pulmonary embolism in acute ischemic stroke. A stepwise approach for assessing the PE risk in AIS patients, integrating the D-dimer interpretation, imaging selection (CTPA, V/Q scan, CUS), and timing of prophylactic or therapeutic anticoagulation based on the reperfusion status, haemorrhagic risk, and neurological stability.
See this image and copyright information in PMC

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