Aplastic anemia pathophysiology

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.

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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]