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Chapter 15. White Blood Cell Disorders. White Blood Cell Disorders.

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chapter 15

Chapter 15

White Blood Cell Disorders

white blood cell disorders
White Blood Cell Disorders
  • In Chapter 15, you will be introduced to the various disorders of leukocytes.  Included in this chapter will be a discussion on the kinetics and functions of neutrophils, disorders of neutrophils, and other morphologic changes of neutrophils.  The function and morphology of lymphocytes will also be covered.  Diseases that affect lymphocytes are discussed. 
circulating kinetics and morphology of neutrophils 1 of 3
Circulating Kinetics and Morphology of Neutrophils 1 of 3
  • Granulocytes are divided into three subsets:
    • Neutrophils
    • Basophils
    • Eosinophils
  • Neutrophils are phagocytic cells.
  • They are capable of movement from the circulatory system into the tissues to engulf and destroy bacteria.
  • They mobilize to sites of infection and play a role in the inflammatory response.
circulating kinetics and morphology of neutrophils 2 of 3
Circulating Kinetics and Morphology of Neutrophils 2 of 3
  • Two types of granules:
    • Primary or azurophilic
    • Secondary or specific
  • All granules contain enzymes which are involved in killing and digesting bacteria and fungi.
  • Neutrophils are very mobile cells.
circulating kinetics and morphology of neutrophils 3 of 3
Circulating Kinetics and Morphology of Neutrophils 3 of 3
  • Once in the circulatory system, the neutrophils divide up into two pools:
    • Marginating pool: These neutrophils remain in the circulatory system searching for an area of inflammation. When inflammation is found, these neutrophils leave the circulatory system by process of diapedesis and enter surrounding tissues.
    • Circulating pool: Leave the blood stream by random migration and do not return to the bloodstream.
  • Neutrophils are believed to survive 2-5 days after entering the tissues.
neutrophil counts in peripheral blood
Neutrophil Counts in Peripheral Blood
  • Variations in the numbers of neutrophils is a useful diagnostic tool; Variations reflect response of neutrophils to underlying disease (i.e. bacterial infection) or of another disorder such as leukemia.
  • Normal ranges vary widely with age:
    • Newborns may have more WBCs
    • Babies may have more lymphocytes
response to infections 1 of 2
Response to Infections 1 of 2
  • Neutrophils play central role in fighting infections and inflammatory agents.  Can reach area of inflammation within minutes by migrating (diapedesis) from circulatory system to site of infection.
  • Neutrophilia is increase in relative number of neutrophils in response to infection or inflammatory process. Accelerated release from bone marrow seen as "shift to left" which is defined as increased number of metamyelocytes and bands in peripheral blood.  Rarely see more immature neutrophil forms in infections (will see more immature forms in leukemia).
response to infections 2 of 2
Response to Infections 2 of 2
  • In addition to changes in neutrophil number, will see morphologic changes such as toxic granulation, Dohle bodies, and cytoplasmic vacuoles:
    • Toxic granulation: granules become larger and stain more darkly.  Granules tend to be primary granules that are peroxidase positive.  Frequently seen in severe infections.
    • Dohle bodies: pale blue cytoplasmic inclusions.  Seen on periphery of cell.  Consist of few strands of rough endoplasmic reticulum that have banded together.
    • Vacuoles: Neutrophils may develop vacuoles in cytoplasm.  May see ingested microorganisms as well. 
  • Presence of any of these changes may suggest progression toward sepsis; however, are not specifically related to infections.  May see in massive trauma, during pregnancy, in inflammatory responses, and in drug reactions.
neutrophil function10
Neutrophil Function
  • Main function is destruction of microorganisms through process called phagocytosis. 
  • Once bacteria infiltrate tissues, neutrophils immediately respond.  Phagocytosis begins.
  • Phagocytosis consists of three phases: 
    • migration and diapedesis
    • opsonization and recognition
    • ingestion, killing, and digestion
migration and diapedesis phase 1
Migration and DiapedesisPhase 1
  • Neutrophils are attracted to the area by chemical signals produced by inflammation, injury, and infectious agents.
  • Chemotaxis is the movement of neutrophils towards the chemoattractant.
  • Neutrophils migrate from the vessels by diapedesis between the endothelial cells of the vessels, and migrate towards the chemoattractor.
opsonization and recognition phase 2
Opsonization and RecognitionPhase 2
  • Neutrophils cannot recognize or attach to microorganisms.  They need help.
  • Opsonization is process which facilitates recognition and attachment of neutrophil to organism.  Marks organism for ingestion by neutrophil.
  • As chemotaxis occurring, immunoglobulins and complement components coat surface of bacteria.  Marked bacteria (opsonin) easily recognized by neutrophil and ingested.
  • Ingestion requires presence of membrane-bound immunoglobulin.
ingestion killing and digestion phase 3 1 of 2
Ingestion, Killing and DigestionPhase 3 1 of 2
  • Ingestion begins as soon as organism and neutrophil bind together.  Membrane pseudopods surround organism, forming isolated vacuole within cytoplasm of neutrophil.  Called a phagosome.
  • Simultaneously, cytoplasmic granules migrate to and fuse with phagosome, forming a phagolysosome.
  • Once phagolysosome formation complete, granules release contents.  Ingested organism exposed to lytic activity of granular enzymes that leads to death of organism and its eventual digestion.
ingestion killing and digestion phase 3 2 of 2
Ingestion, Killing and Digestion Phase 3 2 of 2
  • In the leukocyte, there are pH changes, dumping of digestive enzymes into the phagolysosome, production of hydrogen peroxide and superoxides. These digestion processes are collectively called respiratory burst.  These oxygen metabolites injure the organism and interact with other granular contents to produce toxic agents such as hydrochloric acid (household bleach).
disorders of neutrophils
Disorders of Neutrophils
  • Neutrophil disorders may be classified as quantitative (abnormal numbers) or qualitative (abnormal function).
quantitative disorders of neutrophils
Quantitative Disorders of Neutrophils
  • Leukocytosis: an increase in the number of WBCs.
  • Leukopenia: a decrease in the number of WBCs.
  • Neutropenia: an absolute decrease in the number of circulating neutrophils.
acquired neutropenia
Acquired Neutropenia
  • Five factors associated with acquired neutropenia:
    • Viral infections
    • Ingestion of medications
    • Alloantibody formation (from transfusion or pregnancy, much like HDN)
    • Autoantibody formation
    • Secondary condition due to another process (aplastic anemia, bone cancer)
qualitative disorders of neutrophils
Qualitative Disorders of Neutrophils
  • Involve neutrophil function.
  • Extremely rare occurrences.
  • Classified according to major defect expressed:
    • Cytoplasmic granules
    • Disturbance of respiratory burst
    • Chemotaxis
    • Combination of defects
chediak higashi syndrome 1 of 2
Chediak-Higashi Syndrome 1 of 2
  • Rare autosomal recessive condition.  
  • Features include recurrent bacterial infections, partial albinism, and presence of giant lysosomal granules in cells such as granulocytes, monocytes, lymphocytes, and platelets.  Mild bleeding tendencies may occur.
  • Have progressive neurologic complications during childhood.  Many patients die as result of infection during childhood.  Adults enter into accelerated phase that progresses through pancytopenia, organomegaly, systemic infections, and eventually, death.  Staphylococcus aureus primary cause of infections.
chediak higashi syndrome 2 of 2
Chediak-Higashi Syndrome 2 of 2
  • **Have inefficient and prolonged bacterial killing.  Release of lysosomal enzymes impaired by abnormal granules.  In Wright's stain, giant granules more likely seen in lymphocytes (stain deep purple to dark red).
  • Management includes prophylactic antibiotic treatment and high daily doses of ascorbic acid.  In cases of infection, aggressive intravenous treatment required.
  • Bone marrow transplant only hope of cure.  Should be performed before accelerated phase begins.
chronic granulomatous disease cgd 1 of 2
Chronic Granulomatous Disease(CGD) 1 of 2
  • Heterogeneous disorder of neutrophil that can be chronic or intermittent.
  • **Attributed to failure in activation of respiratory burst that results in little or no superoxide production.
  • Patients present with lymphadenitis, deep tissue infections such as osteomyelitis, and visceral and hepatic abscesses.  Have frequent pulmonary infections, organomegaly, and infected eczematoid rashes.
  • Patients have neutrophilia rather than neutropenia.
  • Hallmark characteristic is formation of granulomas during chronic inflammatory reactions that keep organisms localized.
chronic granulomatous disease cgd 2 of 2
Chronic Granulomatous Disease(CGD) 2 of 2
  • May be inherited as either sex-linked-recessive or as autosomal-recessive.  Regardless of form, end result is that superoxide can not be produced, and in turn, bacterial killing is ineffective.  Ingestion of bacteria, degranulation, and phagolysosome formation normal.
  • Diagnosis made by demonstrating bactericidal defect resulting from absence of respiratory burst on nitroblue tetrazolium test (NTB), or by measuring respiratory burst activity by flow cytometry.
  • Aggressive prophylactic antibiotic therapy begun as soon as diagnosis made.  Gamma interferon effective in limiting frequency of infections.  Granulocyte transfusions useful.  Bone marrow transplants beneficial in children.
hypersegmentation of neutrophils
Hypersegmentation of Neutrophils
  • Larger than normal neutrophils (and sometimes eosinophils) with six or more nuclear lobes present.
  • May be an indicator of megaloblastic anemia or of benign autosomal recessive condition called benign hypersegmentation of neutrophils.
hyposegmentation of neutrophils
Hyposegmentation of Neutrophils
  • Characteristic of Pelger-Huet anomaly.
  • Nucleus is bilobed or lacks lobes altogether. Nuclear chromatin excessively coarse and condensed.  Nuclei described as "dumbbell" or "pince-nez"  appearing with two symmetric lobes being joined by filament.
  • True Pelger-Huet is autosomal-dominant condition.  Is benign condition.
cytoplasmic changes
Cytoplasmic Changes
  • Cytoplasmic changes may also occur.
  • Alder anomaly or Alder-Reilly inclusions:
    • Presence of prominent, dark staining, coarse granules in many or all cell lines. Prominent granules are similar to toxic granulation, except they are larger and permanent (not a transient change cause by infection or toxins).
  • May-Hegglin anomaly:
    • Demonstrates larger, blue-staining cytoplasm in the granulocytes, resembling Dohle bodies.
lymphocyte disorders28
Lymphocyte Disorders
  • Lymphocytosis: An excess of lymphocytes in peripheral blood.
  • Reactive lymphocytes: Used to describe transformed or benign lymphocytes. You should use the term “reactive”, not “atypical”. The word “atypical” is used to describe malignant-appearing cells.
  • A few reactive lymphocytes is not abnormal.
lymphocyte morphology
Lymphocyte Morphology
  • Lymphocytes are supposed to vary in size; In malignant disorders, the lymphocytes appear the same size and shape because they arise from the same monoclonal cell.
  • Reactive lymphocytes:
    • May have azurophilic granules
    • Cytoplasm stains unevenly, with the peripheral regions of the cytoplasm staining darker.
plasma cells
Plasma Cells
  • Plasmacytoid lymphocytes (plasma cells) have coarse, clumped nuclear chromatin, a perinuclear halo, and an eccentric nucleus.
causes of reactive lymphocytosis
Causes of Reactive Lymphocytosis
  • Infectious mononucleosis, which is caused by the Epstein-Barr Virus (EBV), is most commonly seen in young adults between the ages of 17 and 25 years of age.
  • Cytomegalovirus Infection (CMV), which belongs to the herpes virus family, is usually asymptomatic in immunocompetent individuals.
  • Other viral infections.
malignant conditions
Malignant Conditions
  • The lymphocytes seen in malignant disorders, such as leukemia, may be confused with reactive lymphocytosis.
  • Malignant cells in leukemia have the same appearance and, therefore, are morphologically different from reactive lymphocytes seen in reactive conditions.
laboratory examination 1 of 2
Laboratory Examination 1 of 2
  • Tests include CBC, serology, and microbiologic cultures.  The most useful tests are still the CBC with differential and serology tests.
  • Proper evaluation of peripheral blood smear crucial for correct diagnosis of absolute lymphocytosis - especially for patients with infectious mononucleosis.
  • Serology tests important, especially Monospot test for infectious mononucleosis.  A positive Monospot and a differential with reactive lymphocytes diagnostic for infectious mononucleosis in some labs. 
  • Further serology testing differentiates among variety of viral infections. 
laboratory examination 2 of 2
Laboratory Examination 2 of 2
  • Can trace course of disease by testing for IgM and IgG antibodies.  IgM antibodies formed early in infection, while IgG antibodies formed after a couple of weeks.  Periodic testing of antibody titers can trace course of disease through acute and convalescent phases.
  • If malignancies suspected, lymphocytes may be distinguished by immunophenotyping tests.