Aplastic anemias

I. Problem/Condition

Aplastic anemia (AA) is a disorder of hematopoietic stem cells that results in pancytopenia in the setting of a hypocellular bone marrow and normal spleen size. Depleted cell lines lead to symptoms of fatigue from anemia, bleeding symptoms from thrombocytopenia, or infections from neutropenia.

AA can be inherited or acquired. Inherited AA is rare, accounting for 10-20% of cases. Acquired AA is much more common, although is classified asprimary or idiopathic in the majority of cases as no known cause is found. Acquired AA can be caused by certain medical conditions (such as pregnancy or lupus) or exposure to some toxins or drugs (including chemotherapy). AA is also associated with a blood disorder called paroxysmal nocturnal hemoglobinuria (PNH).

II. Diagnostic Approach

A. What is the differential diagnosis for this problem?

Hematologic/malignant: Pure red cell aplasia, paroxysmal nocturnal hemoglobinuria, hypocellular myelodysplastic syndromes, aleukemic leukemia, myelofibrosis, hairy cell leukemia, hemophagocytic lymphohistiocytosis, and T-cell granular lymphocyte disease
Pregnancy-induced aplastic anemia
Congenital: Fanconi’s anemia, dyskeratosiscongenita, Shwachman-Diamond syndrome, and amegakaryocytic thrombocytopenia
Infectious: Tuberculosis, histoplasmosis and human immunodeficiency virus (HIV)
Vitamin/nutritional: Anorexia nervosa and folate or vitamin B12 deficiency
Iatrogenic/environmental: Medication effect, toxic chemical exposure and radiation exposure
Autoimmune/connective tissue disease: eosinophilic fasciitis, immune thyroid disease, systemic lupus erythematosus (SLE), and thymoma

B. Describe a diagnostic approach/method to the patient with this problem

Without consideration of the patient’s presenting condition and history, any disease with pancytopenia may be mistaken for aplastic anemia. If aplastic anemia is being entertained, a careful history and physical can help distinguish either an inciting event, or a competing diagnosis.

1. Historical information important in the diagnosis of this problem.

While a history of taking chloramphenicol, penicillamine or gold is classic, careful investigation of the patient’s medication list for potential idiosyncratic drug reactions is advised.

Has the patient received chemotherapy or radiation therapy?
Has the patient been exposed to toxins such as benzene, chlorinated hydrocarbons or organophosphates through their occupation?
Does the patient have risk factors for HIV and/or tuberculosis (TB) infection?
Does the patient have a family history of similar blood findings?
Does the patient have unusual dietary habits?
Has the patient noted frequent episodes of dark-colored urine?

2. Physical Examination maneuvers that are likely to be useful in diagnosing the cause of this problem.

Special attention should be paid to examination for organomegaly, which suggests an infiltrative or malignant process rather than AA. Lymphadenopathy may suggest infectious etiology. Skeletal abnormalities suggest a congenital cause.

3. Laboratory, radiographic and other tests that are likely to be useful in diagnosing the cause of this problem.

The following tests aid in narrowing the differential diagnosis for AA:

Reticulocyte count in conjunction with complete blood count (CBC) demonstrating pancytopenia can determine hypoproliferation of bone marrow. Lactate dehydrogenase (LDH), haptoglobin and Coombs test may also help in investigating for hemolysis. Tests for liver function are also needed.
In AA, the peripheral smear should demonstrate morphologically normal cells. The peripheral smear is helpful in distinguishing an infiltrative process from bone marrow failure. Teardrop cells, poikilocytes and leukoerythroblastic changes suggest an infiltrative process.
Bone marrow biopsy is essential in the workup of AA and classically shows profound hypocellularity with the residual cells being morphologically normal. Bone marrow biopsy can rule out other causes of pancytopenia, such as infectious or infiltrative processes. The specimen should also be sent for karyotyping.
Flow cytology of peripheral blood helps establish or rule out paroxysmal nocturnal hemoglobinuria (PNH).
Chromosome fragility test and detailed family history in patients less than 40 years old to investigate for Fanconi’s anemia.
Serologic testing for hepatitis and other viral entities, such as Epstein-Barr virus (EBV), cytomegalovirus (CMV) and HIV may be useful in finding a trigger for acquired AA.
Studies for autoimmune diseases should be pursued in cases of suspected collagen-vascular disease.
Histocompatibility (human leukocyte antigen (HLA) typing) is helpful if done at diagnosis, since availability of the information in a timely fashion is important in the management of AA.
Skeletal survey may be helpful in diagnosis of congenital AA.

C. Criteria for Diagnosing Each Diagnosis in the Method Above

AA is diagnosed by the presence of low reticulocyte percentage with anemia, coupled with leukopenia and thrombocytopenia, without qualitative cell abnormalities on peripheral smear and with hypocellular marrow (less than 30% cellular in patients younger than 60 and less than 20% in patients older than 60).

Staging of aplastic anemia is based on the criteria of the International Aplastic Anemia Study Group as follows:

Blood

– Neutrophils less than 0.5 x 10⁹/L

– Platelets less than 20 x 10⁹/L

– Reticulocytes less than 1% corrected (percentage of actual hematocrit (Hct) to normal Hct)

Marrow

– Severe hypocellularity

– Moderate hypocellularity, with hematopoeitic cells representing less than 30% of residual cells

Severe aplasia is defined as including any two or three peripheral blood criteria and either marrow criterion
Very severe aplastic anemia is a subclassification of individuals with neutrophils counts below 0.2 x 10⁹. This group is less likely to respond to immunosuppressive therapy.

Myelodysplastic syndrome may show specific cell abnormalities such as dysplastic megakaryocytes, Pelger-Huet cells, and immature cells on peripheral smear. Demonstration of specific clonal cytogenetic abnormalities, such as trisomies of chromosome 8 or 21 and deletions of 5, 7 and 20 are diagnostic.

Hypocellular leukemia may also have immature cells in the peripheral blood and should have specific clonal cytogenetic abnormalities.

Hairy cell leukemia has a “dry tap” with increased fibrosis and eosinophilic material on biopsy. The diagnosis includes positive tartrate-resistant acid phosphatase or flow cytometry for chronotropic dose 25 (CD25).

Anorexia nervosa, when accompanied by cytopenia, may have a hypocellular bone marrow with replacement by eosinophilic material.

Vitamin B12 and folate deficiency typically have megaloblastic changes, measurable serologic deficiency, and hypercellular bone marrow.

PNH is diagnosed by having decreased glycosylphosphatidylinositol anchor protein (CD59) on flow cytometry.

Fanconi’s anemia is associated with physical abnormalities such as microcephaly, hypogonadism, internal strabismus, hyperreflexia, and malformations of the thumb and kidney. The diagnosis includes chromosome fragility, i.e. damage to chromosomes with exposure to the deoxyribonucleic acid (DNA) cross-linking agent diepoxybutane.

HIV/acquired immune deficiency syndrome (AIDS) can be associated with cytopenias, morphologic abnormalities and hypocellular bone marrow in 10% of cases.

D. Over-utilized or “wasted” diagnostic tests associated with the evaluation of this problem.

N/A

III. Management while the Diagnostic Process is Proceeding

A. Management of aplastic anemias.

Any potentially offending agent should promptly be withdrawn. Some medication-induced aplasia will resolve with withdrawal of the agent. Pregnancy-associated aplastic anemia may resolve upon delivery.

Supportive Care

Supportive care for AA includes transfusion of packed red blood cells (PRBC) for symptoms of anemia and of transfusion of platelets for severe thrombocytopenia or bleeding. Neutropenic precautions may be instituted. Neutropenic fever should be treated appropriately. Growth factors are not standard supportive care, but may be considered in dire cases.

Treatment

AA can be cured with hematopoetic stem cell transplant (HSCT) and can be successfully treated with immunosuppressive therapy (IST).

Currently, HSCT is the treatment of choice if the patient can tolerate it. HSCT is the preferred treatment for inherited AA. For acquired AA, HSCT is indicated in patients <50 years old with a well-matched donor.

Of note, a recent Cochrane review (2013) reported insufficient data to make a firm conclusion on the comparative effectiveness of HSCT compared to IST.

Success of stem cell transplant depends on a number of factors, among them prior sensitization to blood products, including non-HLA tissue antigens. Therefore, it is imperative that candidates for transplant receive transfusion only sparingly, be transfused with irradiated, leukocyte-depleted products and not receive products from family members. In addition, if the patient is CMV-negative, CMV-negative blood products should be used.

Immunosuppressive therapy, chosen in patients who cannot receive transplant, typically involves a combination of anti-thymocyte globulin (ATG), cyclosporine, and prednisone. Response to immunosuppressive therapy is delayed, and often seen after 3-4 months.

Rescue therapies for patients with refractory disease are currently being studied and include thrombopoietin mimetics such as eltrombopag.

B. Common Pitfalls and Side-Effects of Management of this Clinical Problem

Again, supportive care includes transfusion of irradiated, leukocyte-depleted blood products that are CMV-negative if the patient is. Complications may include transfusion-induced iron overload and platelet refractoriness.

ATG can result in serum sickness, usually 7-10 days after the first dose. Further treatment may require desensitization or substitution of rabbit ATG for horse ATG. Cyclosporine can cause renal impairment and neurologic toxicity.

In patients receiving stem cell transplant, the goal is cure, but graft-versus-host disease and infection are common. With immunosuppressive therapy, long-term transfusion-free survival can be achieved in the majority of patients. Late clonal disorders, such as PNH, myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML), can occur after immunosuppressive therapy.

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