Hematology: Wbc Anomalies & Mpd

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Benign neutrophilia

Back 1

- Occurs most often as a result of physiologic or pathologic process= reactive neutrophilia
- Occurs in stress, tachychardia, fever, labor, strenuous exercise, epinephrine & cortisone therapy

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Influence neutrophil count.

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- Input from the bone marrow
- Changes in proportion of marginating to circulating pools
- Changes cause by disease

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Immediate neutrophilia

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- May occur w/o pathologic stimulation
- Probably due to re-distribution of the marginated granulocyte pool to the circulation
- Last only 20-30mins

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Acute neutrophilia

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- Occurs w/in 4-5 hrs of a pathologic stimulus
- Due to increase flow from BM; mor immature cells

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Chronic neutrophilia

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- Stimulus persists for a few days.
- Storage pool become depleted & increased production of neutrophils to met the increased demand
- Characteristics: WBC < 50X10^3/uL; shift to the left; toxic changes, elevated LAP

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Conditions associated w/ reactive, chronic neutrophilia

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- Bacterial infections: most common cause of neutrophilia
- Tissue destruction/injury, inflammation
- Leukomoid reactions
- Acute hemorrhage, hemolysis
- Leukoerythroblastic rxn
- BM stimulation from other hematopoietic cells or treatment
- Physologic neutrophilia: stress, exercise, albor

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Leukomoid reactions

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- Extreme neutrophilic reponse to infection (severe infection, necrotizing tissue)
- WBC usually >50X10^3/uL w/ circulating WBC maturing cells/precursors
- High LAP
- Transient & disappears when stimulus is removed.

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Leukomoid rxn vs. CML

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Can be differentiate using chromosome studies and/or Leukocyte Alkaline Phosphatase (LAP)

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Leukoerythroblastic reaction

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- Presence of nRBs & neutrophilic left shift in the peripheral blood.
- Often see poikilocytosis (tear drop cells) & anisocytosis
- Most often associated w/ MPD (myelofibrosis, myelonephritis), or severe hemolytic anemia (Rh-HDN).

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Neutropenia

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- Decreased normal neutrophils count.
- Input from the BM functional storage pool fails to satisfy tissue demand--> fewer neutrophils that reach the peripheal blood
- Decreased BM production, increased cell loss (immune destruction or migration to tissue), increased neutrophilic margination (pseudo-)

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Neutropenia: decreased BM production

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- BM shows myelod hypoplasia
- Defective production--> overwhelming infections
- Causes: stem cell d/o, megaloblastic anemia, chemicals/drugs, & congenital/familial neutropenia

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Neutropenia: increased cell loss

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- Due to passage of WBCs from circulation to tissue pool
- Causes: immune neutrophenia (direct cell lysis or sensitization & removal n the spleen), alloimmune (transfer of maternal antibodies--> neonatal neutropenia), autoimmune (primary: idiopathic; secondary: lupus, arthritis), hypersplenism
- Neutrophilic hyperplasia in BM

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Pseudoneutropenia

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Transfer of increased proportion of circulating neutrophils to the marginal neutrophil pool w/o change in te total peripheral blood pool.

Front 14

Spurious/false neutropenia

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- Due to lab manipulations of the blood
- EDTA related adherence to RBCs; delay in blood testing (neutroils disintegrate faster than other WBCs); fragile cells in some conditions may rupture while preparing blood to be analyzed, WBC clumping/aggregation

Front 15

Vacuoles in WBC

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- Vacuoles form by the injestion and degradation of bacteria/fungi and are unevenly distributed.
- Clinically significant when seen with toxic granulation, degranulation, Dohle bodies

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Necrobiosis

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Large number of dead granulocytes in the peripheral smear indicate a severe strain in granulocyte development pools.
Chemotherapy
Poorly preserved (old) specimen

Front 17

Hypogranulation

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Decrease number or absence of specific granules.
Myelodysplastic syndrome (MDS)
Infection

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Toxic granulation

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Abnormally large or dominant primary granules
Stress response to bacterial infection
Inflammation
Burns
Chemotherapy
GM-CSF treatment

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Hypersegmentation

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Neutrophils with 5 or more lobes
General rule: 5 neuts with 5 lobes in 100 cell differential
OR
1 neut with =/>6 lobes
Megaloblastic anemia
B12 Folate deficiency
Myelodysplasia (MDS)

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Dohle Bodies

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- Round to oval neutrophils accumulation of ribosomal RNA
- 1-5um in diamter
- Gray to light blue in Wright stain
- Associated w/ infections, burns, surgery, pregnancy, GM-CSF, chemotherapy

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Alterations of neutrophil nucleus

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- Pelger-Huet anomaly
- Hypersegmentation
- Pyknotic nucleus (necrobiosis)

Front 22

Alterations of neutrophil cytoplasm

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- Alder-Reilly anomaly
- Chediak-Steinbrinck-Higashi anomaly
- May-Hegglin anomaly

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Pelger-Huet anomaly

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- Benign inherited condition
- Neutrophil does not sgment beyond the two lobed stage (prince-nez cells)
- Can apper round w/ no segmentation (rare homozgotes)
- Normal cell w/ no loss of cellular function
- Acquire in some MPD, MDS, burns, AML, chemotherapy

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Alder-Reilly anomaly

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- Large purple granules in the cytoplasm of all WBCs
- Cells function normally
- Recessive d/o in w/c mucpolysaccharides in the cytoplam of nearly all WBCs

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Chediak- Steinbrinck- Higashi anomaly

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- Death often occurs because of serious infection
- Cells engulf bacteria but do not kill it.
-Anormal fusion of cytoplasmic membranes prevent the granules from being delivered into phagosomes.
- Recessive d/o: abnormally large peroxidase positive lysosomes are seen in most cells of the body

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May-Hegglin anomaly

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- Granulocytes contain inclusions similar to dohle bodies (consisting mainly of RNA from rough ER)
- Characteristics: variable thrombocytopenia w/ giant plts w/ decreased functions & shortened life span.
- Rare autosomal dominant condition tat can increase risk for infections & hemorrhage
- Associated w/ a mutation in MYH9 (non muscle myosin heavy chain)

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Intracellular organisms

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- Bacteria/fungi: stain basophilic w/ Wright stain
- Morulae-Ehrlichia/Anaplasma species: ick borne pathogen (characterized by fever, leukopenia, hrombocytopenia, elevated liver dz)

Front 28

Chronic Granulomatous Dz (CGD)

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- Defects in respiratory burst oxidase--> cells ingest but don't kill the microorganism
- Normal neutrphil morph
- CGD--> death from bacterial infection usually at 5-7y.o
- Peripheral smear: toxic granulation, vacuoles, Dohle bodies

Front 29

Alterations of monocyte cytoplasm

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- Quantitative d/os: associated w/ monocytes
- Qualitative d/os: associated w/ macrophages

Front 30

Monocytosis

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- Absolute monocyte count >1.3X10^3/uL
- Indicates:
* Strenuous exercise
* Active TB
* Bacterial endocarditis
* Syphilis
* Certain autoimmune dz
* Trauma
* Hematological d/os (MDS, AML)

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Gaucher Disease

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- Deficiency in enzyme needed to breakdown lipid (glucocerebrosidase)--> accumulation of lipid in macrophages
- Most commn lipid storage d/o
- Gaucher cell: large w/ eccentric nucleus & cytoplasm that appears "chicken scratched"; usually found in the BM
- Pancytopenia due to replacement of normal hematopoietic cells.

Front 32

Reactive eosinophilia

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- Increase in eosinophils
- Appears to be induced by substances secreted by T lymphocytes

Front 33

Conditions characterized by eosinophilia

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- Parasitic infection
- Allergic conditions
- Hypersensitivity rxn
- Cancer
- Chronic inflammatory states

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Hypereosinophilic Syndrome

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- Persistent blood eosinophilia over 1.5X10^3/uL w/ tissue infiltration & no apparent cause (idiopathic)
- Chronic MPD by WHO classification

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Basophilia

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- Increase in basophils > 0.15X10^3/uL
- Associated w/ immediate hypersensitivity & chronic MPD (myelofibrosis, PV, CML)

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Lymphocytosis

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- Increase in lymphocytes
- Can be with or w/o an increase in WBC
- USually self-limiting; reactive process in response to infection or inflammatory condition
- Both T & B lymphocytes are affected, but normal functions

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Conditions that favor benign conditions

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- Heterogeneous, rective lymphocytes
- Positive serlogic tests for the presence of specific antibodies against infectious organisms.
- Absence of anemia, thrombocytopenia

Front 38

Lymphocytopenia

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- Decrease in absolute lymphocyte count
- Causes: decreased production, increased destruction, changes in lymphocyte circulation, or unknown (idiopathic) causes
- Malutrition the most common cause

Front 39

Alterations of lymphocytes

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- Mostly related to antigenic stimulation
- Referred to as reactive, stimulated, variant, transformed
- Cytoplasmic basophilia, visible nucleoli, large nucleus (more euchromatin)
- Nucleus: clefting sometimes seen in malignancies (lymphomas)
- Cerebriform pattern seen in patients w/ Sezary syndrome

Front 40

Infectious mono

Back 40

- Variant/reactive lymphs
- Caused by EBV that infects in children & young adults
- Virus infects B cells
- 3-7 weeks incubation period
- Elevated WBC (11-20X10^3/uL)
- Lymphocytes > 60% reactive & represent differentiated T-cells
- Transient antibodies are called heterophile antibodies
- Therapy: self-limiting

Front 41

Other lympocytosis

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- Toxoplasmosis & CMV
- Infectious lymphocytosis
- Bordatella pertussis

Front 42

Plasmacytosis

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- May be present w/ intense stimulation of the immune system
- Most often associated w/ neoplastic d/o (plasma cell leukemia & multiple myeloma)

Front 43

Acquired Immune Deficiency Syndrome (AIDS)

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- CD4 < 200 cells/uL
- Hematologic abnormalities: pancytopenia, lymphopenia
- Macrocytosis occurs in up to 70% of patients (secondary to medication)

Front 44

Congenital immune deficiencies

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- Characterized by decrease in lymphocytes & impairment of either cell mediated immunity (T cells), humoral immunity (B cells) or both
- Lymphocytes are usually normal in appearance
- Severe combined immunodeficiency syndrome

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Wiscott-Aldrich Syndrome

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Associated w/ thrombocytopenia as well as immunodeficiency (abnormality in CD43)
- Often fatal in childhood due to infection and/or bleeding

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DiGeorge Syndrome

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Absence (or hypoplasia) of thymus w/ normal B cells number & function--> 10% normal circulating T-cells

Front 47

Benign

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- Formed from highly organized, differentiated cells
- Do not spread or invade surrounding tissue

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Malignant

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- Clone of identical, anaplastic (undifferentiated) proliferating cells
- Can metastasize

Front 49

Leukemia

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Abnormal cells are seen in both the BM & peripheral blood.

Front 50

Aleukemic leukemia

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Abnormal cells are found only in the BM

Front 51

Lymphoma

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Solid tumors: abnormal proliferation of lymphoid cells w/in the lymphatic tissue or lymph nodes`

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Leukemic phase of lymphoma

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Affects the BM & lymphoma cells found in the peripheral circulation

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Acute leukemia

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- Increase in immature cells/blasts.
- An aggressive, rapidly progressing dz (AML, ALL)

Front 54

Chronic leukemia

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- Increase in developing or mature cells.
- Less aggressive, slowly progressing form (CML/CLL)

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French-American-British (FAB) clasification (1976) for leukemia

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- Based on morphologic characteristics
- Blast count >30% (BM) diagnostic for leukemia
- MDS: blast count & degree of dysplasia in teh BM.
- MPD: characterized by increase in RBCs, WBCs, and/or plts
- Both MDS & MPD have blast counts <30%

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WHO classification of leukemia according to...

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- Cell lineage
- Combination of cell morph, immumophenotyping, genetic features, & clinical syndrome

Front 57

Myeloproliferative Disorder (MPD)

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- Pan-hypercellularity of the BM
- Erythrocytosis, granulocytosis, or thrombocytosis in peripheral blood
- Neoplastic cell is HSC
- Usually occurs in middle-aged/older adults
- Clinical findings: anemia or polycythemia, leukoerythroblastosis, leukocytosis, thrombocytosis w/ bizarre plts.

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MPD subgroups

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- CML (CGL): overproduction of granulocytes
- Polycythemia vera (PV): overproduction of RBCs
- Essential thrombocythemia (ET): overproduction of platelets
- Agnogenic myeloid metaplasia: fibrotic (not neoplastic) BM; myelofibrosis

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Polycythemia Vera (PV)

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- Increased RBCs production independent of the mechanisms that normally regulate erythropoiesis
- Panmyelosis in the BM
- Increases in RBCs, granulocytes, & plts in teh peripheral blood
- PV clonal stem cells are ultra sensitive to EPO and/or EPO independent.

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PV: WHO criteria (2008) for dx

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MUST have:
- Hb > 18.5 g/dL (male); 16.5 g/dL (female) or,
- PResence of JAK2 (V
F) mutation (cytoplasmic tyrosine)

Must have 2 minor criteria:
- Tri-lineage marrow proliferation
- Low serum EPO levels
- Endogeneous erythroid colony formation in the absence of EPO

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PV: Laboratory findings

Back 61

- RBC count in teh range of 6-10X10^6/uL
- Normocytic/normochromic--> microcytic/hypochromic cells in 50% patients
- Occasionally, shift to the left (rarely pros/blasts); increased basophils
- LAP score >100
- BM: hypercellular increase in myeloid & erythroid precursor (normal M:E ratio)

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Three phases of PV

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- Pre-polycythemic phase: borderline-mild erythrocytosis
- Overt polycythemic phase: significantly increased red cell mass
- Spent or post- polycythemic myeofibrosis phase: post- PV MF

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Classification of polycythemia

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- Polycythemia Vera: MPD
- Secondary polycythemia: underlying cause (i.e. hypoxia, tumors)
- Relative polycythemia: normal or decreased RBC mass (due to decrease in plasma volume)

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Therapy for PV

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- Phlebotomy: reduce blood volume & iron supplies (lack of iron should slow down RBC production)
- Myelosuppressive therapy: chemo/radiation

Front 65

Essential Thrombocythemia (ET)

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- Clonal MPD affecting primarily the megakaryocytic lineage
- Increased megakaryopoiesis & extreme thrombocytosis in peripheral blood (usually > 1milliion/uL)
- Median age at diagnosis= 60 y.o

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ET: Diagnosis criteria

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- Platelets > 600,000/uL
- Hb < 13 g/dL
- Philadelphia chromosomes absent
- Absent/minimal marrow fibrosis (<1/3)

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ET: WHO diagnosis criteria

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- Platelets =/>450,000/uL
- Megakaryocyte proliferation
- No evidence of other MPD or myeloid neoplasm
- JAK2 mutation (V617F) or other clonal marker or no eidence of reactive thrmbocytosis

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ET: Laboratory findings

Back 68

- Extreme/consistent thrombocytosis w/ agranular, giant/bizarre plts
- Often normal plt morph
- Normocytic/normochromic anemia w/ increased neutrophils (33%); rarely increased basophils
- LAP score is normal or increased
- BM: hyperplasia w/ striking increase in megakaryocytes

Front 69

Chronic Myeloid Leukemia (CML)

Back 69

- Arises as a clonal process from HSC
- Characterized by a neoplastic growth of primarily myeloid cells in the BM & an extreme elevation of these cells in the peripheral blood.
- Balanced translocation between chromsome 9 & 22--> BCR/ABL hybrid gene
- Abnormal tyrosine kinase activity --> continual state of proliferation.
- Most patients eventually transform to acute leukemia

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Three phases of CML

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- CML begins w/ chronic clinical phase that progresses to an
- Accelerated phase in 3-4 years
- Acute leukemia (blast crisis)

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CML: laboratory findings

Back 71

- Peripheral blood: leukocytosis w/ segmented neutrophils, bands, metamyelcytes, & myelocytes
- Immature & mature eosinophils & increased basophils
- Myeloblasts & promyelocytes usually present in small numbers (1-5%)
- Decereased LAP
- BM: hypercellular w/ striking increase in myeoid to erythroid ratio w/ immature granulocytes

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CML: terminal phase

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- Blast crisis: invoves the peripheral blood, BM, & extramedulary tissues
- Blasts constitute > 20% (WHO) of BM cells (30% for FAB classification)
- Poor prognosis & survival is < 6 mths

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CML: similar diseases

Back 73

- Juvenile CML: 10-14 y.o; myelocytes are not teh prominent cell & eos/baso are absent
- Chronic Eosinophilic Leukemia: Philadelphia chromosome negative variant of CML w/ 30-70% eosinophils & normal LAP
- Chronic basophilic leukemia: rarest variant of CML; Philadelphia chromosome negative w/ 40-80% basophils & normal to low LAP
- Chronic Neutrophilic Leukemia: difficult to distinguish w/o cytochemical/molecular techniques; Philadelphia chromosome negative (bcr/abl gene present) & increased LAP

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Myelofibrosis w/ Myeloid Metaplasia (MMM)

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- Clonal MPD due to hematopoietic stem cell d/o w/ unregulated proliferation of hematopoietic cells.
- Ineffective hematopoiesis--> extramedullary hematopoiesis; splenomegaly, hypercellular BM, progressive fibrosis w/ increased megakaryocytes
- WBC usually elevated
- Peripheral blood: immature granulocytes & normoblasts, teardrop cells, & other bizarre RBC shapes
- Fibrotic tissue eventually disrupts the normal marrow & replace hematopoietic tissue
- CD34+ cells may be 300 times normal

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Myelofibrosis prognosis/therapy

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- Average survival time: 4-5 years
- Main cause of death: infection, hemorrhage, transformation
- Supportive w/ transfusions, splenectomy
- Allogeneic stem cell transplantation: successful therapy for <60 y.o

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Myelophthisic anemia (or leukoerythroblasic anemia)

Back 76

- Reduction of cells formed in normal BM due to neoplastic d/o
- i.e BM tumor
- WBC is usually normal or decreased