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Grand Rounds |

Evolution of Novel Small-Molecule Therapeutics Targeting Sickle Cell Vasculopathy

Gregory J. Kato, MD; Mark T. Gladwin, MD
JAMA. 2008;300(22):2638-2646. doi:10.1001/jama.2008.598.
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A 34-year-old African American woman with sickle cell disease and history of relatively severe hemolysis, chronic leg ulcers, and mild pulmonary hypertension presented with a new ischemic stroke. Recent research has suggested a syndrome of hemolysis-associated vasculopathy in patients with sickle cell disease, which features severe hemolytic anemia and leads to scavenging of nitric oxide and its biochemical precursor L-arginine. This diminished bioavailability of nitric oxide promotes a hemolysis-vascular dysfunction syndrome, which includes pulmonary hypertension, cutaneous leg ulceration, priapism, and ischemic stroke. Additional correlates of this vasculopathy include activation of endothelial cell adhesion molecules, platelets, and the vascular protectant hemeoxygenase-1. Some known risk factors for atherosclerosis are also associated with sickle cell vasculopathy, including low levels of apolipoprotein AI and high levels of asymmetric dimethylarginine, an endogenous inhibitor of nitric oxide synthase. Identification of dysregulated vascular biology pathways in sickle vasculopathy has provided a focus for new clinical trials for therapeutic intervention, including inhaled nitric oxide, sodium nitrite, L-arginine, phosphodiesterase-5 inhibitors, niacin, inhaled carbon monoxide, and endothelin receptor antagonists. This article reviews the pathophysiology of sickle vasculopathy and the results of preliminary clinical trials of novel small-molecule therapeutics directed at abnormal vascular biology in patients with sickle cell disease.

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Figure 1. Presentation of Patient With Sickle Cell Disease
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A, The patient had a left medial ankle ulcer of 17 years' duration. B, One day after hospital admission with vaso-occlusive pain crisis, the patient developed a pulmonary infiltrate, encephalopathy, and renal insufficiency. Induced sputum demonstrated lipid-laden macrophages by oil red O stain (magnification × 1000), which is indicative of fat embolus to the lung from infarcted marrow. C, Approximately 2 weeks later, the patient presented with acute dysarthria and right-hand weakness. Diffusion-weighted magnetic resonance imaging (MRI) showed a bright signal in the left hemisphere (left image, arrowhead), indicating acute edema and new stroke. Additional images at the same time using the FLAIR technique (fluid-attenuated inversion recovery) demonstrated right frontal lobe cavitation (right image, left [blue] arrowhead) and chronic watershed zone infarcts (right image, right [yellow] arrowhead) from previously unsuspected ischemic strokes. Magnetic resonance angiography revealed nearly absent flow in the internal carotid arteries (not shown).

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Figure 2. Pathological Cascade Caused by Intravascular Hemolysis and Targets for Pharmacologic Intervention in Sickle Cell Disease
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apo AI indicates apolipoprotein AI; cGMP, cyclic guanosine monophosphate; CO, carbon monoxide; ET, endothelin; Fe, iron; GTP, guanosine triphosphate; NO, nitric oxide.

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