Causes of Acquired aplastic anemia

• Definition of Acquired Aplastic Anemia
• Causes of Acquired aplastic anemia
• Symptoms of Acquired aplastic anemia
• Acquired aplastic anaemia treatment

Causes of Acquired aplastic anemia

lists the potential Causes of Acquired aplastic anemia.

The final common pathway to the clinical disease is a decrease in blood cell formation in the marrow. The number of marrow CD34+ cells (multipotential hematopoietic progenitors) and their derivative colony-forming unit–granulocyte-macrophage (CFU-GM) and burst-forming unit–erythroid (BFU–E) are reduced markedly in patients with aplastic anemia.^19–22 Long-term culture-initiating cells, an in vitro surrogate assay for hematopoietic stem cells, also are reduced to approximately 1 percent of normal values.²² Potential mechanisms responsible for acquired marrow cell failure include (1) direct toxicity to hematopoietic multipotential cells, (2) a defect in the stromal microenvironment of the marrow required for hematopoietic cell development, (3) impaired production or release of essential multilineage hematopoietic growth factors, (4) cellular or humoral immune suppression of the marrow multipotential cells, and (5) progressive erosion of chromosome telomeres. There is little experimental evidence for a stromal microenvironmental defect or a deficit of critical hematopoietic growth factors, and the role of telomerase mutations with consequent telomere shortening is unclear, although present in as much as 40 percent of patients.²³ Deficiencies in telomere repair could predispose to aplastic anemia by affecting the size of the multipotential hematopoietic cell compartment and by decreasing the multipotential cell’s response to a marrow injury, and could play a role in the evolution of aplastic anemia to a clonal myeloid disease by contributing to genome instability.²³ Thus, 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.²⁴ A small fraction of cases is initiated by a toxic exposure, drug exposure, or viral infection, but in these cases the pathogenesis also may relate to autoimmunity as there is evidence of immune dysfunction in seronegative hepatitis, after benzene exposure, and many such patients respond to anti–T-cell therapy.

Drugs that cause of Acquired aplastic anemia

Chloramphenicol is the most notorious drug documented to cause aplastic anemia. Although this drug is directly myelosuppressive at very high dose because of its effect on mitochondrial DNA, the occurrence of aplastic anemia appears to be idiosyncratic, perhaps related to an inherited sensitivity to the nitroso-containing toxic intermediates.³⁷ This sensitivity may produce immunologic marrow suppression, as a substantial proportion of affected patients respond to treatment with immunosuppressive therapy.³⁸ The risk of developing aplastic anemia in patients treated with chloramphenicol is approximately 1 in 20,000, or 25 times that of the general population.³⁹ Although its use as an antibiotic has been largely abandoned in industrialized countries, global reports of fatal aplastic anemia continue to appear with topical or systemic use of the drug.

Epidemiologic evidence established that quinacrine (Atabrine) increased the risk of aplastic anemia.⁴⁰ This drug was administered to all U.S. troops in the South Pacific and Asiatic theaters of operations as prophylaxis for malaria during 1943 and 1944. The incidence of aplastic anemia was 7 to 28 cases per 1,000,000 personnel per year in the prophylaxis zones, whereas untreated soldiers had 1 to 2 cases per 1,000,000 personnel per year. The aplasia occurred during administration of the offending agent and was preceded by a characteristic rash in nearly half the cases. Many other drugs have been reported to increase the risk of aplastic anemia, but owing to incomplete reporting of information and the infrequency of the association, the spectrum of drug-induced aplastic anemia may not be fully appreciated. Table 34–3 is a partial list of drugs that have been implicated.^41–51

Table 34–3. Drugs Associated with Aplastic Anemia

Category High Risk Intermediate Risk Low Risk Analgesic Phenacetin, aspirin, salicylamide Antiarrhythmic Quinidine, tocainide Antiarthritic Gold salts Colchicine Anticonvulsant Carbamazepine, hydantoins, felbamate Ethosuximide, phenacemide, primidone, trimethadione, sodium valproate Antihistamine Chlorpheniramine, pyrilamine, tripelennamine Antihypertensive Captopril, methyldopa Antiinflammatory Penicillamine, phenylbutazone, oxyphenbutazone Diclofenac, ibuprofen, indomethacin, naproxen, sulindac Antimicrobial   Antibacterial Chloramphenicol Dapsone, methicillin, penicillin, streptomycin, -lactam antibiotics   Antifungal Amphotericin, flucytosine   Antiprotozoal Quinacrine Chloroquine, mepacrine, pyrimethamine Antineoplastic drugs   Alkylating agent Busulfan, cyclophosphamide, melphalan, nitrogen mustard   Antimetabolite Fluorouracil, mercaptopurine, methotrexate   Cytotoxic antibiotic Daunorubicin, doxorubicin, mitoxantrone Antiplatelet Ticlopidine Antithyroid Carbimazole, methimazole, methylthiouracil, potassium perchlorate, propylthiouracil, sodium thiocyanate Sedative and tranquilizer Chlordiazepoxide, chlorpromazine (and other phenothiazines), lithium, meprobamate, methyprylon Sulfa derivative Sulfonamides   Antibacterial Numerous sulfonamides   Diuretic Acetazolamide Chlorothiazide, furosemide   Hypoglycemic Chlorpropamide, tolbutamide Miscellaneous Allopurinol, interferon, pentoxifylline, penicillamine

NOTE: Drugs that invariably cause marrow aplasia with high doses are termed high risk; drugs with 30 or more reported cases are listed as moderate risk; others are less often associated with aplastic anemia (low risk).

Many of these drugs are known to also induce selective cytopenias, such as agranulocytosis, which usually are reversible after discontinuation of the offending agent. These reversible reactions are not correlated with the risk of aplastic anemia, casting doubt on the effectiveness of routine monitoring of blood counts as a strategy to avoid aplastic anemia.

Because aplastic anemia is a rare event with drug use, it may occur because of an underlying metabolic or immunologic predisposition (gene polymorphism) in susceptible individuals. In the case of phenylbutazone-associated marrow aplasia, there is delayed oxidation and clearance of a related compound, acetanilide, as compared to either normal controls or those with aplastic anemia from other causes. This finding suggests excess accumulation of the drug as a potential mechanism for the aplasia. In some cases, drug interactions or synergy may be required to induce marrow aplasia. Cimetidine, 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.⁵² This drug accentuates the marrow-suppressive effects of the chemotherapy drug carmustine.⁵³ In several instances, it has been reported as a possible cause of marrow aplasia when given with chloramphenicol.

There appears to be little difference in the age distribution, gender, response to immunotherapy, marrow transplantation, or survival whether or not a drug exposure preceded the onset of the marrow aplasia.

Toxic Chemicals Causes of Acquired aplastic anemia

Benzene was the first chemical linked Causes of Acquired aplastic anemia , based on studies in factory workers before the 20th century.^54–59 Benzene is used as a solvent and is employed in the manufacture of chemicals, drugs, dyes, and explosives. It has been a vital chemical in the manufacture of rubber and leather goods and has been used widely in the shoe industry, leading to an increased risk for aplastic anemia (and acute myelogenous leukemia) in workers exposed to a poorly regulated environment.⁵⁶ In studies in China, aplastic anemia among workers was sixfold higher than in the general population.

The U.S. Occupational Safety and Health Administration has lowered the permissible atmospheric exposure limit of benzene to 1 part per million (ppm). Previous to that regulatory change, the frequency of aplastic anemia in workers exposed to greater than 100 ppm benzene was approximately 1 in 100 workers, which decreased to 1 in 1000 workers at 10 to 20 ppm exposure.

Organochlorine and organophosphate pesticide compounds have been suspected in the onset of aplastic anemia^57,58 and several studies have indicated an increased relative risk, especially for agricultural exposures^11,16,59,60 and household^11,60 exposures. These relationships are suspect because dose–disease relationships and other important factors have not been delineated, and several studies have not found an association with environmental exposures.^12,61 DDT (dichlorodiphenyltrichloroethane), lindane, and chlordane are insecticides that have also been associated with cases of aplastic anemia.^16,58 Occasional cases still occur following heavy exposure at industrial plants or after its use as a pesticide.⁶² Lindane is metabolized in part to pentachlorophenol (PCP), another potentially toxic chlorinated hydrocarbon that is manufactured for use as a wood preservative. Many cases of aplastic anemia and related blood disorders have been attributed to PCP over the past 25 years.^58,63 Prolonged exposures to petroleum distillates in the form of Stoddard solvent⁶⁴ and acute exposure to toluene through the practice of glue sniffing^65,66 also have been reported to cause marrow aplasia. Trinitrotoluene (TNT), an explosive used extensively during World Wars I and II, is absorbed readily by inhalation and through the skin.⁶⁷ Fatal cases of aplastic anemia were observed in munitions workers exposed to TNT in Great Britain⁶⁸ from 1940 to 1946. In most cases, these conclusions have not been derived from specific studies but from accumulation of case reports or from patient histories, making conclusions provisional, although the argument for minimizing exposures to potential toxins is logical in any case.Non-A, -B, -C, -D, -E, -G Hepatitis Virus

A relationship between hepatitis and the subsequent development of aplastic anemia has been the subject of a number of case reports, and this association was emphasized by two major reviews in the 1970s.^69,70 In the aggregate, these reports summarized findings in more than 200 cases. In many instances, the hepatitis was improving or had resolved when the aplastic anemia was noted 4 to 12 weeks later. Approximately 10 percent of cases occurred more than 1 year after the initial diagnosis of hepatitis. Most patients were young (ages 18 to 20 years); two-thirds were male, and their survival was short (10 weeks). Although hepatitis A and B have been implicated in aplastic anemia in a small number of cases, most cases are related to non-A, non-B, non-C hepatitis.^71–73 Severe aplastic anemia developed in 9 of 31 patients who underwent liver transplantation for non-A, non-B, non-C hepatitis, but in none of 1463 patients transplanted for other indications.⁷⁵ Several lines of evidence indicate there is no causal association with hepatitis C virus, suggesting that an unknown viral agent is involved.^16,75,76 Hepatitis virus B or C can be a secondary infection, if carefully screened blood products are not used for transfusion. In 15 patients with posthepatitic aplastic anemia, no evidence was found for hepatitis A, B, C, D, E, or G, transfusion-transmitted virus, or parvovirus B19.⁷⁶ Several reports suggest a relationship of parvovirus B19 to aplastic anemia,^77,78 whereas others have not.⁷⁹ This relationship has not been established (see Chap. 35). The effect of seronegative hepatitis may be mediated through an autoimmune T-cell effect because of evidence of T-cell activation and cytokine elaboration.²⁴ These patients also have a similar response to combined immunotherapy as does idiopathic aplastic anemia (see “TREATMENT, Combination Immunotherapy”).

Epstein-Barr Virus Causes of Acquired aplastic anemia

Epstein-Barr virus (EBV) has been implicated in the pathogenesis of aplastic anemia.^80,81 The onset usually occurs within 4 to 6 weeks of infection. In some cases, infectious mononucleosis is subclinical, with a finding of reactive lymphocytes in the blood film and serological results consistent with a recent infection (see Chap. 84). EBV has been detected in marrow cells, but it is uncertain whether marrow aplasia results from a direct effect or an immunologic response by the host. Patients have recovered following therapy with antithymocyte globulin.

Other Viruses Causes of Acquired aplastic anemia

Human immunodeficiency virus (HIV) infection frequently is associated Causes of Acquired aplastic anemia with varying degrees of cytopenia. The marrow is often cellular, but occasional cases of aplastic anemia have been noted.^82–84 In these patients, marrow hypoplasia may result from viral suppression and from the drugs used to control viral replication in this disorder. Human herpes virus (HHV)-6 has caused severe marrow aplasia subsequent to marrow transplantation for other disorders.

Autoimmune Diseases

The incidence of severe aplastic anemia was sevenfold greater than expected in patients with rheumatoid arthritis.⁴⁷ It is uncertain whether the aplastic anemia is related directly to rheumatoid arthritis or to the various drugs used to treat the condition (gold salts, D-penicillamine, and nonsteroidal antiinflammatory agents). Occasional cases of aplastic anemia are seen in conjunction with systemic lupus erythematosus.⁸⁶ In vitro studies found either the presence of an antibody⁸⁷ or suppressor cell^88,89 directed against hematopoietic progenitor cells. Patients have recovered after plasmapheresis,⁸⁷ glucocorticoids,⁸⁹ or cyclophosphamide therapy,^88,90 which is compatible with an immune etiology.

Eosinophilic fasciitis, an uncommon connective tissue disorder with painful swelling and induration of the skin and subcutaneous tissue, has been associated with aplastic anemia.^91,92 Although it may be antibody-mediated in some cases, it has been largely unresponsive to therapy.⁹¹ Nevertheless, (1) stem cell transplantation, (2) immunosuppressive therapy using cyclosporine,⁹¹ (3) immunosuppressive therapy using antithymocyte globulin (ATG), or (4) immunosuppressive therapy with ATG and cyclosporine cures or significantly ameliorates the disease in a few patients.⁹²

Severe aplastic anemia also has been reported coincident with immune thyroid disease (Graves disease)^93–97 and the aplasia has been reversed with treatment of the hyperthyroidism. Aplastic anemia has occurred in association with thymoma.^98–103 Autoimmune renal disease and aplastic anemia have occurred concurrently. The underlying relationship may be the role of cytotoxic T lymphocytes in the pathogenesis of several autoimmune diseases and in aplastic anemia.¹⁰⁴

Pregnancy

There are a number of reports of pregnancy-associated aplastic anemia, but the relationship between the two conditions is not always clear.^105–110 In some patients, preexisting aplastic anemia is exacerbated with pregnancy, only to improve following termination of the pregnancy.^105,106 In other cases, the aplasia develops during pregnancy with recurrences during subsequent pregnancies.^106,107 Termination of pregnancy or delivery may improve the marrow function, but the disease may progress to a fatal outcome even after delivery.^105–107 Therapy may include elective termination of early pregnancy, supportive care, immunosuppressive therapy, or marrow transplantation after delivery. Pregnancy in women previously treated with immunosuppression for aplastic anemia can result in the birth of a normal newborn.¹¹⁰ In this latter study of 36 pregnancies, 22 were uncomplicated, 7 were complicated by a relapse of the marrow aplasia, and 5 without marrow aplasia required red cell transfusion during delivery.¹¹⁰ One death occurred from cerebral thrombosis in a patient with paroxysmal nocturnal hemoglobinuria (PNH) and marrow aplasia.

Iatrogenic Causes of Acquired aplastic anemia

Although marrow toxicity from cytotoxic chemotherapy or radiation produces direct damage to stem cells and more mature cells, resulting in marrow aplasia, most patients with acquired aplastic anemia cannot relate an exposure that would be responsible for marrow damage.

Chronic exposure to low doses of radiation or use of spinal radiation for ankylosing spondylitis is associated with an increased, but delayed, risk of developing aplastic anemia and acute leukemia.^111,112 Patients who were given thorium dioxide (Thorotrast) as an intravenous contrast medium suffered numerous late complications, including malignant liver tumors, acute leukemia, and aplastic anemia.¹¹³ Chronic radium poisoning with osteitis of the jaw, osteogenic sarcoma, and aplastic anemia was seen in workers who painted watch dials with luminous paint when they moistened the brushes orally.¹¹⁴

Acute exposures to large doses of radiation are associated with the development of marrow aplasia and a gastrointestinal syndrome.^115,116 Total body exposure to between 1 and 2.5 Gy leads to gastrointestinal symptoms and depression of leukocyte counts, but most patients recover. A dose of 4.5 Gy leads to death in half the individuals (LD₅₀) owing to marrow failure. Higher doses in the range of 10 Gy are universally fatal unless the patient receives extensive supportive care followed by marrow transplantation. Aplastic anemia associated with nuclear accidents was seen after the disaster that occurred at the Chernobyl nuclear power station in the Ukraine in 1986.¹¹⁷

Antineoplastic drugs such as alkylating agents, antimetabolites, and certain cytotoxic antibiotics have the potential for producing marrow aplasia. In general, this is transient, is an extension of their pharmacologic action, and resolves within several weeks of completing chemotherapy. Although unusual, severe marrow aplasia can follow use of the alkylating agent, busulfan, and may persist indefinitely. Patients may develop marrow aplasia 2 to 5 years after discontinuation of alkylating agent therapy. These cases often evolve into hypoplastic myelodysplastic syndromes.

Stromal Microenvironment and Growth Factors

Short-term clonal assays for marrow stromal cells have shown variable defects in stromal cell function. Serum levels of stem cell factor (SCF) have been either moderately low or normal in several studies of aplastic anemia.^118,119 Although SCF augments the growth of hematopoietic colonies from aplastic anemia patient’s marrows, its use in patients has not led to clinical remissions. Another early acting growth factor, FLT-3 ligand, is 30- to 100-fold elevated in the serum of patients with aplastic anemia.¹²⁰ Fibroblasts grown from patients with severe aplastic anemia have subnormal cytokine production. However, serum levels of granulocyte colony-stimulating factor,¹²¹ erythropoietin,¹²² and thrombopoietin (TPO)¹²³ are usually high. Synthesis of IL-1, an early stimulator of hematopoiesis, is decreased in mononuclear cells from patients with aplastic anemia.¹²⁴ Studies of the microenvironment have shown relatively normal stromal cell proliferation and growth factor production.¹²⁵ These findings, coupled with the limited response of patients with aplastic anemia to growth factors, suggest that cytokine deficiency is not the etiologic problem in most cases. The most compelling argument is that most patients transplanted for aplastic anemia are cured with allogeneic donor stem cells and autologous stroma.¹²⁶

A rare exception is the homozygous or mixed heterozygous mutation of the TPO receptor gene, MPL, which can cause amegakaryocytic thrombocytopenia that evolves, later, into aplastic anemia