Table 1.

Hemolysis-related mechanisms in PH in SCD patients

eDAMPs	Released during massive tissue injury associated with activation of innate immunity pathways via the toll-like receptors and the nucleotide-binding oligomerization domain-like receptors of the inflammasome leading to persistent intravascular hemolysis in PH
ADA and PNP	Released after hemolysis leading to enzymatic action of decreased circulating levels of adenosine, inosine, and guanosine leading to decreased anti-occlusive effects and increasing vascular constriction
Arginase 1	Increased levels are seen in hemolytic activity. Its function consists of metabolizing L-arginine to ornithine, thereby reducing levels of L-Arginine. L-Arginine is required for de novo nitric oxide synthesis by eNOS enzyme; thereby, reductions of L-arginine lead to lower arginine: ornithine ratios. Increased ornithine levels are associated with smooth muscle cell proliferation, peribronchial, and perivascular collagen deposition. This is associated with the increased severity of PH and mortality [9, 10]
ADMA and hyperhomocysteinemia	Endogenous NOS inhibitor hydrolyzed by DDAH. Associated with hyperhomocysteinemia as homocysteine can inhibit DDAH activity leading to elevated plasma ADMA levels and decreased NO production. NO deficits have been associated with PH in SCD patients
ROS (xanthine oxidase, NADPH, SODs)	Generated during intravascular hemolysis. Can form ROS causing endothelial dysfunction activating downstream oxidases promoting vascular oxidative stress. Lower levels of SOD are seen in SCD due to higher tricuspid regurgitant velocity, thereby leading to increased oxidative stress [11]

PH, pulmonary hypertension; SCD, sickle cell disease; eDAMPs, erythrocyte danger-associated molecular patterns; ADA, adenosine deaminase; PNP, purine nucleoside phosphorylase; ADMA, asymmetric dimethylarginine; NADPH, nicotinamide adenine dinucleotide phosphate; SODs, superoxide dismutases; eNOS, endothelial NO synthase; NOD, nucleotide-binding oligomerization domain; DDAH, dimethylarginine dimethylaminohydrolase.