1. MLAB 1415- Hematology Keri Brophy-Martinez
Chapter 19:
Granulocyte and Monocyte Disorders

2. Review: Neutrophil Function
The contents of primary, secondary and tertiary granules in neutrophils are enzymes which are involved in killing and digesting bacteria and fungi.

3. Review: Neutrophil Function
Primary function is phagocytosis which occurs in three stages.
Stage 1: Migration and diapedesis
Chemotaxis is the process of directional migration which occurs under the guidance of chemoattractants which are produced by the site of injury.
The neutrophil transforms from smooth and round to rough and flat.
Diapedesis is the movement of the neutrophil through the vessel wall.

4. Review: Neutrophil Function
Stage 2: Opsonization and recognition
Opsonization is the mechanism which facilitates recognition and attachment to the organism to be ingested.
After the bacteria is coated by immunoglobulin and complement, it is referred to as an opsonin.

5. Review: Neutrophil Function
Stage 3: Phagocytosis: Ingestion, killing and digestion
The cytoplasm of the neutrophil forms a pseudopod which surrounds and envelops the microorganism forming a vacuole called a phagosome.
Cytoplasmic granules migrate to the vacuole and release their lytic contents which kill and digest the organism.

6. Disorders Affects granulocytes and monocytes
Response to various nonmalignant disease states and toxic changes
Changes can be qualitative or quantitative

7. Terms Leukocytosis Leukopenia
Total leukocyte count is more than 11.0 x 109/L in adult
Most commonly caused by increase in neutrophils
Leukopenia
Decrease in leukocytes below 4.5 X 109/L
Most commonly caused by decrease in neutrophils

8. Disorders of Neutrophils: Quantitative
Causes
Malignant
Neoplastic transformation of hematopoietic stem cell (discussed later)
Benign
Acquired
Neutrophilia: increase in total circulating absolute neutrophil concentration
Neutropenia

9. Neutrophilia ANC > 7.0 x 109/L
Occurs as a result of a reaction to a pathologic or physiologic process (reactive neutrophilia)
Immediate
Increase lasts about minutes
Redistribution of neutrophils from marginal pool to circulating pool
Neutrophils are mature
Seen in acute exercise, anxiety
“shift neutrophilia” or “pseudoneutrophilia”
Acute
Occurs 4-5 hours post-pathologic stimulus (i.e bacterial infection)
Increase in flow of neutrophils from the bone marrow pool to the blood
Immature neutrophils numbers may increase
Chronic
Follows acute neutrophila, if the stimulus continues beyond a few days
Storage pool in bone marrow depletes
Bone Marrow show increased numbers of early neutrophil precursors
“shift to the left”

10. Conditions Associated with neutrophilia
Reactive Chronic neutrophilia
Leukocytes< 50 x 10 9/L
Shift to the left
Presence of toxic granulation, DÖhle bodies and cytoplasmic vacuolization

11. Dohle bodies
Toxic granulation

12. Neutrophilic Conditions
Bacterial Infection
Most common cause of neutrophilia
Seen with staphylocci and streptococci infections
Bone marrow increases output of storage neutrophils to peripheral blood, see shift to the left
Physiologic leukocytosis
No shift to the left
Birth to the first days of life
Childbirth
Extreme temperatures
Emotional stimuli
Tissue destruction/Injury, Metaboloic disorders
Neutrophil input is increased from the bone marrow to the tissue
Examples include: Rheumatoid arthritis, burns, gout, uremia, trauma

13. Neutrophilic Conditions
Leukoerythroblastic reaction
Presence of nRBCs
Shift to the left
Poik, tear drops, aniso
Associated with chronic neoplastic myeloproliferative conditions

14. Neutrophilic Conditions
Leukemoid reaction
Leukocytes> 50 x 10 9/L
Advanced degree of leukocytes in the blood that is not a result of leukemia
Transient; leaves when stimulus is removed
Many circulating immature leukocyte precursors seen
Seen in chronic infections, carcinoma of certain organ systems
Blood picture similar to chronic myelocytic leukemia(CML)
Leukocyte Alkaline Phosphatase, is used to differentiate leukemoid reaction from CML
LAP increased in leukemoid reaction, decreased in CML

15. Neutropenia ANC <1.5 x 109/L Causes Increased cell loss
Increased neutrophil diapedesis (Tissue egress)
Bone marrow can not keep up with cell utilization
Examples: immune neutropenia, hypersplenism
Megaloblastic Anemia
Hypeplastic bone marrow
Abnormal myeloid cells destroyed
Decreased bone marrow production
M:E ratio decreased
Myeloid hypoplasia
Storage pool in bone marrow decreased, as is circulating and marginal pool
Examples: stem cell disorders, aplastic anemia, chemicals/drugs

16. Cytoplasmic Inclusions
Characteristic
Composition
Conditions
Döhle body
Light gray-blue oval near periphery
Rough endoplasmic reticulum (RNA)
Infections, burns, cancer, inflammatory states
Toxic granules
Large blue-black granules
Primary granules
Same as above
Cytoplasmic vacuole
Clear, unstained circular area
Open spaces from phagocytosis
Bacteria
Small basophilic rods or cocci
Phagocytized organisms
Bacteremia or sepsis
Fungi
Round or oval basophilic inclusions, larger than bacteria
Fungal infections
Morulae
Basophilic, granular, irregular shape
Clusters of Ehrlichia rickettsial organims
Ehrlichiosis

17. Nuclear Abnormalities
Anomaly
Description
Conditions
Pelger-Huët
Neutrophil nucleus is bi-lobed or has no lobes
May have a “pince-nez” appearance
clumped chromatin
Can be real or pseudo caused by drug ingestion or leukemia
Hypersegmentation
larger than normal neutrophils with 6 or more nuclear lobes.
Megaloblastic anemia
Pyknotic nucleus
Degenerating nucleus
Dying neutrophils
Pelger-Huët
Pyknotic

18. Inherited Functional Abnormalities
Condition
Morphologic or Functional Defect
Clinical Features
Alder-Reilly
Large, dark cytoplasmic granules in all leukocytes
Cells function normally
Associated with mucopolysaccharidosis
Chediak-Higashi Syndrome
Giant fused granules in neutrophils and lymphs
Cells engulf but do not kill microorganisms
Often fatal due to recurrent pyrogenic infections
May-Hegglin
Blue, Döhle-like cytoplasmic inclusions in granulocytes
Bleeding tendency from thrombocytopenia
Giant platelets
Chronic granulomatous disease
Defective respiratory burst
Recurrent infections, esp. in childhood
Prognosis poor
Myeloperoxidase deficiency
Low or absent myeloperoxidase enzyme
Cell morphology normal
benign

19. Monocyte/Macrophage Disorders
Quantitative
Monocytes only
Qualitative
Monocytes and macrophages

20. Quantitative Monocytosis AMC > 0.8 x 109/L
Seen in inflammatory conditions and malignancies
Monocytopenia
AMC < 0.2 x 109/L
Seen in stem cell disorders

21. Qualitative LIPID (LYSOSOMAL)STORAGE DISEASES Inherited disorders
Accumulation of unmetabolized material in the lysosomes of various cells. They are caused by various enzyme defects (inborn errors) in lipid metabolism linked to an enzyme deficiency
Three main disorders

22. Disorder #1 Gaucher’s Disease Enzyme deficiency: β-glucocerebrosidase
Prevalent in the Ashkenazi Jewish population (eastern European)
Macrophage can not digest the stroma of ingested cells
Results in an accumulation of glucocerebroside

23. Gaucher’s Cell Large histiocyte (20-100 µm)
Displaced nucleus which contains one or more round nucleoli
Cytoplasm is faintly blue/white with characteristic “crumpled tissue paper” appearance which is probably the result of glycolipid deposition

24. Disorder #2 Niemann-Pick Disease Enzyme deficiency: sphingomyelinase
Increased incidence in the Jewish population
Causes an accumulation of unmetabolized sphingomyelin and cholesterol
Classic form presents with jaundice at birth, hepatosplenomegaly, enlarged lymph nodes, neurological symptoms, retarded physical and mental development. Death occurs by age 3.

25. Niemann-Pick Cell
Lipid-laden giant foamy cell found in BM, tissues and other organs

26. Disorder #3 Tay Sachs Disease Enzyme deficiency: hexosaminidase A
Higher incidence in Ashkenazi Jewish population
Severity of the disease correlates with residual enzyme activity.
The buildup of unmetabolized GM2 ganglioside in the tissues has devastating effects in the central nervous system and eye.
Physical and mental deterioration occur along with seizures and paralysis. Death comes by age 4.

27. Tay Sachs Disease Foamy lymphocytes are present but are not diagnostic
The blue cells seen here are abnormally enlarged neurons