Aplastic anemia

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-In-Chief: Priyamvada Singh, M.D. [2] Nazia Fuad M.D.

Anemia is the condition of having fewer red blood cells than normal, or fewer than needed to function properly. Typically, anemia refers to low red blood cell counts, but aplastic anemia patients have lower counts of all three blood cell types: red blood cells, white blood cells, and platelets. Bone marrow is a sponge-like tissue inside the bones. It makes stem cells that develop into red blood cells, white blood cells, and platelets. Aplastic anemia is a condition where bone marrow does not produce sufficient new cells to replenish blood cells. The term ‘aplastic’ means the marrow suffers from an aplasia that renders it unable to function properly. Red blood cells carry oxygen to all parts of your body. They also carry carbon dioxide (a waste product) to your lungs to be exhaled. White blood cells help your body fight infections. Platelets are blood cell fragments that stick together to seal small cuts or breaks on blood vessel walls and stop bleeding. It’s normal for blood cells to die. The lifespan of red blood cells is about 120 days. White blood cells live less than a day. Platelets live about 6 days. As a result, the bone marrow must constantly make new blood cells. If the bone marrow can’t make enough new blood cells, many health problems can occur. These problems include arrhythmias, an enlarged heart, heart failure, infections, and bleeding. Severe aplastic anemia can even cause death.

Paul Ehrlich in 1988 made known the notion of aplastic anemia. He narrated the case of a pregnant lady, who died of bone marrow failure. In1904 Anatole Chauffard named this disorder aplastic anemia. In 1920s and 1930s Alice Hamilton and Harrison recognised bone marrow failure in workers who were exposed to benzene in the United States. In the late 1940s and early 1950s, an epidemic of aplastic anemia started showing up in people who were recieving chloramphenicol, and then aplastic anemia has been related to many classes of drugs generally used in medical practice. Neal Young from john hopkins in 1980s introduced an immunosuppressive regimen which proved to be very effective treatment for aplastic anemia.

Aplastic anemia may be classified according to blood cell counts into 3 subgroups, moderately severe aplastic anemia or non severe AA (nSAA), severe aplastic anemia (SAA), and very severe aplastic anemia(vSAA).

Bone marrow is a spongy tissue, found within the spongy or cancellous portions of bones. It is higly vascularized and richly innervated Bone marrow is the primary site of hematopoiesis and is composed of hematopoietic cells, marrow adipose tissue, and stromal cells. The most defenitive feature in pathophysiology of aplastic anemia is loss of hematopoietic stem cells. It may be in the form of hematopoietic failure or immune mediated destruction of bone marrow. Drugs, chemicals, viruses, and different kind of mutations change the immunologic appearance of HSCs resulting in autoimmune destruction of marrow cells. AA may develop gradually into other hematologic disorder which include paroxysmal nocturnal hemoglobinuria [PNH], myelodysplastic syndromes [MDS] and acute myeloid leukemia [AML]). Clonal evolution in AA can occur due to mutations or cytogenetic abnormalities. The genes that are commonly found to be mutated are DMNT3A, ASXL1, BCOR, BCORL1, PIGA.

Common causes of aplastic anemia include hepatitis, Epstein-Barr virus, cytomegalovirus, parvovirus B19, and HIV. Medicines, such as Albendazole, Cefadroxil, Chlorpromazine, chloramphenicol , Carbamazepine, Hydroxychloroquine, Methimazole, Orphenadrine, Oxcarbazepine, Phenytoin, Quinine, Phenylbutazone, Sulindac, Sulfadiazine, Sulfasalazine, Valganciclovir hydrochloride. Other causes include radiation, chemotherapy, toxins, such as pesticides, arsenic, and benzene, and metastasis to bone marrow. Less common causes of aplastic anemia are Lupus (SLE), rheumatoid arthritis, .pregnancy, Thymoma, and collagen vascular disease.

The primary diagnostic dilemma is differentiating aplastic anemia from a hypocellular myelodysplastic syndrome.

People of all ages can develop aplastic anemia. It is more common in adolescents, young adults, and the elderly

Men and women are equally likely to develop aplastic anemia

Aplastic anemia is two to three times more common in Asians

Aplastic anemia is a rare but serious blood disorder. Common risk factors in the develpment of aplastic anemia are radiation treatment, drugs and toxin exposure, chemotherapy, PNH, and viral hepatitis. Less common risk factors are pregnancy, benzene, pesticides, rheumatoid arthritis and SLE.

Aplastic anaemia has a mixed clinical course. Untreated aplastic anemia leads to rapid death, typically within six months. Complications following development of aplastic anemia are infections, bleeding and paroxysmal nocturnal hemoglobinuria. Graft-versus-host disease and graft failure are the possible complications following bone marrow transplant in these patients. Mild cases resolve on their own requiring little or no treatment. Well-matched bone marrow transplants from siblings have been successful in young individuals with a long-term survival rate of 80%-90%

Bone marrow biopsy is the gold standard test for the diagnosis of aplastic anemia, These findings on performing bone marrow biopsy are confirmatory for aplastic anemiahypoplasia with <20% cellularity, normal maturation of all cell line, fat cells and stroma in bone marrow space. Residual hematopoietic cells are morphologically normal and hematopoiesis is not megaloblastic.

Aplastic anemia is seen as a result of hypoplastic bone marrow causing pancytopenia (anemia, neutropenia, thrombocytopenia). The history and symptoms seen are secondary to these abnormalities.

Common physical examination findings of aplastic anemia include pale color, short stature, dyspnea, petechiae ,Purpura, Ecchymoses, Jaundice, Pallor ,bruises. patients can present with, oral leukoplakia, pharyngeal ulcers, necrotizing gingivitis and tonsillitis.

Patients with aplastic anemia have a hypoplastic bone marrow (<20% cellularity), pancytopenia (transfusion-dependent anemia, thrombocytopenia, and severe neutropenia), a low reticulocyte count, and a normal maturation of all cell lines.

There are no imaging study associated with aplastic anemia.

Treatments for aplastic anemia include blood transfusions, blood and marrow stem cell transplants, and medicines.

There is no surgical treatment for aplastic anemia.

There are no primary preventive measures available for aplastic anemia.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Nazia Fuad M.D.

Paul Ehrlich in 1988 made known the notion of aplastic anemia. He narrated the case of a pregnant lady, who died of bone marrow failure. In1904 Anatole Chauffard named this disorder aplastic anemia. In 1920s and 1930s, Alice Hamilton and Harrison recognized bone marrow failure in workers who were exposed to benzene in the United States. In the late 1940s and early 1950s, an epidemic of aplastic anemia started showing up in people who were receiving chloramphenicol, and then aplastic anemia has been related to many classes of drugs generally used in medical practice. Neal Young from John Hopkins in 1980s introduced an immunosuppressive regimen which proved to be very effective treatment for aplastic anemia.

• Paul Ehrlich in 1988 made known the notion of aplastic anemia.
• He narrated the case of a pregnant lady, who died of bone marrow failure.
• In 1904, Anatole Chauffard named this disorder aplastic anemia.
• In 1920s and 1930s, Alice Hamilton and Harrison recognized bone marrow failure in workers who were exposed to benzene in the United States.
• In the late 1940s and early 1950s, an epidemic of aplastic anemia started showing up in people who were receiving chloramphenicol,
• Since late 60s, aplastic anemia has been related to many classes of drugs generally used in medical practice.
• Neal Young from John Hopkins in 1980s introduced an immunosuppressive regimen which proved to be very effective treatment for aplastic anemia.^[1]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-In-Chief: Priyamvada Singh, M.D. [2] Nazia Fuad M.D.

Aplastic anemia may be classified according to blood cell counts into 3 subgroups, moderately severe aplastic anemia or non severe AA (nSAA), severe aplastic anemia (SAA), and very severe aplastic anemia(vSAA).

Aplastic anemia may be classified according to blood cell counts into 3 subgroups:^[1]

• Moderately severe aplastic anemia or non severe AA (nSAA)
• Severe aplastic anemia (SAA)
• Very severe aplastic anemia(vSAA)

This classification is of prognostic relevance and has an influence on therapeutic procedures.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-In-Chief: Priyamvada Singh, M.D. [2] Nazia Fuad M.D.

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Bone marrow is a spongy tissue, found within the spongy or cancellous portions of bones. It is higly vascularized and richly innervated Bone marrow is the primary site of hematopoiesis and is composed of hematopoietic cells, marrow adipose tissue, and stromal cells. The most defenitive feature in pathophysiology of aplastic anemia is loss of hematopoietic stem cells. It may be in the form of hematopoietic failure or immune mediated destruction of bone marrow. Drugs, chemicals, viruses, and different kind of mutations change the immunologic appearance of HSCs resulting in autoimmune destruction of marrow cells. AA may develop gradually into other hematologic disorder which include paroxysmal nocturnal hemoglobinuria [PNH], myelodysplastic syndromes [MDS] and acute myeloid leukemia [AML]). Clonal evolution in AA can occur due to mutations or cytogenetic abnormalities. The genes that are commonly found to be mutated are DMNT3A, ASXL1, BCOR, BCORL1, PIGA.

The normal physiology of bone marrow can be understood as follows:^[1]

• Bone marrow is a spongy tissue, found within the spongy or cancellous portions of bones
• It is higly vascularized and richly innervated
• Bone marrow is the primary site of hematopoiesis.
• It is composed of hematopoietic cells, marrow adipose tissue, and stromal cells.
• Hematopoietic stem cells (HSC) in the bone marrow are the source of all mature cells in the peripheral blood and tissues and are multipotent.
• HSC are recognized and isolated according to their immunophenotype.
• HSCs make a small population within the CD34+/CD38 fraction of bone marrow cells.
• The hematopoiesis is controlled by a various regulatory mechanisms, including growth factors.
• The normal bone marrow structure can be damaged or displaced by aplastic anemia, malignancies or infections.
• This leads to decrease production of blood cells and blood platelets.

.

The most defenitive feature in pathophysiology of aplastic anemia is loss of hematopoietic stem cells.^[2][3]

Pathophysiologic mechanisms that result in loss of HSCs and cause aplastic anemia include:

• CD34 cells are almost absent aplastic anemia.
• Progenitor cells capable of forming erythroid, myeloid, and megakaryocytic are greatly reduced.
• The primitive hematopoietic cells which are closely related to stem cells are consistently deficient.
• The white blood cells in aplastic anemia have short telomeres.
• Telomeres are repeats at the end of eukaryotic chromosome and are essential for chromosome protection and complete DNA replication.

• • Drugs, chemicals, viruses, and different kind of mutations change the immunologic appearance of HSCs resulting in autoimmune destruction of marrow cells.^[4]
  • In patients with acquired aplastic anemia, lymphocytes are responsible for the destruction of the hematopoietic cells.
  • These T cells produces an inhibitory factor, interferons , tumor necrosis factor, and interleukin-2, resulting in hematopoietic cell death by apoptosis.
  • CD4+CD25+FOXP3+ regulatory T cells are deficient in these patients, similar to what is seen in other autoimmune conditions.
  • Deficiency of these regulatory T cells result in increase of T-bet protein levels in T cells, increased interferon (IFN)-γ,2 and stem cell destruction.
  • Increased immune response, including tumor necrosis factor -α, IFNγ, and interleukin-6, are also very common in AA patients.

• AA may develop gradually into other hematologic disorder which include^[3]

• • Paroxysmal nocturnal hemoglobinuria
  • Myelodysplastic syndromes
  • Acute myeloid leukemia

• Clonal evolution in AA can occur due to mutations or cytogenetic abnormalities.

• The genes that are commonly found to be mutated are
  • DMNT3A
  • ASXL1
  • BCOR
  • BCORL1
  • PIGA

Genes involved in the pathogenesis of aplastic anemia include:^[3]

• HLA-DR15
• CD4+ CD25+ FOXP3+ regulatory T cells
• STAT3
• TERT
• TERC

Aplastic anemia is associated with following conditions:^[4]

• Fanconi’s anemia
• PNH Paroxysmal Nocturnal Hemoglobinuria

Aplastic anemia does not exhibit any gross pathology

In aplastic anemia bone marrow microscopy reveals hypo and even acellularity, adipose tissue and pale stroma.^[3]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-In-Chief: Priyamvada Singh, M.D. [2]

Common causes of aplastic anemia include hepatitis, Epstein-Barr virus, cytomegalovirus, parvovirus B19, and HIV. Medicines, such as Albendazole, Cefadroxil, Chlorpromazine, chloramphenicol , Carbamazepine, Hydroxychloroquine, Methimazole, Orphenadrine, Oxcarbazepine, Phenytoin, Quinine, Phenylbutazone, Sulindac, Sulfadiazine, Sulfasalazine, Valganciclovir hydrochloride. Other causes include radiation, chemotherapy, toxins, such as pesticides, arsenic, and benzene, and metastasis to bone marrow. Less common causes of aplastic anemia are Lupus (SLE), rheumatoid arthritis, .pregnancy, Thymoma, and collagen vascular disease.

• There are no life-threatening causes of aplastic anemia.

Common causes of aplastic anemia may include:^[1]

• Idiopathic
• Infectious diseases, such as hepatitis, Epstein-Barr virus, cytomegalovirus, parvovirus B19, and HIV.
• Medicines, such as Albendazole, Cefadroxil, Chlorpromazine, chloramphenicol , Carbamazepine, Hydroxychloroquine, Methimazole, Orphenadrine, Oxcarbazepine, Phenytoin, Quinine, Phenylbutazone, Sulindac, Sulfadiazine, Sulfasalazine, Valganciclovir hydrochloride.
• Radiation
• chemotherapy
• Toxins, such as pesticides, arsenic, and benzene
• Metastasis

Less common causes of aplastic anemia include:^[1]

• Lupus (SLE)
• Rheumatoid arthritis.

• Pregnancy
• Thymoma
• Collagen vascular disease

Certain genetic conditions can damage the stem cells and lead to aplastic anemia:^[2]

• Fanconi anemia
• Shwachman-Diamond syndrome
• Dyskeratosis congenita
• Diamond-Blackfan anemia.

• Autoimmune diseases
• Albendazole
• Arsenic
• Benzene
• Ceftazidime
• Cefaclor
• Cefaclor
• Certolizumab pegol
• Chlorpropamide
• Chloramphenicol sodium succinate
• Dactinomycin
• Dapsone
• Dyskeratosis congenita
• Diamond-Blackfan anemia.
• Eltrombopag
• Fanconi anemia
• Felbamate
• Flurbiprofen
• Flucytosine
• interferon alfacon-1
• Isoniazid
• Lincomycin Hydrochloride
• Meprobamate
• Nilutamide
• Oxaprozin
• Penicillamine
• Probenecid
• pesticides
• Tolbutamide
• Tolazamide
• Sodium aurothiomalate
• Sodium phenylbutyrate
• Sulfamethoxazole/Trimethoprim
• Sulfasalazine
• Sulfacetamide
• Thymoma

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Aric Hall, M.D., Beth Israel Deaconess Medical Center, Boston, MA [2]

The primary diagnostic dilemma is differentiating aplastic anemia from a hypocellular myelodysplastic syndrome.

Aplastic anemia must be differentiated based on different laboratory findings including mean cell volume (MCV), reticulocytosis, and hemolysis.

To review the differential diagnosis of anemia, see below table.

To review the differential diagnosis of microcytic anemia, click here.

To review the differential diagnosis of normocytic anemia, click here.

To review the differential diagnosis of macrocytic anemia, click here.

To review the differential diagnosis of hypochromic anemia, click here.

To review the differential diagnosis of normochromic anemia, click here.

To review the differential diagnosis of anisochromic anemia, click here.

To review the differential diagnosis of hemolytic anemia, click here.

To review the differential diagnosis of anemia with intrinsic hemolysis, click here.

To review the differential diagnosis of anemia with extrinsic hemolysis, click here.

To review the differential diagnosis of anemia with low reticulocytosis, click here.

To review the differential diagnosis of anemia with normal reticulocytosis, click here.

To review the differential diagnosis of anemia with high reticulocytosis, click here.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-In-Chief: Priyamvada Singh, M.D. [2] Nazia Fuad M.D.

Aplastic anemia is a rare condition with incidence of two cases per million individuals per year in Western countries with rates two to three times as high in Asia.

• Incidence is two cases per million individuals per year in Western countries^[1]

• People of all ages can develop aplastic anemia.
• Common in adolescents, young adults, and the elderly.^[1]

Men and women are equally likely to develop aplastic anemia

In a population-based Australian cohort of 3273 adult the cumulative incidence of late mortality was 22.2% at 10 years.

• Two to three times more common in Asians.

Incidence of aplastic anemia is 3 times higher in asia.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-In-Chief: Priyamvada Singh, M.D. [2]

Aplastic anemia is a rare but serious blood disorder. Common risk factors in the develpment of aplastic anemia are radiation treatment, drugs and toxin exposure, chemotherapy, PNH, and viral hepatitis. Less common risk factors are pregnancy, benzene, pesticides, rheumatoid arthritis and SLE.

• Common risk factors in the development of aplastic anemia include:^[1]
  • High dose radiation treatment
  • Drugs and toxin exposure
  • Chemotherapy
  • Paroxysmal nocturnal hemoglobinuria (PNH)
  • Recent hepatitis

• Less common risk factors in the development of aplastic anemia include:^[1]
  • Pregnancy
  • Benzene
  • Pesticides
  • Rheumatoid arthritis
  • SLE

There is no direct screening for aplastic anemia but screening can be done for the underlying causes of the disease.

There is no direct screening for aplastic anemia but screening can be done for the underlying causes of the disease.

Editor(s)-in-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-In-Chief: Priyamvada Singh, M.D. [2] Nazia Fuad M.D.

Aplastic anaemia has a mixed clinical course. Untreated aplastic anemia leads to rapid death, typically within six months. Complications following development of aplastic anemia are infections, bleeding and paroxysmal nocturnal hemoglobinuria. Graft-versus-host disease and graft failure are the possible complications following bone marrow transplant in these patients. Mild cases resolve on their own requiring little or no treatment. Well-matched bone marrow transplants from siblings have been successful in young individuals with a long-term survival rate of 80%-90%.

• Aplastic anaemia has a mixed clinical course. ^[1]
• Some patients develop mild symptoms that require little or no therapy.
• Others develop life-threatening pancytopenia presenting with a medical emergency.
• Untreated aplastic anemia leads to rapid death, typically within six months.

Aplastic anemia patients can develop following complications:^[2]

• Infections
• Bleeding
• paroxysmal nocturnal hemoglobinuria (PNH, anemia with thrombopenia and/or thrombosis)
• Graft-versus-host disease
• Graft failure.
• Myelodysplastic syndrome

• Correct and prompt diagnosis with early therapy improves the 5 year survival rate.^[3]
• Occasionally, milder cases of the disease resolve on their own.
• Relapses of previously controlled disease are, much more common.
• Well-matched bone marrow transplants from siblings have been successful in young, otherwise healthy people, with a long-term survival rate of 80%-90%.
• Most successful BMT recipients eventually reach a point where they consider themselves cured for all practical purposes, although they need to be compliant with follow-up care permanently.
• Older people (who are generally too frail to undergo bone marrow transplants) and people who are unable to find a good bone marrow match have five year survival rate of up to 75%.