Red Blood Cells, Anemia, and Polycythemia

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Red Blood Cells, Anemia, and Polycythemia

• Guyton Chapter 32

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• Pluripotential stem cell in the bone marrow gives
  rise to all of the cellular blood components
• Erythrocytes, non-lymphoid leukocytes (monocytes
  and granulocytes) and megakaryocytes divide and
  develop in the marrow
• Lymphoid precursors replicate in secondary
  lymphoid tissues
• (lymph node, thymus, spleen)

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Erythrocytes (RBCs)

• Major function of RBCs is to transport hemoglobin
  (Hb)
• Hb carries oxygen from the lungs to the tissues
• RBCs contain carbonic anhydrase that catalyzes
  the reversible reaction between carbon dioxide
  (CO2) and water to form carbonic acid (H2CO3)

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RBC Shape and Size

• Size varies with species
• - canine (7 um)
• - caprine (4 um)
• Shape varies with species
• - most species have round RBCs
• - Camelidae are ellipsoidal
• Reptiles, birds and amphibians have nucleated red
  blood cells

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Production of Red Blood Cells

• RBCs are produced in the bone marrow exclusively
  by birth
• Extramedullary hematopoiesis
• - liver and spleen can make red blood cell
  precursors during times of anemia
• Bone marrow collection sites
• - trochanteric fossa
• - iliac crest
• - proximal humerus
• - sternebrae (horse)

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Genesis of Blood Cells

• Stem cells can divide and give rise to any cell
  type (or become another stem cell)
• Growth inducers promote growth and reproduction
  of all cell lines (IL-3)
• Differentiation inducers cause differentiation
  of one type of committed cell toward a final
  adult cell
• - RBCs erythropoietin(Epo)

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Differentiation of RBCs

• Morphologic changes during
• maturation of RBCs
• 1. Cells become smaller
• 2. Nuclei become smaller
• 3. Nucleus is extruded at the
• metarubricyte stage and
• a reticulocyte is formed
• 4. cytoplasm changes from
• blue (RNA in reticulocyte)
• to orange (Hb)

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Regulation of RBC Production

• Total RBC mass in the system is regulated within
  narrow limits
• - adequate numbers for
• sufficient oxygen transport
• - not so numerous that they
• impede blood flow
• Factors that decrease oxygenation stimulate Epo
• 1. low blood volume
• 2. anemia
• 3. low hemoglobin
• 4. poor blood flow
• 5. pulmonary disease

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Regulation of RBC Production

• Tissue oxygenation is the most essential
  regulator
• Red blood cell production increases with
  decreased oxygen transport to the tissues
• - Percentage of hemoglobin is almost
  always near the maximum concentration in each RBC
  
• - With hypoxia, RBC mass must increase
  rather than increasing the hemoglobin in each RBC

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Stimulation of RBC Production

• Erythropoietin (Epo) is the principal stimulus
  for RBC production (erythropoiesis) in low oxygen
  states
• 90 of Epo is formed in the kidneys the
  remainder is formed mainly in the liver
• In the absence of Epo, hypoxia has little effect
  in stimulating RBC production

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Effect of Epo in Erythropoiesis

• Epo begins to be formed within hours of detecting
  hypoxia, reaching maximum production within 24
  hours
• - no new RBCs appear in
• circulation for 2-3 days
• Epo stimulates the production of rubriblasts
  from stem cells
• Causes rubriblasts to pass more readily through
  the different stages of RBC differentiation
• Epo levels decreases once hypoxia is no longer
  present

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Maturation of RBCs

• Maturation and rate of production affected by
  nutritional status (RBCs are constantly growing
  and reproducing)
• Two vitamins are especially important for final
  maturation
• (essential for DNA synthesis)
• - Vitamin B12
• - Folic acid
• Vitamin B12 or folic acid deficiency
• - failure of nuclear maturation
• and cell division
• - large (macrocytic) cells that are
• fragile, causing shortened
  survival
• of RBCs and anemia

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Formation of Hemoglobin

• Synthesis of Hb begins in the rubriblast and
  continues through the reticulocyte stage
• Hb composition
• - heme molecule containing
• Fe2 (ferrous iron)
• - 4 globin chains
• Slight variations in the different subunit
  hemoglobin chains depends on the amino acid
  composition of the polypeptide
• - (a, ß, ?, d)
• Adult hemoglobin (2 a, 2ß)

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Hemoglobin

• Four molecules of 02 can be transported by each
  Hb molecule
• The types of amino acid chains in the Hb molecule
  determine the binding affinity of Hb for 02
• - fetal Hb has a higher
  affinity
• for 02 than adult Hb
• Abnormalities of the Hb chains have not been
  described in animals (sickle cell anemia in
  humans results in deformed red cells that rupture
  within capillaries)

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Iron Metabolism

• About 65 of the iron in the body is in the form
  of Hb
• About 25 of iron is in storage
• - liver
• - reticuloendothelial system
• lt 10 of iron
• - myoglobin
• - cytochromes
• - transferrin
• Total body iron is regulated mainly by altering
  the rate of absorption from the intestines

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Transport and Storage of Iron

• Iron absorbed through the small intestines
  combines with a ß globulin apotransferrin to form
  transferrin
• In the cell cytoplasm, iron combines with a
  protein, apoferritin, to form ferritin
• Iron stored as ferritin is called storage iron
• Smaller quantities of iron in the storage pool
  are in an insoluble form called hemosiderin
  (especially when the total iron is more than the
  apoferritin storage pool can accommodate

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Life Span and Destruction of RBCs

• Average RBC lifespan in circulation varies with
  species
• - Cow 160 days
• - Sheep 150 days
• - Horse 145 days
• - Human 120 days
• - Dog 110 days
• - Pig 86 days
• - Cat 70 days
• - Bird 35 days
• Mature RBCs have cytoplasmic enzymes capable of
  metabolizing glucose and forming ATP (but no
  nucleus, mitochondria, or endoplasmic reticulum)
• Aged RBCs are removed by the spleen

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Life Span and Destruction of RBCs

• Aged RBC membranes become fragile and often
  self-destruct in the red pulp of the spleen
• When the spleen is removed, the number of old
  abnormal cells circulating in the blood increases
• Old RBCs are phagocytized by macrophages,
  predominantly in the spleen and liver
• The hemoglobin is broken down
• - iron is transported back into
• the blood by transferrin
• - amino acids of the globulin
• chain are re-utilized
• - porphyrin ring becomes bilirubin
• ( a waste product put into bile)

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Anemias

• Definition deficiency of hemoglobin in the
  blood
• - too few red blood cells
• - too little Hb in each RBC
• Classification
• 1. a primary bone marrow defect
• (non-regenerative anemia)
• 2. peripheral destruction of RBCs
• (regenerative anemia)
• - blood loss anemia
• - hemolytic anemia

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Anemias

• Blood loss anemia
• - fluid and RBCs are equally lost
• - anemia is detectable when
• the fluid portion (plasma) is
• replaced (occurs within hours
• and continues 24-72 hours)
• - RBC concentration returns to
• normal within 3-6 weeks
• after one acute hemorrhage
• Chronic blood loss will result in iron-deficiency
  anemia that is poorly regenerative, microcytic
  and hypochromic

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Anemias

• Hemolytic anemia
• - RBCs are destroyed in the
• periphery faster than they
• can be replaced by the bone
• marrow (hypercellular marrow)
• Destruction of the RBCs can occur within the
  blood vessels (intravascular hemolysis) or occur
  by macrophage phagocytosis (extravascular
  hemolysis)
• Severe hemolytic anemias cause hyperbilirubinemia
  (jaundice)

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Effects of Anemia on Function of the Circulatory
System

• Viscosity ot the blood depends on the
  concentration of RBCs
• Anemia (decreased blood viscosity)
• decreases the resistence to blood flow in
  the peripheral vessels
• More blood flows through the tissues and returns
  to the heart
• (? cardiac output)
• Hypoxia causes peripheral vasodilation (?
  cardiac output)
• One of the major effects of anemia is greatly
  increased cardiac output and increased workload
  on the heart

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Polycythemia

• Secondary (most common)
• - Occurs with tissue hypoxia
• 1. Insufficient oxygen in the
• breathed air (high altitude)
• 2. Failure of oxygen delivery to
• the tissues (cardiac failure,
• pulmonary disease)
• Primary (rare) Polycythemia vera
• - caused by a genetic aberration
• in the erythroid precursors
• - no longer respond to negative
• feedback to stop RBC production
• - RBCs and total blood volume ?

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Effects of Polycythemia on Function of the
Circulatory System

• Increased blood viscosity causes sluggish blood
  flow through the peripheral blood vessels
• 1. Increased blood viscosity
• decreases the rate of venous
• return to the heart
• 2. Increased blood volume
• increases rate of venous return
• Cardiac output is fairly normal b/c
• 1 and 2 neutralize each other
• Arterial pressure is normal to high
• Bluish (cyantoic) tint to the skin

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Questions?