Non-Neoplastic WBC abnormalities Flashcards
Factors affecting neutrophil concentration in blood (3)
- bone marrow production and release
- rate of egress to tissue or survival time in blood
- rate of marginated to circulating neutrophils in peripheral blood (MGP/CGP)
Neutrophilia
Absolute neutrophil count (ANC) > 7.0 x 10^9/L in adult. (higher than normal)
A response to physiological or pathological process
What are the kinetics of neutrophilia (immediate, acute, chronic)
Immediate: (20-30 minutes) redistribution from marginated to circulating pool (stress, steroids, epinephrine, IL-6)
Acute: (4-5 hours) release from marrow storage pool into blood
Chronic: (days) increase in marrow mitotic pool
Causes of neutrophilia
- acute inflammation
- acute infection: bacteria, fungi, virus, parasite, spirochetes
- tissue necrosis
- drugs, toxins, metabolic: corticosteroids, smoking, growth factors, uremia, ketoacidosis, lithium
- physiological: stress, exercise, pregnancy
- neoplastic
features associated with REACTIVE neutrophilia
- usually <30x10^9/L
- -Shift to LEFT in myeloid maturation (immature cells released, typically response to infection)
- frequently associated with morphological alterations in neutrophil precursors (toxic granulation, Dohle Bodies, vacuolization)
Leukemoid Reaction
benign leukocyte proliferation with WBC usually >50x10^9/L with many circulating IMMATURE leukocyte precursors.
Blasts occasionally present; exclude chronic myelogenous leukemia with cytogenetics and LAP score
Leukoerythroblastic Reaction
characterized by the presence of NUCLEATED RBCs and LEFT SHIFT in granulocyte maturation
often associated with myelophthisic processes, SEVERE HEMORRHAGE, hemolytic anemia, or myelodysplastic syndromes
Neutropenia
ANC < 2.0 in whites, 1.3 in blacks
Agranulocytosis: ANC<0.5
mechanisms for neutropenia
- decreased or ineffective marrow production
- increased cell loss of tissue egress
- pseudoneutropenia (endotoxin)
causes of neutropenia
- drugs
- intrinsic defects (rare)
- overwhelming infection
- hematologic disorders
- autoimmune
- cachexia and debilitating states
what types of infections are associated with neutropenia
bacterial, viral, rhickettsial, and protozoal. see slide 10
Myeloid hypoplasias
Fanconi’s anemia, Kostmann’s syndrome, Schwachman-Diamond syndrome, Cyclic neutropenia
Fanconi’s Anemia
PANMYELOID HYPOPLASIA
HETEROGENOUS DISEASE CAUSED BY CHROMOSOMAL INSTABILITY
PRESENTS IN CHILDHOOD WITH APLASTIC ANEMIA AND CONGENITAL PHYSICAL MALFORMATIONS
SUSCEPTIBLE TO HEMATOPOIETIC AND SOLID ORGAN MALIGNANCIES
Kostmann’s Syndrome
infantile genetic congenital agranulocytosis
ANC <200/UL
VARIABLE MODES OF INHERITANCE
EARLY MYELOID PRECURSORS IN MARROW, BUT DO NOT MATURE
ELA2 AND HAX-1 IMPLICATED
Genes implicated with Kostmann’s syndrome
ELA-2 and HAX-1
Cyclic Neutropenia
Presents in infancy or childhood
Rare autosomal dominant trait with variable expression
21-30 day periodicity
ANC < 0.2 x 109/L for several days
Infection, fever, malaise during neutropenic period
Associated with transient marrow hypoplasia
Associated with ELA2 gene mutation (neutrophil elastase)
most common congenital neutropenias
pregnancy induced hypertension and infection
toxic granulation
Large, blue-black granules
Primary (azurophilic) granules retain basophilia, perhaps due to lack of maturation
Often associated with Döhle bodies and vacuolization
Rule out staining artifact
Dohle Bodies
Remnants of free ribosomes and rough endoplasmic reticulum
Seen in severe bacterial infections, pregnancy, burns, cancer, aplastic anemia, and toxic states
Often occur with toxic granulation and vacuolization
Vacuolization
End stage of phagocytosed material, or fat or other substance
Often associated with Döhle bodies and toxic granulation
Often a predictor of sepsis
May be artifactual in stored blood
Pelger- Huet Anomaly
Autosomal dominant trait occurring in 1:5,000 people
Clinically asymptomatic with normal neutrophil function
Heterozygous form
Homozygous form
Distinguish from reactive left-shift
Pseudo-Pelger-Huet anomaly
Hypersegmentation
Definition: >5% neutrophils with five lobes or any with six
Associated with megaloblastic anemia (B12 def), chronic infection, myelodysplastic syndromes
Hereditary hypersegmentation: autosomal dominant, rare, not associated with disease
Alder-Reilly Anomaly
Autosomal recessive trait
Large, purplish granules in cytoplasm
Granules stain metachromatically with Toluidine blue
Associated with mucopolysaccharidoses (Hunter’s syndrome, Hurler’s syndrome)
Chediak-Higashi
Partial albinism, photophobia, immune deficiency, frequent pyogenic infections
Autosomal recessive trait
Giant gray-green peroxidase- positive bodies in cytoplasm of leukocytes and other cells
Defects in fusion of cytoplasmic membranes, locomotion, and chemotaxis
Abnormal melanosomes (skin hypopigmentation, photophobia)
Lymphadenopathy and hepatosplenomegaly
May-Hegglin Anomaly
Autosomal dominant trait
Large Döhle body-like inclusions in granulocytes
Involves myosin heavy chain 9
Inclusions contain RNA
Associated with thrombocytopenia and giant oval platelets with few granules
Typically present with bleeding disorder due to platelet defect
normal granulocyte function
Chronic Granulomatous Disease
Sex-linked and autosomal recessive inheritance patterns
Defect in respiratory burst oxidase system
Presents in childhood with recurrent infections with low-grade pathogens
Formation of granulomas when neutrophils phagocytose, but do not kill, organisms
Defects in membrane-associated cytochrome b (subunits gp91 and p22), and cytosol-associated p47 and p67.
diagnosis of chronic granulomatous disease
Nitroblue Tetrazolium Test (NBT): normal neutrophils produce H2O2 and O2- which reduce yellow NBT to blue formazan; CGD neutrophils cannot reduce NBT.
Myeloperoxidase (MPO) Deficiency
Autosomal recessive inheritance (can be acquired)
Absence of MPO in neutrophils and monocytes
Infections not a usual complication
diagnosing MPO deficiency
Histochemistry: Myeloperoxidase stain
NB: May be recognized on WBC histogram using Technicon instruments
Leukocyte Adhesion Deficiency
LAD Type I - CD11a/CD18
LAD Type II - Selectins
LAD Type III - CD11a/CD18 activation
Delayed separation of umbilical cord , Recurrent pyoderma gangrenosum
Eosinophilia
Absolute eosinophil count >0.45 x 109/L in adults
Often associated with cellular immune response
Causes of eosinophil disorders
- parasitic infection
- allergic disorders
- infections
- ADDISON’S DISEASE
- malignancies
- collagen disorders
- idiopathic
- leukemia
- GI disorders
Hypereosinophilic Syndromes
Eosinophilic Leukemia
Loffler’s Syndrome
Eosinophilic Leukemia
Persistent absolute eosinophil count >1.5 x 109/L in adults with tissue infiltration and no apparent cause
Loffler’s Syndrome
Pulmonary infiltrate with eosinophilia syndrome
Tropical eosinophilia
Eosinopenia
Hypercorticosteroids: Corticosteroids sequester eosinophils in lymph nodes. Cushings disease, ACTH, acute stress/ Epi, inflammation, prostaglandins, bacterial infection
Basophilia (values and cause)
Absolute basophil count > 0.2 109/L in adults
Causes
Immediate hypersensitivity reactions
Chronic myeloproliferative disorders (PV)
CML
Basophilic Leukemia
Irradiation
Quantitative monocyte disorders
Monocytosis:
Absolute monocyte count > 0.8 x 109/L in adults
Monocyte count varies with age
Unexplained monocytosis is a frequent finding in malignancies
Monocytopenia:
Absolute monocyte count < 0.2 x 109/L in adults
Causes of monocytosis
- inflammatory
- monocytic disorders
- infections
- HEMATOLOGIC MALIGNANCY (main cause)
- recovery status
- post splenectomy
causes of monocytopenia
STEM CELL DISORDERS
aplastic anemia
*HAIRY CELL LEUKEMIA
GLUCOCORTICOID THERAPY
Gaucher Disease
Autosomal recessive trait glucocerebrosidase deficiency Macrophages in bone marrow, lymph node, liver, spleen Serum acid phosphatase increased Types I, II, and III
Lymphocytosis
Absolute lymphocyte count >4.0 x 109/L in adults and >9.0 x 109/L in children
Most changes in lymphocyte count are due to changes in numbers of T lymphocytes, which normally account for 60-80% of peripheral blood lymphocytes
Majority of circulating lymphs are CD4+ T-helper cells
Absolute lymphocytosis with leukocytosis
Acute infectious lymphocytosis Persistent polyclonal B cell lymphocytosis Infectious mononucleosis (EBV) Bordatella pertussis infection Cytomegalovirus infection (CMV) Toxoplasmosis Retrovirus infection (HTLV-1) lymphocytic leukemias
acute infectious lymphocytosis
CONTAGIOUS, MAINLY OCCURRING IN CHILDREN
VARIABLE SYSTEMIC MANIFESTATIONS
COXSACKIE VIRUSES A, B6, ECHOVIRUS, ADENOVIRUS
12-21 DAY INCUBATION
LYMPHOCYTOSIS LASTS 3-5 WEEKS
Persistent polyclonal B cell lymphocytosis
UNCOMMON EVENT
SHOULD RAISE SUSPICION FOR A CHRONIC LEUKEMIA
infectious mononucleosis
SELF-LIMITED, USUALLY UNNOTICED (3-5 WK INCUBATION)
VIRUS GAINS ENTRY VIA CD21 (RECEPTOR), INFECTS OROPHARYNGEAL MUCOSA AND LYMPHOID TISSUE
SORE THROAT, MALAISE, LYMPHADENOPATHY, SPLENOMEGALY
WBC 12-25 X 109/L
ATYPICAL LYMPHOCYTOSIS (NOT UNIQUE TO MONO)
POSITIVE HETEROPHIL ANTIBODY
reactive/ atypical lymphocytes
Type I (plasmacytoid lymphocyte) Type II (infectious mononucleosis cell) Type III (immunoblast)
causes of lymphocytopenia
- destructive
- debilitating
- infection
- AIDS
- congenital immune deficiency
- abnormal lymphatic circulation
severe combined immune deficiency syndrome
Most severe immunodeficiency disease 75% of affected are male Both T and B lymphoid systems deficient Recurrent infections, failure to thrive X-linked form (Xq13) Absent to severely reduced T cells; thymic hypoplasia Autosomal form Severe deficiency of T and B cells (ADA deficiency) Treatment: Bone marrow transplant
Wiskott-Aldrich Syndrome
X-linked recessive inheritance (Xp11.3-Xp11.22)
Eczema, thrombocytopenia, and immunodeficiency
Increased risk of secondary neoplasm
Progressive decrease in thymus-dependent immunity
Absent antibodies to blood group antigens
Abnormal antibody production by B cells
No mitogenic response to CD43
May present with abnormal bleeding in neonatal period
DiGeorge Syndrome
Absence or hypoplasia of thymus Hypoparathyroidism Congenital heart defects Dysmorphic facies Hypocalcemia Normal B cell function Pathogenesis: del(22)(q11.2)
X-linked Agammaglobulinema
Frequent respiratory and skin infections
Xq21.3-22
Block in B cell maturation at pre-B cell stage due to failure of variable and constant regions of IgM to connect
Decreased B lymphocytes and absent plasma cells
Marked decrease in serum immunoglobulins
Treatment: gammaglobulin
Hereditary Ataxia-Telangiectasia
Autosomal recessive inheritance
Progressive ataxia, immune dysfunction, increased risk of malignancy
Defect in cell-mediated immunity with thymic hypoplasia or dysplasia
Diagnosis: increased chromosome breakage, t(14;14)
Gene product functions in DNA repair
