chapter 21 nonmalignant leukocytes, granulocytes and monocytes

Leukopenia

< 4.5x 10^3 mcl

Absolute cell count

diff count x wbc count

Neutrophilia

>7000

Factors affecting neutrophil number

bone marrow production and release, rate of egress to tissue or survival time in blood. ratio of marginating to circulating neutrophils in pb

reactive neutrophilia

occurs in response to physiologic or pathologic process, can be immediate, acute, chronic

Immediate neutrophilia

50% freely circulating, 50% loosley attached to endothelial cells of blood vessels (marginated). can occur without stimulus. last 20 to 30 min. independent of bm input and tissue egress. pseudoneutrophilia or demargination. normal mature cells. happens due to active exercise, epinephrine, anesthesia, anxiety, childbirth, extreme temps, stress

Acute neutrophilia

occurs within hours of pathologic stimulus. neutrophil egress from bm storage pool into peripheral blood. shift to the left. increase proportion of immature cells: bands metamyelocytes. hemorrhage, vaccines, venoms, burns, autoimmune disorders

chronic neutrophilia

follows acute. depleted storage pool. increased production of mitotic pool. early neutrophil precursors. bm myoblasts, promyelocytes, myelocytes. pb metamyelocytes, myelocytes. persistent infections, persistent inflammation, drugs, hormones, toxins, eclampsia, adrenocorticotropic hormone, cancers

characteristics of neutrophilia

< 50x10^3 leukocytes. left shift cell population (more immature). toxic morphology: toxic granulation, dohle bodies, vacuolization

bacterial infections

most common cause of neutrophilia. fungi, rickettsia, parasites, spirochetes and virus. 7-70x10^3 (usually 10-25). poor prognostic sign with severe infections

neutrophilia conditions

tissue destruction/ injury, inflammation, metabolic alterations. increase neutrophil egress from bm to circulation in response to increase diapedesis. tissue infarctions, burns, neoplasms, uremia, ra, gout.

Leukemoid reaction

extreme neutrophilic reaction. necrotizing tissue, benign leukocyte proliferation. wbc count <50. left shift (immature leukoctyes). May resemble CML, leukemoid reaction- transient neutrophilia, normal karyotype, elevated LAP scores. CML-philadelphia chromosome, decrease LAP scores

Chronic myeloid leukemia (CML)

> 50. includes promyelocytes, blasts, increased eosinophils and basophils, erythrocytes often decreased. platlets increased or decreased. philadelphia chrom present, BCR/ABL1 gene present, clinical systemic (splenomegaly, enlarged nodes, bone pain)

Leukoerythroblastic reaction

associated with neoplastic myeloproliferative conditions, especially myelofibrosis or myelophthisis (marrow replacement with fibrosis). HDFN. contains NRBCs and neutrophilic left shift, total count of neutrophils increased or decreased, rbcs have anisocytosis, poikilocytosis (teardrops cells)

stimulated bm states

neutrophilia with hematopoietic growth factor or cytokine stimulation, GM-CSF (CSF2), after BM transplant, chemotherapy, bm failure. corticosteroid therapy increased bm output coupled with decreased migration to tissue.

Physiologic leukocytosis

> 11x10^3/mcl. at birth, first few days of life, physiologic stress, extreme temps, emotional stimuli, exercise, labor during delivery. no left shift

Neutropenia

neutrophil count <1.5-2x10^3. Agranulocytosis <.5x10^3. high probability of infection, basophils and eosinophils commonly depleted. increased cell loss (immune destruction or increased neutrophil egress to tissue). decreased bm production, pseudoneutropenia (increased neutrophil margination) morning pseudoneutropenia.

decreased bm production

Bm myeloid hypoplasia, decreased M:E ratio. BM storage pool decreased, PB circulating and marginated pool decrease. lack of neutrophils at inflammatory sites, increased risk infections, stem cell disorders like aplastic anemia, radiotherapy, chemotherapy, infiltration of hematopoietic tissue by malignant cells (myelophthisis)

megaloblastic anemia and myelodysplastic syndrome

marrow is usually hyperplastic, neutropenia resutls from destruction of abnormal myeloid precursors in BM (ineffective granulopoiesis)

chemicals and drugs

wide variety can cause leukopenia and neutropenia. chemotherapy and radiation treatment. immunologic reactions to drugs. drug induced immune neutropenia.

congenital neutropenia (cyclic neutropenia)

recurring episodes of severe neutropenia cycling 21-30 days. begins in infancy or childhood. lasts few days, increased risk of infection. mutations in neutrophil elastase gene (ELANE). therapy G CSF (granulocyte colony stimulating factor- filgrastim)

congenital neutropenia (severe congenital neutropenias (SCN))

heterogeneous group of disorders, rare, often fatal, extreme neutropenia <.2x10^3, total leukocyte count normal, mutations of elastase gene, G CSF, Kostmann syndrome mouth is messed up (autosomal recessive, HAX1 and SBDS)

Congenital neutropenia (familial neutropenia)

Rare, benign anomaly, absolute decrease in neutrophils, normal total leukocyte count, autosomal dominant, detected by chance, no infectious complications

increased cell loss (neutropenia)

bm cannot produce cells as rapidly as they are being utilized, infections cause tissue damage and increased neutrophil demand. toxic granulocytes, poor prognostic indicator, test for anti neutrophil Antibodies or neutrophil surface Abs

Neutropenia (immune neutropenia)

abs directed against neutrophil specific ags, may be precipitated by drugs, may be direct cell lysis or sensitization and removal by spleen. (alloimmune, autoimmune)

immune neutropenia (alloimmune neonatal neutropenia)

similar to HDFN. can result from transfusion reaction. transplacental passage of maternal IgG to neutrophil specific antigens. antigens inherited from infants father. neutropenia of limited duration (up to 4 months)

Immune neutropenia (autoimmune neutropenia (AIN))

primary- develops as Ab coated neutrophils destroyed by spleen. seen in children, spontaneous remission usually after 13 -20 months. secondary- autoimmune diseases (SLE, RA) usually found in older patients, actual target of Abs not known

increased cell loss (hypersplenism)

selective splenic culling of neutrophils, mild neutropenia. May occasionally see thrombocytopenia and anemia as well.

Pseudo Neutropenia

alterations in circulating and marginated pools, similar to pseudo neutrophilia. Results from transfer of circulating neutrophils to marginated neutrophil pool with no change in total pool, temporary shift

False neutropenia

in vitro artifacts. EDTA induced neutrophil adherence to erythrocytes, disintegration of neutrophils over time prior to testing, disruption of abnormally fragile leukocytes during preparation of the blood for testing, neutrophil aggregation

Qualitative or Morphologic Abnormalities

not detected by automated hematology analyzers, identified by observation of blood smears. cytoplasmic abnormalities more common than nuclear abnormalities, most are reactive, transient changes accompanying infectious states

Nuclear abnormalities (Pelger Huet)

autosomal dominant inheritance, decreased spegmentation of the granulocyte nucleus, with course chromatin clumping in nucleus, round or oval nucelus homozygouts, bilobed heterozygotes, pince nez cells. cells functionally normal, acquired (pseudo pelger huet pelgeroid) myeloproliferative/ myelodysplastic states, nucleus round, hypogranular, intense clumping

nuclear abnormalities (hypersegmentation)

six or more nuclear segments, five or more neutrophils with five lobes. megaloblastic anemias (early indicators), hereditary hypersegmentation (benign).

Pyknotic nucleus (confused with NRBCs)

dying neutrophils, nuclear chromatin condenses, segments disappear, become smooth, dark staining sphere

cytoplasmic abnormalities (dohle bodies)

aggregates of RER gray blue inclusions in cytoplasm of neutrophils or eosinophils, seen in severe infections, burns, cancer, toxic drugs. made of RNA

cytoplasmic abnormalities (toxic granulation)

same condition as dohle bodies, large, deeply stained blue black primary granules in segmented neutrophils, bands and metamyelocytes. true toxic granulation must be distinguished from artifact, true toxic granulation will not appear equally in all neutrophils

cytoplasmic abnormalities (cytoplasmic vacuoles)

clear, unstained areas, end stage phagocytosis, seen in same condition as toxic granulation and dohle bodies. artifact when blood stored in EDTA.

cytoplasmic abnormalities (intracellular organisms)

interpret with care, sign. finding in neutro. Bacteria, histoplasmosis, candida, ehrlichia (morulae) some purple sphere- bacteria, anaplasma (singular dot)- bacteria. do indirect fluorescent ab assays, identify DNA sequence by PCR. fungi is rounder than bacteria

Inherited Functional Abnormalities

patients with recurrent, severe infections, abscesses, delayed wound healing, antibiotic resistant sepsis. Alder reilly anomaly, chediak higashi syndrome, may hegglin anomaly, chronic granulomatous disease (CGD), Myeloperoxidase deficiency, leukocyte adhesion deficiency (LAD)

Alder reilly anomaly

inherited condition with large purplish granules in cytoplasm. incomplete degradation of mucopolysaccharides that accumulate in lysosomes. Hunters syndrome- Enlarged forehead and face., hurlers syndrome. toxic granules, cells function normally, seen in bm cells.

Chediak-Higashi syndrome

Rare autosomal recessive disorder. CHS1, defects in granule morphogenesis, death occurs in first or second decade of life. recurrent bacterial infections. giant, gray green peroxidase positive bodies and giant lysosomes in cytoplasm of leukocytes. fusion of primary granules. patients have neutropenia, thrombocytopenia, lymphadenopathy, skin hypopigmentation, silver hair, photophobia

May Hegglin anomaly

Granulocytes contain dohle body like inclusions consisting of RNA from rough ER. usually larger and more round than Dohle bodies. results from defect in myosin heavy chain type IIA gene. MYHA gene, leads to the precipitation of non muscle myosin heavy chains. neutrophils function normally, giant platelts, variable thrombocytopenia, bleeding from low platelets

Chronic Granulomatous Disease (CGD)

defective respiratory burst, cells engulf microorganisms but don't kill them. childhood

Myeloperoxidase deficiency

low or absent myeloperoxidase enzyme cell morphology normal. Usually benign, compensated systems prevent infections.

Leukocyte adhesion deficiency (LAD)

absence of cell surface adhesion proteins affecting multiple cell functions, serious conditions with recurrent infections and high mortality

Eosinophil disorders (hypereosinophilia (HE))

increase in eosinophil potentially serious- clonal (neoplastic or primary), reactive (nonclonal, AKA secondary). hard to determine (reference interval low). observed in acute infections, inflammation and glucocorticoid administration. normal eos .4

Nonclonal (reactive) hypereosinophilia

HE >.4. infections with helminthic parasites (tissue invasive phase). allergic conditions, GI disease, skin and connective tissue disorders

clonal (neoplastic) hypereosinophilia

>1.5 with tissue infiltration. eosinophilic leukemia/myeloproliferative disease. Idiopathic HE-striking eosinophilia without apparent cause. Chronic HE hypereosinophilic syndrome (HES) extensive tissue damage as the granules are released from disintegrating eosinophils

Basophil disorders (basophilia)

normal 0-.2. basophilia >.2. associated with immediate type hypersensitivity reactions and chronic myeloproliferative disease. Basophilic leukemia- rare, >80% basophils total leukocyte population

Basophil disorders (basopenia)

difficult to determine, inflammatory states, immunologic reactions

monocytosis

>.8. seen most often in inflammatory conditions and certain malignancies (CML, CMML, some acute leukemias).

Monocytopenia

<.2. stem cell disorders aplastic anemia

Lysosomal storage disorders

defect of normal degradative enzymes leads to accumulation of substrates unable to be transported out of cell. Leads to cell dysfunction and pathological phenotypes. Most are autosomal recessive. two categories based on accumulated material. Mucopolysaccharidoses (MPS), lipidoses

Gaucher disease

deficiency of beta glucosidase. enzyme needed to break down glucocerebroside. lipid accumulates in macrophages. Cells are large with small eccentric nuclei, cytoplasm wrinkled or striated. similar cells seen in marrow of individuals with rapid granulocyte turnover (CML). large stomach from large spleen and liver

Niemann Pick disease

often fatal by 3 years old. Type A and B. deficiency in sphingomyelinase. enzyme needed to break down lipids, excess of sphingomyelin (breaks done different molecules). Foamy macrophages: large, eccentric nucleus, globular cytoplasmic inclusions. leads to retardation

Miscellaneous lysosomal storage disorders

tay sachs disease, sandhoff disease, wolmans disease, hurlers and hunters syndrome. Deficiency of one or more enzymes that metabolize lipids or mucopolysaccharides. accumulation of lipids in lysosomes of tissue cells, often fatal, affects mostly nonhematologic tissue

Histiocytoses

langerhans cells, dendritic cells, monocytes/ macrophages, Ag processing and Ag presenting cells, Three classes of histiocytosis

Sea blue histiocytosis syndrome

sea blue staining macrophages found in liver, spleen, bm. large cells, dense eccentric nucleus, cytoplasm contains blue or blue green granules, also seen in niemann pick disease, gaucher disease, hematopoietic disease, infection. (really bad rash)