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Meet the Red Cell. K. Krishnan MD. FRCP, FACP. The red cell. Durability of red cell is remarkable No nucleus to direct regenerative processes No mitochondria available for efficient oxidative metabolism No ribosomes for regeneration of lost or damaged protein

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meet the red cell
Meet the Red Cell
  • K. Krishnan MD. FRCP, FACP
the red cell
The red cell
  • Durability of red cell is remarkable
  • No nucleus to direct regenerative processes
  • No mitochondria available for efficient oxidative metabolism
  • No ribosomes for regeneration of lost or damaged protein
  • No de novo synthesis of lipids
red cell survival
  • Survives constant mechanical stress like hydrostatic pressure and turbulence and shear stress
  • Survives biochemical stress of osmotic and redox fluxes as it travels through the renal collecting system, sluggish vascular system of the spleen, muscle and bone
  • Survives the ambient oxygen pressures occurring in the lungs
red cell survival tools
  • Adaptive membrane structures
  • Pathways of intermediary energy metabolism and redox regulation and
  • Ability to maintain Hb in the soluble and nonoxidized form
  • The membrane and enzymes of the red cell are crafted to protect the cell from external ravages of the circulation and the internal assaults of the massive amount of iron rich and oxidizing protein represented by the hemoglobin molecules
basics of erythropoiesis
Basics of Erythropoiesis
  • Erythropoiesis is the process of producing red cells.
  • Regulated by a series of steps beginning with the pluripotent hematopoeitic stem cell
  • Erythroid cells come from a common erythroid/megakaryocyte progenitor
  • Needs transcription factors, GATA-1 and FOG-1 (friend of GATA-1)
basics of erythropoiesis1
Basics of Erythropoiesis
  • After lineage commitment is achieved, growth factors and hormones regulate development
  • Erythropoeitin induces the committed progenitor to expand in number.
  • Epo is regulated by Oxygen availability
  • Glycoprotein
  • Released by specialised cells- the peritubular capillary lining cells in the kidney
  • Small amount of Epo from hepatocytes
  • Oxygen tension in the kidney is the stimulus for Epo production
  • Epo binds to specific receptors on the surface of marrow erythroid precursors
concept of the erythron
Concept of the Erythron
  • Dynamic organ made up a pool of rapidly proliferating marrow erythroid precursors and a large mass of circulating red blood cells
  • The size of the red cell mass reflects a balance between production and destruction
elements of erythropoiesis
Elements of Erythropoiesis
  • Eythropoeitin production
  • Iron availability
  • Proliferative capacity of the bone marrow
  • Effective maturation of the red cell precursors
what are these
What are these?

What stains were used?

reticulocyte count
Reticulocyte Count
  • An accurate reticulocyte count is key to the initial classification of anemia
  • Represent new, young, just released red cells
  • Signature- supravital dye that identifies the ribosomal RNA
  • Blue or black punctate spots
  • The residual RNA is metabolised over time
  • Measure of red cell production
  • Reticulocytosis
    • Acute blood loss
    • Splenic sequestration
    • Hemolysis
      • Immune
      • Non-immune
      • Infection
      • Membrane
  • Reticulocytopenia
    • Early iron deficiency
    • Primary bone marrow failure
    • Secondary bone marrow failure
use of reticulocyte count
Use of reticulocyte count
  • Two corrections necessary
    • Adjusts reticulocyte count based on the reduced number of circulating red cells (with anemia the reticulocyte percentage is increased but not the absolute number). The reticulocyte percentage is multiplied by the ratio of the patient’s hemoglobin/hematocrit for the age and gender. This provides a reticulocyte count corrected for the anemia
    • For example, if the reticulocyte count is 8 and hemoglobin is 8, then the corrected reticulocyte count is 8/16 x 8=4
    • A further correction of the corrected reticulocyte count (reticulocyte production index) is necessary for an index of marrow production to account for the premature release of reticulocytes from the marrow
      • Examine smear and see if there are polychromatophilic, macrocytes-these are prematurely released reticulocytes called SHIFT RETICULOCYTES. If no polychromatic red cells are seen second correction is not required
      • These reticulocytes live in the peripheral blood for a longer time than normal reticulocytes and hence provide a falsely high estimate of daily red cell production
      • If polychromasia is present, the reticulocyte count corrected for anemia should be further divided by a factor of 2.
functional classification of anemias
Functional classification of anemias
  • Marrow production defect
    • Hypoproliferative
  • Red cell maturation defect
    • Ineffective erythropoeisis
  • Decreased red cell survival
    • Blood loss/hemolysis
hypoproliferative anemias
Hypoproliferative anemias
  • Serum iron, TIBC, renal and thyroid function, bone marrow biopsy, serum ferritin
microcytic hypochromic red cells
Microcytic hypochromic red cells
  • Iron deficiency
  • Thalassemias
  • Lead poisoning
  • Sideroblastic anemias
  • Anemia of chronic diseases
thalassemic syndromes
Thalassemic syndromes
  • Hypochromic microcytic red cells
  • “Chip munk” facies
  • Hemolytic anemia
  • Hepatosplenomegaly
  • Leg ulcers
  • Gallstones
  • High output heart failure
  • Endocrine dysfunction
  • Infections
beta thalassemic syndromes
Beta-thalassemic syndromes
  • Microcytes
  • Bizarre poikilocytes
  • Tear drop cells
  • Target cells, nucleated red cells
  • Extraordinarily folded red cells called LEPTOCYTES containing alpha-globin inclusion bodies
what is the hematological defect
What is the hematological defect?
  • Failure of synthesis of the globin chains either alpha or beta chains
  • Low supply of globin chains and not enough to form hemoglobin tetramers
  • Leads to microcytosis and hypochromia
  • Unbalanced accumulation of the normal chain
  • Toxic inclusions and intramedullary hemolysis
  • Eythropoeitin surge but ineffective hematopoeisis
  • Builds up erythroid masses that does not produce hemoglobin
alpha thalassemia syndromes1
Alpha-thalassemia syndromes
  • Hemoglobin H disease
hemoglobin h inclusions
Hemoglobin H inclusions
  • Alpha-thalassemia intermedia
  • Hemolysis and splenomegaly
  • Supravital staining
  • Multiple small inclusions due to excess beta-globin
blood smear in a 43 year old man with history of a motor vehicle accident 12 years ago
Blood smear in a 43 year old man with history of a motor vehicle accident 12 years ago.

What is this?

What may have happened?

  • Slit-shaped central pallor
  • Usually alcoholic liver disease and other liver diseases
    • No hemolysis
  • Hereditary forms due to red cell overhydration
    • Na and water gain
    • Hemolysis +
target red cells
Target red cells
  • Increased membrane surface
    • obstructive liver disease due to excess lipoprotein, cholesterol and post-splenectomy states
    • no hemolysis, cells are flexible
  • Volume loss
    • Decreased Hb: iron deficiency, thalassemia
    • Poorly soluble hemoglobin: Hb S, Hb C; interact with membrane and cause water loss
  • Irregularly spiculated red cells with net gain in lipids and an asymmetry between the 2 lipid layers
  • Causes:
    • Severe liver disease
      • Hemolytic and non-hemolytic
    • Abetalipoproteinemia
    • Mcleod’s syndrome
  • Cholesterol loading causes spur cell anemia and severe hemolysis; no hemolysis if not cholesterol loaded
  • Microspherocytosis: deficiency of red cell surface
  • Immune hemolytic anemias
  • Hereditary spherocytosis
  • Heinz-body hemolytic anemia
  • Clostridial sepsis, Severe burns
  • Hypophosphatemia
mechanisms of spherocytosis
Mechanisms of Spherocytosis
  • Loss of membrane lipids leading to a reduction in surface area due to deficiencies of red cell-hereditary spherocytosis
  • Removal of membrane material form antibody coated red cells by macrophages- Immune hemolytic anemia
  • Removal of membrane associated Heinz bodies with the adjacent membrane lipids by the spleen- Heinz body hemolytic anemia
hereditary spherocytosis
Hereditary spherocytosis

Rabbit spleen showing how RBC need to elliptically deform in order to pass through the very narrow slits in the wall of the splenic cords of Billroth and enter the sinusoids from which they can return to the circulation. A microspherocyte, deprived of its excess surface area, cannot ellipitically deform and is thus trapped in the cords.

osmotic fragility test
Osmotic fragility test

Lower panel: Hereditary spherocytosis-lysis occurs in mildy hypotonic solutions

red cell membrane proteins
Red cell membrane proteins

A model depicting the major proteins of the erythrocyte membrane is shown: α and β spectrin, ankyrin, band 3, 4.1 (protein 4.1), 4.2 (protein 4.2), actin, and GP (glycophorin).

  • Hereditary elliptocytosis
  • Acquired elliptocytosis
    • Myelofibrosis
    • Thalassemic syndromes
    • Iron deficiency
cold agglutinin diseases
Cold agglutinin diseases
  • Red cell autoantibodies not cryoglobulins
  • Causes
    • Monoclonal
      • Idiopathic/chronic
      • B cell disorders
    • Polyclonal
      • Benign
      • Postinfectious-mycoplasma, EBV, HIV
  • Paraproteinemias
tear drop red cells
Tear drop red cells
  • Bone marrow infiltration
    • Fibrosis
    • Tumors
    • Granulomas
what are these1
What are these?

What stains were used?

basophilic stippling
Basophilic stippling
  • Hemolytic anemias
    • Pyrimidine-5’nucleotidase deficiency
  • Iron deficiency
  • Thalassemias
  • Lead poisoning
  • Diffuse fine or coarse blue dots in the red cell representing usually RNA residue
mechanisms of basophilic stippling
Mechanisms of basophilic stippling
  • Many small bluish dots in portion of erythrocytes; from staining of clustered polyribosomes in young circulating red cells
  • Failure to digest/clear residual RNA due to
    • Acquired and congenital hemolytic anemias
    • Lead poisoning (lead inhibits pyrimidine 5’ nucleotidase which normally digests residual RNA)
heinz bodies in red cells
Heinz bodies in red cells
  • This is a positive Heinz Body preparation, with multiple red cells containing Heinz Bodies, visible only with a supravital stain (methyl crystal violet)
  • Heinz Bodies are large, blue-purple intracytoplasmic inclusions, mostly attached to the inner cell membrane.
  • Heinz bodies consist of either precipitated normal or unstable hemoglobin.
  • Represent oxidative injury to the red cell
  • These inclusions are found in cases of hemolysis due to unstable hemoglobins, oxidant drugs (such as primaquine or dapsone), hemolytic anemia associated with severe liver disease and G-6PD deficiency and other enzymopathies.
heinz body hemolytic anemias
Heinz-body hemolytic anemias
  • Failure of mechanisms that prevent autooxidation (NADH/NADPH, catalase, glutathione, peroxidase)
  • Oxidative hemolysis
  • Bite cells, Heinz bodies
  • G6 PD deficiency states
  • Nitrites, paraquat, dapsone, hydrogen peroxide
  • Unstable Hbs
  • Post-splenectomy
howell jolly bodies
Howell-Jolly bodies
  • Usually one or at most a few purplish inclusions in the red cell visible on routine peripheral smear exam
mechanisms of howell jolly bodies
Mechanisms of Howell Jolly bodies
  • The bodies represent aggregates of denatured hemoglobin
  • Associated with states of splenic hypofunction or splenectomy
hb c disease
Hb C disease
  • Intracellular and extracellular crystals
hemoglobin c disease1
Hemoglobin C disease
  • Hemoglobin C-2 normal alpha chains and 2 variant beta chains in which lysine has replaced glutamic acid at position 6.
  • Unstable hemoglobin
  • Precipitates in red blood cells to form crystals. These intracellular crystals lead to a decrease in red blood cell deformability and an increase in the viscosity of the blood. The spleen effectively removes these crystal-containing cells.
  • The amino acid change in the hemoglobin C molecule impairs malaria growth and development. It reduces parasitemia and confers protection against malaria.
  • Heterozygotes for hemoglobin C have a survival advantage in endemic areas. The risk of malaria is lower still in persons who are homozygous for hemoglobin C.
  • In terms of geographic distribution, the hemoglobin C allele is found at the highest frequencies in West Africa, where it has been associated with protection against malaria. Also in African Americans and those of Sicilian ancestry
  • Without megalobastosis
    • Reticulocytosis
    • Liver disease
    • Aplastic anemia
    • MDS
    • Hypoxemia, smokers
  • With megalobastosis
  • Spurious increases: Cold agglutinin disease, marked hyperglycemia, older individuals
macrocytosis megalobastosis
  • B12 and folate moprhology is the same
  • Smear: High MCV, macro-ovalcoytes, nuclear hypersegmentation, thrombocytopenia, leucoerythroblastosis
  • Marrow: hypercellular, orthochromatic megalobasts, giant metamyelocyte
hypersegmented neutrophil
Hypersegmented Neutrophil
  • Megalobastic anemia
  • Myelodysplastic syndromes
  • Orthochromic megaloblast
  • Nuclear-cytoplasmic asynchony
macrocytosis and megaloblastosis
Macrocytosis and megaloblastosis
  • Nuclear maturation defect
    • B12, folate, drug damage or myelodysplasia
    • DNA metabolism
  • Microangiopathic process
microangiopathic hemolytic anemia maha
Microangiopathic hemolytic anemia (MAHA)
  • Damaged microvasculature
  • Atrioventricular malformations
  • Cardiac abnormalities
  • This series of containers holds urine of a patient with paroxysmal nocturnal hemoglobinuria, showing the episodic nature of the dark urine (hemoglobinuria) during intravascular hemolysis, usually occurring at night. Early morning urine is cola-colored. This may occur at different times of the day and vary from patient to patient. (This image has been from the American Society of Hematology Slide Bank, 3rd edition)
  • Acquired chronic hemolytic anemia
  • Triad
    • Intravascular hemolysis
    • Pancytopenia
    • Venous thrombosis
the ham test
The Ham Test

The Ham test (acidified serum lysis) establishes the diagnosis of paroxysmal nocturnal hemoglobinuria (PNH), demonstrating a characteristic abnormality of PNH red blood cells by acidified fresh normal serum. Here is a PNH patient's (Pt) red blood cells lysed by normal serum at room temperature (RT) and at 37°C compared with normal red cells (no hemolysis) (control [C]). Heated serum at 56°C inactivates complement and prevents hemolysis in PNH cells.

(Taken from Image bank American Society of Hematology Slide Bank, 3rd edition.

pig a mutation
PIG-A mutation

Shortage of glycolipid molecule, GPI, due to a mutation in an X-linked gene called PIG-A

Somatic mutations and hence the patient’s marrow is a mosaic of PNH and normal cells