What every physician needs to know:


Aplastic anemia (AA) can be inherited or acquired. Inherited forms usually present during the first decade of life, but in rare cases may manifest in adulthood. These two forms should be distinguished early on in a patient’s course.

Acquired aplastic anemia, the subject of this chapter, is a potentially fatal bone marrow failure disorder that is characterized by pancytopenia and a hypocellular bone marrow. Most cases are due to an autoimmune-mediated immunological attack against bone marrow stem/progenitor cells. Aplastic anemia is more common in children and young adults but can occur in any age group. Although all patients present with cytopenias and a hypocellular bone marrow, it is the degree of pancytopenia that most influences survival.

Aplastic anemia is characterized as non-severe (nSAA), severe (SAA), or very severe (vSAA) depending on the depth of pancytopenia. SAA and vSAA have a high mortality rate if they are not treated appropriately. NSAA is not usually life-threatening and may not require treatment.

Continue Reading

  • SAA

Hypocellular bone marrow (less than 25% cellularity) and at least two of the following three blood counts:

– Absolute neutrophil count less than 0.5 x 109/L

– Absolute reticulocyte count less than 60 k/mm3

– Platelet count less than 20 x 109/L

  • VSAA

Same as SAA except absolute neutrophil count less than 0.2 x 109/L.

  • NSAA

Hypocellular bone marrow and peripheral blood cytopenias that do not meet criteria for SAA.

Etiology and treatment

Acquired aplastic anemia can occasionally be traced to a clear precipitant such as hepatitis (almost always seronegative hepatitis), drugs, toxins (benzene), or pregnancy, but the overwhelming majority of cases are idiopathic.

Allogeneic hematopoietic stem cell transplantation (HSCT) from a matched sibling donor remains the treatment of choice for children and young adults (age less than 30 years) with SAA or vSAA. Bone marrow source of stem cells is thought to be best in aplastic anemia. Immunosuppressive therapy (usually antithymocyte globulin and cyclosporine) is the treatment of choice for older individuals (usually greater than 40 years old) and for those who do not have a matched sibling donor.

Alternative donor transplants (unrelated and mismatched donors) are usually reserved for SAA and vSAA patients who have not responded to immunosuppressive therapy first.

Are you sure your patient has aplastic anemia? What should you expect to find?

The differential of pancytopenia is broad; however the differential of pancytopenia with a hypocellular marrow is more restricted (see below). It is important to recognize that bone marrow cellularity normally decreases with age. A rough estimate of what constitutes normal cellularity can be calculated by subtracting the patient’s age from 100. Thus, a 25 year old patient should have a 75% cellular bone marrow, whereas, a 60 year old patient would be expected to have a 40% cellular bone marrow. Therefore, making the diagnosis of acquired aplastic anemia in an 80 year old can be challenging.

The adequacy of the biopsy specimen can also confound the diagnosis. Subcortical bone is usually less cellular; thus, it is imperative to have at least a 1 to 2 cm core biopsy to establish the diagnosis of aplastic anemia.

Aplastic anemia may present with the following signs and symptoms:

  • Fatigue

  • Dyspnea on exertion

  • Easy bruising and bleeding (for example, epistaxis, gum bleeding, heavy menses, subconjunctival hemorrhages, melena, etcetera.)

  • Petechiae (most commonly in the mouth or on the pretibial region)

  • Pallor

  • Headache

  • Fever due to infection

Beware of other conditions that can mimic aplastic anemia:

The differential diagnosis of aplastic anemia includes:

  • Myelodysplastic syndromes (MDS)

MDS usually has a hypercellular bone marrow but about 15% of cases have a hypocellular bone marrow. This is often called hypoplastic MDS (hMDS) in the literature. MDS is more common in older patients (median age ~60 years) but may occur at any age.

  • Large granular lymphocyte leukemia (LGL)

LGL is a disorder of clonal T cells that can present with pancytopenia and can be difficult to distinguish from idiopathic aplastic anemia. The bone marrow is often involved with interstitial lymphocytic infiltrates. LGL is best diagnosed by flow cytometry from the peripheral blood (as opposed to the bone marrow). There is also usually splenic involvement which is distinct from AA. T-cell gene rearrangements may also help make this diagnosis.

  • Paroxysmal nocturnal hemoglobinuria (PNH)

PNH is a clonal hematopoietic stem cell disease that may present with pancytopenia.

  • Inherited bone marrow failure syndromes (i.e. Fanconi anemia, dyskeratosis congenita, and Shwachman-Diamond syndrome)

These disorders usually present in the first decade of life but rare cases can present in adulthood. Specific testing is available to rule out these disorders.

Which individuals are most at risk for developing aplastic anemia:

Acquired aplastic anemia is extremely rare. The estimated incidence is two to five per million persons in the United States. The disease is most common between the ages of 15 and 30 years, but a second peak occurs after age 60. Environmental toxins such as insecticides and benzene may slightly increase the risk for developing bone marrow failure, and certain medications (for example, antiseizure medications) may rarely lead to aplastic anemia. Children and young adults who develop non-A to -G (seronegative) hepatitis are at increased risk for developing aplastic anemia. In fact, up to 20% of patients who receive a liver transplant for seronegative hepatitis will develop aplastic anemia, usually 1.5 to 3 years later.

What laboratory studies should you order to help make the diagnosis and how should you interpret the results?

Complete blood count with leukocyte differential

This will reveal pancytopenia. Typically the ratio of neutrophils to lymphocytes (normally 3 to 4:1) is inverted. The presence of nucleated red blood cells, blasts, or dysplastic appearing neutrophils is atypical and should raise suspicion for MDS or leukemia.

Reticulocyte count

Absolute or corrected reticulocyte count is always low in aplastic anemia.

Biochemical profile and lactate dehydrogenase

Markedly elevated bilirubin and transaminases should raise suspicion for the hepatitis/aplasia syndrome. Mild elevations in lactate dehydrogenase (LDH) (one and half to two times the upper limit of normal) may suggest the presence of a small to moderately sized paroxysmal nocturnal hemoglobinuria (PNH) clone.

Peripheral blood flow cytometry to detect cells missing glycosylphosphatidyl-inositol anchored proteins

Glycosylphosphatidylinositol anchored protein (GPI-AP) deficiency is a hallmark of PNH; however, small to moderate populations of GPI-AP deficient cells (usually 0.1 to 15%) can be found at diagnosis in up to 70% of patients with acquired aplastic anemia. Finding a PNH clone in patients with aplastic anemia can be helpful in excluding congenital forms of the disease. It is important to order the test on both red cells and granulocytes. PNH flow cytometry on granulocytes is much more sensitive, especially in patients who have received blood transfusions.

Fanconi anemia screen on peripheral blood

Increased chromosomal breakage in response to clastogenic agents (diepoxybutane or mitomycin C) is diagnostic of Fanconi anemia. Patients with acquired aplastic anemia do not show an increase in chromosomal breaks. Patients with vSAA sometimes don’t have sufficient cells to perform this assay.

Bone marrow aspirate, biopsy, iron stain, and flow cytometry

A hypocellular bone marrow biopsy is required for the diagnosis of aplastic anemia. However, cellularity may be patchy. Spicules from an aspirate may be surprisingly cellular despite overall marrow hypocellularity, as some patients will have residual pockets of ongoing hematopoiesis. Thus, a core biopsy of 1 to 2 cm is essential for assessing cellularity.

Mild dyserythropoiesis is not uncommon in aplastic anemia, especially in cases with simultaneous small to moderate sized PNH populations; however, the presence of a small percentage of myeloid blasts or dysplastic features in the myeloid or megakaryocyte lineages favors a diagnosis of hMDS. Stainable iron is usually increased; however, the presence of increased ringed sideroblasts suggests a diagnosis of MDS. The percentage of CD34+ progenitor cells in the bone marrow aspirate can be useful in distinguishing between aplastic anemia and MDS. The percentage of CD34+ cells is markedly decreased in aplastic anemia (usually less than 0.2%) and normal or elevated (greater than 0.5%) in MDS. Repeated bone marrow evaluations may be required at specialized centers to do ancillary testing and firmly establish the diagnosis.

Bone marrow karyotyping (cytogenetics) and fluorescence in-situ hybridization to exclude MDS

Abnormal cytogenetic studies in the setting of a hypocellular bone marrow suggest a diagnosis of hMDS (de novo or MDS that evolve from aplastic anemia). The most common and worst prognostic cytogenetic abnormality to evolve from aplastic anemia is monosomy 7. Trisomy 8 and 13q abnormalities have a more favorable prognosis and sometimes respond to immunosuppressive therapy.

Somatic mutational testing has been performed in the context of retrospective reviews and single prospective clinical trials. This testing is not currently standard of care in SAA but is an evolving area of research as we learn how to utilize this testing modality. These panels are more often sent in the setting of expected MDS where evidence of mutations in some setting is considered diagnostic of the MDS.

What imaging studies (if any) will be helpful in making or excluding the diagnosis of aplastic anemia?

Imaging studies are not routinely necessary to establish a diagnosis of aplastic anemia.

If you decide the patient has aplastic anemia, what therapies should you initiate immediately?

Patients diagnosed with SAA will have significant supportive care requirements. An individual’s requirements for supportive care will depend on the severity of symptoms and degree of pancytopenia. Patients with severe cytopenias require urgent support with blood products, such as packed red blood cells to correct or avoid cardio-pulmonary complications. The goal of platelet therapy should be to maintain a platelet count to prevent spontaneous bleeding. Blood products should be irradiated to prevent transfusion-associated graft-versus-host disease (GVHD) in patients who could proceed to transplantation. Blood products should also be filtered to reduce the incidence of viral infections and prevent alloimmunization. Transfusions from family members should be avoided, to decrease sensitization to potential bone marrow donors.

More definitive therapies?

The choice of initial definitive therapy will depend on the age of your patient. HSCT is potentially curative. This should be the first line choice for patients under 30 years old with SAA who have a known HLA-matched sibling donor bone marrow transplant (BMT). An advantage of this approach initially is a marked reduction in both the risk of relapse and the evolution of late clonal disorders such as MDS/AML or PNH. However, the majority of patients will not have an HLA-matched sibling donor.

The results of HSCT from an unrelated donor or mismatched donor are improving, but at this time, unrelated and mismatched HSCT should be reserved for SAA patients who do not respond to or relapse after immunosuppressive therapy. It should be noted that there is the possibility of autologous recovery after HSCT for AA.

Immunosuppressive therapy (IST) with antithymocyte globulin and cyclosporine (ATG/CsA) (and in some settings combined with eltrombopag) is first line therapy for patients with SAA who are over age 30 years, lack HLA-matched sibling donors, or are not HSCT candidates for other reasons. The response rates after ATG/CsA are 60% to 70% with a probability of survival at 5 years between 60 and 85%. However, up to 40% of patients will relapse after IST. There is also an incidence of secondary clonal diseases. At 5 years, 10 to 15% of patients will develop MDS or PNH. The most common chromosomal abnormality arising from aplastic anemia is monosomy 7.

High-dose cyclophosphamide (CY) is another therapy that is well established as an effective therapy for patients with SAA. High-dose CY is given at a dose of 50mg/kg/day for 4 days. The response rates after high-dose CY are 70% and there appears to be slightly lower risk for relapse and secondary clonal diseases, but this has not been proven in a randomized controlled trial. High CY is less effective for patient with refractory SAA, but about 25% of patients still respond with durable hematopoietic remissions.

Additionally there has been a single new drug approved for relapsed SAA in the past 30 years: eltrombopag. Unfortunately this drug has limitations. There is only a 20% response rate (using traditional response criteria) and even in responders, there remains the association with relapse and secondary clonal disease similar to IST. This is currently an option for patients in whom HSCT may not be possible to attempt to decrease the depth of cytopenias. A recently published prospective trial has added it in treatment-naïve patients. The addition of eltrombopag may increase the response by ~10% but there remains the concern for clonal evolution.

What other therapies are helpful for reducing complications?

Fungal and bacterial infections are the major cause of death in patients with SAA. There is no standardized approach to antibiotic therapy but neutropenic precautions should be instituted in patients with an absolute neutrophil count (ANC) less than 500. Vigilance and proactive prescription of clinically appropriate antibiotics, antivirals, and antifungals in these patients is imperative. The first fever should be treated empirically with broad spectrum antibiotics and then tailored as culture data indicates. The second fever is often fungal and should again be treated empirically with broad spectrum antifungals, including coverage for Aspergillus.

The use of hematopoietic growth factors to support blood counts is of limited value in these patients, except possibly G-CSF (granulocyte colony-stimulating factor) administration in an attempt to stimulate a neutrophil response in the presence of severe infection.

ATG can cause serum sickness. To reduce the incidence of this, methylprednisolone 1mg/kg should be administered with the ATG and then steroids continue and are tapered over the subsequent 1 to 2 months as quickly as the patient’s symptoms allow.

What should you tell the patient and the family about prognosis?

The mortality risk from AA correlates best with the peripheral blood counts.

Patients with vSAA and SAA are at greatest risk if not treated promptly. The mortality rate in these patients (vSAA and SAA) can approach 50% in the first year without therapy.

NSAA is rarely life-threatening and, in some cases, may not require therapy. For guidance, the patients could anticipate that one-third of patients with NSAA improve spontaneously, one-third continue with cytopenias in the NSAA range, and one-third progress to SAA over time.

Patients who are refractory to therapy can develop complications related to transfusional iron overload. Progression to MDS, leukemia, and PNH may also be life-threatening in a subset of patients.

What if scenarios.

What if my patient with acquired SAA doesn't respond to IST? How long should I wait for a response?

Most patients who are going to respond to ATG/CsA do so within 6 to 12 weeks after treatment, although some rare patients can take up to 4 to 6 months to show a response. Thus, if a patient is not showing evidence of response 3-4 months after ATG/CsA, it is time to start considering alternative therapies. Time to response is even slower after high-dose CY. The median time to a neutrophil response is 2 months; the median time to platelet transfusion and red cell transfusion independence is 6 and 8 months respectively.

Remember, it can take up to 3 months to find an alternative marrow donor through the registry; thus, preliminary typing results should be sent as early as possible if one is considering a matched unrelated donor HSCT. The chance of finding a donor in the registry can be as high as 60% for Caucasians of European extraction, but is less than 10% for African Americans and other minority groups. Alternative donors, such as mismatched donors, are becoming more common, and these may be located more easily as they are often family members, such as parents or siblings.

How do I adjust the cyclosporine dose?

The dosage of cyclosporine should be adjusted based upon trough levels in the blood and toxicity. Cyclosporine is usually dosed every 12 hours. When checking levels, the patient should be instructed to not take the morning dose until after the blood level is drawn. Target trough levels are 200 to 300 ng/ml for at least 6 months, as long as the patient is tolerating the drug and responding to therapy. It is not uncommon to see mild abnormalities in transaminases and a rise in the creatinine level in patients on cyclosporine. Mild tremors, hypertension, gingival hyperplasia, gastrointestinal disturbances, and hirsutism are also common side effects.

When should I stop/taper cyclosporine?

If there is no response to cyclosporine after 4 to 6 months of therapeutic levels, the drug should be stopped and other treatment options should be considered. However, if the patient is responding to IST, cyclosporine should be maintained for at least 6 to 12 months. At that point, the drug should be tapered (roughly 25% every 1 to 2 months). If the peripheral blood counts remain stable, the drug can eventually be discontinued. If the counts drop, the dosage should be increased and maintained at the lowest levels that maintain transfusion independence.

What if my patient relapses after an initial response to immunosuppressive therapy?

Options include bone marrow transplantation for potential cure or retreatment with immunosuppression.

The response rate to retreatment with ATG/CsA is less than in treatment naive patients–roughly 30% to 40%. In patients with a matched sibling donor who choose to try immunosuppressive therapy first, HSCT should strongly be considered if the patient is in good health. Alternative donor transplantation should also be strongly considered at the time of relapse in those lacking a matched donor but who are otherwise in good health and fit for transplantation.


Aplastic anemia can be inherited or acquired. Inherited forms may result from DNA repair defects (Fanconi anemia), abnormally short telomeres (dyskeratosis congenita), or abnormalities of ribosomal biogenesis (Shwachman-Diamond syndrome). Acquired forms of aplastic anemia are most commonly the result of an autoimmune attack directed at hematopoietic stem/progenitor cells.

The immune attack is primarily directed by cytotoxic T cells that target hematopoietic stem cells (CD34 positive cells) and cause apoptosis leading to hematopoietic failure. It remains unclear what antigen the T cells are targeting. There does appear to be a role for antigen recognition, as HLA-DR2 is overexpressed among patients with SAA and its presence is predictive of a better response to IST.

What other clinical manifestations may help me to diagnose aplastic anemia?

  • Ask the patient about exposures and review medication history thoroughly

  • Ask the patient if there is a family history of cytopenias, physical anomalies, or pulmonary fibrosis. A family history of other blood dyscrasias and/or pulmonary fibrosis may suggest an inherited bone marrow failure disorder

  • Ask the patient if they have had previous blood counts checked to determine how long they may have had this before progressing to SAA

Physical examination
  • Look for signs of pallor in the conjunctiva and nail beds

  • Petechiae may be seen in the pretibial region or on the posterior pharynx

  • Splenomegaly is unusual

  • Weight loss, lymphadenopathy, fevers, or other systemic complaints would be unusual in AA

  • Look for signs of inherited bone marrow failure disorders (short stature, skin and nail abnormalities, early graying of the hair, missing or abnormal digits, or other physical anomalies.)

What other additional laboratory studies may be ordered?

Telomere length by flow/fluorescence in situ hybridization (Flow-FISH) if dyskeratosis congenita is suspected.

HLA typing.

Jump to Section