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4 – Leukocytic Disorders

Leukocytes

Protection from non-self-cells and from altered self-cells

Two broad groups:

o

Phagocytes – granulocytes, monocytes

o

Immunocytes – lymphocytes, plasma cells

Formation of Neutrophil and Monocyte Phagocytes Eosinophils and basophils are also formed in the marrow in a process similar to that for neutrophils.

in the marrow in a process similar to that for neutrophils. Granulopoiesis Proliferative/mitotic production: progenitor

Granulopoiesis

Proliferative/mitotic production:

progenitor cells, myeloblasts, promyelocytes, myelocytes

Post-mitotic maturation compartment:

metamyelocytes, bands, segmenters Reserve/storage pool

In bloodstream, two pools:

1) circulating; 2) marginating

Kinetics:

6-10 hours in circulating pool 4-5 days in tissue 6-10 days – bone marrow

pool 4-5 days in tissue 6-10 days – bone marrow Neutrophil Kinetics CSF, colony-stimulating factor. G,

Neutrophil Kinetics CSF, colony-stimulating factor. G, granulocyte. IL, interleukin. M, monocyte. SCF, stem cell factor.

White cells: Normal blood counts

 

TOTAL LEUCOCYTES

Adults

4.0

– 11.o X 10 9 /L

Neonates

10.0 – 25.0 X 10 9 /L

1

year

6.0

– 18.0 X 10 9 /L

4

– 7 years

6.0

– 15.0 X 10 9 /L

8

– 12 years

4.5

– 13.5 X 10 9 /L

Reference Ranges for the Differential Leukocyte Count in Adults

Cell

Proportional Count

Absolute Count (X10 9 /L)

(%) n

Neutrophils

37-80

Adults: 1.8 – 7.0 Pedia: 1.0 – 8.5

Lymphocytes

10-50

Adults: 1.5 – 4.0 Pedia: 1.5 – 8.8

Monocytes

0

- 12

.03 - .9

Eosinophils

0

– 9.5

0.0

– 0.67

Basophils

0

– 2.5

0.0

– 0.20

Factors influencing neutrophil count:

Rate of inflow of cells from the marrow (mitosis/proliferation, maturation/storage release)

Proportion of neutrophils between the marginal (cells adhering to vessels walls) granulocytic pool and the circulating (non-adhering cells) granulocytic pool

Rate of outflow of neutrophils from the blood (migration from and through vessels into tissues, both randomly and at sites of inflammation, infection, etc.)

Host factors that can modify degree of neutrophil response:

Age: children respond more intensely than adults

Virulence of infecting agent

Hematinic deficiency &/or marrow failure

rainwater@mymelody.com || 1 st semester, AY 2011-2012

agent • Hematinic deficiency &/or marrow failure rainwater@mymelody.com || 1 s t semester, AY 2011-2012

Leucocyte Count

NV: 4-11 x 10 9 /L

Calculation of absolute values for each leucocyte class is encouraged

Absolute vs. relative leucocytosis

Use of absolute values has made the definition of normal range more precise and provides best value for determining abnormality

Leucocytosis

Increase in WBC count above upper limit of normal for age and sex

Specify: neutrophilia, lymphocytosis, monocytosis, eosinophilia, basophilia

Leucopenia

Decrease in total WBC count below the lower limit of normal for age and sex

Neutropenia, lymphocytopenia NB: Increase in any cell type maybe clinically important but decrease is usually significant only for neutrophils.

Neutrophilic Leucocytosis

Neutrophilic Leucocytosis

Absolute count >7.5 X 10 9 /L bands & neutrophils

Pathophysiologic mechanisms:

1.

Increased cell production

2.

Accelerated release of cells from marrow into blood

3.

Shift from marginal to circulating pool

4.

Reduced egress of neutrophils from blood to tissues

5.

Combination

Causes of Neutrophilia

Increased production:

chronic disorders - infections, tumors, inflammation, endocrinopathies, myeloproliferative disorders

Increased production and peripheral cell survival:

CML

Accelerated release from the marrow:

stress, intoxication, infections, inflammation, corticosteroids, endotoxins

Increased shift from marginal pool to circulating pool:

stress, intoxication, hypoxia, infections, exercise,

adrenalin

Decreased egress from circulating pool:

corticosteroids

“Shift to the left”: increase in immature peripheral blood granulocytes, usually seen in acute infection

Leukemoid reaction: reactive and excessive leucocytosis usually characterized by release of immature cells(myeloblasts, promyelocytes, myelocytes)

- WBC >50 x 10 9 /L with shift to the left

- Conditions: severe and chronic infection, severe hemolysis , metastatic CA

- High leucocyte alkaline phosphatase (LAP) score

Causes of Neutrophilic Leukocytosis

Bacterial infections (especially pyogenic bacterial, localized or generalized)

Inflammation and tissue necrosis (e.g., myositis, vasculitis, cardiac infarct, trauma)

Metabolic disorders (e.g., uremia, eclampsia, gout, acidosis)

Neoplasms of all types (carcinoma, lymphoma, melanoma)

Acute hemorrhage or hemolysis

Drugs (e.g., corticosteroids, lithium, tetracycline)

Chronic myelogenous leukemia, myeloproliferative diseases such as polycythemia vera, myelofibrosis, essential thrombocytosis

Treatment with myeloid factors (e.g., G-CSF, GM-CSF)

Rare inherited disorders

Asplenia

Neutropenia: ANC<1.5 x 10 9 /L Degree of Neutropenia and ANC

Normal:

> 1.5 x 10 9 /L

Mild:

ANC 1.0-1.5 x 10 9 /L

Moderate:

ANC .5-1.0 x 10 9 /L (some increased risk for infection)

Severe:

ANC < .5 x 10 9 /L (significant risk of infection)

Mechanisms for Production of Neutropenia

Decreased flow of neutrophils from the marrow due to lack of production or ineffective production (i.e., proliferation or production defect)

Increased removal of neutrophils from the blood (survival defect)

Altered distribution between circulating and marginal granulocytic pools

Combination of factors

Neutropenia and the risk of infection

ANC <1.5 x 10 9 /L

Risk of infection depends on 3 factors

1. Absolute neutrophil count (ANC)

2. Neutrophil reserve in the bone marrow

3. Duration

Neutrophil reserve: normal if with the ff:

No prior cytotoxic therapy

Appropriate ANC increases in response to infections or stress

Normal bone marrow biopsy

Duration of neutropenia

Periodic or episodic (e.g. post chemo)

Chronic

Causes of Neutropenia

Bone marrow failure

Aplastic anemia; leukemia; myelodysplasia; myelofibrosis; marrow infiltrations; megaloblastic anemia

Splenomegaly

Infections

Immune-related

Drug-induced

Some Drugs Associated with Neutropenia

Anti-inflammatory: Aminopyrine, phenylbutazone

Antibacterial: Chloramphenicol, sulfas, penicillins, cephalosporins, antivirals vs AIDS

Anticonvulsants: Phenytoin, phenobarbital

Antithyroids: Carbimazone

Phenothiazines: Chlorpromazine, promethazine

Cardiac meds: antiarrhythmics, digoxin, diuretics, ACEI

Chemotherapy

Tolbutamide, phenidione, H2 antagonists

• Chemotherapy • Tolbutamide, phenidione, H2 antagonists rainwater@mymelody.com || 1 s t semester, AY 2011-2012

rainwater@mymelody.com || 1 st semester, AY 2011-2012

Lymphocytosis

Lymphocytosis • Absolute count: >4.0 X 109/L • Maybe categorized as either monoclonal or polyclonal •

Absolute count: >4.0 X 109/L

Maybe categorized as either monoclonal or polyclonal

Review of peripheral smear important:

- reactive lymphocytes seen in viral infections

- large granular lymphocytes in large granular lymphocytic leukemia

- smudge cells seen in CLL

- blasts of acute leukemia

Causes of Lymphocytosis

Monoclonal lymphocytosis: due to underlying lymphoproliferative disorders - lymphocytes are increased due to an intrinsic defect in the expanded lymphocyte population Ex: Lymphoproliferative disorders

Polyclonal lymphocytosis: secondary to stimulation or reaction to factors extrinsic to the lymphocyte. (Inflammation and/or infections) Acute infections: Rubella, pertussis, mumps,

infectious mononucleosis, acute infectious lymphocytosis Chronic infections: Tuberculosis, brucellosis, infective hepatitis, syphilis

Immune mediated: drug sensitivity, vasculitis, graft rejection, Grave’s, Sjogren’s

Stress – acute, transient

Lymphocytopenia

Absolute count:

Adults < 1.0 X 10 9 /L Children < 2.0 X 10 9 /L

Causes of Lymphocytopenia

Destruction – radiation, chemotherapy, corticosteroids

Debilitative – starvation, aplastic anemia, terminal cancer, collagen vascular disease

Infectious- viral hepatitis, influenza, typhoid fever, TB

Abnormal lymphatic circulation – intestinal lymphangiectasia, obstruction, thoracic duct drainage/rupture, CHF

obstruction, thoracic duct drainage/rupture, CHF Monocytosis • Absolute count >0.8 X 10 9 /L •

Monocytosis

Absolute count >0.8 X 10 9 /L

Causes:

>50%

10%

8%

due to hematologic disorders

(e.g, AML, MDS, lymphomas) inflammatory and immune disorders malignant diseases

Causes of Monocytosis

Infectious – tuberculosis, subacute bacterial endocarditis, syphilis, protozoan, rickettsial

Recovery from neutropenia

Hematologic – leukemias, myeloproliferative disorders, lymphomas, multiple myeloma

Inflammatory – collagen vascular diseases, chronic ulcerative colitis, sprue, myositis, polyarteritis, temporal arteritis

Others – solid tumors, immune thrombocytopenic purpura, sarcoidosis

Eosinophilia

Mild:

<1500 cells/uL

Moderate:

1500-5000 cells/ uL

Severe:

>5000 cells/uL

Causes of Eosinophilia

• Severe: >5000 cells/uL Causes of Eosinophilia • Allergic diseases especially hypersensitivity of the

Allergic diseases especially hypersensitivity of the atopic type (e.g., bronchial asthma, hay fever, urticarial and food sensitivity)

Parasitic diseases (e.g., amoebiasis, hookworm, ascariasis, tapeworm infection, filariasis, schistosomiasis, trichinosis)

Recovery from acute infection

Certain skin diseases (e.g., psoriasis, pemphigus and dermatitis herpetiformis, urticarial and angioedema, atopic dermatitis)

Inflammatory-eosinophilic fasciitis, Churg-Strauss syndrome, polyarteritis nodosa, vasculitis, serum sickness

Non-parasitic infections – systemic fungal, scarlet fever, chlamydial pneumonia of infancy

Respiratory – pulmonary eosinophilic syndromes (Ioeffler’s, tropical pulmonary eosinophilia), Churg- Strauss syndrome

Neoplastic – CML, Hodgkin’s lymphoma, T-cell lymphoma

Idiopathic hypereosinophilic syndromes

Others – certain drugs, hematologic and visceral malignancies, GI inflammatory diseases, sarcoidosis, Wiskott-Aldrich

Primary hypereosinophilic syndrome

Criteria:

>1500 eosinophils/uL for more than 6

months

Absence of an underlying cause of eosinophilia despite extensive evaluation Presence of end-organ damage or dysfunction related to eosinophilia: skin, heart, nervous system

related to eosinophilia: skin, heart, nervous system Basophilia • Absolute count >0.2 X 10 9 /L

Basophilia

Absolute count >0.2 X 10 9 /L

Causes:

Myeloproliferative diaseases

Allergic – food, drugs, foreign proteins

Infectious – variola, varicella

Chronic hemolytic anemia

Especially post-splenectomy

Inflammatory – collagen vascular diseases, ulcerative colitis

rainwater@mymelody.com || 1 st semester, AY 2011-2012

– collagen vascular diseases, ulcerative colitis rainwater@mymelody.com || 1 s t semester, AY 2011-2012

Acute Leukemia

Characterized by accumulation of malignant white cells (blasts) in the blood and bone marrow

Defined by presence of >20% blasts in the blood and bone marrow

Laboratory features

1. Anemia

2. Thrombocytopenia

3. Leukocyte count

- May be high, low, normal

- <5000/uL in half of patients

- Note for “absolute lymphocytosis”

- High WBC count with high lymphocyte %

Can present with pancytopenia

Myelogenous vs. lymphocytic

May be difficult to differentiate based on clinical manifestations and simple morphology

Other tests

o

Cytochemical stains

o

Immunophenotyping

Flow cytometry

Chronic Myelogenous Leukemia Laboratory features

A complete spectrum of myeloid cells in the peripheral blood (WBC’s in all stages of maturation). The levels of neutrophils and myelocytes exceed those of blasts and promyelocytes.

Increased basophils

Normochromic, normocytic anemias

Platelet count frequently increased but may be normal or decreased

Leucocyte alkaline phosphatase is low

Bone marrow is hypercellular with myeloid hyperplasia

Ph chromosome on cytogenetic analysis (conventional or FISH)

Serum uric acid is usually elevated

Chronic Lymphocytic Leukemia Laboratory Evaluation

Absolute lymphocytosis

Absolute neutrophil count is variable

Anemia or thrombocytopenia

o

30% of patients

o

15% Hgb less than 11mg/dL or platelets less than 100,000

rainwater@mymelody.com || 1 st semester, AY 2011-2012

o 15% Hgb less than 11mg/dL or platelets less than 100,000 rainwater@mymelody.com || 1 s t