12 - Disorders of White Blood Cells: Number and Function Flashcards
HEMATOPOESIS
LEUKOCYTES
- In unstained blood smear, leukocytes are colorless; “Leuko” meaning white
- From bone marrow (except T-lymphocytes) → peripheral blood → tissues
- Leukopoiesis generates 1-5 x 1011 cells/day
- Protect host against infections/toxins/pathogens:
*** Granulocyte/neutrophils – Phagocytosis (innate immunity) - Basophils – Hypersensitivity reactions; release histamine
- Eosinophils – Allergic reactions, chronic inflammation, parasites
- Monocytes – Phagocytosis(innate)/APC(adaptive immunity)
- Lymphocytes (B and T cells) – Adaptive immunity**
GRANULOCYTE KINETICS/DISTRIBUTION
- Bone Marrow
▪ Mitotic/proliferating pool
▪ Myeloblasts, promyelocytes, myelocytes
▪ 3-6 days
▪ Maturation/storage pool
▪ Metamyelocytes, bands, segmented neutrophils
▪ 5-7 days → ~2 days in infection - Peripheral Circulation
▪ Marginating pool (along the vessels)
▪ Circulating pool (freely circulating)
▪ 7-8 hours
* Tissue-Phase
▪ 1-2 days
White Blood Cell Disorders
LEUKOCYTOSIS
Quantitative WBC disorder
❑ WBC >11,000/microL or 2 SD above the mean in
adults
❑ Terminology:
* Left Shift: significant increase in % of bands in
peripheral blood along with some
metamyelocytes and myelocytes
* Leukemoid reaction: when WBC>50,000 and
more significant increase in earlier precursors
such as metamyelocytes and myelocytes and
sometimes promyelocytes
▪ Infections
NEUTROPHILIA ETIOLOGY
Quantitative WBC disorder
❑ ANC >7000-7500/ml
❑ Primary
* Myeloproliferative disorders (CML, ET, PV)
* Leukocyte adhesion factor deficiency
❑ Secondary
* INFECTION
* Inflammation/tissue necrosis/burns
* Malignancy
* Stress (physical/emotional stress, vigorous exercise, heat stroke)
* Cigarette smoking
* Drugs (Glucocorticoids, lithium, G/M-CSF)
* Asplenia
monocytosis (AMC>800) - LEUKOCYTOSIS
Quantitative WBC disorder
- Acute bacterial infection
- TB, endocarditis, syphilis
- Sarcoidosis
- AML, ALL
- Chronic myelomonocytic
leukemia (CMML) –
MDS/MPD
Basophilia (ABC>200) - LEUKOCYTOSIS
Quantitative WBC disorder
- Infections
- CML
- Hodgkins Lymphoma
- Type I hypersensitivity
reactions
Lymphocytosis (ALC >5000) - LEUKOCYTOSIS
Quantitative WBC disorder
- Infections
-Viral/bacterial/parasitic/
protozoal - Drug hypersensitivity
- Stress
- LGL, CLL, ALL
Eosinophilia (AEC>500) - Leukocytosis
Quantitative WBC disorder
- Allergic/atopy
- Drugs (PCNs, NSAIDs, ranitidine,
ASA, DRESS) - Parasitic/helminths
- Hypereosinophilic syndrome (HES)
- Hodgkins Lymphoma
- Organ-specific
- Adrenal insufficiency
LEUKOPENIAS
Quantitative WBC disorder
❑Lymphopenia
* Sepsis/infections
* Postoperative state
* Glucocorticoids
* Chemotherapy (Rituximab,
ATG)
* Radiation
* Autoimmune disorders
* Lymphomas
❑Monocytopenia
* Sepsis
* Chemotherapy
* Aplastic anemia
* MonoMAC syndrome
* GATA2 deficiency
* Late child/new adult
onset
❑Low eosinophils/basophils
* Drugs/Chemotherapy
* Not usually clinically significant
NEUTROPENIA
Quantitative WBC disorder
❑ ANC <1500/microL
* 1500-1000: mild
* 1000-500: moderate
* <500: severe or agranulocytosis
❑ Risk of infection:
* Proportional to ANC level
NEUTROPENIA ETIOLOGY
Quantitative WBC disorder
- DANC (Duffy-null Associated Neutrophil Count) –
previously called benign ethnic
neutropenia/constitutional neutropenia - Nutritional deficiencies
- Medications
- Severe infections
- Rheumatologic/autoimmune disorders; SLE, RA
- Congenital disorders
- Bone marrow disorders; MDS
- Hypersplenism
NEUTROPENIA MECHANISMS
Quantitative WBC disorder
- Decreased production
- Increased utilization
- Increased destruction
- Shift to marginating pool
APPROACH TO NEUTROPENIA Diagnosis
Quantitative WBC disorder
❑ History is key !!!
* Recurrent infections
* Family history
* Congenital neutropenia:
▪ Shwachman-Diamond Syndrome
▪ WHIM syndrome
▪ Cyclic neutropenia
▪ Severe congenital neutropenia (CSF3R gene)
▪ Kostmann Syndrome
- Alcohol
- Nutritional deficiencies (B12, folate, copper)
- Medication/drug list
- Autoimmune process
DRUG-INDUCED NEUTROPENIA - mechanism
Quantitative WBC disorder
- Onset 7-21 days after starting medication
- Effects can last 1-3 weeks
- Mechanisms: decreased production; increased destruction
- It is a clinical diagnosis
- Bone marrow
▪ Absent precursors
▪ Maturation arrest
DRUG-INDUCED NEUTROPENIA - causes
Quantitative WBC disorder
▪ H2 antagonists
▪ Anti-thyroid (Propylthyiouracil, methimazole)
▪ NSAIDs, sulfasalzine
▪ Anti-seizures (carbamazepine, phenytoin)
▪ Antibiotics/antifungals
▪ Antiarrhythmic agents
▪ Isotretinoin
▪ Diuretics
▪ Cytotoxic chemotherapies
CYCLIC NEUTROPENIA
Quantitative WBC disorder
- Autosomal dominant
- Elastase gene (ELANE, ELA2)
- Recurring neutropenia every 21 days
- Onset first few years of life
- Symptoms:
▪ Fevers
▪ Malaise
▪ Recurrent infections (clostridium septicum)
▪ Apthous ulcers
▪ Gingival inflammation
Treatment:
▪ Neupogen (G-CSF) to keep ANC
>1000
▪ Supportive care
DANC – Duffy Null associated neutrophil count
Quantitative WBC disorder
❑ Pathogenesis:
* Normal neutrophil production, but issue is
redistribution of circulating to marginating
pools or decrease granulocyte reserves
* Polymorphism in the ACKR1 gene that
encodes Duffy antigen receptor chemokine
(DARC)
* Patients are negative for Duffy (Fy) Ag in their
RBC
* Approx 2 in 3 people in US of African or
middle eastern genetic ancestry have Duffy
null phenotype
❑ Clinical manifestations
* No increased risk of infection
❑ Diagnosis
* Isolated decrease in PMN
* Persistent over time
* No history of unusual or severe infections
* Family history helpful but not essential
❑ Treatment
* No therapy needed
IMMUNE NEUTROPENIA
Quantitative WBC disorder
- Antibodies against antigens on neutrophils
- Alloimmune neonatal neutropenia
- Maternal Abs against Fetal Ag on neutrophils
(paternal origin) - Autoimmune neutropenia
- Idiopathic
- Secondary
- SLE, RA
FELTY SYNDROME
Quantitative WBC disorder
- Triad
- Rheumatoid arthritis
- Splenomegaly
- Neutropenia
- Recurrent infections
- Portal Hypertension
- Pathogenesis
- Anti-neutrophil antibodies destroy coated
neutrophils
LARGE GRANULAR LYMPHOCYTIC LEUKEMIA (LGL)
Quantitative WBC disorder
❑Clonal proliferation of large granular lymphocytes
* T-cells
* Natural killer (NK) cells
❑Clinical manifestations
* Neutropenia
* Recurrent infection
* Splenomegaly
* 25 – 50% have rheumatoid arthritis
* Pulmonary hypertension
❑ Diagnosis
* LGLs in peripheral blood and/or bone marrow
* Flow cytometry
* T-cell gene rearrangement (TCR)
* Negative in NK cell LGL, but positive in T-cell LGL
NEUTROPHIL STRUCTURE
❑Membrane receptors
❑Granules
* Primary (azurophilic)
* MPO, defensins, Cathepsin
* Secondary (specific)
* Lactoferrin, Collagenase, Heparinase
GRANULOCYTE DEVELOPMENT
NEUTROPHIL FUNCTION
DEFECTS IN NEUTROPHIL FUNCTION
neutrophil DEGRANULATION AND KILLING
❑Oxygen Dependent
* Mediators
▪ Oxygen free radicals
▪ Halides
* NADPH oxidase
▪ Respiratory burst
❑ Oxygen Independent
* Lysozyme
* Hydrolases
* Anionic protein
* Lactoferrin
* Collagenase
* Defensins
PHAGOCYTE OXIDASE FORMATION
DEFECTS IN NEUTROPHIL FUNCTION
LAD - Leukocyte adhesion defects
LEUKOCYTE ADHESION DEFICIENCY
TYPE I
❑ Very rare (~75 reported cases)
❑ Autosomal recessive
* Heterogeneous defects 21q22.3
* Abnormal CD18
* Abnormal CD11/CD18 integrin function
▪ Absent, decreased, dysfunction
▪ Impaired CD11/CD18-ICAM interaction
▪ Impaired firm adhesion
LEUKOCYTE ADHESION DEFICIENCY TYPE I - Clinical features
❑ Clinical features
* Recurrent, chronic or gangrene infections
▪ Soft tissue, gums (periodontitis)
* No pus formation
* Delayed umbilical cord separation
* Delayed wound healing
LEUKOCYTE ADHESION DEFICIENCY TYPE I - Laboratory features and therapies
❑ Laboratory features
* Neutrophilia
▪ baseline 15 - 60,000/ul
▪ infection > 100,000/ul
* BM myeloid hyperplasia
* Rebuck skin window test→ rare PMN
* Flow cytometry abnormal CD18 expression
❑ Therapy
* Prophylactic antibiotics
* Allogeneic SCT for severe disease
LEUKOCYTE ADHESION DEFICIENCY TYPE 2
❑ Deficient sLex
* Impaired binding to E-selection
* Impaired rolling
❑ Autosomal recessive
* Consanguineous parents
* Bombay phenotype (hh) – No H antigen to produce A, B
antigens on RBCs
* Short stature
* Cognitive deficits
Leukocyte adhesion deficiencies - appearance
CHEDIAK-HIGASHI SYNDROME
❑ Rare autosomal recessive disorder
❑ Generalized defect of protein trafficking and granule
morphogenesis
* Lysosomal granules
❑ Chromosome 1q42-q44
* CHS1 (LYST) gene mutated
CHEDIAK-HIGASHI SYNDROME - CLINICAL FEATURES
- Oculocutaneous albinism
- Sable hair
- Sun sensitivity
- Photophobia
- Neuropathy
- Recurrent pyogenic infections
CHEDIAK-HIGASHI SYNDROME - Diagnosis and treatment
❑ Large inclusions in all nucleated cell lines
❑ Accentuated by peroxidase stain
TREATMENT:
❑ Supportive care
❑ Prophylactic antibiotics
❑ Some data on vitamin C
CHRONIC GRANULOMATOUS DISEASE
❑ Incidence 1/200,000 - 1/1,000,000
❑ Male:Female 6:1
* X-linked
* Autosomal recessive
Pathogenesis:
* Decreased NADPH oxidase activity
* Impaired respiratory burst
* Decreased H2O2 generation
* Impaired killing of catalase positive organisms
2H2O2 ——Catalase——-> 2H2O + O2
Chronic granulomatous disease infections
❑ Catalase positive organisms
▪ Staph
▪ Klebsiella
▪ Serratia
▪ E. coli
▪ Pseudomonas
▪ Salmonella
▪ Enteric bacteria
▪ Aspergillus
▪ Candida
▪ Nocardia
▪ Mycobacterium
Chronic granulomatous disease - Clinical features
*Lymphadenopathy
*Hepatosplenomegaly
*Oral infections
*Chronic diarrhea
*Stomatitis
*Restrictive lung disease
*Hydronephrosis
*Anemia chronic disease
*Abscess
Chronic granulomatous disease diagnosis and treatment
❑ Impaired nitroblue tetrazolium (NBT) reduction
❑ Decreased superoxide or H2O2 generation
Treatment:
* Antibiotics (prophylactic +/- therapeutic)
* Anti-Inflammatory based treatments
* Allogenic stem cell transplant (ASCT)
* Gene therapy
MYELOPEROXIDASE DEFICIENCY
- Most common phagocytic disorder (1:4000)
- Autosomal recessive (MPO gene)
- Most patients asymptomatic; some have mucocutaneous
infections such as thrush (Candida)
C. Recombinant granulocyte colony-stimulating factor (e.g. Neupogen) support
The likely diagnosis in this case is B. Benign ethnic neutropenia. Benign ethnic neutropenia is a condition that can be seen more commonly in individuals of African descent. It is characterized by a persistent mild to moderate decrease in neutrophil count without associated clinical symptoms or increased susceptibility to infections. In this case, the patient’s history of neutropenia for at least 8 years, absence of recurrent infections, and normal physical examination support the diagnosis of benign ethnic neutropenia.
The compartment of granulocyte production that is not correct is:
A. Marginating pool in peripheral blood
The correct statement is that the marginating pool refers to the neutrophils that are temporarily adherent to the vascular endothelium but not actively participating in granulopoiesis. The main compartments involved in granulocyte production include the mitotic pool in the bone marrow, maturation pool in the bone marrow, storage pool in peripheral blood, and tissue-phase where neutrophils migrate to tissues in response to inflammation or infection.
D. Chediak-Higashi syndrome
Chediak-Higashi syndrome is a rare autosomal recessive disorder characterized by recurrent bacterial infections, oculocutaneous albinism, and a bleeding diathesis. The peripheral blood smear often shows giant granules in leukocytes, which is indicative of this syndrome. Additionally, the history of recurrent infections, albinism, and nystagmus in this patient and his mother is consistent with Chediak-Higashi syndrome.
A. Nitro Blue-Tetrazolium (NBT) test
The NBT test is commonly used to diagnose CGD. In this test, neutrophils are exposed to a substance (NBT) that they should be able to convert into a visible blue form. However, in individuals with CGD, the neutrophils are unable to produce this color change due to a defect in their ability to generate reactive oxygen species. This test helps in identifying the impaired function of phagocytes, which is characteristic of CGD.
The defect in Chronic Granulomatous Disease (CGD) is:
D. NADPH oxidase activity
In CGD, there is a defect in the NADPH oxidase enzyme, which is responsible for generating reactive oxygen species (ROS) in phagocytes. This impaired function of NADPH oxidase results in the inability of neutrophils and other phagocytes to effectively kill certain bacteria and fungi.
