Leukopenia - DSA Flashcards
Neutropenia
absolute neutrophil count less than 1500/uL
congenital or acquired
If d/t chemo, marrow failure, or marrow exhaustion - higher rates of infection
Primary causes of neutropenia
Ethnic and benign familial (constitutional) neutropenia Severe congenital neutropenia Cyclic neutropenia Shwachman-Diamond syndrome Fanconi anemia Dyskeratosis congenita Glycogen storage dz type Ib Myeljkathexis Chediak-Higashi syndrome Grisella syndrome type II Herman sky-Pudlak syndrome II Barth syndrome
Secondary causes of neutropenia
Infection Post infection Drug induced Immune neutropenia Primary bone marrow failure Margination and hypersplenism Vit. and mineral deficiencies - B12, folate, copper chronic idiopathic neutropenia in adults (CINA)
Ethnic and Benign Familial (Constitutional) Neutropenia
Constitutional neutropenia - compared to normal range based on young, white individuals
AA, Yemenite Jews, Falasha Jews, African Bedouins
single nt polymorphism in Duffy antigen receptor for chemokine (DARC)
AD - benign familial neutropenia: neutrophil counts 800-1400/uL range
Severe Congenital Neutropenia
Severe neutropenia - less than 500/uL
Presents in neonatal period - recurrent bacterial infections first months of life (omphalitis, perirectal abscesses)
Increase other myeloid cell lines - monocytes, eosinophils
Maturation arrest in marrow - absent mature neutrophil elements
Neutrophil elastase (ELA2 or ELANE) - high in promyelocyte stage, packaged in primary granules
- mutations –> defective cellular trafficking, cytoplasmic accumulation triggering apoptosis
- accumulation of mutant elastase in ER activates unfolded protein response –> apoptosis
Hax-1: mt protein like BCL2 - absence leads to mt-dependent apoptosis
AR: Kostmann syndrome
WASP - Wiskott-Aldrich syndrome protein - regulates actin polymerization in hematopoietic cells –> small platelets in low numbers, sinopulmonary infections, eczema
-X linked: thrombocytopenia and neutropenia
Glucose-6-phosphatase catalytic subunit 3 (G6PC3) mutation: homozygous loss –> activation of unfolded protein response, increased apoptosis in neutrophil precursors
Tx: G-CSF allows children to survive; predisposes to myelodysplasia and acute leukemia (MDS/AML) - 2%/yr, 30% over 10 yrs
- higher transformation in refractory or high doses
- acquired mutation of G-CSF receptor:
- —block ligand binding = G-CSF resistant SCN
- — missense mutation- hypersensitivity –> deletion of distal intracellular domain of receptor responsible for differentiation signaling –> proliferation of progenitors at expense of maturation
Cyclic Neutropenia
less than 200/uL lasting 3-5 days in 21 day intervals
Recurrent fevers, mouth sores, infections of skin, upper respiratory tract, ears
Congenital: Mutations in neutrophil elastase in all cases
Dx: sequence neutrophil elastase gene
Tx: G-CSF, no increased risk of leukemic transformation
Acquired in adulthood (rare) - assoc. w/ systemic dz - large granular lymphocytosis or T cell lymphoma
Shwachman-Diamond syndrome
isolated neutropenia progresses to marrow failure
associated with pancreatic dysfunction and skeletal abnormalities
Shwachman-Bodian-Diamond syndrome gene (SBDS) - regulates rRNA
Increased risk for leukemic tranformation
Fanconia anemia
mutations in DNA repair genes - more time for marrow failure to develop (median age 7 yo)
Short stature, upper limb anomalies, cafe au last spots
1/3 no physical abnormalities
Screen:
- chromosomal fragility testing following exposure to diepoxybutane or mitomycin C
- direct assessment for Fanconi gene mutations
Cure: stem cell transplant - high risk for M&M
Dyskeratosis congenita (DKC)
nail dystrophy, leukoplakia, skin pigmentation abnormalities
assoc. w/ neutropenia or aplastic anemia or both
AD or AR or X linked
mutations in telomere maintenance –> pulmonary fibrosis, hepatic cirrhosis, bone marrow failure
Presents in 2nd decade of life
Glycogen storage disease Ib
AR
intermittent neutropenia d/t defects in neutrophil respiratory burst with subsequent apoptosis of circulating neutrophils
Hepatomegaly and metabolic crises
mutations in glucose-6-phosphatase translocase
Myelokathexis
retention of mature neutrophils in marrow despite low peripheral count
Infection: sudden rise in neutrophil count = benign clinical course
WHIM syndrome: warts, hypogammaglobinemia, immunodeficiency, myelokathexis
Chediak-Higashi syndrome
mutations in lysosomal trafficking regulator gene (LYST)
oculocutaneous albinism, bleeding, progressive neurologic dz, increased susceptibility to hemophagocytic syndrome
Griscelli syndrome II
increased susceptibility to hemophagocytic syndrome
albinism, periodic neutropenia
mutations in guanosine triphosphatase RAB27A - release of myeloperoxidase from primary granules of neutrophils
Hermanski-Pudlack syndrome II
mutations in AP3B1 gene
vesicular trafficking, including trafficking of neutrophil elastase
albinism, platelet abnormalities, pulmonary fibrosis
Barth syndrome
X linked, AR
Neutropenia, cardiomyopathy, growth retardation
High mortality rate in early childhood - heart dz
TAZ gene mutation - tafazzin protein: critical to remodeling cardiolipin in mt membrane
Infection-related neutropenia
Viral infections - transient neutropenia, resolves as viremia abates
-varicella, measles, rubella, HAV, HBV, EBV, influenza, parvovirus, CMV
Redistribution, decreased production, immune destruction of neutrophils
HIV, AIDS - multifactoral leukopenia, neutropenia
splenomegaly with increased sequestration
More commonly: immune-mediated destruction
bacteria causing moderate neutropenia: M. tuberculosis, ehrlichiosis, rickettsia, tularemia, brucellosis, staph
Overwhelming sepsis - consumption of marrow neutrophil reserve - newborns and elderly
Increased margination during sepsis due to systemic activation of compliment - exacerbating neutropenia
Drug-induced neutropenia
Most common cause of neutropenia
suppression of marrow granulopoiesis, increased destruction or clearance of peripheral neutrophils
Dose dependent - predictable, mild
Idiosyncratic immune mediated destruction - profound agranulocytosis
Typical pattern: 1-2 weeks of exposure - neutrophil count decline, recovery begins within 1-2 days of stopping drug
Atypical: present long after drug initiation or longer interval before recovery
Acute sepsis - significant risk for acute mortality
Recovery - preceded by appearance of monocytes and immature neutrophil forms
-more hyper cellular marrow is at dx, earlier recovery
Drugs: antineoplastic, antiviral, immunosuppressive agents, clozapine, carbimazole, methimazole, propylthiouracil, quinidine, procainamide, sulfasalazine, Levamisole (cocaine-assoc neutropenia)
Speed recovery with G-CSF
neutropenia due to marrow injury
Radiation - acute or chronic marrow failure state
High dose - risk for myelodysplasia and leukemia, which cause marrow failure and marrow fibrosis –> cytopenias
Metastatic carcinoma to bone –> marrow failure, marrow replaced by metastatic cells
Primary autoimmune neutropenia
children younger than 4, median onset 6-12 mo
infectious risk increased
-Prophylactic abx; G-CSF only for acute infectious episodes
95% spontaneous remissions within 2 years
Antineutrophil Ab against FcyIIIb - mediate destruction by sequestration in spleen or complement mediated lysis
Secondary autoimmune neutropenia
Adults
assoc w/ hyperthyroidism, Wegener granulomatosis, RA, SLE
50% SLE have antineutrophil Ab but may have normal neutrophil counts
Felty syndrome and large granular lymphocyte syndrome
Felty: long standing RA, splenomegaly, profound neutropenia; polyclonal
Large granular lymphocyte syndrome: RA or isolated; monoclonal
Both:
proliferation of large granular lymphocytes
CD3+, CD8+, CD16+, CD57+
90% of RA have HLA-DR4+
Immune mediated neutrophil destruction - antineutrophil Ab and cell mediated destruction
Some have G-CSF resistance d/t G-CSF Ab
Isoimmune neonatal neutropenia
moderate to severe neutropenia
Newborn - transplacental passage of maternal IgG against alleles inherited from father –> neutropenia similar to Rh hemolytic dz
Pure white cell aplasia
rare
assoc w/ severe pyogenic infections, thymoma in 2/3
Following Ibu tx
complete absence of myeloid precursors
Removal of thymoma may not cause remission
Adjuvant tx: cyclophosphamide, corticosteroids, cyclosporine, IV Ig
Neutropenia d/t increased margination and hypersplenism
compliment activation –> acute and chronic neutropenia
-increased margination of circulating pool
C5a makes neutrophils more adherent - prone to aggression within pulmonary vasculature
Seen in burn and transfusion reaction patients
Neutrophil destruction in paroxysmal nocturnal hemoglobinuria
Hypersplenism - less common, less pronounced than the anemia and thrombocytopenia associated with enlarged spleen
B12, folate, copper deficiencies
Copper deficiency: total parenteral nutrition w/o Cu supplement, protein-losing enteropathies, celiac dz, gastric bypass surgery, postgastrectomy, malabsorption syndromes, zinc toxicity
Low serum Cu and ceruloplasm levels
Hypo granularity and hypolobation (PHA) on smear
Cytoplasmic vacuolization of myeloid and erythroid precursors and ringed sideroblasts
All these deficiencies: ineffective myelopoiesis, maturation arrest, megaloblastic changes with nuclear cytoplasmic dyssynchrony
-megaloblastic anemia, hyper segmentation of neutrophils
Chronic idiopathic neutropenia
Adults - acquired disorder of granulopoiesis
prolonged neutropenia in absence of any underlying etiology
incidental finding
heterogenous, wide range of counts
ANC below 200 - generally benign
When very low - tx with G-CSF when develop fever
Recurrent infections or aphthous ulcers require chronic G-CSF tx
Respond to low doses of G-CSF, no increase in MDS/AML development
Greek predisposed: increased TGF-b suppresses granulopoiesis; mild neutropenia, ANC rarely less than 800
Diagnostic approach to neutropenia
Fever, localizing signs:
Yes: If ANC less than 500/mL - admit for IV abx, consider G-CSF
No: stop potential drugs, look for toxins
If it is new: Isolated neutropenia: bone marrow exam -abnormal cytogenetics - myelodysplasia -LGL by flow - large granular lymphocyte syndrome - all normal - idiopathic neutropenia
Pancytopenia:
- check for autoimmune disease, if no bone marrow exam (see above)
- Vitamin levels - B12 low - megaloblastic anemia
Established neutropenia:
- Family history:
- —check ELANE mutation - if present: cyclic neutropenia
- —Appropriate ethnic group - constitutional or familial neutropenia
-No family history: If cyclic, check ELANE mutation
