In sickle cell disease (SCD),
HBB MUTATION AND HbS POLYMERIZATION
ARE KEY DRIVERS OF SCD PATHOPHYSIOLOGY1-3
SCD is characterized by red blood cell (RBC) dysfunction1-3
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
See the impact that a mutation in HBB and polymerization of HbS have on RBC function
SCD AND END-ORGAN DAMAGE
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 can cause RBC sickling, which may trigger
hemolysis, as well as
anemia and vaso-occlusion8,9
Sickled cells often die prematurely3,10
HbS polymerization damages the cell membrane and results in fragile RBCs that can die prematurely due to hemolysis.
AVERAGE RBC LIFESPAN
HEMOLYSIS AND VASCULOPATHY
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
Chronic hemolytic anemia can contribute to long-term organ damage in SCD14-17
Anemia can impact the daily lives of people with SCD
Clinically, anemia can manifest in many ways that affect day-to-day life.14-21
Moderate to severe anemia can lead to:
- Fatigue
- Weakness
- Reduced physical performance
- Impaired cognitive function
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
ANEMIA AND THE CARDIOVASCULAR SYSTEM
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
ANEMIA AND CEREBROVASCULAR RISK
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
ANEMIA AND KIDNEY DAMAGE
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
Vaso-occlusive crises9,11
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
VAS0-OCCLUSION AND END-ORGAN DAMAGE
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.
Vaso-occlusion
Silent damage can occur even during periods of subclinical disease3,9
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