The Hematopoietic

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The Hematopoietic Lymphatic Systems

• Dr. Imran Mirza
• Department of Laboratory Medicine Pathology
• University of Alberta

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LEARNING OBJECTIVES

• Following this lecture you will be able to
• List the major constituents of blood
• Explain the principles by which anemias are
  classified
• Describe the cause and features of infectious
  mononucleosis
• List the malignancies of blood cells

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COMPOSITION OF BLOOD

• 1. Plasma component
• 2. Cellular component

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BLOOD PLASMA COMPONENTS

• Water
• Dissolved ions
• Proteins
• Albumin, transferrin,
• haptoglobin, transcobalamin,
• lipoproteins, coagulation proteins,
• immunoglobulins, complement,
• growth factors, hormones, cytokines.

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BLOOD CELLS

• Erythrocytes (aka. red blood cells)
• Oxygenation of the tissues
• Leukocytes (aka. white blood cells)
• Granulocytes are involved in phagocytosis and
  destruction of microbial invaders
• Lymphocytes exert immunoregulatory control and
  produce immunoglobulins and cytokines
• Thrombocytes (aka. platelets)
• Essential for coagulation

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HEMATOPOIETIC SYSTEM

• Primary Organs
• 1. Bone marrow
• 2. Thymus
• Secondary Organs
• 1. Spleen
• 2. Lymph nodes

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BONE MARROW
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BONE MARROW STEM CELLS
Hematopoietic Stem Cell
Self-renewal
Apoptosis
Lineage Commitment
Multilineage Early, Late Progenitor Cells
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HEMATOPOIETIC SYSTEM

• Primary Organs
• 1. Bone marrow
• 2. Thymus
• Secondary Organs
• 1. Spleen
• 2. Lymph nodes

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Simplified Approach to Blood Disorders

• Cells and proteins in blood can be
• Increased
• Decreased
• Functionally abnormal

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RED BLOOD CELLS

• Devoid of a nucleus and intracellular organelles.
• Glycolysis is the main energy source.
• Lifespan of 120 days.
• Shape allows
• increased surface area for gas exchange
• deformability for passage through capillaries

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RETICULOCYTES

• Stage just before full maturation.
• Polychromatophilic.
• Larger than mature RBCs.
• Retic 0.4-2.0
• Absolute 20-90 x 109/L

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COULTER INSTRUMENT FOR Complete Blood Count (CBC)
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x 109/L
x 1012/L
g/dL

fl
pg
g/L

x 109/L
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HEMOGLOBIN (HGB)

• 90 of dry weight of red cells
• 2 pairs of polypeptide chains
• In adults, 2 alpha and 2 beta globin chains form
  a tetramer (?2?2).
• Each chain binds noncovalently with a single heme
  molecule which is responsible for transporting an
  oxygen molecule

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HEMOGLOBIN
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RBCs/HGB INCREASED (polycythemia)

• Polycythemia - increased hemoglobin and RBC mass
• Causes of Polycythemia
• 1. Primary malignant (Polycythemia vera)
• 2. Secondary
• Hypoxia (i.e. altitude, smoking, etc.)
• Increased erythropoietin secretion/renal lesions

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RBCs/HGB DECREASED (anemia)

• Can approach in two major ways
• 1. Morphologic
• 2. Etiologic
• Morphologic approach requires
• MCV, RDW and a peripheral smear
• Etiologic approach
• Clinical history, reticulocyte count

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MORPHOLOGIC CLASSIFICATION OF ANEMIA

• 1. Normochromic Normocytic
• N MCV MCH
• examples hemolysis, blood loss
• 2. Hypochromic Microcytic
• ? MCV MCH
• example iron deficiency
• 3. Macrocytic
• ? MCV N MCH
• examples Vitamin B12 deficiency, folate
  deficiency, liver disease

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ETIOLOGIC CLASSIFICATION OF ANEMIA
? Reticulocytes

• 1. Increased Loss or Destruction
• A. Hemorrhage
• B. Hemolysis
• 2. Decreased Production
• A. Nutritional deficiencies (Fe, B12, Folate,
  etc.)
• B. Stem Cell Disorders
• C. Anemia of Chronic Disease
• D. Marrow Failure - due to marrow replacement or
  loss

? Reticulocytes
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IRON METABOLISM
Circulating erythrocytes
Marrow erythroid precursors
RES stores
Liver
Plasma transferrin iron
Intestinal absorption
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Microcytic Hypochromic Anemia
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Koilonychia Brittle spoon shaped nails
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Glossitis Inflammation of the tounge
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Laboratory Evaluation of Iron Deficiency Anemia

• RBC Size and Shape/Hgb content
• Microcytic and hypochromic
• Reticulocyte Production
• Low
• Clinical Circumstances
• Chronic blood loss, poor dietary intake
• Additional Tests Useful in Diagnosis
• Low serum iron low serum ferritin

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Macrocytic Anemia Hypersegmented Neutrophil
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Laboratory Evaluation of Anemia from B12
Deficiency

• RBC Size/Hgb content
• Macrocytic
• Reticulocyte Production
• Low
• Clinical Circumstances
• ? absorption or intake ? degradation
• Additional Tests Useful in Diagnosis
• ? serum vitamin B12 hypersegmented
  neutrophils antiparietal cell Abs /or anti-IF
  Abs

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Laboratory Evaluation of Folate Deficiency Anemia

• RBC Size/Hgb content
• Macrocytic
• Reticulocyte Production
• Low
• Clinical Circumstances
• ? absorption or intake ? degradation drugs
  dialysis
• Additional Tests Useful in Diagnosis
• ? RBC folate hypersegmented neutrophils

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B12 AND FOLATE DEFICIENCY

• B12 deficiency in adults causes irreversible
  neurological damage in adults
• Folate deficiency does not result in neurological
  damage in adults.
• Folate deficiency in an expecting mom causes
  neural tube defects in the baby.

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Neural Tube Defect Folate Deficiency
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Iron, Vitamin B12 and Folate

• Nutrient Daily Requirement Body Reserve
• Iron 1 mg depends
• Vitamin B12 1 mg 2-5 years
• Folate 50-100 mg 2-5 months

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HEREDITARY HEMOLYTIC ANEMIAS

• Abnormal shaped cells e.g. Hereditary
  spherocytosis
• Abnormal hemoglobin e.g. Sickle cell disease
• Defective hemoglobin synthesis e.g. thalassemia
• Enzyme deficiencies e.g. G6PD

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HEREDITARY HEMOLYTIC ANEMIASHEREDITARY
SPHEROCYTOIS
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HEREDITARY HEMOLYTIC ANEMIASSICKLE CELL ANEMIA
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HEREDITARY HEMOLYTIC ANEMIASGlucose 6-phosphate
Dehydrogenase Deficiency

• ? RBC ability to reduce powerful oxidants.
• O2- and H2O2 denature Hgb, which then forms
  insoluble aggregates or Heinz bodies.
• Heinz bodies attach to RBC membrane compromising
  deformability.
• RBCs are hemolyzed by liver and spleen.

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HEREDITARY HEMOLYTIC ANEMIASGlucose 6-phosphate
Dehydrogenase Deficiency

• G6PD gene is present on the X chromosome.
• Full expression of disease in males
• Partial expression in heterozygote females.
• Many drugs can cause clinically significant
  hemolytic anemia in G6PD deficiency.

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ACQUIRED HEMOLYTIC ANEMIASDrug Induced Immune
Hemolysis

• 1. Adsorption of immune complexes to RBC membrane
• IgM and complement are involved.
• e.g. sulfonamides, quinine, rifampin.
• 2. Adsorption of drug to red cell membrane
• IgG and splenic macrophages are involved.
• e.g. penicillin and cephalosporin.
• 3. Induction of autoantibody
• e.g. methyldopa.

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LEUKOCYTES

• Neutrophils
• Eosinophils
• Basophils
• Monocytes
• Lymphocytes

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BAND SEGMENTED NEUTROPHILS

• Bands U-shaped or deeply indented nucleus. The
  chromatin is heavily clumped.
• Neutrophil Definite lobation with thin
  thread-like filaments of chromatin joining the
  2-5 lobes.

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NEUTROPHILS INCREASED

• Neutrophilia is gt7.5 x 109/L neutrophils.
• Reactive Neutrophilia
• Bacterial infections
• Inflammation e.g. collagen diseases
• Trauma/surgery
• Malignancy e.g. Chronic neutrophilic leukemia

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NEUTROPHILS DECREASED

• Neutropenia is defined as lt1.5 x 109/L
  neutrophils in the peripheral blood.
• lt1.0 x 109/L neutrophils - ?ability to fight
  infection.
• Agranulocytosis (lt 0.5 x 109 /L).
• The causes of leukopenia may be
• peripheral destruction
• shift into the storage or marginated
  compartments.
• marrow failure

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EOSINOPHILS

• Large cells with nuclear characteristics
  identical to neutrophils
• Abundant cytoplasm filled by large uniform,
  coarse, orange-red granules.

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EOSINOPHILS INCREASED

• Eosinophilia (gt0.6 x 109/L)
• Reactive Eosinophilia
• allergic and hypersensitivity reaction
• drug reactions
• invasive parasitic infections
• Malignancy e.g. Chronic eosinophilic leukemia

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BASOPHILS

• Least numerous granulated cells within the
  peripheral blood.
• Dense purple specific granules, of different size
  and shapes frequently overlay and obscure the
  nucleus.

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MONOCYTE

• The mature cell is slightly larger than the
  neutrophil.
• The nuclear chromatin is less condensed than the
  neutrophil and has a lacy appearance.
• May contain granules and vacuoles.

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LYMPHOCYTES

• Lymphocytes differentiate and mature in thymus (T
  cells) and bone marrow (B cells).
• Lymph nodes, spleen, and RES are also involved.
• Majority of peripheral blood lymphs are T cells
  (70).

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LYMPHOCYTES INCREASED

• Lymphocytosis (gt4.0 x 109/L)
• Reactive Lymphocytosis
• infectious mononucleosis, caused by Epstein-Barr
  Virus
• other viral infections
• drug reactions
• whooping cough
• Malignancy e.g. Chronic lymphocytic leukemia

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Jonathan Epstein
Yvonne Barr
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Oropharynx
Incoming virus
Virus egress into saliva
B-cell
Productively infected cells release virus
Crypt lumen
Infected B-cells home to tonsillar crypts
Proliferation of infected cells
Blood Stream
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INFECTIOUS MONONUCLEOSIS
Patients,
35 Years and Younger
40 Years and Older
Feature
Lymphadenopathy
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Pharyngitis
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Fever
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Splenomegaly
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Hepatomegaly
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Rash
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Jaundice
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INFECTIOUS MONONUCLEOSISCLINICAL FEATURES
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INFECTIOUS MONONUCLEOSISATYPICAL LYMPHOCYTES
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• LEUKEMIA
• MYELOID LYMPHOID
• Acute Chronic Acute Chronic

Pre-leukemia (myelodysplastic syndromes)
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ACUTE LEUKEMIA
Blast Cells gt20 in Blood or Bone Marrow
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ACUTE LEUKEMIAEPIDEMIOLOGY

• AML
• Age-specific incidence rate increases with age.
• 80-90 of acute leukemias in adults are AML.
• ALL
• Age-specific incidence rate peaks between ages
  2-10 years, declines, and then rises after age
  55.
• 80-85 of acute leukemias in children are ALL.

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ACUTE LEUKEMIACLINICAL FEATURES

• 1. Bone marrow replacement
• ?RBCs - pallor, weakness, fatigue
• ?WBCs - fever, chills, infections
• ? Platelets - petechiae, bruising, bleeding
• 2. Tissue infiltration
• Enlarged liver, spleen, lymph nodes etc.

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Severe thrombocytopenia with petechial hemorrhages
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Staphylococcus aureus infection in AML
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Bilateral viral pneumonia in a child with AML
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12-year-old girl with AML
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41-year-old man with AML
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Leukemic cell infiltration in gums in AML
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Mediastinal widening in a 4-year-old boy with ALL
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CHRONIC LEUKEMIACHRONIC LYMPHOCYTIC LEUKEMIA
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CHRONIC LEUKEMIACHRONIC MYELOID LEUKEMIA