Pathophysiology of Sickle Cell Anemia | GetWellGo

Understand the pathophysiology of sickle cell anemia, including how abnormal hemoglobin affects red blood cells and leads to pain, fatigue, and other complications.

Pathophysiology of Sickle Cell Anemia | GetWellGo

  • Category

    Oncology

  • Published By

    GetWellGo Team

  • Updated on

    30-Jun-2025

Pathophysiology of Sickle Cell Anemia

Sickle Cell Anemia is an inherited blood disease resulting from a mutation in the β-globin gene of hemoglobin (HBB gene), which results in the production of abnormal hemoglobin referred to as hemoglobin S (HbS). The disease's pathophysiology results from multiple interdependent processes:

Pathophysiology of Sickle Cell Anemia:

Genetic Mutation and Hemoglobin Structure

  • Cause: A point mutation in the β-globin gene on chromosome 11.
  • Result: Replacement of glutamic acid by valine at position 6 of the β-globin chain.
  • Effect: Production of sickle hemoglobin (HbS) rather than normal adult hemoglobin (HbA).

Polymerization of Hemoglobin S

  • Under low oxygen (hypoxic) conditions, HbS polymerizes (gels), resulting in long, hard rods.
  • This deforms red blood cells (RBCs) into a sickle or crescent shape.

Red Blood Cell Sickling

Sickled RBCs are:

  • Hard and less flexible
  • Susceptible to hemolysis (breaking up prematurely)
  • Have a shorter life span (~10–20 days compared to 120 days for healthy RBCs)

Vaso-occlusion

Sickled cells:

  • Become trapped in small capillaries
  • Produce blockages (vaso-occlusion) in blood flow
  • Result in tissue ischemia, pain (sickle cell crises), and damage to organs

Hemolysis and Anemia

Chronic sickled cell destruction leads to:

  • Hemolytic anemia (low hemoglobin levels)
  • Hyperbilirubinemia (due to RBC breakdown)
  • Gallstones (due to elevated bilirubin)

Inflammation and Endothelial Dysfunction

Vaso-occlusion and ischemia induce:

  • Inflammatory cytokines
  • Endothelial activation and damage
  • More adhesion of leukocytes and sickled cells to blood vessel walls

Complications Derived from Pathophysiology of Sickle Cell Anemia

  • Pain crisis
  • Stroke
  • Acute chest syndrome
  • Infection (resulting from splenic dysfunction)
  • Damage to organs (kidneys, liver, eyes)

Red blood cell sickling process

The sickling of the red blood cells (RBCs) is at the heart of Sickle Cell Anemia pathophysiology. Here is an oversimplified account of what happens:

Normal Oxygenated RBC

  • An ordinary RBC is round and pliable.
  • In healthy people, hemoglobin A (HbA) makes RBCs soft and disc-shaped.

Oxygen Depletion (Hypoxia)

  • When oxygen levels are low (e.g., at high altitudes, dehydration, or infection), HbS becomes unstable.
  • In sickle cell anemia, hemoglobin S (HbS) polymerizes in low oxygen states.

Hemoglobin S Polymerization

  • HbS molecules clump together, creating long, stiff rods (polymers) within the RBC.
  • The polymers force the cell membrane out of shape.

RBC Becomes Sickle-Shaped

The RBC becomes:

  • Crescent or sickle-shaped
  • Rigid and less flexible
  • This abnormal shape impairs the cell's ability to flow through capillaries.

Microvascular Obstruction

Sickled cells occlude small blood vessels, leading to:

  • Decreased blood flow
  • Tissue ischemia (insufficiency of oxygen)
  • Sickle cell crises (painful)

Repeated Sickling-De-Sickling Cycles

  • When re-oxygenated, some cells will return to normal shape.

But repeated cycles:

  • Permanently damage the RBC membrane
  • Cause irreversible sickling

Hemolysis (Cell Rupture)

Sickled, rigid cells:

  • Wear easily in circulation
  • Produce hemolytic anemia
  • Reduced lifespan: 10–20 days (normal: ~120 days)

Chronic hemolysis in sickle cell disease

Chronic hemolysis is a persistent red blood cell (RBC) breakdown, a characteristic feature of Sickle Cell Disease (SCD). This persistent destruction leads to anemia, jaundice, and various organ complications.

Mechanism of Chronic Hemolysis in SCD:

Sickled RBCs are Fragile

Sickled red blood cells:

  • Are stiff and abnormally shaped
  • Have a compromised cell membrane
  • Cannot be easily passed through microcirculation

Shortened Lifespan

  • Normal RBC lifespan: ~120 days
  • Sickled RBC lifespan: 10–20 days

Destruction Pathways

Extravascular hemolysis (primary pathway):

  • Happens in the spleen and liver
  • Macrophages ingest sickled RBCs
  • Intravascular hemolysis:
  • RBCs rupture right within the blood vessels

Sickle cell anemia complications

Sickle Cell Anemia (SCA) is a multisystem disease resulting from abnormal hemoglobin S, causing chronic hemolysis, vaso-occlusion, and organ injury. Complications are either acute or chronic, involving almost all the organ systems.

Acute Complications

Painful Crises (Vaso-occlusive Crisis)

  • Most frequent; because of obstructed blood supply in small blood vessels; bone, chest, and abdominal pain

Acute Chest Syndrome

  • Deadly; pain in the chest, fever, hypoxia; because of infection or fat emboli; mimics pneumonia

Stroke (Ischemic or Hemorrhagic)

  • Frequent in children and young adults because of occlusion of cerebral vessels

Splenic Sequestration Crisis

  • Abrupt accumulation of blood in the spleen → hypovolemia and shock; predominantly in children

Aplastic Crisis

  • Commonly precipitated by parvovirus B19; abrupt decrease in RBC output → profound anemia

Hemolytic Crisis

  • Acute RBC destruction resulting in escalating anemia, jaundice

Priapism

  • Prolonged, painful erection caused by penile blood vessel occlusion; may lead to irreversible damage

Chronic Complications

Hematologic

  • Chronic anemia, gallstones (due to bilirubin), retarded growth

Skeletal

  • Avascular necrosis (hip, shoulder), osteoporosis, bone infarcts

Neurologic

  • Silent strokes, intellectual impairment, overt stroke

Ophthalmologic

  • Proliferative sickle retinopathy → blindness

Renal

  • Hematuria, hyposthenuria (failure to concentrate urine), chronic kidney disease

Hepatic

  • Liver congestion, gallstones, hepatomegaly

Pulmonary

  • Pulmonary hypertension, chronic lung disease

Cardiac

  • Cardiomegaly, heart failure, predisposition to sudden death

Immunologic

  • Functional asplenia → predisposition to infection (particularly encapsulated organisms such as Streptococcus pneumoniae)

Dermatologic

  • Leg ulcers (particularly about the ankles)

Inflammation in sickle cell disease

Inflammation is the hallmark of Sickle Cell Disease and is central to both acute complications and organ damage in the long term. It is not only a byproduct of sickling and hemolysis—but also a cause of disease severity.

How Inflammation Arises in SCD?

Chronic Hemolysis

  • When red blood cells that are sickled hemolyze, they release:
  • Free hemoglobin → binds to nitric oxide → vasoconstriction
  • Heme and iron → tissue toxins → causes oxidative stress
  • These induce pro-inflammatory signaling in the lining of the blood vessel (endothelium)

Vaso-occlusion Initiates Inflammatory Cascade

  • Sickled RBCs, WBCs, and platelets adhere to the vascular endothelium.

This results in:

  • Activation of endothelium
  • Release of cytokines (e.g., TNF-α, IL-1, IL-6)
  • Recruitment of additional neutrophils and monocytes
  • Blood clot formation and occlusion

Ischemia-Reperfusion Injury

When blood flow is resumed following a blockage:

  • Re-entry of oxygen induces oxidative stress
  • Additional inflammatory mediators are released
  • Injures tissues and induces more sickling

Role of White Blood Cells (WBCs)

  • SCD patients tend to have increased WBCs even in stable state.

Activated neutrophils are responsible for:

  • Vascular inflammation
  • Augmented adhesion of sickled RBCs
  • Exacerbation of vaso-occlusion

Endothelial dysfunction in sickle cell anemia

Endothelial dysfunction is a primary cause of the vascular complications in Sickle Cell Anemia (SCA). It is defined as the defective function of the inner lining of blood vessels, which under normal circumstances assists in regulating blood flow, clotting, and inflammation.

Why Endothelial Dysfunction Develops in SCA?

In Sickle Cell Anemia, multiple mechanisms injure the vascular endothelium (inner blood vessel lining):

Chronic Hemolysis and Free Hemoglobin

Ruptured sickled RBCs release:

  • Free hemoglobin (Hb) → consumes nitric oxide (NO)
  • NO is essential for vasodilation and anti-inflammatory signaling
  • Outcome: Vasoconstriction, hypertension, platelet activation

Free Heme and Iron

Released heme induces:

  • Oxidative stress
  • Endothelial cell activation and damage
  • Expression of adhesion molecules

Inflammatory Cytokines

Activated white cells and platelets secrete:

  • TNF-α, IL-6, IL-8
  • These cytokines further injure the endothelium

Increased Adhesion Molecule Expression

Endothelial cells in SCA overexpress:

  • VCAM-1, ICAM-1, E-selectin, P-selectin
  • Facilitates adhesion of sickled RBCs, WBCs, and platelets
  • Leads to vaso-occlusion

Ischemia–Reperfusion Injury

Intermittent blood supply (due to obstruction) leads to:

  • Oxidative stress
  • Tissue damage
  • Worsening of endothelial dysfunction

Oxidative stress in sickle cell disease

Oxidative stress is a central pathologic characteristic of Sickle Cell Disease and plays a role in cell injury, inflammation, endothelial dysfunction, and organ failure. Oxidative stress results when ROS overwhelm the body's antioxidant protections.

Sources of SCD Oxidative Stress

Chronic Hemolysis

Hemolysis of sickled red blood cells releases:

  • Free hemoglobin, heme, and iron
  • These catalyze the formation of ROS (e.g., hydroxyl radicals)

Sickled RBCs Are Intrinsically Unstable

HbS is susceptible to auto-oxidation, which results in:

  • Superoxide (O₂⁻) and hydrogen peroxide (Hâ‚‚Oâ‚‚)

Activated White Blood Cells (WBCs)

  • SCD neutrophils and monocytes are in a state of chronic activation
  • Spew out ROS and inflammatory cytokines

Reperfusion Injury

Upon ischemia-reperfusion, acute oxygen influx:

  • Induces bursts of ROS
  • Injures lipids, proteins, and DNA

Adhesion molecules in sickle cell pathophysiology

In Sickle Cell Disease, adhesion molecules are key players in the pathogenesis of vaso-occlusion, one of the cardinal complications of the disease. These molecules mediate the inappropriate adherence of sickled red blood cells (RBCs), white blood cells (WBCs), and platelets to the endothelial lining of blood vessels. 

How Adhesion Molecules Contribute to SCD Pathophysiology?

Endothelial Activation

Initiated by:

  • Chronic inflammation
  • Hemolysis (free heme, ROS)
  • Hypoxia
  • Results in upregulation of adhesion molecules on endothelial cells

Increased Cell Adhesion

  • Sickled RBCs contain unusual surface proteins and adhere more readily
  • Leukocytes and platelets also stick, creating multicellular aggregates
  • These adhesions disrupt blood flow, leading to vaso-occlusion and ischemia

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