Etiology

Acquired AA is most often an idiopathic disorder. However, it occasionally results from drug exposure (e.g., chloramphenicol, nonsteroidal anti-inflammatory drugs). Other drugs and exposures with a weak association to AA, which may be coincidental, include penicillamine, gold therapy, benzene, and dipyrone.[2][3] The lag time between exposure and disease presentation is usually several weeks to months.[2] AA may also occur following an episode of hepatitis (although not by the common A-E hepatitis viruses) or other viral illnesses.[18] Other conditions associated with the development of acquired AA are paroxysmal nocturnal hemoglobinuria (PNH), pregnancy, and more rarely eosinophilic fasciitis, celiac disease, and systemic lupus erythematosus.

PNH is a rare acquired disorder of the blood characterized by intravascular hemolysis and thrombophilia due to the absence of glycosylphosphatidylinositol-anchored proteins on the membrane surface of blood cells.

PNH and AA are closely related. Patients with PNH can develop AA, and patients with AA often harbor PNH clones even if they do not have the clinical manifestations of PNH. One hypothesis for this relationship is that PNH cells somehow escape the autoimmune attack seen in AA and thus can grow out of proportion to non-PNH cells.[19]

Inherited marrow failure syndromes, as their name implies, are congenital disorders. They include Fanconi anemia, dyskeratosis congenita, Shwachman-Diamond syndrome, and GATA2 deficiency.

  • Fanconi anemia is the most common. It is usually autosomal recessive, but can also be X-linked. Mutations in 13 genes have been identified, and these code for proteins that form a nuclear complex involved in the DNA damage response. However, the precise mechanisms by which the mutations produce bone marrow failure are not known.[4]

  • Dyskeratosis congenita (DC): classical X-linked DC is characterized by the triad of abnormal nails, reticulated skin rash, and leukoplakia. Autosomal-dominant and autosomal-recessive inheritance patterns have been observed. The genetic defects all decrease telomerase function. Telomeres maintain chromosomal stability, and the bone marrow is heavily dependent on telomere preservation to support its high rate of cell proliferation. Loss of telomerase produces bone marrow failure.[5]

  • Shwachman-Diamond syndrome is a rare autosomal-recessive disease that produces exocrine pancreatic dysfunction, neutropenia (which can be intermittent), aplastic anemia, myelodysplastic syndrome/acute myelogenous leukemia (often with abnormalities of chromosome 7), and skeletal abnormalities. About 90% of patients harbor mutations in a gene known as the SBDS gene, but the relationship of the mutations to bone marrow failure is not fully understood.[6]

  • GATA2 is an important zinc finger transcription factor involved in hematopoiesis. Germline mutations of GATA2 (leading to GATA2 deficiency) have been described and linked to a wide spectrum of clinical phenotypes including cytopenias, myelodysplastic syndromes, acute leukemias, infections (bacterial, mycobacterial, viral), immunodeficiency, lymphedema, and pulmonary alveolar proteinosis.[7][8][20] Heterozygous GATA2 mutations have been identified in approximately 10% of patients with congenital neutropenia and AA.

Pathophysiology

The pathophysiology of acquired and congenital forms of AA is very different. Acquired AA is usually an idiopathic occurrence. While in some cases the disease reflects direct toxic injury to the hematopoietic stem cells, in most cases the pathogenesis is thought to be a CD4 T cell-mediated autoimmune attack directed against the hematopoietic system. Deficiency and dysfunction of T regulatory cells and increase in CD4 T-helper cells (namely Th17, Th1, and Th2 cells) in AA are believed to contribute to impaired suppression of oligoclonal cytotoxic CD8 T-cells, which creates a proinflammatory environment that results in apoptosis of hematopoietic stem cells.[2][21][22][23][24][25]

Congenital AA has different pathophysiology. In Fanconi anemia, the underlying defect is in the DNA damage repair mechanisms; in the case of the other inherited marrow failure syndromes, abnormalities of telomerase maintenance and of ribosomal function seem to be the cause of the disease.[5][6][13][14][15][16][26][27] Heterozygous mutations of GATA2, an important hematopoietic transcription factor, are also linked to AA.[7][8][20]

Classification

AA subtypes

Acquired AA

  • Idiopathic (most common)

  • Secondary

    • Drug or toxin exposure (strong association with chloramphenicol and nonsteroidal anti-inflammatory drugs; weak association with penicillamine, gold therapy, benzene, and dipyrone)[2][3]

    • Viral; in particular post-hepatitis (although not by the common A-E hepatitis viruses)

    • Pregnancy

    • Paroxysmal nocturnal hemoglobinuria

    • Eosinophilic fasciitis, systemic lupus erythematosus, celiac disease, Sjogren syndrome, thymoma.

Inherited marrow failure syndromes

  • Fanconi anemia

  • Dyskeratosis congenita

  • Shwachman-Diamond syndrome

  • GATA2 deficiency.

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