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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
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

  • ALL CONSPIRE TO DAMAGE RED CELLS BUT IT SURVIVES FOR 120 DAYS!!!


Red cell survival tools
RED CELL SURVIVAL TOOLS

  • SIMPLE but EXQUISITE

  • 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



Erythropoeitin
Erythropoeitin tension

  • 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 tension

  • 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 tension

  • Eythropoeitin production

  • Iron availability

  • Proliferative capacity of the bone marrow

  • Effective maturation of the red cell precursors


What are these
What are these? tension

What stains were used?


Reticulocyte count
Reticulocyte Count tension

  • 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


Reticulocytes
Reticulocytes tension

  • 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 tension

  • 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 tension

  • Marrow production defect

    • Hypoproliferative

  • Red cell maturation defect

    • Ineffective erythropoeisis

  • Decreased red cell survival

    • Blood loss/hemolysis



Hypoproliferative anemias
Hypoproliferative anemias tension

  • Serum iron, TIBC, renal and thyroid function, bone marrow biopsy, serum ferritin




Microcytic hypochromic red cells
Microcytic hypochromic red cells tension

  • Iron deficiency

  • Thalassemias

  • Lead poisoning

  • Sideroblastic anemias

  • Anemia of chronic diseases


Thalassemic syndromes
Thalassemic syndromes tension

  • 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 tension

  • 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? tension

  • 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 tension

  • Hemoglobin H disease


Hemoglobin h inclusions
Hemoglobin H inclusions tension

  • 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?


Stomatocytosis
Stomatocytosis vehicle accident 12 years ago.

  • 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 vehicle accident 12 years ago.

  • 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


Acanthocytosis
Acanthocytosis vehicle accident 12 years ago.

  • 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


What is the abnormality what is the mechanism
What is the abnormality? What is the mechanism? vehicle accident 12 years ago.


Spherocytosis
Spherocytosis vehicle accident 12 years ago.

  • Microspherocytosis: deficiency of red cell surface

  • Immune hemolytic anemias

  • Hereditary spherocytosis

  • Heinz-body hemolytic anemia

  • Clostridial sepsis, Severe burns

  • Hypophosphatemia


Spherocytosis1
Spherocytosis vehicle accident 12 years ago.


Mechanisms of spherocytosis
Mechanisms of Spherocytosis vehicle accident 12 years ago.

  • 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 vehicle accident 12 years ago.

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 vehicle accident 12 years ago.

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


Red cell membrane proteins
Red cell membrane proteins vehicle accident 12 years ago.

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).


Elliptocytosis
Elliptocytosis vehicle accident 12 years ago.

  • Hereditary elliptocytosis

  • Acquired elliptocytosis

    • Myelofibrosis

    • Thalassemic syndromes

    • Iron deficiency



Cold agglutinin diseases
Cold agglutinin diseases vehicle accident 12 years ago.

  • Red cell autoantibodies not cryoglobulins

  • Causes

    • Monoclonal

      • Idiopathic/chronic

      • B cell disorders

    • Polyclonal

      • Benign

      • Postinfectious-mycoplasma, EBV, HIV


Rouleaux
Rouleaux vehicle accident 12 years ago.

  • Paraproteinemias


Rouleaux and agglutination
Rouleaux and Agglutination vehicle accident 12 years ago.


Tear drop red cells
Tear drop red cells vehicle accident 12 years ago.

  • Bone marrow infiltration

    • Fibrosis

    • Tumors

    • Granulomas


What are these1
What are these? vehicle accident 12 years ago.

What stains were used?


Basophilic stippling
Basophilic stippling vehicle accident 12 years ago.

  • 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 vehicle accident 12 years ago.

  • 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)


What do you call these cells
What do you call these cells? vehicle accident 12 years ago.

How was it stained?


Heinz bodies in red cells
Heinz bodies in red cells vehicle accident 12 years ago.

  • 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 vehicle accident 12 years ago.

  • 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


Bite cells or blister cells in g6pd oxidant hemolysis
Bite cells or blister cells in G6PD oxidant vehicle accident 12 years ago.hemolysis


Oxidant hemolysis and g6pd deficiency
Oxidant hemolysis and G6PD deficiency vehicle accident 12 years ago.


Embden meyerhof glycolytic pathway
Embden Meyerhof Glycolytic Pathway vehicle accident 12 years ago.


Howell jolly bodies
Howell-Jolly bodies vehicle accident 12 years ago.

  • 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 vehicle accident 12 years ago.

  • The bodies represent aggregates of denatured hemoglobin

  • Associated with states of splenic hypofunction or splenectomy


What is this
What is this? vehicle accident 12 years ago.


Hb c disease
Hb C disease vehicle accident 12 years ago.

  • Intracellular and extracellular crystals


Hemoglobin c disease1
Hemoglobin C disease vehicle accident 12 years ago.

  • 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


Macrocytic anemia
Macrocytic anemia vehicle accident 12 years ago.


Macrocytosis
Macrocytosis vehicle accident 12 years ago.

  • Without megalobastosis

    • Reticulocytosis

    • Liver disease

    • Aplastic anemia

    • MDS

    • Hypoxemia, smokers

  • With megalobastosis

  • Spurious increases: Cold agglutinin disease, marked hyperglycemia, older individuals


Macrocytosis megalobastosis
Macrocytosis/megalobastosis vehicle accident 12 years ago.

  • B12 and folate moprhology is the same

  • Smear: High MCV, macro-ovalcoytes, nuclear hypersegmentation, thrombocytopenia, leucoerythroblastosis

  • Marrow: hypercellular, orthochromatic megalobasts, giant metamyelocyte


Cabot s rings
Cabot’ s rings vehicle accident 12 years ago.


Hypersegmented neutrophil
Hypersegmented Neutrophil vehicle accident 12 years ago.

  • Megalobastic anemia

  • Myelodysplastic syndromes


Megalobast
Megalobast vehicle accident 12 years ago.

  • Orthochromic megaloblast

  • Nuclear-cytoplasmic asynchony


Macrocytosis and megaloblastosis
Macrocytosis and megaloblastosis vehicle accident 12 years ago.

  • Nuclear maturation defect

    • B12, folate, drug damage or myelodysplasia

    • DNA metabolism


Cbc in maha
CBC in MAHA vehicle accident 12 years ago.


Schistocytes
Schistocytes vehicle accident 12 years ago.

  • Microangiopathic process


Microangiopathic hemolytic anemia maha
Microangiopathic hemolytic anemia (MAHA vehicle accident 12 years ago.)

  • Damaged microvasculature

  • Atrioventricular malformations

  • Cardiac abnormalities


PNH vehicle accident 12 years ago.

  • 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)


PNH vehicle accident 12 years ago.

  • Acquired chronic hemolytic anemia

  • Triad

    • Intravascular hemolysis

    • Pancytopenia

    • Venous thrombosis


The ham test
The Ham Test vehicle accident 12 years ago.

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 vehicle accident 12 years ago.

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


Type iii pnh cells lacking cd 59 by flow cytometry
Type III PNH cells lacking CD 59 by flow vehicle accident 12 years ago.cytometry


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