Aplastic Anemia

Introduction

Aplastic anemia (AA) is a disease characterized by pancytopenia and hypocellular (or fatty) marrow. It is a rather rare disorder, with an annual incidence of about 2-6 per million population. In about 50% of these cases, the etiology is unknown (Idiopathic Aplastic Anemia). The second leading cause of AA is drug and chemical use. Based on the severity of disease, AA can be considered as a severe or moderate disease.

Severe AA

Blood criteria:

• Neutrophils <500/mm3,

• Platelets <20,000/mm3,

• Corrected reticulocytes <1%

Marrow criteria:

Severe hypocellularity (<25%)

Moderate cellularity (<50%) with less than 30% of hematopoietic cells.

Moderate AA

• Platelets <40,000/mm3

• Neutrophils <1,500/mm3 with hypocellular marrow biopsy.

If left untreated, 80-90% of patients with severe AA will die within a year. These patients die from infections (immunocompromised patients) or bleeding. The prognosis for patients with moderate AA is considerably better, although many patients will die of complications of pancytopenia or transfusion-related hemosiderosis. Prognostic systems have been developed and, in general, may be used to try to individualize treatment in particular patients.

Overall, age and level of granulocytopenia are the two most important prognostic determinants.

Table 1 : Causes of Pancytopenia in Childhood

• Artefact: clot in sample
• Genuine (by dominant mechanism)
• Destruction of mature elements
  • Infection, most commonly viral
  • Immune mediated
    • Infection
    • SLE
    • Complement - PNH
  • Marrow failure (stem cells, mature elements)
  • Infiltration
    • Leukemia
    • Other malignancies
    • Panhypoplasia
    • Myelosclerosis
    • Osteopetrosis
• Severe megaloblastosis

  • Sequestration
  • Hypersplenism (most common cause portal hypertension)
  • Mechanism obscure
• Organic acidemias

Blood Picture in Aplastic Anemia

Pancytopenia is usually severe (Hb to about 3 g/dl). In about 40% of cases, erythrocytes are macrocytic. Reticulocytes are usually decreased, but occasionally are inexplicably excessive for the anemia. HbF may be increased, especially in genetic types and those with macrocytosis, to about 15% of the total, with heterogeneous distribution.

As a result of diminution in the erythron, serum iron and transferrin saturation are increased; B12 and folate may be increased. Erythrocyte I (and in some cases) I antigen may be increased. Lymphocytes are normal to decrease. Platelet size is not increased (cf immune thrombocytopenias)

The first sign of recovery is a rise in reticulocyte count, followed by an increase in Hb, then neutrophils, with platelets slowest to recover; if at all.

Marrow Picture in Aplastic Anemia

Hypoplasia may be patchy, especially early in the disease. Marrow consists of little more fat, stromal cells, lymphocytes, and plasma cells; mast cells may be prominent. Because of diminution in the erythron, storage iron and sideroblasts may be increased; ring sideroblasts are not seen, except in rare specific syndromes e.g. Pearson's.

Recognized Causes of Aplastic Anemia

Drugs:

Drugs may cause predictable, dose-related, reversible marrow suppression, and unpredictable, dose-unrelated, idiosyncratic, usually irreversible damage. Drugs that can seriously damage marrow usually do so in unpredictable and devastating fashion and in only in minuscule proportion of those exposed. Susceptibility is presumably genetic. This effect usually does not occur until after the cessation of the drug - with chloramphenicol at least 6-10 weeks, and up to 12 months later.

Some drugs e.g. chloramphenicol, have both dose-related and idiosyncratic effects, rarely one following the other. Some (e.g. benzol) have a potential for causing leukemia, which usually does not occur until many years after exposure

Table 2: Dose-related effects of chloramphenicol

Table 3: Pediatric drugs and chemicals which may cause marrow aplasia

• Cytotoxics

  * Antibacterial: Chloramphenicol (more often oral than intravenous), Sulphonamides

  * Antimalarial: Mepacrine, Quinacrine, Chloroquine, Trimethoprim, Pyrimethamine

• Antihistamine: Cimetidine, Ranitidine, Chlorpheniramine

• Anticonvulsants: Phenytoin, Other hydantoins

• Tranquillizers: Promazine, Chlorpromazine, Carbamazepine

• Anti-inflammatory: Indomethacin, Diclofenac, Gold

• Antipurines: Azathioprine

• Anti-diabetic: Chlorpropamide, Tolbutamide

• Antithyroid: Propylthioracil, Methimazole

• Other drugs: Allopurinol, Quinidine, Acetazolamide, Penicillamine

• Solvents: Benzol, White spirit (benzene, naphtha and other synonyms), Carbon tetrachloride, Kerosene, Glue (sniffing), Model aeroplane dope, Hair dyes

• Insecticides: DDT, Lindane, Chlordane, Organophosphates

Infection

Viral infection

As with idiosyncratic reaction to drugs, hypoplasia occurs in only a minuscule proportion of those exposed. However, the viral infection is probably an under-diagnosed cause: EBV for example may be demonstrable in patients without the typical clinical features of infective mononucleosis and acyclovir may produce hematologic improvement when a virus etiology cannot be proven. The destructive effect of the virus may be due to direct action or an immune effect such as T-lymphocyte mediated suppression.

The best-known association is with viral hepatitis - usually non-A, -B, -C. Hypoplasia is usually severe, though preceding hepatitis may not be and manifests at a mean of 9-10 weeks after onset of hepatitis.

Hypoplasia occurs in isolated instances of infection with EBV, HIV, Varicella, CMV, dengue-type viruses, measles, mumps, and parvovirus. Hypoplasia is more likely if there is associated immunodeficiency either drug-induced or natural, eg. EBV in x-linked lymphoproliferative disorder. Although the effect of parvovirus is ordinarily restricted to the erythroid, panhypoplasia occasionally occur in apparently normal persons.

Transient hypoplasia may occur in rickettsial infection, e.g. Q fever and ehrlichiosis.

Genetic syndromes and panhypoplasia

Fanconi's syndrome

Diagnosis is most reliably made by quantitation of chromosomal breaks (cultured blood lymphocytes) induced by the DNA cross-linking agent, diepoxybutane (DEB, Auerbach et al 1989). Abnormal fragility appears to be specific for Fanconi's anemia and is detectable from birth and before the onset of cytopenias. A scoring system for diagnosis, using other characteristics, has been devised.

Approximately 7% of patients do not have malformations. The DEB procedure is therefore recommended for all cases of panhypoplasia, whether associated with malformations or not. The DEB procedure does not reliably detect the carrier state (autosomal recessive). Sibs and parents may share some of the somatic anomalies but do not have blood changes. Heterogeneity is in part explicable by the existence of at least 2 genes for the disorder (chromosome 9 and 20).

Blood abnormalities are rare before 18 months and may not manifest until about 20 years. The average age at onset of pancytopenia is about 6 and 1/2 years for boys and about 8 and 1/2 years for girls. Thrombocytopenia is usually the first sign and may be misdiagnosed as idiopathic if the association with somatic anomalies is not recognized; granulocytopenia and then anemia follow, evolving over months to years. Fetal features e.g. macrocytosis and increased HbF (heterogeneous distribution and I antigen are common, even before the onset of anemia.

Dyserythropoiesis is common, with megaloblastic, internuclear bridges, karyorrhexis, and defective hemoglobinization. In the pre-symptomatic period, the marrow may appear normal or show hyperplasia.

There is a risk (about 20%) of malignancy, especially AML-M4 and squamous cell carcinoma. Malignancy is occasionally the presenting feature.

Dyskeratosis congenita

Ectodermal dysplasia is characteristic - in skin, nails, and teeth and in the hair (loss or premature graying); leukoplakia of squamous surfaces may produce stricture of hollow viscera (e.g. esophagus) and is a risk (about 10%) for malignancy. Growth retraction is common.

Table 4: Genetic syndromes and marrow panhypoplasia

• DNA repair detect: Fanconi, Dyskeratosis congenita

• Pancreas-marrow syndromes: Shwachman, Pearson, Atypical cystic fibrosis

• Others: Defective cellular uptake of folate, Aplasia preceded by congenital amegakaryocytosis