Mod2.2 Anemia and Hemoglobinuria
Recalls
RBC PHYSIOLOGY RBC Structure:
(Boron and Boulpaep Medical Physiology ● Red blood cells (RBCs) are non-nucleated, biconcave cells with a diameter of ∼7.5 μm and a volume of ∼90
3rd edition Chapter 18, Blood) femtoliters (90 × 10⁻¹⁵ L).
● Their shape maximizes the surface-to-volume ratio, improving gas exchange efficiency by increasing
diffusion area and minimizing intracellular diffusion distances.
● The RBC cytoskeleton is anchored to the plasma membrane by glycophorin and the Cl-HCO₃ exchanger
AE1 (also called band 3 protein).
Major Functions of RBCs:
1. Carrying oxygen (O₂) from the lungs to systemic tissues.
2. Carrying carbon dioxide (CO₂) from tissues to the lungs.
3. Assisting in buffering acids and bases.
Hemoglobin (Hb) and RBC Composition:
● Hemoglobin synthesis begins in the proerythroblast stage and is completed by the orthochromatic
erythroblast stage.
● Normal hemoglobin levels are ∼14.0 g/dL in adult women and ∼15.5 g/dL in adult men.
● The concentration of hemoglobin in RBC cytosol is ∼5.5 mM, with a mean cell hemoglobin concentration of
∼35 g/dL RBC.
● The high concentration of hemoglobin is contained in RBCs to prevent its loss from the plasma through
capillary walls.
Metabolism in RBCs:
● Mature RBCs lack a nucleus and other organelles, so they cannot synthesize proteins or perform oxidative
metabolism.
● RBCs generate ATP exclusively through glycolysis, which consumes 90% of glucose, while 10% goes to
the pentose phosphate pathway.
● 2,3-Diphosphoglycerate (2,3-DPG), synthesized via DPG mutase, reduces hemoglobin’s affinity for oxygen
(O₂). Its concentration is 4-5 mM in RBCs.
● RBCs contain high levels of glutathione (GSH), ∼2 mM, crucial for protecting against oxidative damage.
Glutathione reductase regenerates GSH from oxidized glutathione (GSSG) using NADPH, which is
produced from the pentose phosphate pathway.
CO₂ Transport and Carbonic Anhydrase:
● RBCs carry two isoforms of carbonic anhydrase (CA I and CA II), which rapidly interconvert CO₂ and
HCO₃⁻. This is essential for transporting CO₂ from tissues to the lungs for exhalation.
● The Cl-HCO₃ exchanger AE1 (band 3 protein) is the most abundant membrane protein in RBCs (∼1 million
copies per cell). It facilitates rapid ion transport (∼50,000 ions per second).
● AE1 is part of the SLC4 family of HCO₃⁻ transporters and can be inhibited by DIDS (disulfonic stilbene).
● AQP1 (aquaporin 1) is the second most abundant membrane protein in RBCs (∼200,000 copies per cell)
and contributes to RBC membrane permeability, including CO₂ permeability.
, HEMOLYTIC ANEMIAS
Harrison’s 21st ed., Immune Mediated Adverse Reaction,s p. 892
HEMOLYTIC ANEMIAS Hemolytic Anemias (HAs) Overview
● Classification of Anemias:
○ Anemias can be classified into three groups:
■ Decreased production of red cells.
■ Increased destruction of red cells (hemolytic anemias).
■ Acute blood loss.
● Commonality in Increased RBC Destruction and Acute Blood Loss:
○ Both increased RBC destruction (as in hemolytic anemias) and acute blood loss result in anemia
due to overconsumption of red cells from peripheral blood.
○ In these conditions, the bone marrow function is normal and usually increased, as it tries to
compensate by producing more red cells.
● Difference Between Hemolysis and Acute Blood Loss:
○ Acute blood loss involves the physical loss of RBCs from the bloodstream or body (e.g., through
hemorrhage).
○ Hemolytic anemias (HAs) involve destruction of red cells within the body, either within blood
vessels (intravascular hemolysis) or in organs like the spleen (extravascular hemolysis).
● Types of Hemolytic Anemias (HAs):
○ Primary Etiology:
■ Inherited HAs: Genetic causes leading to defective red cell survival.
■ Acquired HAs: Result from immune, toxic, or mechanical factors.
○ Clinical Presentation:
■ Hemolytic anemias can be acute (rapid onset) or chronic (long-standing).
■ Severity can vary from mild to severe.
○ Site of Hemolysis:
■ Intravascular Hemolysis: RBC destruction occurs within blood vessels.
■ Extravascular Hemolysis: RBCs are destroyed outside blood vessels, usually in organs
like the spleen or liver.
● Mechanisms of Hemolysis:
○ Intracorpuscular Causes: These are due to defects within the red blood cell itself, such as:
■ Membrane defects (e.g., hereditary spherocytosis).
■ Enzyme deficiencies (e.g., glucose-6-phosphate dehydrogenase deficiency).
■ Hemoglobin abnormalities (e.g., sickle cell disease, thalassemia).
○ Extracorpuscular Causes: These are due to factors external to the red cell, such as:
■ Immune-mediated destruction (e.g., autoimmune hemolytic anemia).
■ Mechanical damage (e.g., microangiopathic hemolytic anemia).
■ Infections, toxins, or hypersplenism.
● Common Features of Hemolytic Anemias:
○ Regardless of the type, hemolytic anemias share certain clinical and pathophysiological
characteristics, such as:
■ Increased reticulocyte count: Bone marrow compensates by producing immature RBCs.
, ■ Elevated lactate dehydrogenase (LDH): Released from lysed red cells.
■ Elevated bilirubin: Due to breakdown of hemoglobin from destroyed RBCs.
■ Low haptoglobin: This protein binds free hemoglobin released during hemolysis, leading to
low circulating levels in hemolysis.
■ Jaundice: From elevated bilirubin levels due to excess red cell destruction.
■ Splenomegaly: Enlarged spleen due to increased extravascular hemolysis.
GENERAL CLINICAL AND LABORATORY General Clinical and Laboratory Features of Hemolytic Anemias (HAs)
FEATURES ● Clinical Presentation:
○ Onset: The symptoms of anemia vary based on how quickly it develops:
■ Abrupt onset: Hemolytic anemias (HAs) are often a medical emergency.
■ Gradual onset: In milder forms of hemolytic anemia, like hereditary spherocytosis (HS) or
cold agglutinin disease (CAD), diagnosis may take years as the body adapts to the slow
progression.
○ Key Symptoms and Signs of Hemolysis:
■ Jaundice: A hallmark of hemolysis due to increased bilirubin from the breakdown of red
blood cells.
■ Discolored urine: Patients may report dark or tea-colored urine due to hemoglobinuria.
■ Splenomegaly: Enlargement of the spleen due to its role as a major site of RBC
destruction.
■ Hepatomegaly: In some cases, the liver may also be enlarged.
■ Skeletal changes: Overactivity of the bone marrow may cause skeletal abnormalities in
severe congenital hemolytic anemias, though not as pronounced as in thalassemia major
due to less ineffective erythropoiesis.
● Laboratory Features of Hemolytic Anemias:
○ Hemolysis-Related Findings:
■ Extravascular hemolysis:
■ Increased unconjugated bilirubin and aspartate aminotransferase (AST) in
serum.
■ Increased urobilinogen in both urine and stool.
■ Intravascular hemolysis:
■ Hemoglobinuria (hemoglobin in urine), often with hemosiderinuria (iron-containing
compounds in urine).
■ Free hemoglobin in serum.
■ Increased lactate dehydrogenase (LDH).
■ Reduced haptoglobin (binds free hemoglobin).
■ Serum bilirubin may be normal or only mildly elevated.
○ Bone Marrow Erythropoietic Response:
■ Increased reticulocyte count: Indicates active bone marrow response to anemia.
■ Reticulocyte percentage and absolute count rise, showing increased red cell
production.
■ Increased mean corpuscular volume (MCV): Reflects larger, immature red cells
(macrocytes) in circulation due to the high reticulocyte count.
Recalls
RBC PHYSIOLOGY RBC Structure:
(Boron and Boulpaep Medical Physiology ● Red blood cells (RBCs) are non-nucleated, biconcave cells with a diameter of ∼7.5 μm and a volume of ∼90
3rd edition Chapter 18, Blood) femtoliters (90 × 10⁻¹⁵ L).
● Their shape maximizes the surface-to-volume ratio, improving gas exchange efficiency by increasing
diffusion area and minimizing intracellular diffusion distances.
● The RBC cytoskeleton is anchored to the plasma membrane by glycophorin and the Cl-HCO₃ exchanger
AE1 (also called band 3 protein).
Major Functions of RBCs:
1. Carrying oxygen (O₂) from the lungs to systemic tissues.
2. Carrying carbon dioxide (CO₂) from tissues to the lungs.
3. Assisting in buffering acids and bases.
Hemoglobin (Hb) and RBC Composition:
● Hemoglobin synthesis begins in the proerythroblast stage and is completed by the orthochromatic
erythroblast stage.
● Normal hemoglobin levels are ∼14.0 g/dL in adult women and ∼15.5 g/dL in adult men.
● The concentration of hemoglobin in RBC cytosol is ∼5.5 mM, with a mean cell hemoglobin concentration of
∼35 g/dL RBC.
● The high concentration of hemoglobin is contained in RBCs to prevent its loss from the plasma through
capillary walls.
Metabolism in RBCs:
● Mature RBCs lack a nucleus and other organelles, so they cannot synthesize proteins or perform oxidative
metabolism.
● RBCs generate ATP exclusively through glycolysis, which consumes 90% of glucose, while 10% goes to
the pentose phosphate pathway.
● 2,3-Diphosphoglycerate (2,3-DPG), synthesized via DPG mutase, reduces hemoglobin’s affinity for oxygen
(O₂). Its concentration is 4-5 mM in RBCs.
● RBCs contain high levels of glutathione (GSH), ∼2 mM, crucial for protecting against oxidative damage.
Glutathione reductase regenerates GSH from oxidized glutathione (GSSG) using NADPH, which is
produced from the pentose phosphate pathway.
CO₂ Transport and Carbonic Anhydrase:
● RBCs carry two isoforms of carbonic anhydrase (CA I and CA II), which rapidly interconvert CO₂ and
HCO₃⁻. This is essential for transporting CO₂ from tissues to the lungs for exhalation.
● The Cl-HCO₃ exchanger AE1 (band 3 protein) is the most abundant membrane protein in RBCs (∼1 million
copies per cell). It facilitates rapid ion transport (∼50,000 ions per second).
● AE1 is part of the SLC4 family of HCO₃⁻ transporters and can be inhibited by DIDS (disulfonic stilbene).
● AQP1 (aquaporin 1) is the second most abundant membrane protein in RBCs (∼200,000 copies per cell)
and contributes to RBC membrane permeability, including CO₂ permeability.
, HEMOLYTIC ANEMIAS
Harrison’s 21st ed., Immune Mediated Adverse Reaction,s p. 892
HEMOLYTIC ANEMIAS Hemolytic Anemias (HAs) Overview
● Classification of Anemias:
○ Anemias can be classified into three groups:
■ Decreased production of red cells.
■ Increased destruction of red cells (hemolytic anemias).
■ Acute blood loss.
● Commonality in Increased RBC Destruction and Acute Blood Loss:
○ Both increased RBC destruction (as in hemolytic anemias) and acute blood loss result in anemia
due to overconsumption of red cells from peripheral blood.
○ In these conditions, the bone marrow function is normal and usually increased, as it tries to
compensate by producing more red cells.
● Difference Between Hemolysis and Acute Blood Loss:
○ Acute blood loss involves the physical loss of RBCs from the bloodstream or body (e.g., through
hemorrhage).
○ Hemolytic anemias (HAs) involve destruction of red cells within the body, either within blood
vessels (intravascular hemolysis) or in organs like the spleen (extravascular hemolysis).
● Types of Hemolytic Anemias (HAs):
○ Primary Etiology:
■ Inherited HAs: Genetic causes leading to defective red cell survival.
■ Acquired HAs: Result from immune, toxic, or mechanical factors.
○ Clinical Presentation:
■ Hemolytic anemias can be acute (rapid onset) or chronic (long-standing).
■ Severity can vary from mild to severe.
○ Site of Hemolysis:
■ Intravascular Hemolysis: RBC destruction occurs within blood vessels.
■ Extravascular Hemolysis: RBCs are destroyed outside blood vessels, usually in organs
like the spleen or liver.
● Mechanisms of Hemolysis:
○ Intracorpuscular Causes: These are due to defects within the red blood cell itself, such as:
■ Membrane defects (e.g., hereditary spherocytosis).
■ Enzyme deficiencies (e.g., glucose-6-phosphate dehydrogenase deficiency).
■ Hemoglobin abnormalities (e.g., sickle cell disease, thalassemia).
○ Extracorpuscular Causes: These are due to factors external to the red cell, such as:
■ Immune-mediated destruction (e.g., autoimmune hemolytic anemia).
■ Mechanical damage (e.g., microangiopathic hemolytic anemia).
■ Infections, toxins, or hypersplenism.
● Common Features of Hemolytic Anemias:
○ Regardless of the type, hemolytic anemias share certain clinical and pathophysiological
characteristics, such as:
■ Increased reticulocyte count: Bone marrow compensates by producing immature RBCs.
, ■ Elevated lactate dehydrogenase (LDH): Released from lysed red cells.
■ Elevated bilirubin: Due to breakdown of hemoglobin from destroyed RBCs.
■ Low haptoglobin: This protein binds free hemoglobin released during hemolysis, leading to
low circulating levels in hemolysis.
■ Jaundice: From elevated bilirubin levels due to excess red cell destruction.
■ Splenomegaly: Enlarged spleen due to increased extravascular hemolysis.
GENERAL CLINICAL AND LABORATORY General Clinical and Laboratory Features of Hemolytic Anemias (HAs)
FEATURES ● Clinical Presentation:
○ Onset: The symptoms of anemia vary based on how quickly it develops:
■ Abrupt onset: Hemolytic anemias (HAs) are often a medical emergency.
■ Gradual onset: In milder forms of hemolytic anemia, like hereditary spherocytosis (HS) or
cold agglutinin disease (CAD), diagnosis may take years as the body adapts to the slow
progression.
○ Key Symptoms and Signs of Hemolysis:
■ Jaundice: A hallmark of hemolysis due to increased bilirubin from the breakdown of red
blood cells.
■ Discolored urine: Patients may report dark or tea-colored urine due to hemoglobinuria.
■ Splenomegaly: Enlargement of the spleen due to its role as a major site of RBC
destruction.
■ Hepatomegaly: In some cases, the liver may also be enlarged.
■ Skeletal changes: Overactivity of the bone marrow may cause skeletal abnormalities in
severe congenital hemolytic anemias, though not as pronounced as in thalassemia major
due to less ineffective erythropoiesis.
● Laboratory Features of Hemolytic Anemias:
○ Hemolysis-Related Findings:
■ Extravascular hemolysis:
■ Increased unconjugated bilirubin and aspartate aminotransferase (AST) in
serum.
■ Increased urobilinogen in both urine and stool.
■ Intravascular hemolysis:
■ Hemoglobinuria (hemoglobin in urine), often with hemosiderinuria (iron-containing
compounds in urine).
■ Free hemoglobin in serum.
■ Increased lactate dehydrogenase (LDH).
■ Reduced haptoglobin (binds free hemoglobin).
■ Serum bilirubin may be normal or only mildly elevated.
○ Bone Marrow Erythropoietic Response:
■ Increased reticulocyte count: Indicates active bone marrow response to anemia.
■ Reticulocyte percentage and absolute count rise, showing increased red cell
production.
■ Increased mean corpuscular volume (MCV): Reflects larger, immature red cells
(macrocytes) in circulation due to the high reticulocyte count.
