RED BLOOD CELLS

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RED BLOOD CELLS

• by
• Mary Yvonnette C. Nerves, MD, FPSP

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Erythropoiesis

• A process by which early erythroid precursor
  cells differentiate to become the mature RBCs
• Primary regulator ERYTHROPOIETIN
• - stimulates red cell precursors at all levels
  of maturation to hasten the maturation process
• - responsible for stimulating the premature
  release of reticulocytes into the bloodstream.

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Erythropoiesis

• Total erythropoiesis
• - total number of red blood cells (RBCs)
• - measured by the myeloid-erythroid (ME)
  ratio from aspirate smears plus the estimate
  of cellularity from biopsy sections

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• Effective erythropoiesis
• - number of viable and functional RBCs
  available for physiologic needs
• - reflects the balance between the number
  of cells produced and their life span
• - measured by the reticulocyte count, which is
  normally 1 of the total RBC count

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Stages of Maturation

• Pronormoblast (Rubriblast)
• Basophilic Normoblast (Prorubriblast)
• Polychromatophilic Normoblast (Rubricyte)
• Orthochromatic Normoblast (Metarubricyte)
• Reticulocyte
• Erythrocyte

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Pronormoblast

• Earliest recognizable and largest cell of
  the erythrocyte series
• Morphology
• - Size 12 20 um
• - Nucleus large round, oval, dark violet
  fine chromatin 1 2 nucleoli
• - Cytoplasm deep blue spotty, basophilic
  w/ a perinuclear halo
• - N/C Ratio 81
• - BM () 1

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Basophilic Normoblast

• Hemoglobin synthesis begins at this stage
• Morphology
• - Size 10 15 um
• - Nucleus large round to sl oval
  condensed, coarse chromatin 0 1 nucleoli
• - Cytoplasm deeply basophilic clusters of
  free ribosomes
• - N/C Ratio 61
• - BM () 1-4

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Polychromatic Normoblast

• Increased production of hemoglobin pigmentation
  and decreasing amounts of RNA
• Last stage in which the cell is capable of
  mitoses
• Morphology
• - Size 10 - 15 um
• - Nucleus round nucleus, deep staining, may
  be centrally or eccentrically located
  coarse clumped chromatin
• - Nucleoli 0

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• Morphology
• - Cytoplasm abundant blue-gray (RNA) to
  pink-gray (hemoglobin)
• - N/C Ratio 41
• - BM () 10-20

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Orthochromatic Normoblast

• The last nucleated stage
• Cannot synthesize DNA and cannot undergo
  cellular division
• The NRBC sometimes seen in the
  peripheral circulation

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• Morphology
• - Size 8 - 10 um
• - Nucleus small pyknotic nucleus dense
  chromatin 0 nucleoli
• - Cytoplasm abundant red-orange
  cytoplasm uniform in color
• - N/C Ratio 12
• - BM () 5-10

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Reticulocyte

• Slightly larger than the mature RBC with
  residual amts of RNA
• Reticulocyte count an index of bone marrow
  activity or effective erythropoiesi
• Morphology
• - Size 8 - 10 um
• - Nucleus anucleate cell containing small
  amt of basophilic reticulum (RNA)
• - Nucleoli 0
• - Cytoplasm large amt of blue-pink
  staining hemoglobin cytoplasm

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Erythrocyte

• A biconcave 6 8 um disc
• Life span 120 days
• Main function to transport hemoglobin,
  a protein that delivers oxygen from the lungs to
  tissues and cells
• Contains 90 hemoglobin and 10 H2O
• normal conc of RBCs varies w/ age, sex
  geographic distribution

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• Morphology
• - Size 7 - 8 um
• - Nucleus anucleated cell
• - Nucleoli 0
• - Cytoplasm pink staining, zone of
  central pallor is 1/3 of cell diameter
  devoid of hemoglobin
• - N/C Ratio NA

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Hemoglobin Structure Function

• A conjugated protein that serves as the vehicle
  for the transportation of O2 and CO2
• When fully saturated, each gram of Hgb can hold
  1.34 mL of O2
• A molecule of Hgb consists of 2 pairs of
  polypeptide chains (globin) and 4
  prosthetic heme grps each contg 1 atom of ferrous
  iron

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DESCRIPTION of TERMS

• SIZE DESCRIPTORS
• Anisocytosis variation in the sizeof the RBCs
  due to a pathologic condition

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• Normocytic normal sized biconcave disc RBC
• - normal MCV

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• Microcytic Smaller RBCs less than 6 um
• - MCV lt 80 fl
• - Defect / Change abn size due to failure
  of hgb synthesis
• - Dse IDA, Thalassemia, Chronic dse
• Macrocytic Larger RBCs greater than 9um
• - MCV gt 90 fl
• - Defect / Change impaired DNA synthesis /
  stress erythropoiesis
• - Dse Megaloblastic anemia / liver dse /
  MDS / Alcoholism / Malaria

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Macrocytic
Microcytic
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• CHROMICITY DESCRIPTORS
• Normochromic normal in color pale central
  area occupies less than 1/3
• - Defect / Change normal amt of Hgb
• - Normal indices
• Hypochromic an RBC that has a decreased Hgb
  complement
• - central pallor exceeds 1/3 of diameter
  of cell
• - Defect / Change reduced Hgb content
  ( MCHC)
• - Assoc conditions IDA / Thalassemia

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• Hyperchromic no central pallor
• - Defect / Change greater than normal
  MCHC
• - Assoc condition Spherocytosis

Hyperchromic
Hypochromic
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• Polychromasia blue-gray coloration
• - Defect / Change presence of RNA
• - Assoc condition increased erythropoietic
  activity / hemorrhage / hemolysis

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• SHAPE DESCRIPTORS
• Poikilocytosis variation in shape of the RBC
• - Defect / Change irreversible alteration
  of membrane
• - Assoc conditions Anemia / Hemolytic
  states

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• Discocyte normal biconcave erythrocyte - 6 8
  um diameter 0 2 um thickness
• - Aka Normocyte

Normal Red Cells (SEM)
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• Acanthocyte spheroid w/ 3 12 irreg
  spikes or spicules
• - Aka spur cell
• - decreased cell volume
• - Defect / Change inc ratio of chole to
  lecithin
• - Assoc conditions
• end-stage liver dse
• Pyruvate kinase def
• Hemolytic anemia
• Abetalipoproteinemia

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• Blister cell contains 1 or more vacuoles
• - Aka Bite cells
• - thinned periphery
• - Defect / Change formed by removal of
  Heinz bodies
• - Assoc conditions
• Hemolytic episodes
• G6PD def
• Hemoglobinopathies

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• Codocyte peripheral rim of Hgb surr by
  clear area central hemoglobinized area
  (bulls eye)
• - Aka target cell
• - Defect / Change excess of surface to
  volume ratio
• - Assoc conditions
• Hemoglobinopathies
• Thalassemia
• Liver dse
• Postsplenectomy

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• Dacryocyte teardrop or pear-shaped w/ single
  elongated point or tail
• - Aka tear drop cell
• - Defect / Change squeezing fragmentation
  during splenic passage
• - Assoc conditions
• Myeloid metaplasia
• Thalassemia
• Megaloblastic anemia
• Hypersplenism

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• Drepanocyte crescent-shaped cell that lacks
  zone of central pallor
• - Aka Sickle cell
• - Defect / Change polymerization
  of deoxygenated Hgb
• - Assoc conditions
• Sickle cell anemia
• SC disease
• S-thalassemia

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• Echinocyte regular 10-30 scalloped
  short projections evenly distributed / spiny-like
• - Aka Burr cell / crenated RBC
• - Defect / Change Depletion of ATP
• Exposure to hypertonic soln
• Artifact in air drying
• - Assoc conditions
• Uremia
• Cirrhosis / Hepatitis
• Chronic renal dse

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• Ovalocyte egglike or oval-shaped cell
• - Defect / Change
• Hgb has bipolar arrangement
• Reduction in membrane chole
• - Assoc conditions
• Megaloblastic BM
• Myelodysplasia
• Sickle cell anemia

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• Elliptocyte rod or cigar shape,
  generally narrower than ovalocytes
• - Defect / Change polarization of Hgb
• - Assoc conditions
• Thalassemia
• Iron def
• Hereditary elliptocytosis

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• Schistocyte Fragmented RBCs varying in
  size shape
• - Aka Helmet cells
• - Defect / Change extreme fragmentation produc
  ed by damage of RBC by fibrin, altered vessel
  walls, prosthetic heart valves
• - Assoc conditions
• DIC / TTP / Burns
• Microangiopathic hemolytic anemia

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• Spherocyte smaller in diameter than normal
  RBC w/ concentrated Hgb content no visible
  central pallor
• - Defect / Change
• lowest surface area to volume ratio
• defect of loss of membrane
• - Assoc conditions
• Hereditary spherocytosis
• Iso- autoimmune hemolytic anemia
• Severe burns
• Hemoglobinopathies

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• Stomatocyte normal sized cell w/ slitlike
  area in center
• - Defect / Change
• artifact of slow drying
• known to have inc permeability to Na
• - Assoc conditions
• Hereditary stomatocytosis
• Acute alcoholism
• Liver dse

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RED CELL INCLUSIONS

• Basophilic Stippling
• - cytoplasmic remnants of RNA
• - Fine thin round dark blue granules
  uniformly distributed
• - Defect/Change represents polychromasia
  (reticulocyte)
• - Coarse medium sized uniformly
  distributed
• - Defect/Change represents impaired
  erythropoiesis

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• Basophilic Stippling
• - Assoc conditions
• Thalassemia
• Lead Poisoning
• Increased reticulocytosis

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• Cabot Ring
• - rings, loops, or figure eights red to purple
• - Defect / Change remnants of
  microtubules of mitotic spindle
• - Assoc conditions
• Megaloblastic anemia
• Dyserythropoiesis

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• Heinz bodies
• - deep purple irregularly shaped
  inclusions found on RBC inner surface of
  membrane
• - Defect / Change represent precipitated,
  denatured Hgb due to oxidative injury
• - Assoc conditions
• Hereditary defects in HMS
• G6PD def
• Unstable Hgbs
• Splenectomized pts
• Thalassemia

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• Howell-Jolly bodies coarse round
  densely stained purple 1-2 um granules
  eccentrically located on periphery of membrane
• - Defect / Change nuclear remnants
  contain DNA
• - Assoc conditions
• Megaloblastic anemia
• Severe hemolytic process
• Thalassemia
• Accelerated erythropoiesis

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• Pappenheimer bodies small, 2-3 um irregular
  basophilic inclusions that aggregate in small
  clusters near periphery w/ Wrights stain
• - Defect / Change unused iron (nonheme)
  deposits
• - Assoc conditions
• Sideroblastic anemia
• Defective erythropoiesis
• MDS
• Hemolytic anemia
• Thalassemia

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• Ringed Sideroblasts
• - Nucleated RBC that contains nonheme
  iron particles (siderotic granules) arranged in
  ring form
• - Defect / Change excessive iron overload in
  mitochondria of normoblasts
• - due to defective heme synthesis
• - Assoc conditions
• Sideroblastic anemia
• MDS

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Ringed Sideroblasts Prussian blue iron stain
showing excess accumulation of iron as ferritin
in mitochondria ringing nucleus.
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• Siderocyte non-nucleated cell containing
  iron granules
• - Defect / Change excessive iron overload in
  mitochondria of normoblasts
• - due to defective heme synthesis
• - Assoc conditions
• Sideroblastic anemia
• MDS

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• Autoagglutination clumping of RBCs
• - Defect / Change presence of antibody
• - Assoc conditions
• Cold agglutinin
• AHA

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• Rouleaux Formation alignment of RBCs linear
  appearing as stacks of coins
• - Defect / Change concentration of
  fibrinogen immunoglobulin
• - Assoc conditions
• MM / Waldenstroms macroglobulinemia

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Red Cell Studies
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• Hematologic tests used to measure several
  important parameters that reflect rbc structure
  and function
• 1) Hemoglobin determination
• 2) Erythrocyte count
• 3) Hematocrit
• 4) Erythrocyte Indices MCH, MCHC, MCV
• 5) Reticulocyte Count
• 6) Osmotic Fragility Test
• 7) Erythrocyte Sedimentation Rate (ESR)

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Adult Reference Ranges for Red Blood Cells
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• Hemoglobin
• - involves lysing the erythrocytes, thus
  producing an evenly distributed solution of
  hemoglobin in the sample
• - Hemiglobincyanide Mtd blood is diluted in
  a soln of K3Fe(CN6). The K3Fe(CN6) oxidizes Hgbs
  to hemiglobin (metHgb) and K cyanide provides
  cyanide ions to form HiCN, w/c has a broad
  absorption max at a wl of 540 nm

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• Erythrocyte Count
• - involves counting the number of rbcs per
  unit volume of whole blood.
• - expressed as number of cells per unit
  volume, specifically cells/µL
• - NV Female 4.2 - 5.4 x 106/µL
• Males 4.7 - 6.1 x  106/µL

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• Hematocrit
• - sometimes referred to as the Packed
  Cell Volume (PCV) or volume of packed red cells
• - is the ratio of the volume of RBCs to that of
  the whole blood
• - varies with age and sex
• - expressed as a percentage or as a decimal
  fraction

Plasma
Buffy coat
Red cells
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• Erythrocyte Indices
• 1) Mean Cell Volume (MCV)
• - average volume of red cells
• - calculated from the Hct and RBC count
• MCV Hct x 1000
• RBC (in millions/uL)
• - expressed in femtoliters (fl) or cubic
  micrometers

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2) Mean Cell Hemoglobin (MCH) - content
(weight) of Hgb of the average red cell -
calculated from the Hgb and RBC count MCH
Hgb (in g/L) RBC (/L) - value
is expressed in picograms (pg)
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• 3) Mean Cell Hemoglobin Concentration (MCHC)
• - the average conc of Hgb in a given volume of
  packed red cells
• - calculated from the Hgb conc the Hct
• MCHC Hgb (in g/dL)
• Hct
• - expressed in g/dL

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• Reticulocyte Count
• - Principle Reticulocytes are immature
  non- nucleated red cells that contain RNA
  and continue to synthesize Hgb after the loss
  of the nucleus
• - Supravital staining blood is briefly
  incubated in a soln of new MB or BCB, the RNA
  is precipitated as a dye-ribonucleoprotein compl
  ex ? dark blue network (reticulum or
  filamentous strand)
• - NV 0.5 1.5 or 24 84 x 109/L

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• Osmotic Fragility Test (OFT)
• - a measure of the ability of red cells to take
  up fluid without lysing
• - Red cells are suspended in a series of tubes
  contg hypotonic solns of NaCl solns varying
  from 0.9 to 0.0, incubated at room temp for
  30 mins and centrifuged
• - the percent hemolysis in the supernatant solns
  is measured plotted for each NaCl conc.

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• - The larger the amount of red cell
  membrane (surface area) in relation to the size
  of the cell, the more fluid the cell is capable
  of absorbing before rupturing
• - Cells that are more spherical, w/ a decreased
  surface/volume ratio, have a limited capacity
  to expand in hypotonic solns lyse at a higher
  conc of NaCl than do normal biconcave cells ?
  OFT

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• - Cells that are hypochromic flatter have a
  greater capacity to expand in hypotonic solns,
  lyse at a lower conc than do normal cells, are
  said to have decreased osmotic fragility
• - Cells with increased surface/volume ratio are
  osmotic resistant ? IDA, thalassemia, liver dse,
  reticulocytosis

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• Erythrocyte Sedimentation Rate (ESR)
• - detect and monitor an inflammatory response
  to tissue injury (an acute phase response) in
  which there is a change in the plasma conc of
  several proteins
• - Principle When well-mixed venous blood is
  placed in a vertical tube, RBCs will tend to
  fall toward the bottom. The length of the fall
  of the top of the column of RBCs in a given
  interval of time is called the ESR

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• - ESR is affected by (3) FACTORS
• a) erythrocytes
• b) plasma composition
• c) mechanical / technical factors
• - Red Cell Factors
• Anemia increases ESR (change in RBC plasma
  ratio favors rouleaux fotn)
• ESR is directly proportional to the weight of
  the cell aggregate inversely proportional to
  the surface area
• Microcytes sediment slower than macrocytes
• Rouleaux accelerate the ESR
• Red cells w/an abnormal or irregular shape
  hinder rouleaux fotn lower the ESR

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• - Plasma Factors
• Elevated levels of fibrinogen accelerate ESR
• Albumin lecithin retard ESR
• Cholesterol accelerate ESR
• - Mechanical / Technical Factors
• A tilt of 3o can cause errors up to 30 ? ESR
• ESR increases as the temp increases
• ESR tubes with a narrower than standard
  bore will generally yield lower ESR
• ESR stands fro gt 60 mins ? falsely elevated ESR
• Greater conc of EDTA ? falsely low ESR
• - Methods Westergren Mtd / Wintrobe Mtd

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ERYTHROCYTE DISORDERS
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• Two main disorders affecting RBCs
• 1. Polycythemia (Erythrocytosis)
• - an elevated Hct level above the normal
  range
• 2. Anemia
• - a reduction below normal limits of the
  total circulating red cell mass

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Pathophysiologic Classification of Polycythemia
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POLYCYTHEMIA

• May be classified into (2) major conditions
• 1) Relative Polycythemia
• - an increase in the Hct or red cell count as
  a result of decreased plasma volume
• - total red cell mass is NOT increased
• - Assoc conditions acute dehydration or
  hemoconcentration / pts on diuretic therapy /
  Gaisbocks syndrome (psedopolycythemia or
  stress erythrocytosis)
• - BM Normal

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• 2) Absolute (or Secondary) Polycythemia
• - an erythropoietin mediated increase in RBCs
  and Hgb due primarily to a hypoxic situation
• - increase in the total red cell mass in the
  body assoc w/ normal or sl increased plasma
  volume
• - Assoc conditions tumors / anabolic
  steroids / renal dso such as cystic dse,
  hydronephrosis / adrenal cortical
  hyperplasia
• - BM Erythroid hyperplasia

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3) Polycythemia rubra vera (Primary
Erythrocytosis) - an absolute increase in all
cell types, RBCs, WBCs and platelets - not
dependent on erythropoietin levels - BM all
three cell lines increased (panhyperplasia)
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ANEMIA

• Decreased oxygen carrying capacity of the blood
• Anemia may also be "defined" in terms of the Hb
  content
• Hb lt 12 g/dL in an adult male
• Hb lt 11 g/dL in an adult female

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• ANEMIAS SECONDARY TO BLOOD LOSS
• Acute e.g., hemorrhage due to trauma,
  massive GI bleeding, or child delivery. Usually
  the iron stores remain normal.
• Chronic e.g., bleeding peptic ulcer or
  excessive menstrual bleeding.

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HYPOPROLIFERATIVE ANEMIAS (Impaired Production)

• reduced production of red cells can be subdivided
  into
• deficiency of haematinics
• iron deficiency
• B12 and folate deficiency
• dyserythropoiesis (production of defective cells)
  
• anaemia of chronic disorders (AOCD)
• myelodysplasia
• sideroblastic anaemia
• marrow infiltration (myelophthisic anemia)
• aplasia (failure of production of cells)
• aplastic anaemia
• red cell aplasia

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Iron Deficiency Anemia

• Normal forms of iron (Fe) and iron metabolism
• Functional iron is found in Hb, myoglobin, and
  enzymes (catalase cytochromes)
• Ferritin physiological storage form
• Hemosiderin degraded ferritin lysosomal debris
  (Prussian blue positive)
• Iron is transported by transferrin

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• causes
• Dietary deficiency elderly, children and poor
• Increased demand children pregnant women
• Decreased absoprtion
• generalized malabsorption
• after gastrectomy
• Chronic blood loss
• GI bleeding (e.g. peptic ulceration, carcinoma
  of stomach or colon)
• menorrhagia
• urinary tract bleeding
• Hook worm (Ancylostoma duodenale adult worm
  sucks 0.2 ml blood/day)

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• Lab Findings
• Microcytic, hypochromic anemia. Low serum iron
• BM show absence of iron
• Ferritin Low serum ferritin indicates low body
  stores of iron
• Transferrin These carrier proteins will be
  unsaturated and available to bind iron, hence the
  Total Iron Binding Capacity (TIBC) is increased
  with anemia.

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Anemia of Chronic Disease (AOCD)

• Char by iron being trapped in BM macrophages
• Can be grouped in 3 categories
• - chronic microbial infections (eg.
  Osteomyelitis)
• - chronic immune disorders (eg. RA)
• - Neoplasms (eg. lymphoma, breast/lung CA)
• Chronic inflamm dso ?inc IL-1, TNF, IF-Gamma ?
• - reduction in renal erythropoietin ? marrow
  erythroid precursors do notproliferate
• - hepcidin synthesis in liver ?inhibits release
  of iron

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• Labs low serum iron
• increased serum ferritin
• decreased TIBC
• normochromic, normocytic anemia or
  hypochromic, microcytic anemia

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Megaloblastic Anemia

• A group of dso in which the blood and BM
  hematopoietic cells display changes
• Pathogenesis impaired DNA synthesis (delayed
  mitoses) while RNA is not impaired this produces
  nuclear-cytoplasmic asynchrony
• Megaloblastic anemias can be divided into groups
• - anemia caused by B12 deficiency
• - anemia caused by folate deficiency
• - anemias nonresponsive to either therapy

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• important background knowledge
• B12
• vitamin B12 is required for DNA replication and
  inhibition of transcription of DNA to RNA
• B12 is normally absorbed from gut by the
  following mechanism
• secretion of intrinsic factor by parietal cells
  in stomach
• binding of intrinsic factor and vitamin B12 in
  lumen
• intrinsic factor- B12 complex is absorbed in
  terminal ileum through pinocytotic vesicles
• Folate
• folate is required for DNA replication and
  inhibition of transcription of DNA to RNA
• lack of B12 or folate means that RNA builds up
  and the cells become too large

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• Causes
• causes of vitamin B12 deficiency (pernicious
  anaemia)
• lack of intrinsic factor
• atrophic gastritis - parietal cells are destroyed
  
• gastrectomy
• malabsorption of B12 not related to lack of
  intrinsic factor
• tropical sprue or bacterial overgrowth of
  terminal ileum
• ileal disease (e.g. Crohn's disease affecting the
  terminal ileum)
• fish tape-worm (these attach to intestinal wall,
  and therefore in large enough numbers, may
  prevent B12-intrinsic factor complex absorption
  in terminal ileum)
• poor diet - rare

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• causes of folate deficiency
• poor diet - especially in alcoholics
• malabsorption - coeliac disease
• increased cell turnover (e.g. leukaemia, chronic
  haemolysis, pregnancy)
• antifolate drugs (e.g. phenytoin)

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• Peripheral Blood Findings

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• Morphologic Abnormalities
• Large RBC's with nuclear-cytoplasmic dyssynchrony
• Ovalocytes The large RBC's tend to have an
  oval-shape.

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• Hypersegmented Neutrophils One of the earliest
  signs of disease. 5 or 6 lobes
• Howell-Jolly Bodies Nuclear fragments seen in
  Megaloblastic anemia.

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Aplastic Anemia

• pancytopenia associated w/ a severe reduction in
  the amt of hematopoietic tissue that results in
  deficient production of blood cells
• Etiology
• Acquired
• idiopathic
• Chemical agents
• Physical agents
• Viral infections
• Inherited
• Fanconis anemia

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• Pure red cell aplasia erythrocyte stem cells are
  suppressed, but the other formed elements of
  blood are unaffected
• Anemia due to isolated depletion of erythroid
  precursors in the marrow, and may be acute or
  chronic.
• Lab Findings
• - Normochromic, normocytic or macrocytic anemia
• - Reticulocytes are decreased or absent because
  it is hypoproliferative.
• - BM hypocellular or dry tap
• reduction in all cell lines

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HEMOLYTIC ANEMIAS (Increased Destruction)

• Grp of dso that can be inherited, acquired,or
  drug-induced
• Char by an increased red cell destruction or
  shortened survival of the RBC
• Char by increased BM activity, polychromasia,
  nucleated RBCs and an increased reticulocyte
  count w/ stress reticulocytes

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• Hemolytic anemias share the ff. features
• 1. shortened red cell life span, that is,
  premature destruction of red cells
• 2. elevated erythropoietin levels and
  increased erythropoiesis in the marrow other
  sites
• 3. accumulation of products of Hgb
  catabolism, due to an increased rate of red
  cell destruction

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• HEMOLYTIC ANEMIAS
• Acquired
• Immune-mediated
• - Autoimmune
• - Alloimmune (Transfusion)
• - Drug-induced
• Microangiopathic
• Infection
• Hereditary
• Enzymopathies
• Membranopathies
• Hemoglobinopathies

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• INTRINSIC DEFECTS
• Hereditary Spherocytosis
• abnormal cell membrane assoc cytoskeleton causing
  red cells to be spherical and fragile
• principle defect is an abnormality of the
  membrane protein ankyrin
• Lab findings Normocytic, hyperchromic anemia
  (normal MCV and increased MCHC)
• - increased pigment catabolism, erythroid
  hyperplasia, reticulocytosis
• - red cells with increased OFT

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• Glucose-6-Phosphate Dehydrogenase Deficiency
• Normal G6PD metabolises glucose, and
  forms small amounts of ATP (which maintains
  the cell cytoskeleton and membrane) and NADPH
  (which mops up free radicals)
• G6PD def renders the cell susceptible to
  damage by free radicals
• an X-linked recessive condition, in which
  haemolytic crises are precipitated by
  infections or certain drugs
• Lab findings poikilocytes spherocytes,
  Heinz bodies (stain w/ methyl violet)

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• HEMOGLOBINOPATHIES
• Normal Hgb
• HbA / HbF / HbA2 (adult)
• Hb Gower-1 and 2 / Hb-Portland (embryonic)

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• THALASSEMIA
• Caused by impaired production of one of the
  polypeptide chains of the Hb molecule
• Epidemiology Mediterranean, African Asian
  ancestry
• autosomal recessive disease
• Types according to clinical severity
• thalassaemia major homozygote
• thalassaemia minor heterozygote
• Types according to molecular defect
• beta thalassaemia
• alpha thalassaemia

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• Beta-Thalassemia
• Major (Homozygous state)
• - severe hypochromic, microcytic anaemia,
  hepato- splenomegaly, marrow hyperplasia causing
  skeletal deformities, haemochromatosis develops
  with repeated transfusions
• Minor (Heterozygous states)
• - reduction in HbA, but increase in HbA2 mild
  anaemia with hypochromia

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• Alpha-Thalassemia
• note that there are 4 copies of the alpha globin
  gene (not 2), and therefore four possible degrees
  of alpha thalassaemia exist
• 3 good copies - silent carrier
• 2 good copies - mild anaemia with microcytosis
• 1 good copy - moderate haemolytic anaemia with
  hypochromia and mycrocytosis HbH (tetramer of
  beta)
• 0 good copies - lethal in utero (hydrops fetalis)
  

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Thalassemia Major Patient with thalassemia major
due to heterozygous hemoglobin E/B thalassemia.
Note prominent target cells, anisopoikilocytosis,
and three nucleated red cells (normoblasts)  
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• Sickle Cell Disease
• Endemic to Sub-saharan Africa, due to
  heterozygous advantage conferred against
  Falciparum Malaria (infected RBC's preferentially
  sickle and are thus taken to the spleen and
  sequestered, limiting the spread of infection)
• PATHOGENESIS Point-mutation of Glu ? Val at 6th
  position of beta-globin chain
• Pathophysio abn Hgb polymerises at low O2
  saturation causing abnormal rigidity and
  deformity of red cells and become abnormality
  fragile (and undergo haemolysis and sludge in
  small vessels)
• autosomal recessive, with a point mutation in
  beta gene forming an abnormal HbS more common
  in Negroes

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• Lab. Findings
• Smear normochromic, normocytic anemia,
  increased polychromasia, normoblasts are present,
  numerous target cells, Howell-Jolly and
  Pappenheimer bodies are present, sickle cells
• OFT decreased
• BM normoblastic hyperplasia w/ increased iron
  storage
• Electrophoresis no HbA, 80 HbS (SCD)

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Sickle Cells (SEM) Scanning electron micrograph
(SEM) showing sickle cells obstructing small
vessel.  
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• EXTRINSIC DEFECTS
• Immune Hemolytic Anemias
• Dso in w/c erythrocyte survival is reduced
  because of the deposition of Ig /or
  complement on the red cell membrane
• Classification
• 1. Autoimmune Hemolytic Anemia
• 2. Isoimmune Hemolytic Anemia
• 3. Drug-induced Hemolytic Anemia
• LAB () direct indirect antiglobulin tests

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Agglutination of erythrocytes is seen on this
peripheral blood smear
Coombs Test
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• Traumatic Hemolytic Anemia
• Char by striking morphologic abn of the red
  cells, w/c include fragments (schistocytes)
  irregularly contracted cells (triangular cells,
  helmet cells)
• MICROANGIOPATHIC HEMOLYSIS RBC's being damaged
  by intravascular fibrin-clots, in small vessels.
  DIC, TTP, HUS.
• MACROANGIOPATHIC HEMOLYSIS Damage by artifical
  heart valves.

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