In SCD, a single point mutation in the HBB gene that encodes hemoglobin subunit β, or beta-globin, leads to the production of hemoglobin S (HbS).1 In low-oxygen environments, HbS can polymerize, causing RBCs to distort into a characteristic crescent or sickle shape.1,4 Sickled RBCs can slow or obstruct blood flow, resulting in vaso-occlusion and diminished oxygen delivery to surrounding tissues and organs. Membrane changes caused by HbS polymers can lead to RBC dehydration, chronic hemolysis, and early cell death, causing anemia.1 Over time, this dysfunction may contribute to progressive tissue and organ damage.5
The degree to which SCD pathophysiology contributes to end-organ damage is not known, as multiple factors—including age, sex, genotype/genogroup, treatment status, and other patient-specific variables—may also affect its etiology.6
The pathophysiology of SCD is complex and involves dysregulation of molecular, cellular, and biophysical processes in a multitude of cell types and organ systems.5,7
The degree to which SCD pathophysiology contributes to end-organ damage is not known, as multiple factors—including age, sex, genotype/genogroup, treatment status, and other patient-specific variables—may also affect its etiology.6
HbS polymerization damages the cell membrane and results in fragile RBCs that can die prematurely due to hemolysis.
When an RBC hemolyzes, hemoglobin and arginase are expelled into the vasculature, where they act to decrease nitric oxide bioavailability. A vicious cycle of arginine dysregulation and continuing hemolysis leads to a further reduction in nitric oxide, causing oxidative stress and endothelial dysfunction. Free heme acts as an inflammatory mediator and can further compound the vascular damage.11-13
The degree to which SCD pathophysiology contributes to end-organ damage is not known, as multiple factors—including age, sex, genotype/genogroup, treatment status, and other patient-specific variables—may also affect its etiology.6
Clinically, anemia can manifest in many ways that affect day-to-day life.14-21
Moderate to severe anemia can lead to:
The degree to which SCD pathophysiology contributes to end-organ damage is not known, as multiple factors—including age, sex, genotype/genogroup, treatment status, and other patient-specific variables—may also affect its etiology.6
In SCD, the heart responds to anemia by increasing stroke volume. This increase in cardiac output, along with vascular stiffness, results in raised systolic blood pressure. High systolic systemic blood pressure is an independent risk factor for the development of multiple cardiovascular morbidities.14
The degree to which SCD pathophysiology contributes to end-organ damage is not known, as multiple factors—including age, sex, genotype/genogroup, treatment status, and other patient-specific variables—may also affect its etiology.6
In response to anemia in patients with SCD, cerebral blood flow is increased to maintain oxygen supply. The ability to increase blood flow under stress, known as cerebrovascular reserve, is diminished in patients with SCD. A high resting blood flow and reduced vascular reserve increase the risk of stroke and silent cerebral infarction (SCI). Multiple factors, including male sex, lower baseline hemoglobin level, higher baseline systolic blood pressure, and history of previous seizures, may also influence risk of SCI.15,16,21
The degree to which SCD pathophysiology contributes to end-organ damage is not known, as multiple factors—including age, sex, genotype/genogroup, treatment status, and other patient-specific variables—may also affect its etiology.6
In SCD, anemia can affect the kidney by causing an increase in systolic pressure, which results in renal hyperperfusion and an increase in glomerular filtration rate (GFR). As a result, renal damage such as glomerular hypertrophy may occur, and those with SCD remain at high risk for progressive renal insufficiency. As renal damage progresses, the kidney is unable to produce appropriate levels of erythropoietin, which, in addition to other factors, can exacerbate the anemia.14,17-19,22
The degree to which SCD pathophysiology contributes to end-organ damage is not known, as multiple factors—including age, sex, genotype/genogroup, treatment status, and other patient-specific variables—may also affect its etiology.6
For many patients, debilitating pain is a significant complication caused by their SCD.9,10 Acute vaso-occlusive pain is thought to be caused by vascular obstruction and tissue ischemia that occur when sickled RBCs and other cells become trapped in the microvasculature.9 Pain symptoms can resolve in a few days. However, vaso-occlusion can continue silently beyond these discrete pain events.7,23
The degree to which SCD pathophysiology contributes to end-organ damage is not known, as multiple factors—including age, sex, genotype/genogroup, treatment status, and other patient-specific variables—may also affect its etiology.6
Vaso-occlusion can result in damage to multiple organ systems, including the renal and cardiovascular systems.5,14,18
Occlusion of postcapillary venules (vaso-occlusion)9,11
Sickled RBCs can interact with leukocytes, platelets, and the vascular endothelium to develop a vaso-occlusion, which can independently lead to hemolysis, inflammation, and painful infarction. Inflammation also increases the expression of adhesion molecules, trapping more cells and worsening vaso-occlusion.
Ischemia-reperfusion9,11
Reperfusion of ischemic tissue generates free radicals and causes oxidative damage, all of which is worsened with the presence of free hemoglobin from ongoing hemolysis.
Vasculopathy and endothelial dysfunction9,11
Inflammation and chronic down-regulation of nitric oxide lead to additional endothelial damage and advanced vasculopathy.
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