Florence Vallelian, Dominik J. Schaer, Benoit Lechartier, Paul W. Buehler, David C. Irwin
University of Zurich. Lausanne University Hospital and University of Lausanne. University of Maryland. Anschutz Medical Campus School of Medicine and University of Colorado.
Switzerland and United States
eBioMedicine
eBioMedicine 2026;
DOI: 10.1016/j.ebiom.2026.106288
Abstract
Sickle cell disease-associated pulmonary hypertension (SCD-PH) affects approximately 10% of adults with SCD and markedly increases mortality, yet mechanistic and haemodynamic heterogeneity complicates classification, trial design, and treatment selection. We propose an integrated framework linking five interacting axes-anaemia/high-output, haemolysis/haem/iron toxicity, hypoxia, inflammation, and thrombosis-to clinically defined phenotypes (post-capillary, pre-capillary, combined, chronic thromboembolic PH [CTEPH], and acute cor pulmonale). Chronic anaemia drives high-output physiology, left ventricular diastolic dysfunction, and post-capillary PH. Intravascular and erythrophagocytic haemolysis cause convergent inside-out and outside-in pulmonary vascular injury via nitric oxide depletion and oxidative damage, promoting pre-capillary PH; hypoxia, inflammation, and thrombosis amplify remodelling, helping explain why combined phenotypes predominate. Management prioritises hydroxyurea and transfusion, while PDE5 inhibition (sildenafil) has shown harm. Emerging avenues include soluble guanylate cyclase stimulation, L-arginine, haemoglobin/haem scavenging (haptoglobin, hemopexin), anti-inflammatory strategies, and iron-targeted interventions. This mechanism-to-phenotype map supports phenotype-stratified, mechanism-guided trials in SCD-PH.
Category
Class V. Pulmonary Hypertension Associated with Hematological, Systemic, Metabolic, Nutritional and Other Disorders
Review Articles Concerning Pulmonary Vascular Disease
Age Focus: Pediatric Pulmonary Vascular Disease or Adult Pulmonary Vascular Disease
Fresh or Filed Publication: Fresh (PHresh). Less than 1-2 years since publication
Article Access
Free PDF File or Full Text Article Available Through PubMed or DOI: Yes