In sickle cell disease (SCD),
HEMOGLOBIN S (HbS)
POLYMERIZATION
IS THE
ROOT CAUSE OF SCD DAMAGE1-3
The core mechanism that drives SCD pathology
In low-oxygen environments, HbS can polymerize, causing red blood cells (RBCs) to distort into a characteristic sickle shape.1,4 This slows or obstructs blood flow, resulting in vaso-occlusion and diminished oxygen delivery to surrounding tissues and organs. Membrane changes caused by hemoglobin S polymers lead to cellular dehydration, chronic hemolysis, and early cell death, causing anemia.1 Over time, this dysfunction may lead to progressive tissue and organ damage.5
Damage starts with HbS polymerization3
Click here to see its impact on SCD progression.
HbS units in
oxygenated RBC
manifestations
begin here
Damage Initiated
HbS polymers form in deoxygenated RBC
Distorted, sickled RBC
Three pathologies driving sickle cell damage
SCD pathophysiology involves multiple biologic processes that radically affect the structure and function of RBCs, other blood cells, and the vasculature.6
HbS polymerization causes RBC sickling,
which can trigger
hemolysis, as well as
anemia and vaso-occlusion7,8
Sickled cells die prematurely3,9
HbS polymerization damages the cell membrane and results in fragile RBCs that die prematurely due to hemolysis.
AVERAGE RBC LIFESPAN
Hemolysis leads to vasculopathy and has been linked to
progressive organ damage10-12
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.
Chronic hemolytic anemia has been linked with negative long-term clinical outcomes13
The burden of anemia was quantified (difference in hemoglobin levels) in a meta-analysis of 41 studies that looked at a number of morbidities in patients with SCD.19,*
Anemia can adversely impact the daily lives of people with SCD13-18,20,21
Clinically, anemia can manifest in many ways that affect day-to-day life.
Moderate to severe anemia can lead to:
- Fatigue
- Weakness
- Reduced physical performance
- Impaired cognitive function
Over time, chronic anemia can progress into increasingly severe complications.
Anemia places significant stress on the
cardiovascular system13
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.
Anemia and cerebrovascular risk14,15
Chronic anemia is one of the strongest risk factors for cerebral vascular injury. In response to anemia, 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).
Anemia contributes to kidney damage in SCD13,16-18,22
Kidney damage can occur through several SCD-mediated pathways. 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, contributes to exacerbating anemia.
Clinical markers associated with severe anemia13
Mean difference in Hb across studies in people with sickle cell disease related morbidity and mortality (P<0.001)19,†
Clinical outcome
Mean difference in
hemoglobin levels (g/dL)
- Elevated
ePASP
(Heart/lung) - Albuminuria
(Kidney) - Death
- Abnormal
TCD velocity
(Brain) - Stroke/SCI
history
(Brain)
Mild-to-moderate reductions in Hb may be of clinical significance
ePASP = estimated pulmonary artery systolic pressure (heart/lung); Albuminuria (kidney); TCD = transcranial doppler (brain);
SCI = silent cerebral infarction (brain); TRV= tricuspid regurgitant velocity
*Based on a meta-analysis of 41 studies representing 9,875 patients, reporting on association between Hb and clinical outcomes of interest (stroke/SCI, abnormal TCD, albuminuria, TRV/ePASP, mortality) in sickle cell disease.
†Statistical significance reached from the differences in hemoglobin concentration between groups of individuals with and without a negative across all clinical outcomes evaluated.
Acute pain and chronic vasculopathy8,10
For many patients, debilitating pain is the most significant complication caused by their SCD.8,9 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.8 Pain symptoms can resolve in a few days. However, vaso-occlusion can continue silently beyond these discrete pain events6,23
Occlusion of postcapillary venules (vaso-occlusion)
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-reperfusion
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 dysfunction
Inflammation and chronic down-regulation of nitric oxide lead to additional endothelial damage and advanced vasculopathy.
Silent damage occurs even during periods of subclinical disease3,8
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