RBC Destruction

Audio Overview

Overview of Erythrocyte Destruction

Purpose To remove aged or damaged red blood cells (RBCs) from circulation, preventing the release of potentially harmful intracellular components and recycling valuable components like iron
Mechanisms
- Extravascular Hemolysis The primary pathway, occurring mainly in the spleen and liver
- Intravascular Hemolysis Occurs within the blood vessels
Lifespan of a Normal RBC Approximately 120 days

Extravascular Hemolysis

Location Mononuclear Phagocyte System (MPS); primarily in the spleen, but also in the liver and bone marrow
Process
1. Senescence (Aging): As RBCs age, they undergo changes:
  - Decreased flexibility
  - Decreased enzyme activity
  - Changes in membrane proteins
  - Increased binding of antibodies and complement proteins
2. Recognition by Macrophages
  - Macrophages in the spleen recognize senescent or damaged RBCs based on surface markers (e.g., altered glycoproteins, bound antibodies)
3. Phagocytosis
  - Macrophages engulf the RBCs
4. Hemoglobin Breakdown
  - Within the macrophage, hemoglobin is broken down:
    - Globin Degraded into amino acids, which are recycled
    - Iron Stored as ferritin or hemosiderin within the macrophage, or transported to the bone marrow by transferrin for new RBC production
    - Heme Broken down into biliverdin, which is then converted to bilirubin
5. Bilirubin Metabolism
  - Bilirubin is released from the macrophage into the plasma, where it binds to albumin (unconjugated or indirect bilirubin)
  - The albumin-bilirubin complex is transported to the liver
  - In the liver, bilirubin is conjugated with glucuronic acid (conjugated or direct bilirubin)
  - Conjugated bilirubin is excreted into the bile and then into the intestines
  - In the intestines, bilirubin is converted to urobilinogen by bacteria
  - Urobilinogen is either:
    - Excreted in the feces (as stercobilin, which gives feces its brown color)
    - Reabsorbed into the bloodstream and excreted in the urine (as urobilin, which gives urine its yellow color)
Mononuclear Phagocyte System (MPS)
- Note: While “Reticuloendothelial System” is an older term, you’ll still encounter it. The more modern and accurate term is the “Mononuclear Phagocyte System.”
Definition The MPS is a diffuse network of phagocytic cells (primarily macrophages) located throughout the body, strategically positioned to filter blood and tissues, remove debris, and participate in immune responses
Key Components
- Macrophages The main effector cells of the MPS. They are derived from monocytes and are capable of phagocytosis (engulfing and destroying particles)
- Locations Macrophages are found in:
  - Spleen Red pulp macrophages are critical for filtering the blood and removing damaged or senescent RBCs
  - Liver Kupffer cells (macrophages in the liver sinusoids) remove bacteria, debris, and old blood cells
  - Bone Marrow Macrophages support erythropoiesis and remove cellular debris
  - Lymph Nodes Macrophages filter lymph and present antigens to immune cells
  - Lungs Alveolar macrophages clear debris and pathogens from the air spaces
  - Connective Tissues Histiocytes (tissue macrophages) engulf debris and participate in inflammation
Functions
- Phagocytosis Engulfing and destroying pathogens, cellular debris, and senescent or damaged cells
- Antigen Presentation Presenting antigens to T lymphocytes to initiate adaptive immune responses
- Cytokine Production Producing cytokines that regulate inflammation and immune responses
- Iron Recycling Recycling iron from senescent RBCs
- Lipid Metabolism Processing and metabolizing lipids

Splenic Functions: Pitting and Culling

The spleen is a key organ of the MPS and plays a vital role in filtering the blood and removing abnormal RBCs. Two important splenic functions are pitting and culling:

Culling
- Definition The process by which the spleen removes entire senescent or damaged red blood cells from the circulation. This is complete phagocytosis and destruction of the RBC
- Mechanism
  - As RBCs circulate through the splenic red pulp, they must squeeze through narrow interendothelial slits to re-enter the circulation
  - Senescent or damaged RBCs are less flexible and have difficulty passing through these slits
  - Macrophages in the spleen recognize and engulf these less deformable RBCs, leading to their complete destruction
- Outcome
  - Removal of old or damaged RBCs, preventing them from causing harm
  - Breakdown of hemoglobin into its components (globin, iron, and porphyrin)
  - Recycling of iron
  - Production of bilirubin (from porphyrin), which is then transported to the liver for excretion
Pitting
- Definition The process by which the spleen removes inclusions or damaged components from RBCs without destroying the entire cell
- Mechanism
  - As RBCs pass through the spleen, macrophages can “pluck out” certain inclusions from the RBCs, such as:
    - Howell-Jolly bodies (nuclear remnants)
    - Heinz bodies (denatured hemoglobin)
    - Parasites (e.g., malaria)
    - Iron granules (Pappenheimer bodies)
  - The RBC membrane reseals after the inclusion is removed, allowing the RBC to continue circulating
- Outcome
  - Removal of harmful inclusions from RBCs, improving their function and lifespan
  - RBCs can continue to circulate and transport oxygen
- Clinical Significance
  - After splenectomy (removal of the spleen), patients may have increased numbers of RBCs with inclusions (e.g., Howell-Jolly bodies) in their peripheral blood, as the pitting function is lost

In Summary

The Mononuclear Phagocyte System (MPS) is a network of phagocytic cells, primarily macrophages, that remove debris and participate in immune responses
The spleen is a key organ of the MPS, responsible for filtering the blood
Culling is the complete removal and destruction of senescent or damaged RBCs by splenic macrophages
Pitting is the removal of inclusions from RBCs by splenic macrophages without destroying the entire cell

Intravascular Hemolysis

Location Within the blood vessels
Causes
- Mechanical trauma (e.g., microangiopathic hemolytic anemia)
- Complement activation via immune-mediated
- Infections
- Toxic substances
Process
1. RBC Lysis: RBCs rupture within the bloodstream, releasing hemoglobin directly into the plasma
2. Hemoglobin Binding to Haptoglobin
  - Free hemoglobin binds to haptoglobin, a plasma protein
  - The hemoglobin-haptoglobin complex is rapidly cleared from the circulation by the liver
3. Hemoglobin Breakdown (When Haptoglobin is Saturated)
  - When haptoglobin is saturated, free hemoglobin can:
    - Be oxidized to methemoglobin (Fe3+), which dissociates into globin and heme
    - Heme binds to hemopexin, a plasma protein, and is transported to the liver
    - Globin is broken down into amino acids
  - Free hemoglobin can also be filtered by the kidneys:
    - Some hemoglobin is reabsorbed by the renal tubules
    - Excess hemoglobin is excreted in the urine (hemoglobinuria)
    - Iron can accumulate in the renal tubular cells as hemosiderin (hemosiderinuria)

Key Enzymes & Proteins Involved

Heme Oxygenase
- Enzyme that breaks down heme into biliverdin
Biliverdin Reductase
- Enzyme that converts biliverdin to bilirubin
UDP-Glucuronosyltransferase (UGT)
- Enzyme in the liver that conjugates bilirubin with glucuronic acid
Haptoglobin
- Plasma protein that binds free hemoglobin
Hemopexin
- Plasma protein that binds free heme
Transferrin
- Protein that transports iron in the plasma
Ferritin
- Storage form of iron within cells

Clinical Significance of Erythrocyte Destruction

Anemia
- Increased RBC destruction can lead to hemolytic anemia
Jaundice
- Elevated bilirubin levels (hyperbilirubinemia) can cause jaundice (yellowing of the skin and eyes)
Splenomegaly
- Enlargement of the spleen due to increased RBC destruction
Hemoglobinuria
- Hemoglobin in the urine
Hemosiderinuria
- Hemosiderin (iron) in the urine
Elevated Lactate Dehydrogenase (LDH)
- Enzyme released from damaged cells, including RBCs
Decreased Haptoglobin
- Due to binding with free hemoglobin and clearance from the circulation

Laboratory Assessment of Erythrocyte Destruction

Complete Blood Count (CBC)
- Hemoglobin (HGB): Low in hemolytic anemia
- Hematocrit (HCT): Low in hemolytic anemia
- Reticulocyte Count: Elevated due to increased RBC production in response to hemolysis
Peripheral Blood Smear
- Schistocytes (fragmented RBCs): Indicate mechanical hemolysis
- Spherocytes: Indicate extravascular hemolysis (e.g., hereditary spherocytosis)
- Polychromasia: Increased number of reticulocytes
Bilirubin Levels
- Total Bilirubin: Elevated, especially the indirect (unconjugated) fraction
- Direct Bilirubin: May be elevated in liver disease or biliary obstruction
Lactate Dehydrogenase (LDH)
- Elevated in hemolytic anemia
Haptoglobin Level
- Decreased in hemolytic anemia
Direct Antiglobulin Test (DAT)
- Detects antibodies or complement proteins on the surface of RBCs
- Used to diagnose autoimmune hemolytic anemia
Coombs Test
- Same as DAT
Urine Hemoglobin and Hemosiderin
- Present in intravascular hemolysis
Osmotic Fragility Test
- Increased fragility in hereditary spherocytosis
Glucose-6-Phosphate Dehydrogenase (G6PD) Assay
- Used to diagnose G6PD deficiency

Key Terms

Hemolysis Destruction of red blood cells
Extravascular Hemolysis RBC destruction outside blood vessels (primarily in the spleen)
Intravascular Hemolysis RBC destruction within blood vessels
Senescence Aging
Schistocytes Fragmented red blood cells
Spherocytes Spherical red blood cells
Haptoglobin Protein that binds free hemoglobin
Hemopexin Protein that binds free heme
Bilirubin Product of heme breakdown
Jaundice Yellowing of the skin and eyes due to elevated bilirubin levels
Reticulocyte Immature red blood cell

RBC Function

Anemais