36 Aplastic Anemia: Acquired and Inherited Flashcards
The diagnosis of Aplastic Anemia usually requires the presence of pancytopenia defined as:
Neutrophil count:
Platelet count:
Hemoglobin:
Absolute Reticulocyte count:
accompanied by a hypocellular marrow without abnormal or malignant cells or fibrosis
Neutrophil count: fewer than 1.5 × 109/L
Platelet count: fewer than 50 × 109/L
Hemoglobin: less than 100 g/L
Absolute Reticulocyte count: fewer than 40 × 109/L
Degree of Severity of Acquired Aplastic Anemia
Moderately severe:
Severe:
Very severe:
Moderately severe: Hgb <100 g/L ARC <40.0 × 109/L NC <1.5 × 109/L PC <50.0 × 109/L
Severe: Hgb <90 g/L ARC <30.0 × 109/L NC <0.5 × 109/L PC <30.0 × 109/L
Very severe: Hgb <80 g/L ARC <20.0 × 109/L NC <0.2 × 109/L PC <20.0 × 109/L
Moderately severe: At the time of diagnosis at least 2 of 3 blood counts should meet these criteria
The highest frequency of aplastic anemia occurs in persons between the ages of_______years; a second peak occurs between the ages of ________years.
15 and 25 years
65 and 69 years
The male-to-female incidence ratio of aplastic anemia in most studies is approximately
One
Toxins that cause AA
- Benzene
- Chlorinated hydrocarbons
- Organophosphates
Viruses that cause AA
- Epstein-Barr virus
- Non-A, -B, -C, -D, -E, or -G hepatitis virus
- HIV
Inherited Causes of AA
- Fanconi anemia
- Dyskeratosis congenita
- Shwachman-Diamond syndrome
- Other rare syndromes
The final common pathway to the clinical disease is
A decrease in blood cell formation in the marrow
Reduced hematopoiesis in most cases of aplastic anemia results from
Cytotoxic T-cell–mediated immune suppression of very early CD34+ hematopoietic multipotential progenitor or stem cells
A relationship between acquired aplastic anemia and hereditary aplastic anemia (FA or dyskeratosis congenita) has been suggested because of the defects in _______________________
Telomerase and telomere repair
The most notorious drug documented to cause aplastic anemia
Chloramphenicol
The occurrence of aplastic anemia appears to be idiosyncratic, perhaps related to an inherited sensitivity to the nitroso-containing toxic intermediates.
Anti-malarial with evidence that it cause AA
Quinacrine (Atabrine)
The aplasia occurred during administration of the offending agent and was preceded by a characteristic rash in nearly half the cases
Causes AA because there is delayed oxidation and clearance of a related compound, acetanilide
Phenylbutazone
A histamine H2-receptor antagonist, is occasionally implicated in the onset of cytopenias and aplastic anemia, perhaps owing to a direct effect on early hematopoietic progenitor cells
Cimetidine
There is drug interactions or synergy with: carmustine and chloramphenicol
Drugs Associated with Aplastic Anemia - High Risk
Antineoplastic drugs:
Alkylating agent
Antimetabolite
Cytotoxic antibiotic
Was the first chemical linked to aplastic anemia, based on studies in factory workers before the 20th century
Benzene
An uncommon connective tissue disorder with painful swelling and induration of the skin and subcutaneous tissue, has been associated with aplastic anemia
Has been largely unresponsive to therapy
Eosinophilic fasciitis
Total-body exposure to radiation between _______Gy leads to gastrointestinal symptoms and depression of leukocyte counts, but most patients recover.
1 and 2.5 Gy
Although unusual, severe marrow aplasia can follow use of the alkylating agent,________, and may persist indefinitely.
Busulfan
Marrow aplasia may develop in patients 2–5 years after discontinuation of alkylating agent therapy.
These cases often evolve into hypoplastic myelodysplastic syndromes.
A rare exception to the negligible pathogenetic role of hematopoietic growth factors in the etiology of aplastic anemia is the homozygous or mixed heterozygous mutation of the TPO receptor gene, MPL, which can cause
Amegakaryocytic thrombocytopenia
Evolves later into aplastic anemia
Eltrombopag, a TPO receptor agonist, can stimulate mono- or, in some patients, bilineage or trilineage recovery of blood counts that may be sustained off therapy
TRUE OR FALSE
Lymphadenopathy and splenomegaly are not features of aplastic anemia; such findings suggest an alternative diagnosis such as a clonal myeloid or lymphoid disease.
TRUE
Lymphadenopathy and splenomegaly are not features of aplastic anemia; such findings suggest an alternative diagnosis such as a clonal myeloid or lymphoid disease.
TRUE OR FALSE
Significant qualitative changes of red cell, leukocyte, or platelet morphology on the blood film are features of classical acquired aplastic anemia.
FALSE
Significant qualitative changes of red cell, leukocyte, or platelet morphology on the blood film are not features of classical acquired aplastic anemia.
TRUE OR FALSE
The plasma contains high levels of hematopoietic growth factors, including EPO, TPO, and myeloid colony-stimulating factors.
TRUE
The plasma contains high levels of hematopoietic growth factors, including EPO, TPO, and myeloid colony-stimulating factors.
Other findings:
* Macrocytes may be present in the blood film and the mean cell volume increased.
* Platelets function normally.
* Occasionally only one cell line is depressed initially
TRUE OR FALSE
Plasma iron values are usually high, and Fe clearance is prolonged, with decreased incorporation into red cells.
TRUE
Plasma iron values are usually high, and Fe clearance is prolonged, with decreased incorporation into red cells.
Marrow Findings in Aplastic anemia
Numerous spicules with empty, fat-filled spaces, and relatively few hematopoietic cells
Refers to spicules that are cellular or even hypercellular
“hot spots”
These focal areas of residual hematopoiesis do not appear to be of prognostic significance.
Cytogenetic analysis in aplastic anemia is
Normal
Clonal cytogenetic abnormalities in otherwise apparent aplastic anemia is indicative of an underlying hypoplastic clonal myeloid disease.
Imaging that can be used to distinguish between marrow fat and hematopoietic cells
Magnetic resonance imaging
Magnetic resonance imaging studies of bone may be useful in differentiating severe aplastic anemia from clonal myeloid syndromes. The former gives a fatty signal and the latter a diffuse cellular pattern.
A reticulocyte percentage of less than ______% is strongly indicative of aplastic erythropoiesis and, when coupled with leukopenia and thrombocytopenia, points to aplastic anemia.
0.5%
As many as_____ of patients with otherwise typical aplastic anemia have evidence of glycosylphosphatidylinositol molecule defects and diminished phosphatidylinositol-anchored protein on leukocytes and red cells as judged by flow cytometry, analogous to that seen in PNH.
50%
As many as____% of patients with aplastic anemia have a five-year probability of myelodysplasia developing.
20%
Mutations that are increased in prevelance with patient age
ASXL1 and DNMT3A
Mutations that were of similar frequency in all age groups
BCOR, BCORL1, and PIGA
Three principal options: for treatment in AA
(1) syngeneic or allogeneic hematopoietic cell transplantation
(2) combination immunosuppressive therapy with ATG and cyclosporine, and
(3) eltrombopag
TRUE OR FALSE
In general, transplantation is the preferred treatment for children and most otherwise healthy younger adults.
TRUE
In general, transplantation is the preferred treatment for children and most otherwise healthy younger adults.
The preferred stem cell source
A histocompatible sibling matched at the HLA-A, -B, -C, and -DR loci
An allele-level HLA-matched unrelated donor can be used in younger patients
TRUE OR FALSE
Red cell and platelet transfusions be used sparingly in potential transplant recipients to minimize sensitization to histocompatibility antigen
TRUE
Red cell and platelet transfusions be used sparingly in potential transplant recipients to minimize sensitization to histocompatibility antigen
Packed red cells to alleviate symptoms of anemia usually are indicated at hemoglobin values:
Below 80 g/L
TRUE OR FALSE
It is important to transfuse patients with red cells (or platelets) from family members if transplantation within the family is possible
FALSE
It is important not to transfuse patients with red cells (or platelets) from family members if transplantation within the family is remotely possible
Because this approach may sensitize patients to minor histocompatibility antigens, increasing the risk of graft rejection after hematopoietic cell transplantation.
Preferred platelet unit for previously pregnant or transfused patients who are already allosensitized or who become so after treatment with leukoreduced platelets
Single-donor HLA-matched apheresis-harvested platelets
The major curative approach in AA
Hematopoietic Cell Transplantation
The results of transplantation are best in patients younger than age 20 years (80%–90% long-term survival) but decrease every decade of increasing age thereafter.
Optimal with HLA-matched sibling transplantation.
TRUE OR FALSE
Marrow stem cells perform better than blood stem cells when used as a source for patients with aplastic anemia, although this is under continued study.
TRUE
Marrow stem cells perform better than blood stem cells when used as a source for patients with aplastic anemia, although this is under continued study.
In patients older than age 40 years, survival in matched-sibling transplant is reduced to approximately________%.
50%
Regimen that appear to improve outcome by decreasing the frequency of chronic graft-versus-host disease, which could make it useful in treating older patients.
Alemtuzumab-containing regimens
If there is an HLA mismatch at one or more loci, especially _____or ____, the outcome is compromised,and immunosuppression with combined therapy may be preferred initially
HLA-A or -DRB1
Act principally by reducing cytotoxic T cells
Release hematopoietic growth factors from T cells
Antilymphocyte and Antithymocyte Globulin
TRUE OR FALSE
Rabit ATG is superior to equine and, if available, is recommended as the first line of therapy
FALSE
Equine ATG is superior to rabbit and, if available, is recommended as the first line of therapy
TRUE OR FALSE
ATG treatment may accelerate platelet destruction, reduce the absolute neutrophil count, and cause a positive direct antiglobulin (Coombs’) test.
TRUE
ATG treatment may accelerate platelet destruction, reduce the absolute neutrophil count, and cause a positive direct antiglobulin (Coombs’) test.
Characterized by spiking fevers, skin rashes, and arthralgia, commonly occurs 7–10 days from the first dose
Serum sickness
Management of Serum sickness
- Glucocorticoid (eg, prednisone 1 mg/kg) from day one of ATG treatment and for two weeks thereafter
- Fever, rigors, rash, hypotention, and hypoxia can be minimized by administration of acetaminophen and diphenhydramine before each dose of ATG.
- Supplementation with intravenous hydration for hypotension and oxygen administration for hypoxia.
- In cases of severe reactions, the administration of ATG can be slowed or temporarily discontinued until improvement occurs, and then reinstituted at a slower rate of infusion if necessary.
Approximately _______of patients no longer require transfusion support after treatment with ATG alone.
One-third
A cyclic polypeptide that inhibits IL-2 production by T lymphocytes and prevents expansion of cytotoxic T cells in response to IL-2
Cyclosporine
Initial dose of Cyclosporine
10–12 mg/kg per day for at least 6 months and with downward dose modification after six months for as long as 12 months.
Responses usually are seen by three months and may range from achieving transfusion independence to complete remission
Trough blood levels of Cyclosporine
200–400 ng/mL
A TPO receptor agonist used to stimulate platelet production in patients with immune thrombocytopenia
May expand stem cell numbers and promote DNA repair
Eltrombopag
Multilineage hematopoietic response occurred, leading to restoration of granulopoiesis, erythropoiesis, and megakaryocytopoiesis with a subsequent increase in neutrophil, erythrocyte, and platelet counts, sometimes to normal levels
MPL receptors are present on hematopoietic stem cells
A higher dose of eltrombopag (150 mg/day) and longer treatment (at least 24 weeks) increases the likelihood of response
Combination Immunotherapy
- ATG (40 mg/kg per day) for 4 day
- Cyclosporine (6 mg/kg per day in divided doses every 12 hours) for 6 months
- Methylprednisolone (1 mg/kg per day) for 2 weeks
- Eltrombopag is given at 150 mg from day 1 for 6 months
TRUE OR FALSE
G-CSF added to the combined immunosuppressive therapy does not increase response rate or survival.
TRUE
G-CSF added to the combined immunosuppressive therapy does not increase response rate or survival.
A monoclonal anti-CD52 antibody that targets that antigen on T lymphocytes, has been an effective immunosuppressive agent in both relapsed and refractory patients
Alemtuzumab
An alternative thrombopoietin receptor agonist that is a larger molecule than eltrombopag and requires parenteral administration
It binds to the thrombopoietin receptor site, cMPL
Romiplostim
Alemtuzumab produces profound and persistent___________.
Lymphopenia
Stimulate the production of EPO, and their metabolites stimulate erythropoiesis when added to marrow cultures in vitro.
May be useful in the treatment of aplastic anemia syndromes resulting from shortened telomeres.
Androgens
Therapy with myeloid growth factors is probably best reserved for
Episodes of severe infection
As a preventive measure before dental work or other procedures that would compromise mucosal barriers in patients who have not responded to hematopoietic cell transplant or immunotherapy
- Generally, prophylactic use of growth factors is not warranted.
TRUE OR FALSE
Prophylactic use of growth factors is warranted.
FALSE
Prophylactic use of growth factors is not warranted.
The most important prognostic feature
Absolute neutrophil count
Hematopoietic cell transplantation is curative for approximately:
Patients younger than 20 years of age:
Between the ages of 20 and 40 years:
Older than age 40 years:
Patients younger than 20 years of age: 80%–90%
Between the ages of 20 and 40 years: 70%
Older than age 40 years 50%
The best outcomes occur in patients who have:
- Allele-based HLA-matched sibling
- Have not been exposed to immunosuppressive therapy before transplantation
- Have not been exposed and sensitized to blood cell products
- Have had a marrow rather than a blood stem cell donor product, and
- Have not been subjected to high-dose radiation in the conditioning regimen for transplantation
Predictive of a better response to therapy
- Higher initial absolute reticulocyte and lymphocyte counts
- High proportion of Treg B cells
AD Rare Inherited Syndromes Associated with Aplastic Anemia
- Ataxia-pancytopenia (myelocerebellar disorder)
- WT syndrome
The rest autosomal recessive
The most common form of constitutional aplastic anemia
The great majority of patients have mutations of FANCA, FANCC, or FANCG
Fanconi anemia (FA)
First step in understanding the genetic basis of FA
Diepoxybutane test
In this test, diepoxybutane results in chromosome fragmentation in the cells of patients with FA.
Hereditary cause of AA: pancreatic insufficiency, steatorrhea
Schwaman Diamond Syndrome
Approximately 5% of patients with FA exhibit the _____________ phenotype
VACTERL with hydrocephalus (VACTERL-H)
This requires having 3 of 8 features, including vertebral anomalies, anal atresia, congenital heart disease, tracheoesophageal fistula, esophageal atresia, renal abnormalities, limb abnormalities, and hydrocephalus
Hereditary cause of AA: nail dystrophy, mucosal leukoplakia
A predisposition to malignant transformation
The disease is a reflection of telomere complex dysfunction and results from defective telomerase activity resulting from mutations in the telomerase-related genes
Dyskeratosis congenita
Responsible for the X-linked recessive form of Dyskeratosis congenita
DKC1 gene
DKC1 encodes dyskerin, which is a conserved multifunctional protein component of the telomerase complex
Homozygous recessive mutations in the TERT gene produce a severe variant of dyskeratosis, referred to as the
Hoyeraal-Hreidarsson syndrome
Used to confirm Dyskeratosis congenita
Genetic analysis for telomerase complex gene mutations
TRUE OR FALSE
In Dyskeratosis congenita, transplantation might improve the cytopenias, but not the abnormalities of other organs or the frequency of secondary nonhematopoietic cancer.
TRUE
In Dyskeratosis congenita, transplantation might improve the cytopenias, but not the abnormalities of other organs or the frequency of secondary nonhematopoietic cancer.
The incidence of squamous cell carcinoma of mucosal sites is increased, and the squamous cell carcinoma often originates in sites of leukoplakia in the skin, gastrointestinal, or genitourinary tracts.
Manifests as exocrine pancreatic insufficiency with secondary steatorrhea, blood cell deficiencies, and skeletal abnormalities
Results from mutations in the SBDS gene on chromosome 7q11, which induces accelerated cellular apoptosis via the FAS pathway
Shwachman-Diamond syndrome
Shwachman-Diamond syndrome
Pancreatic insufficiency can be established by
Low serum trypsinogen
in patients younger than 3 years of age
Cytogenetic abnormalities involving chromosomes _________ have been described in marrow cells of patients with Shwachman-Diamond syndrome
Chromosomes 7 and 20
Have a significant risk of progression to a myelodysplastic syndrome or AML
Results from mutations in the TPO receptor gene, MPL
Congenital (hereditary) amegakaryocytic thrombocytopenia (CAMT)
- CAMT I with mutations leading to complete loss-of-function of the TPO receptor, resulting in more severe thrombocytopenia and a rapid progression to pancytopenia (aplastic anemia)
- CAMT II, resulting from a variety of missense mutations, in which affected children have an increase in platelet count above 50 × 109/L with time and much slower progression to and sometimes less severe pancytopenia
Hereditary cause of AA: cafe au lait spots, VACTERL phenotype
Fanconi anemia
Hereditary cause of AA: bilateral sensorineural deafness, agranulocytosis, SCID
Results from a pluripotential stem cell defect as both lymphoid and granulocytic progenitors are affected.
Reticular dysgenesis
Results from mutations in the ATR gene, and marrow cells exhibit heightened sister chromatid exchange
Seckel syndrome
TRUE OR FALSE
Inherited aplastic anemias can be treated by hematopoietic cell transplantation but, if successful, this step does not correct somatic abnormalities, only the hematopoietic and immunologic defect.
TRUE
Inherited aplastic anemias can be treated by hematopoietic cell transplantation but, if successful, this step does not correct somatic abnormalities, only the hematopoietic and immunologic defect.
