Aplastic Anemia

Aplastic anemia is a condition that occurs when your body stops producing enough new blood
cells. Aplastic anemia leaves you feeling fatigued and with a higher risk of infections and
uncontrolled bleeding.
A rare and serious condition, aplastic anemia can develop at any age. Aplastic anemia may occur
suddenly, or it can occur slowly and get worse over a long period of time. Treatment for aplastic
anemia may include medications, blood transfusions or a stem cell transplant.

Symptoms
By Mayo Clinic Staf

Aplastic anemia symptoms may include:

Fatigue

Shortness of breath with exertion

Rapid or irregular heart rate

Pale skin

Frequent or prolonged infections

Unexplained or easy bruising

Nosebleeds and bleeding gums

Prolonged bleeding from cuts

Skin rash

Dizziness

Headache

Aplastic anemia can progress slowly over weeks or months, or it may come on suddenly. The
illness may be brief, or it may become chronic. Aplastic anemia can be very severe and even
fatal.

Causes
By Mayo Clinic Staf

Aplastic anemia develops when damage occurs to your bone marrow, slowing or shutting down
the production of new blood cells. Bone marrow is a red, spongy material inside your bones that
produces stem cells, which give rise to other cells. Stem cells in the bone marrow produce blood
cells red cells, white cells and platelets. In aplastic anemia, the bone marrow is described in
medical terms as aplastic or hypoplastic meaning that it's empty (aplastic) or contains very
few blood cells (hypoplastic).
Factors that can temporarily or permanently injure bone marrow and affect blood cell production
include:

Radiation and chemotherapy treatments. While these cancer-fighting

therapies kill cancer cells, they can also damage healthy cells, including stem
cells in bone marrow. Aplastic anemia can be a temporary side efect of these
treatments.

Exposure to toxic chemicals. Exposure to toxic chemicals, such as some

used in pesticides and insecticides, may cause aplastic anemia. Exposure to
benzene an ingredient in gasoline also has been linked to aplastic
anemia. This type of anemia may get better on its own if you avoid repeated
exposure to the chemicals that caused your initial illness.

Use of certain drugs. Some medications, such as those used to treat

rheumatoid arthritis and some antibiotics, can cause aplastic anemia.

Autoimmune disorders. An autoimmune disorder, in which your immune

system begins attacking healthy cells, may involve stem cells in your bone
marrow.

A viral infection. Viral infections that afect bone marrow may play a role in
the development of aplastic anemia in some people. Viruses that have been
linked to the development of aplastic anemia include hepatitis, Epstein-Barr,
cytomegalovirus, parvovirus B19 and HIV.

Pregnancy. Aplastic anemia that occurs in pregnancy may be related to an

autoimmune problem your immune system may attack your bone marrow
during pregnancy.

Unknown factors. In many cases, doctors aren't able to identify the cause
of aplastic anemia. This is called idiopathic aplastic anemia.

Confusion with myelodysplastic syndrome

Aplastic anemia can be mistaken for a condition called myelodysplastic syndrome. In this group
of disorders, the bone marrow produces new blood cells, but they're deformed and
underdeveloped. The bone marrow in myelodysplastic syndrome is sometimes called
hyperplastic meaning that it's packed with blood cells. But some people with myelodysplastic
syndrome have empty marrow that's difficult to distinguish from aplastic anemia.

Connections with other rare disorders

Some people with aplastic anemia also have a rare disorder known as paroxysmal nocturnal
hemoglobinuria. This disorder causes red blood cells to break down too soon. Paroxysmal
nocturnal hemoglobinuria can lead to aplastic anemia, or aplastic anemia can evolve into
paroxysmal nocturnal hemoglobinuria.
Fanconi's anemia is a rare, inherited disease that leads to aplastic anemia. Children born with it
tend to be smaller than average and have birth defects, such as underdeveloped limbs. The
disease is diagnosed with the help of blood tests.

Risk factors
By Mayo Clinic Staf

Aplastic anemia is rare. Factors that may increase your risk include:

Treatment with high-dose radiation or chemotherapy for cancer

Exposure to toxic chemicals

The use of some prescription drugs such as chloramphenicol, which is used

to treat bacterial infections, and gold compounds used to treat rheumatoid
arthritis

Certain blood diseases, autoimmune disorders and serious infections

Pregnancy, rarely

Preparing for your appointment

By Mayo Clinic Staf

If you have signs or symptoms of aplastic anemia, start by making an appointment with your
family doctor or a general practitioner. If your doctor suspects aplastic anemia, you'll likely be
referred to a doctor who specializes in treating blood disorders (hematologist). If aplastic anemia
comes on suddenly, you may begin treatment in the emergency room.
Here's some information to help you get ready for your appointment, and what to expect from
your doctor.
What you can do

Write down any symptoms you're experiencing, including any that may
seem unrelated to the reason for which you scheduled the appointment.

Write down key personal information, including any recent life changes,
such as a new job, particularly one that exposes you to chemicals.

Make a list of all medications, as well as any vitamins or supplements,

that you're taking.

Ask a family member or a friend to stay with you while you talk to your
doctor. You may be tired or overwhelmed by all the information. A friend or a
family member can take notes for you, or bring up questions you may forget
to ask.

Write down questions you want to ask your doctor.

Preparing a list of questions ahead of time can help you make the most of your time together. For
aplastic anemia, some basic questions to ask your doctor include:

What's the most likely cause of my symptoms?

Are there other possible causes for my symptoms?

What's my prognosis?

What treatments are available, and which do you recommend?

Are there any alternatives to the primary approach that you're suggesting?

I have another health condition. How can I best manage them together?

Are there any brochures or other printed material that I can take with me?
What websites do you recommend?

In addition to the questions that you've prepared to ask your doctor, don't hesitate to ask
questions during your appointment.
What to expect from your doctor

Your doctor is likely to ask you a number of questions, such as:

Have you had any infections?

Have you had any unexpected bleeding?

Have you felt more tired than usual?

When did you begin experiencing symptoms?

Is there anything new in your life, such as a new job or a new medication?

Does anything seem to improve your symptoms?

Does anything appear to worsen your symptoms?

Tests and diagnosis

By Mayo Clinic Staf

To diagnose aplastic anemia, your doctor may recommend:

Blood tests. Normally, red blood cell, white blood cell and platelet levels
stay within a certain range. Your doctor may suspect aplastic anemia when all
three of these blood cell levels are very low.

Bone marrow biopsy. To confirm a diagnosis, you'll need to undergo a bone

marrow biopsy. In this procedure, a doctor uses a needle to remove a small
sample of bone marrow from a large bone in your body, such as your
hipbone. The bone marrow sample is examined under a microscope to rule
out other blood-related diseases. In aplastic anemia, bone marrow contains
fewer blood cells than normal.

Once you've received a diagnosis of aplastic anemia, you may need additional tests to determine
an underlying cause.

Treatments and drugs

By Mayo Clinic Staf

Treatments for aplastic anemia may include observation for mild cases, blood transfusions and
medications for more-serious cases, and in severe cases, bone marrow transplantation. Severe
aplastic anemia, in which your blood cell counts are extremely low, is life-threatening and
requires immediate hospitalization for treatment.
Blood transfusions

Treatment for aplastic anemia usually involves blood transfusions to control bleeding and relieve
anemia symptoms. Blood transfusions aren't a cure for aplastic anemia. But they do relieve signs
and symptoms by providing blood cells that your bone marrow isn't producing. A transfusion
may include:

Red blood cells. Transfusions of red blood cells raise red blood cell counts.
This helps relieve anemia and fatigue.

Platelets. Transfusions of platelets help prevent excessive bleeding.

While there's generally no limit to the number of blood cell transfusions you can have,
complications can sometimes arise with multiple transfusions. Transfused red blood cells contain
iron that can accumulate in your body and can damage vital organs if an iron overload isn't
treated. Medications can help your body get rid of excess iron. Another possible complication is
that over time, your body may develop antibodies to transfused blood cells, making them less

effective at relieving symptoms. However, the use of immunosuppressant medication makes this
complication less likely.
Stem cell transplant

A stem cell transplant to rebuild the bone marrow with stem cells from a donor may offer the
only successful treatment option for people with severe aplastic anemia. A stem cell transplant,
which is also called a bone marrow transplant, is generally the treatment of choice for people
who are younger and have a matching donor most often a sibling.
If a donor is found, your diseased bone marrow is first depleted with radiation or chemotherapy.
Healthy stem cells from the donor are filtered from the blood. The healthy stem cells are injected
intravenously into your bloodstream, where they migrate to the bone marrow cavities and begin
generating new blood cells. The procedure requires a lengthy hospital stay. After the transplant,
you'll receive drugs to help prevent rejection of the donated stem cells.
A stem cell transplant carries risks. There's a chance that your body may reject the transplant,
leading to life-threatening complications. In addition, not everyone is a candidate for
transplantation or can find a suitable donor.
Immunosuppressants

For people who can't undergo a bone marrow transplant or for those whose aplastic anemia may
be due to an autoimmune disorder, treatment may involve drugs that alter or suppress the
immune system (immunosuppressants).
Drugs such as cyclosporine (Gengraf, Neoral, Sandimmune) and anti-thymocyte globulin
(Thymoglobulin) are examples. These drugs suppress the activity of immune cells that are
damaging your bone marrow. This helps your bone marrow recover and generate new blood
cells. Cyclosporine and anti-thymocyte globulin are often used in combination.
Corticosteroids, such as methylprednisolone (Medrol, Solu-Medrol), are often given at the same
time as these drugs.
Immune-suppressing drugs can be very effective at treating aplastic anemia. The downside is that
these drugs further weaken your immune system. It's also possible that after you stop taking
these drugs, aplastic anemia may return.
Bone marrow stimulants

Certain drugs including colony-stimulating factors, such as sargramostim (Leukine),

filgrastim (Neupogen) and pegfilgrastim (Neulasta), and epoetin alfa (Epogen, Procrit) may
help stimulate the bone marrow to produce new blood cells. Growth factors are often used in
combination with immune-suppressing drugs.

Antibiotics, antivirals

Having aplastic anemia weakens your immune system. You have fewer white blood cells in
circulation to fight off germs. This leaves you susceptible to infections.
At the first sign of infection, such as a fever, see your doctor. You don't want the infection to get
worse, because it could prove life-threatening. If you have severe aplastic anemia, your doctor
may give you antibiotics or antiviral medications to help prevent infections.
Other treatments

Aplastic anemia caused by radiation and chemotherapy treatments for cancer usually improves
once you complete those treatments. The same is true for most other drugs that induce aplastic
anemia.
Pregnant women with aplastic anemia are treated with blood transfusions. For many women,
pregnancy-related aplastic anemia improves once the pregnancy ends. If that doesn't happen,
treatment is still necessary.

Lifestyle and home remedies

By Mayo Clinic Staf

If you have aplastic anemia, take care of yourself by:

Resting when you need to. Anemia can cause fatigue and shortness of
breath with even mild exertion. Take a break and rest when you need to.

Avoiding contact sports. Because of the risk of bleeding associated with a

low platelet count, avoid activities that may result in a cut or fall.

Protecting yourself from germs. You can reduce your risk of infections
with frequent hand-washing and by avoiding sick people. If you develop a
fever or other indicators of an infection, see your doctor for treatment.

Coping and support

By Mayo Clinic Staf

Tips to help you and your family better cope with your illness include:

Research your disease. The more you know, the better prepared you'll be
to make treatment decisions.

Ask questions. Be sure to ask your doctor about anything related to your
disease or treatment that you don't understand. It may help you to record or
write down what your doctor tells you.

Be vocal. Don't be afraid to express any concerns you have to your doctor or
any other health care professional treating you.

Seek support. Ask family and friends for emotional support. Ask them to
consider becoming blood donors or bone marrow donors. Consider joining an
aplastic anemia support group. It may be helpful to talk to others coping with
the disease. Ask your doctor if he or she knows of any local support groups,
or contact the Aplastic Anemia & MDS International Foundation. It ofers a
peer support network and can be reached at 800-747-2820.

Take care of yourself. Proper nutrition and sleep are important to optimize
blood production.

Prevention
By Mayo Clinic Staf

There's generally no prevention for most cases of aplastic anemia. However, avoiding exposure
to insecticides, herbicides, organic solvents, paint removers and other toxic chemicals may lower
your risk of the disease.

Aplastic Anemia (e-Medicine)

Practice Essentials
Aplastic anemia is a syndrome of bone marrow failure characterized by peripheral pancytopenia
and marrow hypoplasia. Although the anemia is often normocytic, mild macrocytosis can also be
observed in association with stress erythropoiesis and elevated fetal hemoglobin levels.
Essential update: FDA approves thrombopoietin receptor agonist for
second-line treatment of severe aplastic anemia

The FDA has approved a supplemental new drug application for eltrombopag (Promacta), an oral
thrombopoietin receptor agonist, for the treatment of severe aplastic anemia in patients who fail
to respond adequately to immunosuppressive therapy. Eltrombopag is already approved for the
treatment of thrombocytopenia in patients with refractory chronic immune thrombocytopenia and
for use in patients with chronic hepatitis C.[1]
Approval for the new application was based on a study of 43 patients with severe aplastic anemia
who had had an insufficient response to at least one prior immunosuppressive therapy. In the
study, eltrombopag administered at 50 mg once daily for 2 weeks and increased to a maximum
dose of 150 mg once daily resulted in a hematologic response in platelets, red blood cells, or
white blood cells after week 12 in 40% of patients.[1]
In an extension phase, eight patients achieved a multilineage response. Four of those patients
subsequently tapered off treatment and maintained their response during a median follow-up of
8.1 months. Nausea, fatigue, cough, diarrhea, and headache were the most common adverse
reactions, and 8 patients developed new cytogenetic abnormalities.[1]
Signs and symptoms

The clinical presentation of patients with aplastic anemia includes symptoms related to the
decrease in bone marrow production of hematopoietic cells (see the image below). The onset is
insidious, and the initial symptom is frequently related to anemia or bleeding, although fever or
infections may be noted at presentation.

Low power, H and E showing a hypocellular bone marrow with increased adipose tissue and decreased
hematopoietic cells in the marrow space.

Signs and symptoms of aplastic anemia may include the following:

Pallor

Headache

Palpitations, dyspnea

Fatigue

Foot swelling

Gingival bleeding, petechial rashes

Overt and/or recurrent infections

Oropharyngeal ulcerations

A subset of patients with aplastic anemia present with jaundice and evidence of clinical hepatitis.
[2, 3]

See Clinical Presentation for more detail.

Diagnosis

Testing
Laboratory testing for suspected aplastic anemia includes the following:

Complete blood count

Peripheral blood smears

Hemoglobin electrophoresis and blood-group testing

Biochemical profile

Serology for hepatitis and other viral entities

Autoimmune-disease evaluation for evidence of collagen-vascular disease

Fluorescence-activated cell sorter profiling

Fluorescent-labeled inactive toxin aerolysin testing

Diepoxybutane incubation

Histocompatibility testing

Kidney function studies

Liver function studies

Transaminase, bilirubin, and lactic dehydrogenase levels

Procedures
Bone marrow biopsy is performed in addition to aspiration to assess cellularity qualitatively and
quantitatively. Bone marrow culture may be useful in diagnosing mycobacterial and viral
infections; however, the yield is generally low.
See Workup for more detail.
Management

Severe or very severe aplastic anemia is a hematologic emergency, and care should be instituted
promptly. Clinicians must stress the need for patient compliance with therapy. The specific
medications administered depend on the choice of therapy and whether it is supportive care only,
immunosuppressive therapy, or hematopoietic cell transplantation.
Pharmacotherapy
The following medications are used in patients with aplastic anemia:

Immunosuppressive agents (eg, cyclosporine, methylprednisolone, equine

antithymocyte globulin, rabbit antithymocyte globulin, cyclophosphamide,
alemtuzumab)

Hematopoietic growth factors (eg, eltrombopag, sargramostim, filgrastim)

Antimetabolite (purine) antineoplastic agents (eg, fludarabine)

Chelating agents (eg, deferoxamine, deferasirox)

Nonpharmacotherapy
Nonpharmacologic management of aplastic anemia includes the following:

Supportive care

Blood transfusions with blood products that have undergone leukocyte

reduction and irradiation

Hematopoietic cell transplantation

Surgical option
Central venous catheter placement is required before the administration of hematopoietic cell
transplantation.
See Treatment and Medication for more detail.

Background
Aplastic anemia is a syndrome of bone marrow failure characterized by peripheral pancytopenia
and marrow hypoplasia. Although often normocytic, mild macrocytosis can also be observed in
association with stress erythropoiesis and elevated fetal hemoglobin levels.
Paul Ehrlich introduced the concept of aplastic anemia in 1888 when he studied the case of a
pregnant woman who died of bone marrow failure. However, it was not until 1904 that Anatole
Chauffard named this disorder aplastic anemia. (See Etiology.)
For more information, see the Medscape Reference articles Anemia, Chronic Anemia,
Megaloblastic Anemia, Myelophthisic Anemia, Hemolytic Anemia, and Sideroblastic Anemias.

Etiology
The theoretical basis for marrow failure includes primary defects in or damage to the stem cell or
the marrow microenvironment.[4, 5, 6] The distinction between acquired and inherited disease may
present a clinical challenge, but more than 80% of cases are acquired. In acquired aplastic
anemia, clinical and laboratory observations suggest that this is an autoimmune disease.
On morphologic evaluation, the hematopoietic elements in the bone marrow are less than 25%,
and they are largely replaced with fat cells. Flow cytometry shows that the CD34 cell population,
which contains the stem cells and the early committed progenitors, is substantially reduced.[5, 7]
Data from in vitro colony-culture assays suggest profound functional loss of the hematopoietic
progenitors, so much so that they are unresponsive even to high levels of hematopoietic growth
factors.
Previously, it had been hypothesized that aplastic anemia may be due to a defect at various
levels, such as an intrinsic defect of hematopoietic cells, external injury to hematopoietic cells,
and defective stroma, which is critical for normal proliferation and functioning of hematopoietic
cells. Theoretically, all of these mechanisms could be responsible for aplastic anemia. This
theory was the basis of many in vitro stem cell culture experiments using a crossover design in

which stem cells from patients with aplastic anemia were cultured with normal stroma and vice
versa. The conclusions from these studies led to the understanding that stem cell defect is the
central mechanism in the majority of patients with aplastic anemia.[8, 9]
In patients with severe aplastic anemia (SAA), stromal cells have normal function, including
growth factor production. Adequate stromal function is implicit in the success of hematopoietic
cell transplantation (HCT) in aplastic anemia, because the stromal elements are almost entirely
(frequently) of host origin.
The role of an immune dysfunction was suggested in 1970, when autologous recovery was
documented in a patient with aplastic anemia who failed to engraft after HCT. Mathe proposed
that the immunosuppressive regimen used for conditioning promoted the return of normal
marrow function. Since then, numerous studies have shown that, in approximately 70% of
patients with acquired aplastic anemia, immunosuppressive therapy improves marrow function.[6,
10, 11, 12, 13]

Immunity is genetically regulated (by immune response genes), and it is also influenced by
environment (eg, nutrition, aging, previous exposure).[14, 15] Although the inciting antigens that
breach immune tolerance with subsequent autoimmunity are unknown, human leukocyte antigen
(HLA)-DR2 is overrepresented among European and United States patients with aplastic anemia,
and its presence is predictive of a better response to cyclosporine.
Suppression of hematopoiesis is likely mediated by an expanded population of CD8+ HLA-DR+,
cytotoxic T lymphocytes (CTLs) that are frequently detectable in the blood and bone marrow of
patients with aplastic anemia. These cells produce inhibitory cytokines, such as gammainterferon and tumor necrosis factor, which can suppress progenitor cell growth. Polymorphisms
associated with an increased immune response are more prevalent in these cytokine genes in
patients with aplastic anemia. These cytokines suppress hematopoiesis by affecting the mitotic
cycle and cell killing by inducing Fas-mediated apoptosis.
In addition, such cytokines induce nitric oxide synthase and nitric oxide production by marrow
cells, which contributes to immune-mediated cytotoxicity and the elimination of hematopoietic
cells. Hirano et al reported that CD8+ cytotoxic T cells raised against kinectin-derived peptides
suppress colony forming units (CFUs) in an HLA class Irestricted fashion, findings that suggest
kinectin may be a candidate autoantigen in the pathophysiology of aplastic anemia.[16]
Constitutive expression of Tbet, a transcriptional regulator that is critical to type 1 T helper cell
(Th1) polarization, occurs in a majority of aplastic anemia patients.[10] Perforin is a cytolytic
protein expressed mainly in activated cytotoxic lymphocytes and natural-killer cells. Mutations
in the perforin gene are responsible for some cases of familial hemophagocytosis[17] ; mutations
in SAP, a gene encoding for a small modulator protein that inhibits undefined-interferon

production, underlie X-linked lymphoproliferation, a fatal illness associated with an aberrant

immune response to herpesviruses and aplastic anemia. Perforin and SAP protein levels are
markedly diminished in some cases of acquired aplastic anemia.
The transcription factors FOXP3 and NFAT1 have key roles in regulatory T-cell (Treg)
development and function, and Tregs play a role in autoimmunity. Tregs are decreased at
presentation in almost all patients with aplastic anemia; FOXP3 protein and mRNA levels also
are significantly lower in patients with this condition, whereas NFAT1 protein levels are
decreased or absent.[18]
Variations in telomere length have been reported in severe aplastic anemia, but their clinical
significance is unknown. However, although telomere length was unrelated to response, it was
associated with the risk of relapse, clonal evolution, and overall survival in patients with severe
aplastic anemia.[19]
Congenital or inherited causes

Congenital or inherited causes of aplastic anemia are responsible for at least 25% of children
with this condition and for perhaps up to 10% of adults.[20] Patients may have dysmorphic
features or physical stigmata, but marrow failure may be the initial presenting feature. Several
loci have been identified that are associated not only with increased susceptibility to aplastic
anemia but also with other physical findings.
Fanconi anemia
Fanconi anemia is characterized by the following:

Multiple congenital anomalies (60-75%): Short stature, abnormal skin

pigmentation, malformations of the thumbs with or without dysplastic or
absent radii, as well as microphthalmos and malformations of the heart,
kidneys, intestines, and ears

Bone marrow failure: Thrombocytopenia, leukopenia, or aplastic anemia;

most patients with Fanconi anemia have bone marrow failure by adulthood

Cancer: Hematologic malignancies are common with Fanconi anemia and

myelodysplasia, with acute myeloid leukemia (AML) being the most common;
solid tumors such as those in squamous cell head and neck cancer, female
genital tumors, and liver tumors are also seen; Fanconi anemia is associated
with increased chromosomal breakage and abnormal sister chromatid
exchange in the presence of agents such as diepoxybutane or mitomycin C

Predominantly autosomal recessive inheritance pattern: Fifteen genes are

now known to be causative for Fanconi anemia; only 1 of these FANCB (Xlined recessive)is not inherited in an autosomal recessive manner

Association between bone marrow progression and a complex pattern of

recurrent chromosomal abnormalities: Some chromosomal abnormalities are
commonly found in non-Fanconi anemia myelodysplastic syndrome (MDS)
and secondary acute myeloid leukemia (eg, -7/7q or RUNX1 abnormalities),
whereas others are specific for Fanconi anemia (eg, 1q+ and 3q+)

Dyskeratosis congenita
Dyskeratosis congenita is characterized by the diagnostic physical triad of dysplastic nails, lacy
reticular pigmentation of the upper torso, and oral leukoplakia. However, over the past decade, it
has been increasingly recognized that patients may have dyskeratosis congenita without the triad.
The following are also features of this condition:

Some signs of premature aging, such as early graying of the hair

Progressive bone marrow failure at any age, which can cause any
combination of cytopenias, including aplastic anemia

Malignancy: Common; frequently MDS or AML; solid tumors such as head and
neck cancer or genital cancers can also be seen

Pulmonary fibrosis

Autosomal dominant, autosomal recessive, and X-linked inheritance patterns;

6 genes are known to cause this disorder

Familial aplastic anemia

This is an isolated aplastic anemia. Mutations have been found in the TERC and TERT genes and
are thought to confer a susceptibility to aplastic anemia. These genes encode proteins that are
part of the telomerase apparatus that restores repeated regions in the telomere.[21]
Cartilage-hair hypoplasia
Cartilage-hair hypoplasia, which is caused by mutations in the RMRP gene, is inherited in an
autosomal recessive manner. This condition is characterized by the following:

Short stature with short and bowed limbs

Sparse, lightly pigmented hair

Variably severe immune deficiency

Anemia during childhood

Hematopoietic malignancies, as well as malignancies of the skin, eyes, and

liver

Gastrointestinal malformations and malabsorption

Pearson syndrome
Pearson syndrome causes sideroblastic anemia and exocrine pancreatic dysfunction. This
condition results from mitochondrial deoxyribonucleic acid (DNA) deletions.
Thrombocytopenia-absent radius syndrome
Thrombocytopenia-absent radius (TAR) syndrome is characterized by deletions located at
chromosome 1q21.1 (which are typically about 200kb in size). Patients have bilateral absence of
the radii with presence of the thumbs, as well as thrombocytopenia. Other congenital anomalies
can also occur (eg, cardiac disease, skeletal anomalies, urogenital anomalies).
Shwachman-Diamond syndrome
Shwachman-Diamond syndrome is caused by mutations in the SBDS gene and is inherited in an
autosomal recessive manner. This disease is characterized by dysfunction of the exocrine
pancreas with malabsorption and growth failure, as well as cytopenias of single or multiple
lineage. Patients with Shwachman-Diamond syndrome also have an increased risk of MDS and
AML.[22]
Dubowitz syndrome
Dubowitz syndrome is caused by an as-yet unknown gene. This condition is characterized by
intrauterine growth retardation, extremely short stature, and wizened facial appearance. Patients
also have microcephaly and mild developmental delay. Dubowitz syndrome is also associated
with eczema, immune deficiency, and aplastic anemia. Malignancy is more common with this
disorder, particularly lymphoma and neuroblastoma.
Diamond-Blackfan anemia
Diamond-Blackfan anemia (DBA) is characterized by a normochromic macrocytic anemia that
can be isolated, or it can be associated with growth retardation or congenital malformation in the
upper limbs, heart, and genitourinary systems. In a small minority of patients, DBA can progress
to aplastic anemia. Nine genes have been found to be causative for DBA, and they are inherited
in an autosomal dominant manner.[23] Approximately 50% of cases are inherited from a parent,
and about 50% result from de novo mutations.

Acquired causes

Acquired causes of aplastic anemia (80%) include the following:

Idiopathic factors

Infectious causes, such as hepatitis viruses, Epstein-Barr virus (EBV), human

immunodeficiency virus (HIV), parvovirus, and mycobacteria

Toxic exposure to radiation and chemicals, such as benzene

Transfusional graft versus host disease (GVHD)

Orthotopic liver transplantation for fulminant hepatitis

Pregnancy

Eosinophilic fasciitis

Anorexia

Severe nutritional deficiencies (B12, folate)

Paroxysmal nocturnal hemoglobinuria (PNH)

MDS

Acute lymphoblastic leukemia (ALL)(rarely)

Drugs and elements (eg, chloramphenicol, phenylbutazone, gold) may cause aplasia of the
marrow. The immune mechanism does not account for the marrow failure in idiosyncratic drug
reactions. In such cases, direct toxicity may occur, perhaps due to genetically determined
differences in metabolic detoxification pathways. For example, the null phenotype of certain
glutathione transferases is overrepresented among patients with aplastic anemia.
PNH is caused by an acquired genetic defect affecting the PIGA gene and limited to the stem cell
compartment. Mutations in the PIGA gene render cells of hematopoietic origin sensitive to
increased complement lysis. Approximately one third of patients with aplastic anemia have
evidence of PNH at presentation, as detected by means of flow cytometry.[24] Furthermore,
patients whose disease responds after immunosuppressive therapy may recover with clonal
hematopoiesis and PNH.

Epidemiology
United States statistics

No accurate prospective data are available regarding the incidence of aplastic anemia in the
United States. Findings from several retrospective studies usually overlap those from Europe and
suggest that the incidence is 0.6-6.1 cases per million population; this rate is largely based on
data from retrospective reviews of death registries.
International statistics

The annual incidence of aplastic anemia in Europe, as detailed in large, formal epidemiologic
studies, is 2 cases per million population.[25] Aplastic anemia is thought to be more common in
Asia than in the West. The incidence was accurately determined to be 4 cases per million
population in Bangkok,[26] but based on prospective studies, it may actually be closer to 6 cases
per million population in the rural areas of Thailand. This increased incidence may be related to
environmental factors, such as increased exposure to toxic chemicals, rather than to genetic
factors, because this increase is not observed in people of Asian ancestry who are living in the
United States.
Race-, sex-, and age-related demographics

Although no racial predisposition for aplastic anemia is reported in the United States, the
prevalence is increased in the Far East. The male-to-female ratio for acquired aplastic anemia is
approximately 1:1, although there are data to suggest that a male preponderance may be
observed in the Far East.
Although aplastic anemia occurs in all age groups, a small peak in the incidence is observed in
childhood because of the inclusion of inherited marrow-failure syndromes. A second peak is
observed in people aged 20-25 years.

Prognosis
The outcome of patients with aplastic anemia has substantially improved because of improved
supportive care. The natural history of aplastic anemia suggests that a small number of patients
may spontaneously recover with supportive care[27] ; however, observational and/or supportive
care therapy alone is rarely indicated.
The estimated 10-year survival rate for the typical patient receiving immunosuppression is 68%,
compared with 73% for hematopoietic cell transplantation (HCT).[28] However, there is a
significantly improved outcome for HCT over time, for matched sibling and alternative donors,
and with younger age.[28] In cases of immunosuppression, relapse and late clonal disease are risks.
In a single-institution analysis of 183 patients who received immunosuppressive treatments for
severe aplastic anemia, the telomere length of peripheral blood leukocytes was unrelated to
treatment response.[19] In a multivariate analysis, however, telomere length was associated with

risk of relapse, clonal evolution, and overall survival.[19] Additional studies are needed to validate
these findings and to determine how this information might be incorporated into treatment
algorithms.
Mortality/morbidity

The major causes of morbidity and mortality from aplastic anemia include infection and
bleeding. Patients who undergo HCT have additional issues related to acute and chronic toxicity
from the conditioning regimen and graft versus host disease (GVHD), as well as a potential for
graft failure.[15, 29, 30, 31, 32, 33] In approximately 25-30% of patients with aplastic anemia, the
condition does not respond to immunosuppression. In cases with a treatment response, relapse
and late-onset clonal disease, such as paroxysmal nocturnal hemoglobinuria (PNH),
myelodysplastic syndrome (MDS), and leukemia, are risksregardless of the treatment response
or degree of response.[11, 34, 35, 36, 37]
Kulasekararaj and colleagues reported that the presence of somatic mutations (including ASXL1,
DNMT3A, and BCOR) in patients with aplastic anemia for more than 6 months was associated
with 40% risk of transformation to MDS. Nearly a fifth of patients with aplastic anemia have
mutations in genes typically seen in myeloid malignancies that predicted for later transformation
to MDS.[38]