Sickle cell disease-associated pulmonary hypertension: an integrated framework linking pathologies, mechanisms, and clinical phenotypes.

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.