Vasculopathy and pulmonary hypertension in sickle cell disease

Abstract

Sickle cell disease (SCD) is an autosomal recessive disorder in the gene encoding the β-chain of hemoglobin. Deoxygenation causes the mutant hemoglobin S to polymerize, resulting in rigid, adherent red blood cells that are entrapped in the microcirculation and hemolyze. Cardinal features include severe painful crises and episodic acute lung injury, called acute chest syndrome. This population, with age, develops chronic organ injury, such as chronic kidney disease and pulmonary hypertension. A major risk factor for developing chronic organ injury is hemolytic anemia, which releases red blood cell contents into the circulation. Cell free plasma hemoglobin, heme, and arginase 1 disrupt endothelial function, drive oxidative and inflammatory stress, and have recently been referred to as erythrocyte damage-associated molecular pattern molecules (eDAMPs). Studies suggest that in addition to effects of cell free plasma hemoglobin on scavenging nitric oxide (NO) and generating reactive oxygen species (ROS), heme released from plasma hemoglobin can bind to the toll-like receptor 4 to activate the innate immune system. Persistent intravascular hemolysis over decades leads to chronic vasculopathy, with ∼10% of patients developing pulmonary hypertension. Progressive obstruction of small pulmonary arterioles, increase in pulmonary vascular resistance, decreased cardiac output, and eventual right heart failure causes death in many patients with this complication. This review provides an overview of the pathobiology of hemolysis-mediated endothelial dysfunction and eDAMPs and a summary of our present understanding of diagnosis and management of pulmonary hypertension in sickle cell disease, including a review of recent American Thoracic Society (ATS) consensus guidelines for risk stratification and management.

Omega 3 (n−3) fatty acids down-regulate nuclear factor-kappa B (NF-κB) gene and blood cell adhesion molecule expression in patients with homozygous sickle cell disease

“…Chronic inflammation, intravascular haemolysis, imbalanced vascular nitric oxide (NO), oxidative stress are known factors that underlie vasculapathy-related complications in SCD [61,62]. Among these complications, pulmonary hypertension (PHT) and stroke stand out as the most prevalent and devastating.…”

ARQ 092, an orally-available, selective AKT inhibitor, attenuates neutrophil-platelet interactions in sickle cell disease

“…The many clinical manifestations in SCD patients include recurrent vaso-occlusive episodes mediated by heterotypic cell-cell adhesion/aggregation, which cause pain crises and increase mortality due to organ damage and acute chest syndrome. 3,4 Hydroxyurea, an important therapy for SCD, induces production of fetal hemoglobin and also has other beneficial effects, including increasing nitric oxide (NO) species and decreasing the level of soluble vascular P revious studies identified the Ser/Thr protein kinase, AKT, as a therapeutic target in thrombo-inflammatory diseases. Here we report that specific inhibition of AKT with ARQ 092, an orally-available AKT inhibitor currently in phase Ib clinical trials as an anti-cancer drug, attenuates the adhesive function of neutrophils and platelets from sickle cell disease patients in vitro and cell-cell interactions in a mouse model of sickle cell disease.…”

Review: Hemodynamic Characteristics and Outcomes of Sickle Cell Disease Associated Pulmonary Hypertension

“…8 In addition, adults with SCD develop progressive vasculopathy, characterized by pulmonary artery endothelial dysfunction, intimal and smooth muscle and adventitia proliferation leading to PH. 9,10 Prevalence and HemodynamIc cHaracterIstIcs of Pulmonary HyPertensIon In sIckle cell dIsease…”