Hematology Notes: Chapter 29 | Study notes Hematology

Chapter 29: Nonmalignant

Leukocyte Disorders

Morphologic Abnormalities with and without

Functional Defects

Pelger-Huët Anomaly

• Also known as true or congenital PHA

• Autosomal dominant disorder characterized by

decreased nuclear segmentation (bilobed, unilobed) and

a characteristic coarse chromatin clumping pattern

(mature neutrophil).

• 1 in 4785 in the United States.

• Mutations in the lamin b-receptor gene (nuclear

changes)

• Nuclei may appear round, ovoid, or peanut shaped.

• “pince-nez” morphologic form

• In homozygous PHA, all neutrophils are affected.

• In the heterozygote, 55% to 93% of the neutrophil

population are affected.

• Neutrophils in Pelger-Huët anomaly appear to function

normally.

Pseudo- or Acquired Pelger-Huët Anomaly

• Neutrophils with PHA morphology can be observed in

• patients with hematologic malignancies such as

myelodysplastic syndromes (MDS), acute myeloid

leukemia, and chronic myeloproliferative neoplasms as

well as with HIV infection, tuberculosis, Mycoplasma

pneumoniae and severe bacterial infections.

• Drugs known to induce pseudo-PHA include

mycophenolate mofetil, valproate, sulfisoxazole,

ganciclovir, ibuprofen, and chemotherapies such as

paclitaxel and docetaxel.

Laboratory Issues in Pelger-Huët Anomaly

(True/Congenital and Pseudo/Acquired)

• An important consideration is the number of cells

present with PHA morphology. In true PHA, the number

of affected cells is much higher than in pseudo-PHA (63%

to 93% vs. ,38%, respectively).

• Also in true PHA, all WBC lineages are potentially

affected in terms of nuclear shape and chromatin

structure.

• In pseudo-PHA the phenomenon is usually seen only in

neutrophils, except for some cases of MDS where

monocytes, eosinophils, and basophils may exhibit PHA

morphology.

• Furthermore, if true PHA is suspected, a careful

examination of peripheral blood smears of family

members may reveal similar findings.

• Hypogranular neutrophils are a common finding in MDS-

related pseudo-PHA. In true PHA, neutrophils exhibit

normal granulation. In both true and pseudo-PHA there

are potential challenges for the clinical lab related to cell

identification.

Neutrophil Hypersegmentation

• Normal neutrophils contain three to five lobes that are

separated by filaments.

• Hypersegmented neutrophils have more than five lobes

and are most often associated with the megaloblastic

anemias.

• In the myelodysplastic syndromes and represent a form

of myeloid dysplasia.

• Less frequently in hereditary neutrophil

hypersegmentation.

• Myelokathexis

→ Refers to a rare hereditary condition characterized

by normal granulocyte production.

• Example:

WHIM syndrome-warts

Neutropenia

Hypogammaglobinemia

Infections

Myelokathexis

Alder-Reilly Anomaly

• A recessive trait and is characterized by granulocytes

with large, darkly staining metachromatic cytoplasmic

Qualitative Disorders of Leukocytes

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Chapter 29 : Nonmalignant

Leukocyte Disorders

Morphologic Abnormalities with and without Functional Defects Pelger-Huët Anomaly

Also known as true or congenital PHA
Autosomal dominant disorder characterized by decreased nuclear segmentation (bilobed, unilobed) and a characteristic coarse chromatin clumping pattern (mature neutrophil).
1 in 4785 in the United States.
Mutations in the lamin b-receptor gene (nuclear changes)
Nuclei may appear round, ovoid, or peanut shaped.
“pince-nez” morphologic form
In homozygous PHA, all neutrophils are affected.
In the heterozygote, 55% to 93% of the neutrophil population are affected.
Neutrophils in Pelger-Huët anomaly appear to function normally. Pseudo- or Acquired Pelger-Huët Anomaly
Neutrophils with PHA morphology can be observed in
patients with hematologic malignancies such as myelodysplastic syndromes (MDS), acute myeloid leukemia, and chronic myeloproliferative neoplasms as well as with HIV infection, tuberculosis, Mycoplasma pneumoniae and severe bacterial infections.
Drugs known to induce pseudo-PHA include mycophenolate mofetil, valproate, sulfisoxazole, ganciclovir, ibuprofen, and chemotherapies such as paclitaxel and docetaxel. Laboratory Issues in Pelger-Huët Anomaly (True/Congenital and Pseudo/Acquired)
An important consideration is the number of cells present with PHA morphology. In true PHA, the number of affected cells is much higher than in pseudo-PHA (63% to 93% vs. ,38%, respectively).
Also in true PHA, all WBC lineages are potentially affected in terms of nuclear shape and chromatin structure.
In pseudo-PHA the phenomenon is usually seen only in neutrophils, except for some cases of MDS where monocytes, eosinophils, and basophils may exhibit PHA morphology.
Furthermore, if true PHA is suspected, a careful examination of peripheral blood smears of family members may reveal similar findings.
Hypogranular neutrophils are a common finding in MDS- related pseudo-PHA. In true PHA, neutrophils exhibit normal granulation. In both true and pseudo-PHA there are potential challenges for the clinical lab related to cell identification. Neutrophil Hypersegmentation
Normal neutrophils contain three to five lobes that are separated by filaments.
Hypersegmented neutrophils have more than five lobes and are most often associated with the megaloblastic anemias.
In the myelodysplastic syndromes and represent a form of myeloid dysplasia.
Less frequently in hereditary neutrophil hypersegmentation.
Myelokathexis → Refers to a rare hereditary condition characterized by normal granulocyte production.
Example: WHIM syndrome-warts Neutropenia Hypogammaglobinemia Infections Myelokathexis Alder-Reilly Anomaly
A recessive trait and is characterized by granulocytes with large, darkly staining metachromatic cytoplasmic Qualitative Disorders of Leukocytes

granules composed primarily of partially digested mucopolysaccharides.

Granules are referred to as Alder-Reilly bodies or Reilly bodies.
Morphology may resemble heavy toxic granulation.
Granules are found in lymphocytes and monocytes, ruling out toxic granulation
Reilly bodies are most commonly associated with Hurler syndrome, Hunter syndrome, and Maroteaux- Lamy polydystrophic dwarfism. Chédiak-Higashi Syndrome
Rare, fatal, autosomal recessive.
Only 800 cases were reported worldwide.
Characterized by abnormal fusion of granules in most cells that contain granules throughout the body.
Hematopoietic cells are affected, but disease manifestations can be found in hair, skin, adrenal and pituitary glands, and nerves.
Giant lysosomal granules in granulocytes, monocytes, and lymphocytes.
Fused granules result in leukocyte dysfunction and recurrent pyogenic infections.
Bleeding issues due to abnormal dense granules in platelets.
Associated with a mutation in the CHS1 LYST gene on chromosome 1q42.1-2 that encodes for a protein involved in vesicle fusion or fission. May-Hegglin Anomaly
Rare, autosomal dominant platelet disorder characterized by variable thrombocytopenia, giant platelets, and large Döhle body–like inclusions in neutrophils, eosinophils, basophils, and monocytes.
Caused by a mutation in the MYH9 gene on chromosome 22q12-13.
Disordered production of myosin heavy chain type IIA which affects megakaryocyte maturation and platelet fragmentation.
Basophilic Döhle body–like leukocyte inclusions are composed of precipitated myosin heavy chains.
Döhle bodies are composed of lamellar rows of rough endoplasmic reticulum.
Asymptomatic, but mild bleeding tendencies that are related to the degree of thrombocytopenia. Normal Morphology with Functional Abnormalities
The majority of genetic functional leukocyte disorders, with the exception of some of the storage disorders, are not characterized by specific morphologic alterations in leukocytes. Chronic Granulomatous Disease
Causes: o Mutation(s) in NADPH oxidase genes leads to failure of neutrophil respiratory burst following phagocytosis of organism
Clinical findings: o Heterogeneous, however most experience recurrent bacterial and fungal infections; granulomas may obstruct organs (liver, spleen, others). Leukocyte adhesion disorder – I
Causes: o Mutation in gene(s) responsible for b2 integrin subunits, leads to decreased or truncated b integrin, needed for neutrophil adhesion to

Genetic B and T Lymphocyte Abnormalities

Genetic disorders that generally result in the decreased production of B cells, T cells, or both.
Associated with an increased risk of infection and secondary malignancy.
T lymphocyte abnormality is best represented by a condition known as DiGeorge syndrome.
Sex-linked agammaglobulinemia (XLA) is a B cell disease that is caused most frequently by a mutation in the gene encoding Bruton tyrosine kinase (BTK).
Combined B lymphocyte/T lymphocyte abnormalities include severe combined immunodeficiency (SCID) and Wiskott-Aldrich syndrome. SCID can be divided into two types: adenosine deaminase deficiency and X-linked SCID. DiGeorge syndrome
Characterized by the absence or underdevelopment of the thymus and thus markedly decreased numbers of T lymphocytes.
Characterized by the absence or underdevelopment of the thymus and thus markedly decreased numbers of T lymphocytes.
Most common chromosome deletion and occurs in ap- proximately 1 in 3500 births.
Defective parathyroid glands, cardiac abnormalities, abnormal facial development, neurologic disorders, and hypocalcemia.
Patients are treated with thymus transplantation, with an approximately 75% survival rate. Sex-linked agammaglobulinemia (XLA) - Decreased production of BTK, which is important for B cell development, differentiation, and signaling. - Infants with XLA start to display symptoms after 1 to 2 months, once maternal antibodies have been cleared. - Recurring bacterial infections ensue and can be life- threatening Combined B lymphocyte/T lymphocyte abnormalities - X-linked SCID is the more common of the two and is caused by a mutation in the gene encoding the IL- 2 receptor g chain, which is shared by several interleukins. - Wiskott-Aldrich syndrome is also X-linked and is caused by a mutation in a gene that encodes a protein called WASp. o Results in low levels or absence of the protein, and affected individuals have immunodeficiency, eczema, and thrombocytopenia Neutrophils - Neutrophilia → Increase in neutrophils bove 7.0 x 10 ^9/L in adults and 8.5 x 10 ^9/L in children. → Should always be evaluated using absolute values. - The normal relative neutrophil count is approximately 50% to 70%. - Catecholamine-induced demargination or a shift in neutrophils from the marginal pool (cells normally adhering to vessel walls) to the circulating pool. - Strenuous exercise, emotional stress, shock, burns, trauma, labor, or an increase in epinephrine. - Increase in bone marrow production or in the shift of neutrophils from the bone marrow storage pool to the peripheral blood. - The latter is almost always accompanied by a shift to the left (presence of immature neutrophils). - Leukemoid reaction → Refers to a reactive leukocytosis above 50 3 109/L with neutrophilia and a marked left shift (presence of immature neutrophilic forms). - Leucoerythroblastic reaction → Refers to the presence of immature neutrophils, nucleated red blood cells, and teardrop RBCs in the same sample. - Neutropenia refers to a decrease in the absolute neutrophil count (ANC). Qualitative Abnormalities of Leukocytes

Alloimmune neonatal neutropenia , maternal IgG crosses the placenta and binds to neutrophil-specific antigens inherited from the father, such as FcyRIIIb, NB1, or HLA.
Autoimmune neutropenia in children is a primary illness, with moderate to severe neutropenia developing as a result of antibodies to HNA-1.
Secondary autoimmune neutropenia is associated with autoimmune disorders such as rheumatoid arthritis and associated Felty syndrome, systemic lupus erythematosis, and Sjogren syndrome.
Shwachman-Diamond syndrome , or Shwachman- Bodian-Diamond syndrome , is an autosomal recessive disorder characterized by marrow failure, pancreatic insufficiency, and skeletal abnormalities.
Congenital severe neutropenia consists of Kostmann syndrome and related diseases. Kostmann syndrome, or infantile genetic agranulocytosis, is an autosomal recessive disease characterized by severe neutropenia (often ,0.2 x 10 ^9/L) that presents shortly after birth and bone marrow granulocyte hypoplasia with maturation arrest at the promyelocyte stage.
Chronic idiopathic neutropenia in adults predominantly affects women 18 to 35 years of age. The bone marrow is quite variable between patients but generally shows more immature neutrophils than mature neutrophils, suggesting that cells are lost during maturation.
Fanconi anemia is a rare autosomal recessive or X-linked inherited disease characterized by variable degrees of bone marrow failure, peripheral cytopenias, and an increased risk for hematologic malignancies and other cancers.

Lymphocytes

Children older than 2 weeks and younger than 8 to 10 years normally have higher absolute lymphocyte counts than adults. Neutrophils - Toxic granulation → Appears as dark, blue-black granules in the cytoplasm. → Inflammation, infection, administration of granulocyte colony stimulation factor (G-CSF). - Döhle bodies → Intracytoplasmic, pale blue round or elongated bodies between 1 and 5 mm, usually adjacent to cellular membranes. → Nonspecific finding, or associated with bacterial infections, sepsis, and normal pregnancy. - Cytoplasmic vacuolation of neutrophils o Small to large circular areas in cytoplasm, rarely may contain organism. o Septicemia or other infection; autophagocytosis secondary to drug ingestion, acute alcoholism, or storage artifact; vacuoles are sometimes seen in conjunction with toxic granulation. Qualitative (Morphologic) Changes

Monocytes

Occasional immature monocytes may be seen in the peripheral blood in response to infection or inflammation, but this is not as common as a neutrophilic left shift.
Reactive changes may be seen in monocytes in infections, during recovery from bone marrow aplasia, and after GM-CSF administration. The nucleus can become thin and band-like in areas and may appear to be segmenting. Lymphocytes
Reactive morphologic changes in lymphocytes have been described using various terms, including variant lymphocytes , reactive lymphocytes , effector lymphocytes , transformed lymphocytes , Turk cells , Downey cells , immunoblasts , and atypical lymphocytes.
Atypical is commonly used, but it is probably the least suitable of all because it implies that the cells are abnormal when in fact the lymphocytes are reacting to antigen in a normal manner.
Reactive lymphocytes are the result of complex morphologic and biochemical events that occur as lymphocytes are stimulated when interacting with antigens in peripheral lymphoid organs. Epstein-Barr Virus (EBV)–Related Infections
Most humans are subclinically infected with EBV, which has been associated with several benign and malignant diseases but has only been proven to be the causative agent in a few, including infectious mononucleosis.
Symptomatic illness that ensues whenever adolescents and adults are infected.
The incubation period of infectious mononucleosis is about 3 to 7 weeks, and during this time the virus preferentially infects B lymphocytes through attachment of viral envelope glycoprotein 350/220 to CD21 (C3d complement receptors).
Rare cases patients may develop aplastic anemia, disseminated intravascular coagulation, thrombotic thrombocytopenic purpura, hemolytic uremic syndrome, Infectious Mononucleosis (IM)

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Chapter 29 : Nonmalignant

Leukocyte Disorders