Mechanisms of Vasculopathy in Sickle Cell Disease and Thalassemia

Abstract

Many mechanisms contribute to the complex pathophysiology of sickle cell disease (SCD), with dysfunction of the vascular endothelium as a unifying theme. Specifically, hemolysis-associated low arginine and nitric oxide (NO) bioavailability, amplified by NO synthase uncoupling, elevated arginase activity, superoxide production, oxidative stress, accumulation of arginine analogs such as asymmetric dimethylarginine, ischemia-reperfusion injury, inflammation, apolipoprotein A-1 depletion, and a hypercoagulable state are significant mechanisms contributing to endothelial dysfunction. Genetic polymorphisms also influence disease severity. Clearly the variable spectrum of disease is the consequence of multiple events and genetic susceptibility that go beyond the occurrence of a single amino acid substitution in the beta globin chain of hemoglobin. Recent studies begin to demonstrate overlap among these seemingly unrelated processes. Impaired NO bioavailability represents the central feature of endothelial dysfunction, and is a common denominator in the pathogenesis of vasculopathy in SCD. The consequences of decreased NO bioavailability include endothelial cell activation, upregulation of the potent vasoconstrictor endothelin-1, vasoconstriction, platelet activation, increased tissue factor, and activation of coagulation, all of which ultimately translate into the clinical manifestations of SCD. Evidence supporting vasculopathy subphenotypes in SCD, including pulmonary hypertension, priapism, cutaneous leg ulceration, and stroke, will be reviewed and relevance to other hemolytic disorders including the thalassemia syndromes will be considered.

Peripheral Vasoconstriction and Abnormal Parasympathetic Response to Sighs and Transient Hypoxia in Sickle Cell Disease

“…This pattern of presentation is consistent with a neuralmediated alteration of regional blood flow. A global background of inflammation, nitric oxide depletion, dehydration, or hypoxia would increase the chance that such regional triggers would cascade into clinically evident VOC (40,41). Consistent with our finding of interindividual differences in sigh-vasoconstriction coupling, the variability in crisis frequency among patients with SCD could be in part caused by such differences in autonomic sensitivity among subjects with SCD.…”

“…Inflammation, nitric oxide depletion, red cell adhesion, and percent hemoblobin F among other factors result in an increased probability of crisis (40,41), but none are likely to be the trigger that brings a patient from steady-state to crisis at a particular moment. We suggest that the ANS is likely to play an important role in the pathophysiology of SCD.…”

Cerebrovascular events in sickle cell‐beta thalassemia treated with hydroxyurea: A single center prospective survey in adult Italians

“…Sickle vasculopathy is strongly associated with intravascular hemolysis. Patients with high LDH, one estimate of intravascular hemolysis, have a greater risk of cerebrovascular disease [31]. Hemolysis reduces bioavailable nitric oxide and is associated with chronic inflammation and endothelial damage [31].…”

“…Patients with high LDH, one estimate of intravascular hemolysis, have a greater risk of cerebrovascular disease [31]. Hemolysis reduces bioavailable nitric oxide and is associated with chronic inflammation and endothelial damage [31]. Intimal proliferation was considered the likely primary event causing thrombosis [32].…”

Low Bone Mass Density is Associated with Hemolysis in Brazilian Patients with Sickle Cell Disease

“…19 Rapid scavenging of nitric oxide (NO) 16 by cell-free hemoglobin and oxygen free radicals, together with low concentrations of the substrate Larginine, 20,21 reduces NO bioavailability in SCD. NO plays a role as a cytoprotective mediator, inhibiting the gene transcription of pro-adhesive and pro-inflammatory molecules, such as endothelial VCAM-1 and P-selectin.…”