1. 1 COLLEGE OF HEALTH SCIENCES, DEPARTMENT OF BIOMEDICAL LABORATORY SCIENCE Chapter 21. Leukocytic disorders

2. 2 COLLEGE OF HEALTH SCIENCES, DEPARTMENT OF BIOMEDICAL LABORATORY SCIENCE Introduction O Quantitative disorders: leukocytosis, leukopenia O Qualitative disorders: functional defects, leukemia Quantitative disorder 1. Leukocytosis (vs Leukemoid reaction) O Leukocytosis: an increase in leukocyte count O Physiological leukocytosis: at birth O Factors affecting leukocyte concentration in peripheral blood - Bone marrow production and release of leukocytes - Rate of leukocyte egress to tissue or survival time in blood - Ratio of marginating to circulating pools in peripheral blood

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4. 4  Nonmalignant Granulocyte and Monocyte Disorders (1) Neutrophilia O An increase in the total circulating absolute neutrophil concentration O Immediate neutrophilia - A simple redistribution of the marginating pool to the circulating pool (50:50) O Acute neutrophilia - From an increase in the flow of neutrophils from the BM storage to the blood O Chronic neutrophilia - Mitotic pool -> increase production 1) Conditions associated with neutrophilia O Total leukocytes: less than 50 X 10 9 /L O increase of band and mature neutrophil O shift to the left O Toxic changes: toxic granulation, Dohle bodies, vacuoles reactive transient changes accompanying infectious state

5. 5 COLLEGE OF HEALTH SCIENCES, DEPARTMENT OF BIOMEDICAL LABORATORY SCIENCE O bacterial infection (vs viral infection: lymphocytosis) - endotoxin: increase in the flow of neutrophils from BM to blood * typhoid: decreased neutrophils (endotoxin: destruction of neutrophils) O tissue necrosis, inflammation O malignant tumor: tumor cell -> production of CSF O chronic myeloproliferative disorders (fully differentiation) - chronic myelogenous leukemia (CML) - polycythemia vera - essential thrombocytosis - myelofibrosis O drugs/hormone - Adrenal cortex hormone: increased flow of neutrophils from BM to blood - Corticosteroid: increased BM output and decreased migration to the tissue - Epinephrine: marginal pool -> circulating pool - Heavy metal poisoning (lead, mercury) O physiological increase: exercise, stress, epinephrine, pregnancy, newborn O acute hemolysis and acute hemorrhage

6. 6 COLLEGE OF HEALTH SCIENCES, DEPARTMENT OF BIOMEDICAL LABORATORY SCIENCE (2) Eosinophilia O An increase in the total circulating absolute eosinophil concentration O parasitic infection, O allergy reaction (asthma) O chronic myeloproliferative disorders - chronic myelogenous leukemia (CML) O respiratory tract, skin/connective tissue disorders (3) basophilia O An increase in the total circulating absolute basophil concentration O allergy reaction O chronic myeloproliferative disorders - chronic myelogenous leukemia (CML), polycythemia vera (4) monocytosis O An increase in the total circulating absolute monocyte concentration O inflammation, tuberculosis, neutropenia, sepsis, syphilis (5) lymphocytosis O An increase in the total circulating absolute lymphocyte concentration O virus infection (infectious mononucleosis) O increased reactive lymphocyte - large with irregular shapes and cytoplasmic basophilia, granules, vacuoles O Lymphadenopathy, splenomegaly O T cell (60-80%) vs B cell (20-40%) in peripheral blood

7. 7 COLLEGE OF HEALTH SCIENCES, DEPARTMENT OF BIOMEDICAL LABORATORY SCIENCE 2. Leukemoid reaction O A benign leukocyte proliferation characterized by a increased leukocyte count with many circulating immature leukocyte precursors O Seen in chronic infection, carcinoma, inflammatory processes O Indistinguishable from that of chronic myelogenous leukemia (CML)

8. 8 COLLEGE OF HEALTH SCIENCES, DEPARTMENT OF BIOMEDICAL LABORATORY SCIENCE 3. Infectious mononucleosis O cause: Epstein Barr virus (EBV) infection O pathophysiology - EBV -> B cell infection -> B cell activation (expression of growth factor receptor) -> increased proliferation - by increased cytotoxic T cell (reactive lymphocyte) -> Inhibit the activation and proliferation of EBV-infected B cells O Clinical findings O Fever, pharyngitis, lymphadenopathy, splenomegaly (Table 20-2) O Laboratory findings - PBS: RBC count: normal, thrombocytopnea lymphocytosis (increased reactive lymphocyte) vs Leukemia: lower N:C ratio, morphologic hetergeneity - Serologic tests increased transient heterophile anti-sheep RBC Ab Ab specific for EBV EBV nuclear antigen (EBNA)

9. 9 COLLEGE OF HEALTH SCIENCES, DEPARTMENT OF BIOMEDICAL LABORATORY SCIENCE 4. Leuko(cyto)penia: a decrease in leukocyte count (1) neutropenia 1) Decreased bone marrow production O Myeloid hypoplasia, the M:E ratio -> decrease, shift to the left O anemia (pancytopenia): aplastic anemia, megaloblastic anemia, paroxysmal nocturnal hemoglobinuria O myelodysplastic syndrome O bone marrow hypoplasia by ionizing radiation, benzene, chemotherapy drug O myelophthisis - acute leukemia, multiple myeloma: tumor in bone marrow O Congenital (hereditary) neutropenia 2) Increased cell loss: increased egress to the tissue, increased destruction O As the result of increased neutrophil diapedesis O In severe infection (cf. typhoid, viral infection) O Immune-mediated neutropenia - Alloimmune neutropenia: neonatal, transfusion reaction - Autoimmune neutropenia: systemic lupus erythematosus(SLE) O Hypersplenism (Banti syndrome), splenomegaly - increased blood cell destruction in spleen (pancytopenia) 3) Increased neutrophilic margination O Produced by alterations in the circulating and marginated pools

10. 10 COLLEGE OF HEALTH SCIENCES, DEPARTMENT OF BIOMEDICAL LABORATORY SCIENCE (2) Eosinopenia O Cushing’s syndrome, adrenal cortex hormone, stress O Glucocorticoid and epinephrine -> inhibit eosinophil release from the BM and increase margination (3) lymphocytopenia O results from - malignant lymphoma - Corticosteroid therapy: by sequestration of lymphocytes in the bone marrow - SLE: by autoantibodies against lymphocyte O Result in immunodeficiency (4) pancytopenia

11. 11 COLLEGE OF HEALTH SCIENCES, DEPARTMENT OF BIOMEDICAL LABORATORY SCIENCE 5. Immunodeficiency disorders O By impaired function of the immune system -> inability to mount a normal adaptive immune response -> increase in infections and neoplasm (1) Acquired immune deficiency syndrome (AIDS) O HIV-1 -> infect helper T cell by binding to the CD4 -> cytolysis -> lymphocytopenia -> abnormal immunity - Monocyte/macrophage: have the CD4 -> infected, not destroyed O Occurrence of repeated infections, increase in malignancies (Kaposi’s sarcoma) O Laboratory findings O Disease monitoring - CD4 lymphocyte count, plasma HIV-1 RNA copy number (viral load) - Normal CD4:CD8 in peripheral blood 2:1 -> decrease

12. 12 COLLEGE OF HEALTH SCIENCES, DEPARTMENT OF BIOMEDICAL LABORATORY SCIENCE  Nonmalignant Lymphocyte Disorders (2) Congenital immune deficiency disorders 1) Severe combined immunodeficiency syndrome (SCID) O quantitative and or qualitative immune defects - Lymphopenia or functionally deficient O T and B cell: affected 2) Wiskott-Aldrich syndrome (WAS) O Eczema, thrombocytopenia, immunodeficiency -> recurrent infections, bleeding O T (CD8) cell: affected 3) DiGeorge syndrome O Congenital immunodeficiency, heart defect, dysmorphic facies O Absence or hypoplasia of the thymus: decrease in peripheral blood T cells 4) Sex-linked agammaglobulinemia (Bruton’s disease) O Block B cell maturation -> serum Ig: decrease O Cell-mediated immunity: normal 5) Ataxia-Telangiectasia O defects in the repair of DNA double-stranded breaks O Neurologic disease, immune dysfunction, predisposition to malignancy O Defect in cell-mediated immunity, abnormal B cell function

13. 13 COLLEGE OF HEALTH SCIENCES, DEPARTMENT OF BIOMEDICAL LABORATORY SCIENCE Quantitative disorder O congenital, abnormal function - defects in migration, phagocytosis, antimicrobial activity -> increased infection 1. Chronic granulomatous disease (CGD) O defects in bactericidal activity (the respiratory burst oxidase system) O can not generate antimicrobial oxygen metabolites (reactive oxygen species) O Can phagocytize the microorganisms but cannot kill them O Granuloma formation 2. Myeloperoxidase deficiency O Characterized by an absence of meyloperoxidase in neutrophils and monocytes O defects in hydrogen peroxide (H 2 O 2 ) production -> decreased antimicrobial activity - Cells are able to utilize an alternative system to kill the microorganism O myeloperoxidase staining: negative - caution: when differentiate between myeloblast and lymphoblast 3. Chediak-Higashi (-steinbrink) syndrome O abnormal lysosome -> defects in phagolysosome formation and degranulation -> defects in bactericidal activity and migration

14. 14 COLLEGE OF HEALTH SCIENCES, DEPARTMENT OF BIOMEDICAL LABORATORY SCIENCE  Nonmalignant Granulocyte and Monocyte Disorders 4. Lazy leukocyte syndrome O defects in migration -> decreased flow of leukocytes from the BM to the blood -> decreased leukocytes in the PB 5. Leukocyte adhesion deficiency (LAD) O Characterized by decreased or absent leukocyte adhesion protein (β 2 -integrin) O Cannot adhere to EC of the blood vessel walls and exit the circulation O Persistent leukocytosis and granulocytosis due to increased stimulation of BM

15. 15 COLLEGE OF HEALTH SCIENCES, DEPARTMENT OF BIOMEDICAL LABORATORY SCIENCE 6. Lysosomal storage disease O Defects in any of the lysosomal enzymes -> accumulation of partially degraded insoluble substrates (mucopolysaccharides) O autosomal recessive, affect infants and young children O hepatosplenomegaly, neuronal damage, cellular dysfunction by abnormal macrophage activation and release of cytokines (1) Gaucher disease O by deficiency of β-glucocerebrosidase (cleave glucose from ceramide) -> glucocerebroside accumulation O Macrophage: unable to digest the stroma of ingested cells O splenomegaly (pancytopenia), hepatomegaly, bone pain O Gaucher cell (Figure 19-15) - histiocyte (tissue macrophage) - Small eccentric nuclei, cytoplasm -> wrinkled tissue paper (fine folding) - PAS, Sudan Black B, acid phosphatase staining: positive O serum acid phosphatase activity: increase

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19. 19 COLLEGE OF HEALTH SCIENCES, DEPARTMENT OF BIOMEDICAL LABORATORY SCIENCE (2) Niemann-Pick disease O by deficiency of sphingomyelinase -> spingomyelin (phosphocholine + ceramide) accumulation O Begin in infancy with poor physical development O splenomegaly (pancytopenia), hepatomeglay, neuropathy O Foam cell (Niemann-Pick’s cell) - macrophage - Large (20-100 um) with small eccentric nuclei and cytoplasmic lipid droplet (3) Tay-Sachs disease (G M2 gangliosidosis) O hexosaminidase A deficiency -> G M2 ganglioside accumulation O CNS (brain), eye (retina) O foam cell, vacuolated histiocyte - whorled configuration within lysosome (4) Mucopolysaccharidoses (MPSs) O MPS degradative enzyme deficiency -> MPS accumulation O coarse facial feature, joint stiffness, cardiac complication, mental retardation O Hunter’s syndrome, Hurler’s syndrome