Wake Non Malignant Leukocytosis And Leukopenia

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2 cell populations within the bone marrow compartment are...

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- those that are in the process of DNA synthesis and maturation
- those that are in a storage phase awaiting release into the circulating pool

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Why do we store mature WBCs in the bone marrow?

Back 2

The storage allows for rapid response to the demand for increased white blood cells, with a two- to threefold increase in circulating leukocytes possible in just 4-6 hrs.

Front 3

Into what categories are the circulating pool of neutrophils separated?

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1. circulating freely in the blood
2. deposited along the margins of blood vessel walls

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What do neutrophils do when they detect bacterial infection or inflammation?

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Neutrophils roll along the endothelium until they tightly adhere, spread and enter into the tissue. The cells use chemotaxis to find the location where they phagocytose before degranulate to release antimicrobial products.

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How do the neutrophils roll and adhere to the endothelium?

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- rolling is augmented by release of glycoproteins and cytokines.
- Cytokines activate neutrophils up-regulating expession of CD11/CD18 which mediates adhesion.
- when the seg reaches the intercellular junction it moves into sub-endothelial space

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Diapedesis

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The passage of blood, or any of its formed elements, through the intact walls of blood vessels

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How much time do neutrophils spend circulating in peripheral blood?

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6-12 hours

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Once neutrophils migrate into extravascular space, how long do they survive?

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1-2 days

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Leukocytosis

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- absolute increase in number of leukocytes in peripheral blood
* Without reference to cell type or level of maturity
* In adults, greater than 10,000-11,000/mm3
* Majority of cases of leukocytosis are due to an increase in neutrophils

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Pathophysiologic Mechanisms of Leukocytosis in Normally responding bone marrow

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- Infection
- Inflammation
- Stress Leukocytosis
- Drugs
- Trauma (splenectomy)
- Hemolytic Anemia

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Pathophysiologic Mechanisms of Leukocytosis in abnormal bone marrow

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- Acute leukemias
- Chronic Leukemias
- Myeloproliferative disorders

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Inflammatory triggers that cause leukocytosis in normal bone marrow

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- tissue necrosis
- infarction
- burns
- arthritis

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Stress triggers that cause leukocytosis in normal bone marrow

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- overexertion
- seizures
- anxiety
- anesthesia
- epinephrine

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Drugs that cause leukocytosis in normal bone marrow

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- corticosteroids
- lithium
- beta agonists

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How long does it take stress leukocytosis to reverse?

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within hours of elimination of the inciting factor

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Leukemoid Reaction

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> An excessive white blood cell response (i.e. 50,000 white blood cells per cm3) associated with a cause outside the bone marrow
> May be neutrophilic, eosinophilic, lymphocytic, monocytic
- Usually caused by relatively benign processes (i.e., infection or inflammation)
- An underlying malignancy is the most serious but least common cause of a leukemoid reaction.
- Down syndrome babies can have leukemoid reactions – resolve spontaneously

Front 17

Corticosteroids

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1. Decrease emigration of neutrophils from blood into the tissues
2. Increase release of mature neutrophils from the bone marrow (release of storage pool)
3. Decrease margination of neutrophils inside vasculature

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Neutrophilia

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Absolute neutrophil count of 8,000/mm3 or higher

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Mechanisms of neutrophilia

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1. Increased production by bone marrow
2. Increased mobilization from storage pool or marginated pools (pseudoneutrophilia) - White cell count not over 15,000/mm3
3. Failure to exit the circulation

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Increased production by bone marrow
(mechanism of neutrophilia)

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1. Infection
2. Inflammatory stimulus
3. Hemolysis and chronic blood loss
4. Exogenously administered hematopoietic growth factors (G-CSF and GM-CSF)

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Increased mobilization from storage pool or marginated pools (pseudoneutrophilia) - White cell count not over 15,000/mm3
(mechanism of neutrophilia)

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1. Vigorous exercise
2. Epinephrine
3. Labor and pregnancy

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Failure to exit the circulation
(mechanism of neutrophilia)

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1. Anatomic or functional asplenia
2. Adhesion deficiency syndromes (decreased endothelial adhesion and migration) - LAD

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Leukocyte Adhesion Deficiency

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- Partial or total deficiency of CD11/CD18
- Number of circulating neutrophils is increased
- Associated with severe and fatal bacterial infections

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Early presentation of Leukocyte Adhesion Deficiency

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Delayed detachment or prolonged healing of umbilical stump

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Tx of Leukocyte Adhesion Deficiency

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Need a bone marrow transplant

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Relative Lymphocytosis

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results when there is a neutrophilic leukocytosis

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Absolute lymphocytosis:

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- >9,000/mm3 in infants and small children (2-3 yrs)
- 7,200/mm3 in older children
- >4,000/mm3 in adults

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Normally, lymphocytes represent what percentage of circulating WBCs?

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Lymphocytes normally represent 20-40% of circulating WBC

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Physiologic lymphocytosis

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seen in children due to rapid tissue growth and development of the immune system

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Etiology of Absolute Lymphocytosis

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1. Acute infections
2. Chronic infections
3. Lymphoid malignancies (CLL)

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Etiology of Relative Lymphocytosis

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1. Normal in young children
2. During viral infections
3. Splenomegaly

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Why is there relative leukocytosis during viral infections?

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Acute viral infections can cause relative lymphocytosis due to suppression of marrow production of the other white cells

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What acute infections cause absolute lymphocytosis?

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1. cytomegalovirus infection
2. Epstein-Barr virus infection
3. pertussis
4. hepatitis
5. toxoplasmosis

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What chronic infections cause absolute lymphocytosis?

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1. tuberculosis
2. brucellosis

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Benign Reactive Lymphocytosis is pronounced by:

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1. Pertussis
2. Acute Infectious Lymphocytosis (Coxsackie)
3. Infectious Mononucleosis (EBV)

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Eosinophilia

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a form of relative leukocytosis in which the greatest proportionate increase is in the eosinophils

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What size is the eosinophil storage pool in the bone marrow?

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5 times the circulating population of eosinophils

Front 38

How long do eosinophils stay in circulation?

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Eosinophils remain in circulation for <24 hours before going to extra-vascular tissues

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Eosinophil function

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- participate in immunologic and allergic events
- play a role in phagocytizing antigen-antibody complexes

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Etiology of Eosinophilia

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1. Allergic events
2. Parasitic Infections
3. Dermatologic Conditions
4. Infections
5. Immunologic disorders
6. Malignancies
7. Myeloproliferative Disorders
8. Adrenal Insufficiency
9. Sarcoidosis
10. Pleural and pulmonary conditions

Front 41

What infections cause eosinophilia?

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1. scarlet fever
2. chorea
3. leprosy
4. genitourinary infections

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What immunologic disorders cause eosinophilia?

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1. rheumatoid arthritis
2. lupus erythematosus
3. eosinophilia-myalgia syndrome

Front 43

What malignancies cause eosinophila?

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1. non-Hodgkin’s lymhoma, 2. Hodgkin’s disease

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What myeloproliferative disorders cause eosinophilia?

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1. chronic myelo-genous leukemia
2. polycythemia vera, myelofibrosis

Front 45

What disease of adrenal insufficiency causes eosinophilia?

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Addison’s disease

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What pleural and pulmonary conditions cause eosinophilia?

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1. Löffler’s syndrome
2. pulmonary infiltrates and eosinophilia

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Etiology of Basophilia

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1. Infections
2. Inflammatory conditions
3. Myeloproliferative disorders
4. Endocrinologic causes
5. Alteration of marrow and reticuloendothelial compartments

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What alterations of marrow and reticuloendothelial compartments cause Basophilia?

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1. chronic hemolytic anemia
2. Hodgkin's Disease
3. Splenectomy

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What are the endocrinologic cause of basophilia?

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1. hypothyroidism
2. Ovulation
3. Estrogens

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Which myeloproliferative disorders cause basophilia?

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1. CML
2. polycythemia vera
3. myelofibrosis

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What inflammatory conditions cause basophilia?

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1. Inflammatory Bowel Disease
2. Chronic airway inflammation
3. Chronic dermatitis

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What infections cause basophilia?

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1. viral infections (varicella)
2. chronic sinusitis

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Neutropenia

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- Decrease in the absolute neutrophil count (ANC) below accepted norms for age
- Age related “lower limits of normal”:
- Term newborn (up to 1 week) < 3,000
- Infant (1 week – 2 years) < 1,100
- Child, adolescent, adult < 1,500
- Ethnic and racial groups < 900
- Benign ethnic neutropenia
- Altitude (lower ANC above 5,000 ft

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ANC=

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WBC x % (bands+PMN)

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What is the risk of infection for ANC of 1000-1500?

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No risk of infection

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What is the risk of infection for ANC of 500-1000?

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Minimal risk of infection

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What is the risk of infection for ANC of 200-500?

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moderate to severe risk of infection
(skin, mucous membranes)

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What is the risk of infection for ANC of <200?

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severe risk of infection
(sepsis, pneumonia)

Front 59

In which conditions is the marrow reserve NORMAL (normal production) when the pt has neutropenia?

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Destruction outside bone marrow:
1. immune neutropenias
2. hypersplanism
3. infection

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In which conditions is the marrow reserve DECREASED (decrease in production) when the pt has neutropenia?

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1. congenital neutropenias
2. marrow failure syndromes
3. chemotherapy

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Neutropenia and primary hematologic disorders

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1. Intrinsic defects in stem cells/granulopoiesis
2. Extrinsic cause for neutropenia (secondary neutropenia...often acquired)

Front 62

When you have a neutropenia you have to ask yourself these questions?

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Is there a problem with the marrow reserve (a production problem) or is it a destruction problem?
Is there a primary hematologic disorder (problem with the stem cells)?

Front 63

Pseudo-neutropenia

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1. Low normal neutrophil count
2. No history of infections
3. Most due to increased neutrophil margination along blood vessel wall
4. Entry into circulation and exit from vascular pool are normal
5. Rapid mobilization of neutrophils from marginal pool with exercise, epinephrine

Front 64

Infection Induced Neutropenia

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- Common during viral infections, usually transient
- Protracted neutropenia can be seen with mononucleosis, hep B and HIV
* Most common benign cause of neutropenia

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Infection Induced Neutropenia
Mechanisms

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1. Increased use
2. Up regulation of adhesion and migration due to complement and cytokines
3. Marrow suppression

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Drug Induced Neutropenia

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More than 100 drugs implicated
- Immune mediated
- Direct destruction of granulocyte precursors

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Immune Neutropenia

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- Antibodies directed to neutrophils or their precursors
- Can be associated with other immune cytopenias (hemolytic anemia and immune thrombocytopenia) or autoimmune disorders
- Chronic Benign Neutropenia

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Chronic Benign Neutropenia

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- occurs in children and adults
- Infections are infrequent despite low ANC.
- Majority resolve spontaneosuly within few yrs from diagnosis
- This is not associated with another immune disease

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Congenital Neutropenia

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Problems with bone marrow
1. Cyclic neutropenia
2. Kostmann Syndrome

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Cyclic neutropenia:

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- Autosomal disorder
- Marked neutropenia every 21 days, nadir last 3-7days
- Patients are subject to recurrent severe infections
- Need treatment with growth factors to stimulate bone marrow to make more neutrophls

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Kostmann syndrome

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a.k.a. severe congenital neutropenia
- Present at birth
- ANC < 200/ul
- Predispose to leukemia and preleukemic conditions
- cured with bone marrow transplant

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Lymphopenia

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Absolute lymphocyte count (ALC) of <1,000/mm3 in adults or <1,500/mm3 in children
* ALC of less than 1000/mm3 in an infant is highly abnormal

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Mechanisms of Lymphopenia

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1. Decreased Production
2. Immunodeficiency Diseases (SCID or AIDS, aplastic anemia)
3. Increased destruction
4. Increased loss --> congenital lymphatic abnormalities

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SCID

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profound abnormalities of B and T cells that can cause fatal infections in infants

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What are causes of increased destruction that lead to Lymphopenia?

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1. acute stress (steroid administration)
2. irradiation
3. immunosuppressive agents
4. chemotherapeutic agents