Hypoproliferative Disorders - Aplastic Anemia
• Aplastic anemia is one of a group of diseases characterized by decreased blood cell growth or production, called hypoproliferative diseases.
• Failure of two or more cell lines
• Anemia, leukopenia, thrombocytopenia + Hypoplasia, or aplasia of the marrow.
Pathology:
• Reduce the amount of hematopoietic tissue-unable to produce mature cells to discharge into the blood.
• Patchy areas of normo/hypercellularity between areas of hypocellularity.
Etiopathogenesis
The deficiency of hematopoietic stem cells may be due to:
1. Acquired injury from viruses, toxins, chemicals
2. Abnormal marrow microenvironment
3. Antibody or cytotoxic T cell-mediated hematopoietic inhibition
4. Gene mutations
• Due to the decrease in the number of pluripotent stem cells and the defects of the remaining cells
or
• The immune response to them prevents them from repopulating the bone marrow.
Pathophysiology
• Direct destruction of hemopoietic progenitors
• Disruption of marrow micro-environment
• Immune-mediated suppression of marrow elements
- Cytotoxic T cells in the blood and bone marrow release γIFN and TNF that lead to inhibition of early and late progenitor cells.
• Small proportion of acquired cases share pathophysiology with the inherited disease – shortened telomeres
Classification:
• Idiopathic
• Secondary:
- Idiosyncratic drug reaction
- Chemical exposure
- Infectious hepatitis
- Paroxysmal nocturnal hemoglobinuria
• Constitutional/ Congenital
Congenital syndromes associated with bone marrow failure.
• Pancytopenia :
1. Fanconi anemia
2. Dyskeratosis congenita
• Single lineage cytopenias:
1. Diamond-Blackfan syndrome
2. Amegakaryoctic thrombocytopenia
3. Thrombocytopenia absent radii
4. Shwachmann-Diamond syndrome
Fanconi Anemia
• Familial
• Autosomal recessive
• M: F=1.3:1
• Onset in the first decade of life (5-10 years)
• DNA repair capacity decreases, and random chromosomal breaks increase during mitosis.
C/F:
• Facies – microphthalmia, sunken nasal bridge, epicanthic fold, micrognathia
• Hyperpigmentation, café-au-lait spots
• Absent / hypoplastic thumb
• Skeletal and renal lesions
• Short stature,
• Microcephaly, subnormal intelligence (Mental Retardation in 10 %)
• Hypogonadism, anomalies of urinary tract
• High risk of transformation to acute myeloid leukemia, myelodysplasia, oral cancer, esophagus cancer, liver cancer.
• Poor prognosis.
Dyskeratosis Congenita
• X-linked, Autosomal recessive, Autosomal dominant
• M: F= 4.3:1
• Hyperpigmentation
• Nail dystrophy, the early loss of teeth
• Leukoplakia
• Ocular abnormalities: cataract
• Short stature but No skeletal/renal lesions
•May transform to skin SCC, myelodysplasia.
Diamond Blackfan Syndrome (DBA)
• Congenital pure red cell aplasia
• Autosomal dominant, Autosomal recessive, Sporadic
• Familial in 15 %
• 90% diagnosed in the first year of life
• Intrinsic defect in RBC, early apoptosis.
• Elevated fetal hemoglobin.
• Macrocytic anemia, reduced reticulocytes, lack of RBC precursors in the normocellular bone marrow.
• Eye – the presence of wide-set eyes, blue sclera, glaucoma, epicanthic fold, cataract, strabismus
• In some cases, cleft lip palate.
• Upper limb anomalies – flattening of the thenar eminence, Triphalangeal thumb.
• Risk of leukemia, myelodysplasia.
C/F:
• Profound anemia at 2-6 months of age
• Short stature
• Renal anomalies and hypogonadism may be present.
• Diagnostic Criteria:
- Age < 1yo
- Macrocytic anemia
- Reticulocytopenia
- Paucity of erythroid precursors in the marrow
• Supporting Criteria:
• Major Criteria
- Pathogenic mutations
- Positive family history
• Minor Criteria
- Elevated red cell ADA
- Congenital anomalies
- Elevated HbF
- No other bone marrow failure syndrome
• Classic DBA: all diagnostic criteria
• Non-classic DBA: various combinations
Amegakaryocytic Thrombocytopenia
• Autosomal recessive
• c-MPL gene mutations (thrombopoietin receptor) at 1p34
• Decreased bone marrow megakaryocytes
- Thrombocytopenia at birth
• Classically red cells macrocytic, increased HgbF.
- Normal platelet size and morphology
- Hemoglobin normal early
• High risk of MDS, AML
• Two phenotypes early (80%) vs late thrombocytopenia and aplasia, are related to specific mutation and c-MPL activity.
Thrombocytopenia Absent Radius Syndrome (TAR)
• Autosomal Recessive
Due to mutation of the RBM8A gene at 1q21.1 (RNA binding motif protein 8A)
- Typically, one allele carries a deletion of 1q21.1 and the other a mutation in the remaining allele
• Thrombocytopenia presenting at birth
• Bilateral absence of radii with the existence of thumbs (in FA the defect is terminal - thumbs are absent if the radii are absent; in TAR intercalary).
• Other cytopenias:
- Leukemoid reaction common >40,000/mm3
- Hypereosinophilia also
• Other congenital anomalies:
- Micrognathia, brachycephaly, hypertelorism
- Webbed neck, hypogonadism
- Various lower limb abnormalities 40%
- 10% congenital heart disease
Shwachman- Diamond Syndrome
• Autosomal recessive – male predominance (1.7:1)
• compound heterozygous mutations in SBDS
• Marrow failure + Pancreatic insufficiency and malabsorption.
• WBC: fluctuating neutropenia, impaired chemotaxis
• Anemia 1/3, thrombocytopenia 20%
• Aplasia in 10-25% à MDS/AML
Acquired aplastic anemia
Causes:
• Radiation
• Drugs and chemicals
- chemotherapy
- benzene
- chloramphenicol
- antiepileptics
• Viruses:
- CMV
- EBV
- Hep B, C, D
- HIV
• Immune diseases:
- eosinophilic fascitis
- thymoma
• Pregnancy
• PNH
• Marrow replacement:
- leukemia
- myelofibrosis
- myelodysplasia
Clinical features
- RBC (anemia)
• Progressive and persistent pallor
• Anemia related symptoms
- WBC (Leucopenia/neutropenia)
• Susceptible to infections - Pyodermas, OM, pneumonia, UTI, GI infections, sepsis.
- Platelets (Thrombocytopenia)
• Petechiae, purpura, ecchymoses
• Hematemesis, hematuria, epistaxis, gingival bleed
• IC bleed- headache, irritability, drowsiness, coma.
- No Hepatomegaly
- No Splenomegaly
- No Lymphadenopathy
- Failure of entire RES. No extramedullary hematopoiesis.
Blood picture:
• Anemia-normocytic, normochromic
• Leukopenia (neutropenia)
• Relative lymphocytosis
• Thrombocytopenia
• Absolute reticulocytes count low
• Mild to moderate anisopoikilocytosis
Other investigations
• Bone marrow examination: dry aspirate, trephine biopsy shows hypocellular with fat (>70% yellow marrow)
Severity
• 2 of 3 peripheral blood criteria:
- ANC < 500/ml
- Platelets < 20,000/ml
- Reticulocytes < 1% corrected (ARC < 40,000/ul)
• 1 of 2 bone marrow criteria:
- < 25% cellularity on biopsy
- 25 – 50% with less than 30% hematopoietic cells
• Very severe aplastic anemia
- ANC < 200/ml
Treatment
• Treatment of underlying cause –if possible
• Removal of the cause
• Supportive care
• Blood & platelet transfusion
• Infection: Broad-spectrum antibiotics
Hematopoietic growth factors
- Limited usefulness
Stem cell transplantation
- For fully histocompatible sibling donors, this is the best treatment for young patients.
- The long-term survival rate of children is about 90% for allotransplantation of perfectly matched siblings.
Immunosuppression:
• Since most patients lack a suitable donor, it is their preferred treatment.
• ATG + Cyclosporine induces hematologic recovery in ≈ 60 % of cases.
• Relapse is frequent, usually after the withdrawal of cyclosporine.
• 15% of patients may develop MDS.
• Glucocorticoids: in cong Pure Red Cell Aplasia
• Increasing age and the severity of neutropenia are the most important factors that determine the balance between transplantation and immunosuppression in adults with suitable family donors.
• Elderly patients use ATG and cyclosporin to treat, and if the neutropenia is severe, transplantation is the first choice
• Androgens
• Thymectomy: for Adult Pure Red Cell Aplasia
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