Aplastic Anemia (AA): A Bone Marrow Failure

What is aplastic anemia?

Aplastic anemia, a rare but serious blood disorder, occurs when the bone marrow, the spongy tissue inside bones that produces blood cells, fails to produce enough new blood cells of all lineages including red blood cells, white blood cells and platelets. This deficiency can lead to life-threatening complications such as infections, bleeding, and heart problems.

In aplastic anemia, the underlying defect is a substantial reduction in the number of hematopoietic pluripotent stem cells and a fault in the remaining stem cells or an immune reaction against them, which makes them unable to divide and differentiate sufficiently to populate the bone marrow. It will cause a reduction in marrow stem cells thus inadvertently increasing the fat spaces to more than 75% of the marrow with no abnormal cells seen.

What causes bone marrow failure?

Bone marrow failure can be caused by aplastic anemia, or marrow infiltration by malignant cells or abnormal cells, ineffective erythropoiesis and abnormal tissue infiltration for example in myelofibrosis. 

Most frequent cause of bone marrow aplasia is due to drugs or radiation therapy especially in malignancy treatment where the drugs may interfere with DNA replication or other critical aspects of cell growth and are therefore toxic to normal cells in the body that are continuously proliferating. 

Myelophthisic anemia occurs when bone marrow space is secondarily invaded by one of several different types of disease processes most frequently metastatic cancer for example breast and lung carcinomas. Metastatic cancers replace the marrow and often activate marrow fibroblasts leading to extensive deposition of collagen. This reactive fibrosis distorts the marrow microenvironment thus disrupts the production of hematopoietic cells and leads to release of immature marrow elements. 

Aplastic or hypoplastic anemia is defined as pancytopenia resulting from aplasia of the bone marrow.

An image highlighting the causes of bone marrow failure, including abnormal infiltration of non-hematopoietic cells and ineffective erythropoiesis, primary reduction of all blood cells and replacement of marrow by malignant cells leading to a disruption in blood cell production.
This microscopic snapshot provides a glimpse into the pathogenesis of bone marrow failure, a condition characterized by a severe reduction in blood cell production.

What is pancytopenia?

Pancytopenia is a condition characterized by a low count of all three major types of blood cells: red blood cells, white blood cells, and platelets. This can lead to a variety of symptoms, including fatigue, weakness, shortness of breath, pale skin, easy bruising or bleeding, and frequent infections.

The causes of pancytopenia can be divided into two main categories: primary and secondary. Primary pancytopenia is caused by a problem with the bone marrow, the spongy tissue inside bones that produces blood cells. This can be due to a number of factors, including:

  • Aplastic anemia: This is a condition in which the bone marrow fails to produce enough new blood cells.
  • Leukemia: This is a type of cancer that affects the blood cells.
  • Lymphoma: This is a type of cancer that affects the white blood cells.
  • Myelodysplastic syndromes (MDS): These are a group of disorders that affect the bone marrow and blood cells.
  • Vitamin B12 deficiency: This can cause a reduction in all three types of blood cells.

Secondary pancytopenia is caused by a problem outside of the bone marrow that is affecting the production or destruction of blood cells. This can be due to a number of factors, including:

  • Infections: Some infections, such as HIV and hepatitis C, can affect the production of blood cells.
  • Medications: Some medications, such as chemotherapy drugs and antibiotics, can cause a reduction in blood cell counts.
  • Autoimmune disorders: In some cases, the immune system mistakenly attacks and destroys blood cells.
  • Radiation exposure: Exposure to radiation can damage the bone marrow and lead to pancytopenia.
  • Splenomegaly: This is an enlargement of the spleen, which can trap blood cells and reduce their numbers in the bloodstream.

What are the causes of aplastic anemia?

The exact cause of aplastic anemia is often unknown, but it is believed to involve a combination of genetic and environmental factors. 

Congenital causes of aplastic anemia include Fanconi anemia, dyskeratosis congenita, Shwachman-Diamond syndrome and Diamond-Blackfan anemia. 

Acquired causes of aplastic anemia are usually idiopathic, where the cause is unknown but secondary causes could include:

  1. Autoimmune disorders: In some cases, the immune system mistakenly attacks and destroys stem cells in the bone marrow. This is thought to be the most common cause of aplastic anemia.
  2. Viral infections: Some viruses, such as hepatitis C, parvovirus B19, and Epstein-Barr virus, have been linked to aplastic anemia.
  3. Exposure to toxins: Certain chemicals, such as benzene, pesticides, and heavy metals, have been linked to aplastic anemia.
  4. Radiation and chemotherapy: These treatments, which are often used to treat cancer, can damage the bone marrow and lead to aplastic anemia.
  5. Medications: Some medications, such as chloramphenicol and phenytoin, have been linked to aplastic anemia.
  6. Pregnancy: In some cases, a woman’s immune system may attack her own bone marrow during pregnancy. This is a rare cause of aplastic anemia.

What is the pathophysiology of idiopathic aplastic anemia (IAA)?

One of the leading hypotheses is that IAA is an autoimmune disorder in which the immune system mistakenly attacks and destroys hematopoietic stem pluripotent cells (HSPCs). This could be triggered by a viral infection or exposure to certain chemicals or medications. The immune system may also be activated by self-antigens, which are molecules that are normally found on the surface of HSPCs but are mistaken by the immune system as foreign invaders.

Another possibility is that IAA is caused by a defect in the HSPCs themselves. This could make them more susceptible to damage by the immune system or other factors. Additionally, there may be problems with the bone marrow microenvironment, which is the environment in which HSPCs develop and mature.

The exact mechanism by which HSPCs are destroyed in IAA is still unknown. However, it is thought to involve a combination of factors, including:

  • Activation of cytotoxic T cells: These are a type of white blood cell that can kill cells that are infected with viruses or other pathogens. In IAA, cytotoxic T cells may mistakenly attack HSPCs.
  • Production of cytokines: These are signaling molecules that can regulate the immune system. In IAA, the production of certain cytokines may be altered, which could lead to the activation of cytotoxic T cells and the destruction of HSPCs.
  • Apoptosis: This is a programmed cell death process that is normally used to remove damaged or unwanted cells. In IAA, apoptosis of HSPCs may be increased, leading to a further reduction in their numbers.
An illustration depicting the autoimmune assault on hematopoietic stem cells by cytotoxic T-cells, leading to the bone marrow failure characteristic of idiopathic aplastic anemia.
This microscopic snapshot provides a glimpse into the pathogenesis of idiopathic aplastic anemia, a condition shrouded in mystery. While the precise mechanisms remain elusive, this illustration highlights the role of cytotoxic T-cells in disrupting the delicate balance of hematopoiesis.

What are the clinical presentations of IAA?

Clinical presentations include

  • Signs and symptoms of anemia like jaundice, pallor, lethargy
  • Infections especially in the mouth and throat due to neutropenia
  • Bruising, bleeding gums, epistaxis and menorrhagia due to thrombocytopenia
  • Lymph nodes, liver and spleen are not enlarged. 

What are the laboratory investigations related to aplastic anemia?

  • Full blood count and peripheral blood smear: Normochromic normocytic or slight macrocytic anemia with extremely low reticulocytes count with leucopenia and thrombocytopenia 
  • Bone marrow examination: hypoplasia especially trephine biopsy with patchy cellular areas with hypocellular backgrounds (more than 75% of marrow fat). The main cells present are lymphocytes and plasma cells. 
  • Cytogenetic testing: Is necessary to differentiate from other forms of pancytopenia for example hypoplastic myelodysplasia. Myelodysplasia will show qualitative abnormalities of the cells and clonal cytogenetic changes. 
  • For patients with a positive chromosome breakage study, next generation sequencing (NGS) is used to analyze multiple causative mutations, up to 22 genes. All pathogenic and likely pathogenic variants, as well as variants of unknown (indeterminate) significance, as determined bioinformatically, are confirmed by Sanger sequencing. 

What are the treatment and management options for IAA?

The treatment and management of idiopathic aplastic anemia (IAA) depend on the severity of the condition and the patient’s overall health. The goal of treatment is to restore blood cell production and manage symptoms. For treatment purposes, the underlying cause like drugs or radiotherapy therapy treatment need to be identified and removed. 

Supportive Care

Supportive care is essential for all patients with IAA. This includes:

  • Blood and platelet concentrates transfusions: Blood transfusions are used to replace the low levels of red blood cells, white blood cells, or platelets. All blood products should be filtered to reduce the risk of alloimmunization and irradiated to prevent grafting of live donor lymphocytes.
  • Iron supplementation: Iron supplementation may be given to patients with anemia to help the body produce new red blood cells.
  • Antimicrobial prophylaxis: Antimicrobial prophylaxis may be given to patients with low white blood cell counts to prevent infections.
  • Nutritional counseling: Nutritional counseling can help patients maintain their strength and overall health.

Immunosuppressive Therapy

Immunosuppressive therapy is the primary treatment for IAA. It involves using medications to suppress the immune system and prevent it from attacking the bone marrow. The most common immunosuppressive agents used for IAA include:

  • Antithymocyte globulin (ATG): ATG is a protein that destroys certain types of white blood cells, including T cells, which are thought to play a role in the pathogenesis of IAA.
  • Cyclosporine: Cyclosporine is a medication that suppresses the immune system by interfering with the production of T cells.
  • Methotrexate: Methotrexate is a medication that interferes with the growth of cells, including T cells.

Immunosuppressive therapy is typically given for several months or even years. The goal is to achieve remission, which is when the bone marrow is producing enough blood cells on its own.

Stem Cell Transplant

A stem cell transplant is a potentially curative treatment for IAA. It involves replacing the patient’s damaged bone marrow with healthy stem cells from a donor. Stem cells can come from a matched unrelated donor, a sibling donor, or the patient’s own blood (autologous transplant).

A stem cell transplant is a complex procedure with significant risks, so it is only considered for patients with severe IAA who have not responded to other treatments.

Key Points of Aplastic Anemia 

Definition of aplastic anemia

Pancytopenia (reduction of all blood cell types: RBCs, WBCs and platelets) due to aplasia (failure) of the bone marrow to function (to produce blood cells). 

Causes of bone marrow failure

  • Primary reduction in hematopoietic cells e.g. aplastic anemia
  • Marrow replacement by malignant cells e.g. leukemia, lymphoma
  • Ineffective hematopoiesis e.g. myelodysplasia, megaloblastic anemia
  • Abnormal tissue infiltration e.g. myelofibrosis, amyloidosis

Causes of aplastic anemia

  • Congenital e.g. Fanconi anemia, dyskeratosis congenita
  • Acquired e.g. idiopathic, drugs, chemical agents, infections 

Signs and symptoms of aplastic anemia

  • Lethargy, pallor (anemia)
  • Infections especially mouth and throat (neutropenia)
  • Bruising, epistaxis, gum bleeding (thrombocytopenia)

Pathophysiology of idiopathic aplastic anemia (IAA)

Hematopoietic stem cells targeted by gamma-interferon and tumor necrosis factor secreted by cytotoxic T-cells. 

Laboratory investigations of IAA

Full blood count and peripheral blood characteristics

Full blood count: anemia, leucopenia, thrombocytopenia, ↓ reticulocytes.

Aplastic anemia peripheral blood smear at 400x magnification showcasing markedly reduced numbers of mature red blood cells, white blood cells, and platelets, reflecting the disease's hallmark pancytopenia.
Aplastic anemia peripheral blood smear at 400x magnification showcasing markedly reduced numbers of mature red blood cells, white blood cells, and platelets, reflecting the disease’s hallmark pancytopenia.

Bone marrow characteristics

Hypoplasia with mainly lymphocytes and plasma cells present

Other important investigations and expected results

  • Cytogenetic analysis for differential diagnosis from hypoplastic myelodysplasia (abnormalities expected)

Treatment and management of IAA

  • Treat the underlying cause. 
  • Transfusion of packed red cells and platelet concentrates. 
  • Prevention of infection.  
  • Specific treatment e.g. antilymphocyte or antithymocyte globulin

Disclaimer: This article is intended for informational purposes only and is specifically targeted towards medical students. It is not intended to be a substitute for informed professional medical advice, diagnosis, or treatment. While the information presented here is derived from credible medical sources and is believed to be accurate and up-to-date, it is not guaranteed to be complete or error-free. See additional information.


  1. Killick SB, Bown N, Cavenagh J, Dokal I, Foukaneli T, Hill A, Hillmen P, Ireland R, Kulasekararaj A, Mufti G, Snowden JA, Samarasinghe S, Wood A, Marsh JC; British Society for Standards in Haematology. Guidelines for the diagnosis and management of adult aplastic anaemia. Br J Haematol. 2016 Jan;172(2):187-207. doi: 10.1111/bjh.13853. Epub 2015 Nov 16. Erratum in: Br J Haematol. 2016 Nov;175(3):546. PMID: 26568159.
  2. Bacigalupo A, Socié G, Hamladji RM, Aljurf M, Maschan A, Kyrcz-Krzemien S, Cybicka A, Sengelov H, Unal A, Beelen D, Locasciulli A, Dufour C, Passweg JR, Oneto R, Signori A, Marsh JC; Aplastic Anemia Working Party of the European Group for Blood Marrow Transplantation. Current outcome of HLA identical sibling versus unrelated donor transplants in severe aplastic anemia: an EBMT analysis. Haematologica. 2015 May;100(5):696-702. doi: 10.3324/haematol.2014.115345. Epub 2015 Jan 23. PMID: 25616576; PMCID: PMC4420220.
  3. Young NS, Calado RT, Scheinberg P. Current concepts in the pathophysiology and treatment of aplastic anemia. Blood. 2006 Oct 15;108(8):2509-19. doi: 10.1182/blood-2006-03-010777. Epub 2006 Jun 15. PMID: 16778145; PMCID: PMC1895575.
  4. Young NS. Acquired aplastic anemia. Ann Intern Med. 2002 Apr 2;136(7):534-46. doi: 10.7326/0003-4819-136-7-200204020-00011. PMID: 11926789.
  5. Goldberg S, Hoffman J. Clinical Hematology Made Ridiculously Simple, 1st Edition: An Incredibly Easy Way to Learn for Medical, Nursing, PA Students, and General Practitioners (MedMaster Medical Books). 2021.
  6. Swathi D, Reddy PRK. A Quick Guide to Aplastic Anemia (Scholars’ Press). 2018. 
  7. Williams S. Danielle’s Story: A Daughter’s Battle with Aplastic Anemia. 2006.
  8. Lande B. Beat Aplastic Anemia – With a Personal Wellness Plan: Diagnosed in 2001 – Thriving Today – Visit http://aplassticcentral.org. (2014).

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