Aplastic anemia is pancytopenia with bone marrow hypocellularity. Acquired aplastic anemia is distinguished from iatrogenic aplasia, marrow hypocellularity after intensive cytotoxic chemotherapy for cancer. Aplastic anemia can also be constitutional: the genetic diseases Fanconi anemia and dyskeratosis congenita, although frequently associated with typical physical anomalies and the development of pancytopenia early in life, can also present as marrow failure in normal-appearing adults. Acquired aplastic anemia is often stereotypical in its manifestations, with the abrupt onset of low blood counts in a previously well young adult; seronegative hepatitis or a course of an incriminated medical drug may precede the onset. The diagnosis in these instances is uncomplicated. Sometimes blood count depression is moderate or incomplete, resulting in anemia, leukopenia, and thrombocytopenia in some combination. Aplastic anemia is related to both paroxysmal nocturnal hemoglobinuria (PNH; Chap. 33) and to MDS, and in some cases, a clear distinction among these disorders may not be possible.
The incidence of acquired aplastic anemia in Europe and Israel is two cases per million persons annually. In Thailand and China, rates of five to seven per million have been established. In general, men and women are affected with equal frequency, but the age distribution is biphasic, with the major peak in the teens and twenties and a second rise in older adults.
The origins of aplastic anemia have been inferred from several recurring clinical associations (Table 11-2); unfortunately, these relationships are not reliable in an individual patient and may not be etiologic. In addition, although most cases of aplastic anemia are idiopathic, little other than history separates these cases from those with a presumed etiology such as a drug exposure.
TABLE 11-2Classification of Aplastic Anemia and Single Cytopenias ||Download (.pdf) TABLE 11-2 Classification of Aplastic Anemia and Single Cytopenias
|Acquired ||Inherited |
|Aplastic Anemia |
|Secondary ||Fanconi anemia |
| Radiation ||Dyskeratosis congenita |
| Drugs and chemicals ||Shwachman-Diamond syndrome |
| Regular effects ||Reticular dysgenesis |
| Idiosyncratic reactions ||Amegakaryocytic thrombocytopenia |
| Viruses ||Familial aplastic anemias |
| Epstein-Barr virus (infectious mononucleosis) ||Preleukemia (monosomy 7, etc.) |
| Hepatitis (non-A, non-B, non-C hepatitis) ||Nonhematologic syndrome (Down, Dubowitz, Seckel) |
| Parvovirus B19 (transient aplastic crisis, PRCA) || |
| HIV-1 (AIDS) || |
| Immune diseases || |
| Eosinophilic fasciitis || |
| Hyperimmunoglobulinemia || |
| Large granular lymphocytosis (LGL) || |
| Thymoma/thymic carcinoma || |
| Graft-versus-host disease in immunodeficiency || |
| Paroxysmal nocturnal hemoglobinuria (PNH) || |
| Pregnancy || |
|Idiopathic || |
|PRCA (see Table 11-4) ||Congenital PRCA (Diamond-Blackfan anemia) |
|Neutropenia/agranulocytosis || |
| Idiopathic ||Kostmann syndrome |
| Drugs, toxins ||Shwachman-Diamond syndrome |
| LGL ||Reticular dysgenesis |
| Pure white cell aplasia (+/– thymoma) || |
|Thrombocytopenia || |
| Drugs, toxins ||Amegakaryocytic thrombocytopenia |
| Idiopathic amegakaryocytic ||Thrombocytopenia with absent radii |
Marrow aplasia is a major acute sequela of radiation. Radiation damages DNA; tissues dependent on active mitosis are particularly susceptible. Nuclear accidents involve not only power plant workers but also employees of hospitals, laboratories, and industry (food sterilization, metal radiography, etc.), as well as innocents exposed to stolen, misplaced, or misused sources. Whereas the radiation dose can be approximated from the rate and degree of decline in blood counts, dosimetry by reconstruction of the exposure can help to estimate the patient’s prognosis and also to protect medical personnel from contact with radioactive tissue and excreta. MDS and leukemia, but probably not aplastic anemia, are late effects of radiation.
Benzene is a notorious cause of bone marrow failure: epidemiologic, clinical, and laboratory data link benzene to aplastic anemia, acute leukemia, and blood and marrow abnormalities. For leukemia, incidence is correlated with cumulative exposure, but susceptibility must also be important, because only a minority of even heavily exposed workers develop myelotoxicity. The employment history is important, especially in industries where benzene is used for a secondary purpose, usually as a solvent. Benzene-related blood diseases have declined with regulation of industrial exposure. Although benzene is no longer generally available as a household solvent, exposure to its metabolites occurs in the normal diet and in the environment. The association between marrow failure and other chemicals is much less well substantiated.
(Table 11-3) Many chemotherapeutic drugs have marrow suppression as a major toxicity; effects are dose dependent and will occur in all recipients. In contrast, idiosyncratic reactions to a large and diverse group of drugs may lead to aplastic anemia without a clear dose-response relationship. These associations rest largely on accumulated case reports until a large international study in Europe in the 1980s quantitated drug relationships, especially for nonsteroidal analgesics, sulfonamides, thyrostatic drugs, some psychotropics, penicillamine, allopurinol, and gold. Association does not equal causation: a drug may have been used to treat the first symptoms of bone marrow failure (antibiotics for fever or the preceding viral illness) or provoked the first symptom of a preexisting disease (petechiae by nonsteroidal anti-inflammatory agents administered to the thrombocytopenic patient). In the context of total drug use, idiosyncratic reactions, although individually devastating, are rare events. Risk estimates are usually lower when determined in population-based studies. Furthermore, the low absolute risk is also made more obvious: even a 10- or 20-fold increase in risk translates, in a rare disease, to just a handful of drug-induced aplastic anemia cases among hundreds of thousands of exposed persons.
TABLE 11-3Some Drugs and Chemicals Associated with Aplastic Anemia ||Download (.pdf) TABLE 11-3 Some Drugs and Chemicals Associated with Aplastic Anemia
|Agents that regularly produce marrow depression as major toxicity in commonly used doses or normal exposures: |
| Cytotoxic drugs used in cancer chemotherapy: alkylating agents, antimetabolites, antimitotics, some antibiotics |
|Agents that frequently but not inevitably produce marrow aplasia: |
| Benzene |
|Agents associated with aplastic anemia but with a relatively low probability: |
| Chloramphenicol |
| Insecticides |
| Antiprotozoals: quinacrine and chloroquine, mepacrine |
| Nonsteroidal anti-inflammatory drugs (including phenylbutazone, indomethacin, ibuprofen, sulindac, aspirin) |
| Anticonvulsants (hydantoins, carbamazepine, phenacemide, felbamate) |
| Heavy metals (gold, arsenic, bismuth, mercury) |
| Sulfonamides: some antibiotics, antithyroid drugs (methimazole, methylthiouracil, propylthiouracil), antidiabetes drugs (tolbutamide, chlorpropamide), carbonic anhydrase inhibitors (acetazolamide and methazolamide) |
| Antihistamines (cimetidine, chlorpheniramine) |
| D-Penicillamine |
| Estrogens (in pregnancy and in high doses in animals) |
|Agents whose association with aplastic anemia is more tenuous: |
| Other antibiotics (streptomycin, tetracycline, methicillin, mebendazole, trimethoprim/sulfamethoxazole, flucytosine) |
| Sedatives and tranquilizers (chlorpromazine, prochlorperazine, piperacetazine, chlordiazepoxide, meprobamate, methyprylon) |
| Allopurinol |
| Methyldopa |
| Quinidine |
| Lithium |
| Guanidine |
| Potassium perchlorate |
| Thiocyanate |
| Carbimazole |
Hepatitis is the most common preceding infection, and posthepatitis marrow failure accounts for approximately 5% of etiologies in most series. Patients are usually young men who have recovered from a bout of liver inflammation 1 to 2 months earlier; the subsequent pancytopenia is very severe. The hepatitis is seronegative (non-A, non-B, non-C) and possibly due to an as yet undiscovered infectious agent. Fulminant liver failure in childhood also follows seronegative hepatitis, and marrow failure occurs at a high rate in these patients. Aplastic anemia can rarely follow infectious mononucleosis. Parvovirus B19, the cause of transient aplastic crisis in hemolytic anemias and of some PRCAs (see below), does not usually cause generalized bone marrow failure. Mild blood count depression is frequent in the course of many viral and bacterial infections but resolves with the infection.
Aplasia is a major consequence and the inevitable cause of death in transfusion-associated graft-versus-host disease (GVHD) that can occur after infusion of nonirradiated blood products to an immunodeficient recipient. Aplastic anemia is strongly associated with the rare collagen vascular syndrome eosinophilic fasciitis that is characterized by painful induration of subcutaneous tissues. Thymoma and hypoimmunoglobulinemia are occasional associations with aplastic anemia. Pancytopenia with marrow hypoplasia can also occur in systemic lupus erythematosus (SLE).
Aplastic anemia very rarely may occur and recur during pregnancy and resolve with delivery or with spontaneous or induced abortion.
Paroxysmal nocturnal hemoglobinuria
An acquired mutation in the PIG-A gene in a hematopoietic stem cell is required for the development of PNH, but PIG-A mutations probably occur commonly in normal individuals. If the PIG-A mutant stem cell proliferates, the result is a clone of progeny deficient in glycosylphosphatidylinositol-linked cell surface membrane proteins (Chap. 33). Small clones of deficient cells can be detected by sensitive flow cytometry tests in one-half or more of patients with aplastic anemia at the time of presentation. Functional studies of bone marrow from PNH patients, even those with mainly hemolytic manifestations, show evidence of defective hematopoiesis. Patients with an initial clinical diagnosis of PNH, especially younger individuals, may later develop frank marrow aplasia and pancytopenia; patients with an initial diagnosis of aplastic anemia may suffer from hemolytic PNH years after recovery of blood counts.
Fanconi anemia, an autosomal recessive disorder, manifests as congenital developmental anomalies, progressive pancytopenia, and an increased risk of malignancy. Chromosomes in Fanconi anemia are peculiarly susceptible to DNA cross-linking agents, the basis for a diagnostic assay. Patients with Fanconi anemia typically have short stature, café au lait spots, and anomalies involving the thumb, radius, and genitourinary tract. At least 16 different genetic defects (all but one with an identified gene) have been defined; the most common, type A Fanconi anemia, is due to a mutation in FANCA. Most of the Fanconi anemia gene products form a protein complex that activates FANCD2 by monoubiquitination to play a role in the cellular response to DNA damage and especially interstrand cross-linking.
Dyskeratosis congenita is characterized by the triad of mucous membrane leukoplasia, dystrophic nails, reticular hyperpigmentation, and with the development of aplastic anemia in childhood. Dyskeratosis is due to mutations in genes of the telomere repair complex, which acts to maintain telomere length in replicating cells: the X-linked variety is due to mutations in the DKC1 (dyskerin) gene; the more unusual autosomal dominant type is due to mutation in TERC, which encodes an RNA template, and TERT, which encodes the catalytic reverse transcriptase, telomerase. Mutations in TNF2, a component of the shelterin complex, proteins that bind the telomere DNA, also occur.
In Shwachman-Diamond syndrome, presentation is early in life with neutropenia with pancreatic insufficiency and malabsorption; most patients have compound heterozygous mutations in SBDS that may affect both ribosomal biogenesis (as in Diamond-Blackfan anemia; see below) and marrow stroma function.
While these constitutional syndromes can on occasion present in adults, genetic mutations are also risk factors for bone marrow failure. In the recently recognized telomeropathies, mutations in TERT and TERC have subtle effects on hematopoietic function. Typical presentations include not only severe but also moderate aplastic anemia, which can be chronic and not progressive, and isolated macrocytic anemia or thrombocytopenia. Physical anomalies are usually not found in the patient, although early hair graying is a clue to the diagnosis. A careful family history may disclose pulmonary fibrosis and hepatic cirrhosis. Specific involvement of the bone marrow, liver, and lung is highly variable, as is penetrance of clinical phenotype, both within families and among kindreds. Variable penetrance means that TERT and TERC mutations represent risk factors for marrow failure, as family members with the same mutations may have normal or only slight hematologic abnormalities but more subtle evidence of (compensated) hematopoietic insufficiency.
Bone marrow failure results from severe damage to the hematopoietic cell compartment. In aplastic anemia, replacement of the bone marrow by fat is apparent in the morphology of the biopsy specimen (Fig. 11-1) and magnetic resonance imaging (MRI) of the spine. Cells bearing the CD34 antigen, a marker of early hematopoietic cells, are greatly diminished, and in functional studies, committed and primitive progenitor cells are virtually absent; in vitro assays have suggested that the stem cell pool is reduced to ≤1% of normal in severe disease at the time of presentation.
Normal and aplastic bone marrow. A. Normal bone marrow biopsy. B. Normal bone marrow aspirate smear. The marrow is normally 30–70% cellular, and there is a heterogeneous mix of myeloid, erythroid, and lymphoid cells. C. Aplastic anemia biopsy. D. Marrow smear in aplastic anemia. The marrow shows replacement of hematopoietic tissue by fat and only residual stromal and lymphoid cells.
An intrinsic stem cell defect exists for the constitutional aplastic anemias: cells from patients with Fanconi anemia exhibit chromosome damage and death on exposure to certain chemical agents. Telomeres are short in some patients with aplastic anemia, due to heterozygous mutations in genes of the telomere repair complex. Telomeres may also shorten physiologically in acquired marrow failure due to replicative demands on a limited stem cell pool.
Extrinsic damage to the marrow follows massive physical or chemical insults such as high doses of radiation and toxic chemicals. For the more common idiosyncratic reaction to modest doses of medical drugs, altered drug metabolism has been invoked as a likely mechanism. The metabolic pathways of many drugs and chemicals, especially if they are polar and have limited water solubility, involve enzymatic degradation to highly reactive electrophilic compounds; these intermediates are toxic because of their propensity to bind to cellular macromolecules. For example, derivative hydroquinones and quinolones are responsible for benzene-induced tissue injury. Excessive generation of toxic intermediates or failure to detoxify the intermediates may be genetically determined and apparent only on specific drug challenge; the complexity and specificity of the pathways imply multiple susceptibility loci and would provide an explanation for the rarity of idiosyncratic drug reactions.
The recovery of marrow function in some patients prepared for bone marrow transplantation with antilymphocyte globulin first suggested that aplastic anemia might be immune mediated. Consistent with this hypothesis was the frequent failure of simple bone marrow transplantation from a syngeneic twin, without conditioning cytotoxic chemotherapy, which also argued both against simple stem cell absence as the cause and for the presence of a host factor producing marrow failure. Laboratory data support an important role for the immune system in aplastic anemia. Blood and bone marrow cells of patients can suppress normal hematopoietic progenitor cell growth, and removal of T cells from aplastic anemia bone marrow improves colony formation in vitro. Increased numbers of activated cytotoxic T cell clones are observed in aplastic anemia patients and usually decline with successful immunosuppressive therapy; type 1 cytokines are implicated; and interferon γ (IFN-γ) induces Fas expression on CD34 cells, leading to apoptotic cell death. The early immune system events in aplastic anemia are not well understood, but an oligoclonal, T cell response implies antigenic stimulus. The rarity of aplastic anemia despite common exposures (medicines, seronegative hepatitis) suggests that genetically determined features of the immune response can convert a normal physiologic response into a sustained abnormal autoimmune process, including polymorphisms in histocompatibility antigens, cytokine genes, and genes that regulate T cell polarization and effector function.
Aplastic anemia can appear abruptly or insidiously. Bleeding is the most common early symptom; a complaint of days to weeks of easy bruising, oozing from the gums, nose bleeds, heavy menstrual flow, and sometimes petechiae will have been noticed. With thrombocytopenia, massive hemorrhage is unusual, but small amounts of bleeding in the central nervous system can result in catastrophic intracranial or retinal hemorrhage. Symptoms of anemia are also frequent, including lassitude, weakness, shortness of breath, and a pounding sensation in the ears. Infection is an unusual first symptom in aplastic anemia (unlike in agranulocytosis, where pharyngitis, anorectal infection, or frank sepsis occurs early). A striking feature of aplastic anemia is the restriction of symptoms to the hematologic system, and patients often feel and look remarkably well despite drastically reduced blood counts. Systemic complaints and weight loss should point to other etiologies of pancytopenia. Prior drug use, chemical exposure, and preceding viral illnesses must often be elicited with repeated questioning. A family history of hematologic diseases or blood abnormalities, of pulmonary or liver fibrosis, or of early hair graying points to a telomeropathy.
Petechiae and ecchymoses are typical, and retinal hemorrhages may be present. Pelvic and rectal examinations can often be deferred but, when performed, should be undertaken with great gentleness to avoid trauma; these will often show bleeding from the cervical os and blood in the stool. Pallor of the skin and mucous membranes is common except in the most acute cases or those already transfused. Infection on presentation is unusual but may occur if the patient has been symptomatic for a few weeks. Lymphadenopathy and splenomegaly are highly atypical of aplastic anemia. Café au lait spots and short stature suggest Fanconi anemia; peculiar nails and leukoplakia suggest dyskeratosis congenita; early graying (and use of hair dyes to mask it!) suggests a telomerase defect.
The smear shows large erythrocytes and a paucity of platelets and granulocytes. Mean corpuscular volume (MCV) is commonly increased. Reticulocytes are absent or few, and lymphocyte numbers may be normal or reduced. The presence of immature myeloid forms suggests leukemia or MDS; nucleated red blood cells (RBCs) suggest marrow fibrosis or tumor invasion; abnormal platelets suggest either peripheral destruction or MDS.
The bone marrow is usually readily aspirated but dilute on smear, and the fatty biopsy specimen may be grossly pale on withdrawal; a “dry tap” instead suggests fibrosis or myelophthisis. In severe aplasia, the smear of the aspirated specimen shows only red cells, residual lymphocytes, and stromal cells; the biopsy (which should be >1 cm in length) is superior for determination of cellularity and shows mainly fat under the microscope, with hematopoietic cells occupying <25% of the marrow space; in the most serious cases, the biopsy is virtually all fat. The correlation between marrow cellularity and disease severity is imperfect, in part because marrow cellularity declines physiologically with aging. Additionally, some patients with moderate disease by blood counts will have empty iliac crest biopsies, whereas “hot spots” of hematopoiesis may be seen in severe cases. If an iliac crest specimen is inadequate, cells may also be obtained by aspiration from the sternum. Residual hematopoietic cells should have normal morphology, except for mildly megaloblastic erythropoiesis; megakaryocytes are invariably greatly reduced and usually absent. Granulomas may indicate an infectious etiology of the marrow failure.
Chromosome breakage studies of peripheral blood using diepoxybutane or mitomycin C should be performed on children and younger adults to exclude Fanconi anemia. Very short telomere length (available commercially) strongly suggests the presence of a telomerase or shelterin mutation, which can be pursued by family studies and nucleotide sequencing. Chromosome studies of bone marrow cells are often revealing in MDS and should be negative in typical aplastic anemia. Flow cytometry offers a sensitive diagnostic test for PNH. Serologic studies may show evidence of viral infection, such as Epstein-Barr virus and HIV. Posthepatitis aplastic anemia is seronegative. The spleen size should be determined by computed tomography (CT) scanning or ultrasound if the physical examination of the abdomen is unsatisfactory. Occasionally MRI may be helpful to assess the fat content of vertebrae in order to distinguish aplasia from MDS.
The diagnosis of aplastic anemia is usually straightforward, based on the combination of pancytopenia with a fatty bone marrow. Aplastic anemia is a disease of the young and should be a leading diagnosis in the pancytopenic adolescent or young adult. When pancytopenia is secondary, the primary diagnosis is usually obvious from either history or physical examination: the massive spleen of alcoholic cirrhosis, the history of metastatic cancer or SLE, or miliary tuberculosis on chest radiograph (Table 11-1).
Diagnostic problems can occur with atypical presentations and among related hematologic diseases. Although pancytopenia is most common, some patients with bone marrow hypocellularity have depression of only one or two of three blood lines, with later progression to pancytopenia. The bone marrow in constitutional aplastic anemia is morphologically indistinguishable from the aspirate in acquired disease. The diagnosis can be suggested by family history, abnormal blood counts since childhood, or the presence of associated physical anomalies. Aplastic anemia may be difficult to distinguish from the hypocellular variety of MDS: MDS is favored by finding morphologic abnormalities, particularly of megakaryocytes and myeloid precursor cells, and typical cytogenetic abnormalities (see below).
The natural history of severe aplastic anemia is rapid deterioration and death. Historically, provision first of RBC and later of platelet transfusions and effective antibiotics were of some benefit, but few patients show spontaneous recovery. The major prognostic determinant is the blood count. Severe disease has been defined by the presence of two of three parameters: absolute neutrophil count <500/μL, platelet count <20,000/μL, and corrected reticulocyte count <1% (or absolute reticulocyte count <60,000/μL). In the era of effective immunosuppressive therapies, absolute numbers of reticulocytes (>25,000/μL) and lymphocytes (>1000/μL) may be better predictors of response to treatment and long-term outcome.
TREATMENT Aplastic Anemia
Severe acquired aplastic anemia can be cured by replacement of the absent hematopoietic cells (and the immune system) by stem cell transplant, or it can be ameliorated by suppression of the immune system to allow recovery of the patient’s residual bone marrow function. Glucocorticoids are not of value as primary therapy. Suspect exposures to drugs or chemicals should be discontinued; however, spontaneous recovery of severe blood count depression is rare, and a waiting period before beginning treatment may not be advisable unless the blood counts are only modestly depressed. HEMATOPOIETIC STEM CELL TRANSPLANTATION
This is the best therapy for the younger patient with a fully histocompatible sibling donor (Chap. 31). Human leukocyte antigen (HLA) typing should be ordered as soon as the diagnosis of aplastic anemia is established in a child or younger adult. In transplant candidates, transfusion of blood from family members should be avoided so as to prevent sensitization to histocompatibility antigens, but limited numbers of blood products probably do not greatly affect outcome. For allogeneic transplant from fully matched siblings, long-term survival rates for children are approximately 90%. Transplant morbidity and mortality are increased among adults, due to the higher risk of chronic GVHD and serious infections.
Most patients do not have a suitable sibling donor. Occasionally, a full phenotypic match can be found within the family and serve as well. Far more available are other alternative donors, either unrelated but histocompatible volunteers or closely but not perfectly matched family members. High-resolution matching at HLA and more effective conditioning regimens and GVHD prophylaxis have led to improved survival rates in patients who proceed to alternative donor transplant, in some series approximating results with conventional sibling donors. Patients will be at risk for late complications, especially a higher rate of cancer, if radiation is used as a component of conditioning. IMMUNOSUPPRESSION
The standard regimen of antithymocyte globulin (ATG) in combination with cyclosporine induces hematologic recovery (independence from transfusion and a leukocyte count adequate to prevent infection) in 60–70% of patients. Children do especially well, whereas older adult patients often suffer complications due to the presence of comorbidities. An early robust hematologic response correlates with long-term survival. Improvement in granulocyte number is generally apparent within 2 months of treatment. Most recovered patients continue to have some degree of blood count depression, the MCV remains elevated, and bone marrow cellularity returns toward normal very slowly if at all. Relapse (recurrent pancytopenia) is frequent, often occurring as cyclosporine is discontinued; most, but not all, patients respond to reinstitution of immunosuppression, but some responders become dependent on continued cyclosporine administration. Development of MDS, with typical marrow morphologic or cytogenetic abnormalities, occurs in approximately 15% of treated patients, usually but not invariably associated with a return of pancytopenia, and some patients develop leukemia. A laboratory diagnosis of PNH can generally be made at the time of presentation of aplastic anemia by flow cytometry; recovered patients may have frank hemolysis if the PNH clone expands. Bone marrow examinations should be performed if there is an unfavorable change in blood counts.
Horse ATG is administered as intravenous infusions over 4 days. ATG binds to peripheral blood cells; therefore, platelet and granulocyte numbers may decrease further during active treatment. Serum sickness, a flulike illness with a characteristic cutaneous eruption and arthralgia, often develops approximately 10 days after initiating treatment. Methylprednisolone is administered with ATG to ameliorate the immune consequences of heterologous protein infusion. Excessive or extended glucocorticoid therapy is associated with avascular joint necrosis. Cyclosporine is administered orally at an initial high dose, with subsequent adjustment according to blood levels obtained every 2 weeks; rough levels should be between 150 and 200 ng/mL. The most important side effects are nephrotoxicity, hypertension, seizures, and opportunistic infections, especially Pneumocystis jiroveci (prophylactic treatment with monthly inhaled pentamidine is recommended).
Most patients with aplastic anemia lack a suitable marrow donor, and immunosuppression is the treatment of choice. Overall survival is equivalent with transplantation and immunosuppression. However, successful transplant cures marrow failure, whereas patients who recover adequate blood counts after immunosuppression remain at risk of relapse and malignant evolution. Because of excellent results in children and younger adults, allogeneic transplant should be performed if a suitable sibling donor is available. Increasing age and the severity of neutropenia are the most important factors weighing in the decision between transplant and immunosuppression in adults who have a matched family donor: older patients do better with ATG and cyclosporine, whereas transplant is preferred if granulocytopenia is profound.
Outcomes following both transplant and immunosuppression have improved with time. High doses of cyclophosphamide, without stem cell rescue, have been reported to produce durable hematologic recovery, without relapse or evolution to MDS, but this treatment can produce sustained severe fatal neutropenia, and response is often delayed. OTHER THERAPIES
The effectiveness of androgens has not been verified in controlled trials, but occasional patients will respond or even demonstrate blood count dependence on continued therapy. Sex hormones upregulate telomerase gene activity in vitro, which is possibly also their mechanism of action in improving marrow function. For patients with moderate disease, especially if a telomere defect is present, or those with severe pancytopenia in whom immunosuppression has failed, a 3- to 4-month trial is appropriate.
Hematopoietic growth factors (HGFs) such as erythropoietin and granulocyte colony-stimulating factor (G-CSF) are not definitive therapy for severe aplastic anemia, and even their roles as adjuncts to immunosuppression are not clear. In research protocols, thrombopoietin mimetics have shown surprising activity in patients with refractory aplastic anemia, with patterns of blood count recovery suggesting that they act as stem cell stimulants. SUPPORTIVE CARE
Meticulous medical attention is required so that the patient may survive to benefit from definitive therapy or, having failed treatment, to maintain a reasonable existence in the face of pancytopenia. First and most important, infection in the presence of severe neutropenia must be aggressively treated by prompt institution of parenteral, broad-spectrum antibiotics, usually ceftazidime or a combination of an aminoglycoside, cephalosporin, and semisynthetic penicillin. Therapy is empirical and must not await results of culture, although specific foci of infection such as oropharyngeal or anorectal abscesses, pneumonia, sinusitis, and typhlitis (necrotizing colitis) should be sought on physical examination and with radiographic studies. When indwelling plastic catheters become contaminated, vancomycin should be added. Persistent or recrudescent fever implies fungal disease: Candida and Aspergillus are common, especially after several courses of antibacterial antibiotics. A major reason for the improved prognosis in aplastic anemia has been the development of better antifungal drugs and the timely institution of such therapy when infection is suspected. Granulocyte transfusions using G-CSF–mobilized peripheral blood may be effective in the treatment of overwhelming or refractory infections. Hand washing, the single best method of preventing the spread of infection, remains a neglected practice. Nonabsorbed antibiotics for gut decontamination are poorly tolerated and not of proven value. Total reverse isolation does not reduce mortality from infections.
Both platelet and erythrocyte numbers can be maintained by transfusion. Alloimmunization historically limited the usefulness of platelet transfusions and is now minimized by several strategies, including use of single donors to reduce exposure and physical or chemical methods to diminish leukocytes in the product; HLA-matched platelets are often effective in patients refractory to random donor products. Inhibitors of fibrinolysis such as aminocaproic acid have not been shown to relieve mucosal oozing; the use of low-dose glucocorticoids to induce “vascular stability” is unproven and not recommended. Whether platelet transfusions are better used prophylactically or only as needed remains unclear. Any rational regimen of prophylaxis requires transfusions once or twice weekly to maintain the platelet count >10,000/μL (oozing from the gut increases precipitously at counts <5000/μL). Menstruation should be suppressed either by oral estrogens or nasal follicle-stimulating hormone/luteinizing hormone (FSH/LH) antagonists. Aspirin and other nonsteroidal anti-inflammatory agents inhibit platelet function and must be avoided.
RBCs should be transfused to maintain a normal level of activity, usually at a hemoglobin value of 70 g/L (90 g/L if there is underlying cardiac or pulmonary disease); a regimen of 2 units every 2 weeks will replace normal losses in a patient without a functioning bone marrow. In chronic anemia, the iron chelators, deferoxamine and deferasirox, should be added at approximately the fiftieth transfusion to avoid secondary hemochromatosis.