Myeloid Maturation

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Myeloid Maturation Stuff
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Outline

• review granulopoiesis
• discuss normal granulocyte compartments
• discuss conditions where numbers of granulocytes
  is abnormal
• discuss conditions where the appearance of
  granulocytes is abnormal
• look at slides

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Learning Objectives

• 1. Describe granulopoiesis, including conditions
  that influence the process, and factors that
  control it.
• 2. Identify granulocyte compartments their
  contents.
• 3. Describe identify granulocytes at each
  stage of development (Romanowsky stain).
• 4. Describe conditions leading to altered
  numbers of circulating granulocytes.
• 5. Identify describe altered granulocyte
  appearance (due to infection/inflammation or
  hereditary disorders).

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Granulopoiesis
bone marrow precursors
mitotic
post mitotic
blood tissue
mature/storage
proliferating
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0 2 4 6 8 10 12
Another way to look at it...
circulating blood marginating pool
bone marrow
tissues
maturation storage pool
meta
poly
band
utilization destruction
proliferating pool
myelo
of total granulocytes
promy
blast
Days
adapted from Refking Fundamentals of Hematology
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• Cells leave circulation by going out between the
  endothelial cells lining vessels.
• Time spent in tissues is not known
• Once granulocytes leave the blood for tissues
  they never come back
• As cells leave the blood for tissues they are
  replaced by other cells from the BM.
• Normally rate of entry is same as rate of exit
• Total life of a granulocyte is 7 to 11 days

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Granulocytes and Inflammation

• Granulocytes function mainly in tissues
• When tissue damaged, series of reactions take
  place referred to as inflammatory response.
• Neutrophils, eosinophils and basophils all play
  an important role in inflammation.

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Things That Influence Granulopoiesis

• 1. stromal cells ( adequate micro - environment)
• composed of fat cells
• endothelial cells
• fibroblasts
• macrophages
• 2. hemopoietic growth factors or cytokines
• colony stimulating factors (CSF)/ interleukins
• IL-3 ( multi-CSF) - neutrophil,eosinophil,
  basophil
• GM-CSF (granulocyte-macrophage) - neutrophil,
  eosinophil
• G-CSF (granulocyte) - neutrophil
• IL-5 - eosinophil
• IL-4 - basophil

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Where the CSFs go...
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Down-regulators of Granulopoiesis

• Necessary to keep granulopoiesis in balance
• Lactoferrin - suppresses release of GM-CSF
• Granulocyte Chalones - non-specific repressors
  of DNA synthesis
• Interferons - inhibits as well as stimulates
  CSFs

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Changes in Granulocyte Number

• Normal adult WBC count
• 4 - 11 x 109/L
• when more cells are required they are first
  released
• from the marginating pool (physiological
  leukocytosis)
• when demand is greater there is increased release
  of cells from the BM storage pool (pathologic
  leukocytosis)
• may see immature cells in peripheral
  blood-referred to as shift to left

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Physiologic leukocytosis

• Definition
• non-pathological increase in leukocytes
• Possible causes
• age - newborns have higher WBC counts
• emotional stress
• anesthesia
• physical stimuli
• usually attributed to release of cells from
  marginating pool

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Pathological Leukocytosis

• Definition
• leukocytosis caused by disease processes
• Possible Causes
• bacterial infection
• neoplasm - leukemia
• following acute hemorrhage
• uremia, acidosis
• tissue damage
• drugs toxins
• metabolic disorders
• inflammatory disorders
• extra cells come from BM

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What is a Leukemoid Reaction?

• Leukemoid Reaction WBCgt 50x109/L
• non-leukemic rise in leukocyte count
• may be due to increase in granulocytes, or other
  WBCs
• may be marked left shift (bands, metamyleocytes,
  promyelocytes in the peripheral blood)
• toxic changes in cells - döhle bodies, toxic
  granules or vacuolation
• may be due to pregnancy, chronic acute
  infections,severe hemorrhage, severe burns,
  cancers, etc

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Decrease in Granulocytes

• Causes of Neutropenia
• Decreased Production
• drugs (chloramphenicol, chemotherapy)
• nutritional deficiencies (B12, folate)
• PNH or aplastic anemia
• infiltration
• Increased destruction
• neutrophil antibodies, drugs
• Cyclic neutropenia - rare, autosomal dominant,
  periodic stem cell failure
• Pseudo-neutropenia
• temporary shift from circulating to marginating
  pool

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Mechanisms of Neutropenia
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Disorders affecting granulocytes

• Toxicity due to severe bacterial or viral
  infections, drugs, burns,pregnancy etc.
• a) Toxic granulation
• neutrophils have large purple-black granules
• primary granules with altered permeability so
  stain more readily than in normal cells
• b) Toxic vacuolation
• neutrophils have vacuoles in cytoplasm
• c) Döhle bodies
• round or oval pale blue areas in cytoplasm of
  neutrophils
• aggregates of rough endoplasmic reticulum, may
  have RNA attached
• transient, similar to what is seen in May-Hegglin

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Döhle Bodies
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Toxic Vacuoles
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Toxic Granules
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Disorders Affecting Granulocytes

• 1. Pelger Huet
• bilobed neutrophils
• pyknotic chromatin
• benign
• autosomal dominant
• cells function just fine

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Disorders Affecting Granulocytes

• 2. Chediak-Higashi
• fused lysosomal deposits in cytoplasm abnormal
  chemotaxis degranulation patients are
  susceptible to infections

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Disorders Affecting Granulocytes

• 3. Alder Reilly
• dark course mucopolysaccharide granules in
  cytoplasm of neuts, lymphs, monos

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Disorders Affecting Granulocytes

• 4. May Hegglin
• blue Döhle-like body but even larger
• found in neutrophils, eosinophils, monocytes
  basophils
• autosomal dominant
• leukopenia