Aplastic anemia: Etiology, molecular pathogenesis, and emerging concepts

Abstract

Aplastic anemia (AA) is rare disorder of bone marrow failure which if severe and not appropriately treated is highly fatal. AA is characterized by morphologic marrow features, namely hypocellularity, and resultant peripheral cytopenias. The molecular pathogenesis of AA is not fully understood, and a uniform process may not be the culprit across all cases. An antigen-driven and likely autoimmune dysregulated T-cell homeostasis is implicated in the hematopoietic stem cell injury which ultimately founds the pathologic features of the disease. Defective telomerase function and repair may also play a role in some cases as evidenced by recurring mutations in related telomerase complex genes such as TERT and TERC. In addition, recurring mutations in BCOR/BCORL, PIGA, DNMT3A, and ASXL1 as well as cytogenetic abnormalities, namely monosomy 7, trisomy 8, and uniparental disomy of the 6p arm seem to be intimately related to AA pathogenesis. The increased incidence of late clonal disease has also provided clues to accurately describe plausible predispositions to the development of AA. The emergence of newer genomic sequencing and other techniques is incrementally improving the understanding of the pathogenic mechanisms of AA, the detection of the disease, and ultimately offers the potential to improve patient outcomes. In this comprehensive review, we discuss the current understanding of the immunobiology, molecular pathogenesis, and future directions of such for AA.

Eltrombopag treatment of a dog with idiopathic aplastic pancytopenia

“…6,7,9,10 The mechanism by which this thrombopoietin receptor agonist stimulates multi-lineage recovery is not completely understood but is thought to be related to stimulation and proliferation of primitive hematopoietic stem cells and other progenitor cells that may express the thrombopoietin receptor. 11 Aside from patients with refractory disease, eltrombopag has been used alongside immunosuppression in treatment-naive human patients with severe aplastic pancytopenia and has been shown to accelerate cell count recovery. One study described the use of eltrombopag for a set period of 10 weeks in treatment-naive human patients and found a response rate of 87% at 3 months after starting treatment and response rates were sustained at 6 months, 3 months KELLY ET AL.…”

Alternative Immune-Mediated-Based Methods in the Aplastic Anemia Treatment

“…AA is associated with exposures to chemical agents (pesticides and benzene), cytotoxic drugs (antineoplastics, antibiotics, non-steroidal anti-inflammatory drugs), active viral infections exposure (Epstein Barr, hepatitis virus, human immunodeficiency virus parvovirus) and radiation exposure [18,24,25]. However, these causes considered Alternative Immune-Mediated-Based Methods in the Aplastic Anemia Treatment DOI: http://dx.doi.org/10.5772/intechopen.89090 secondary etiologies, since the studies are directed to the primary etiology of AA to autoimmunity [26,27]. AA pathogenesis involves an immunity dysfunction, initially provoked by the activated T cells [23], which leads to an abnormal hematopoietic microenvironment, destruction of hematopoietic stem/progenitor cell and differentiation deficiency.…”

“…Although the definitive mechanism has not been identified, some genetic factors are the targets of ongoing research, such as the molecular basis of the aberrant immune response and hematopoietic cell deficiency, telomere repair gene mutations in the target cells and unregulated T cell activation pathways and cytokine genes polymorphisms [9,26,28]. These changes in the nucleotide sequence and gene regulation are associated with an increased immune response and suggest a genetic basis for aberrant T cells activation in BM failure [35].…”

“…The progress in dissecting the underlying and complex pathophysiology of AA has been gain space over the past years in the hematology research community [26]. In addition to that, the need for an optimal alternative of a targeted treatment for this disorder.…”

Acquired Aplastic Anemia as a Clonal Disorder of Hematopoietic Stem Cells

“…The second group of mutations is of great importance for clinicians because PIGA and BCOR may predict a favourable response to immunosuppressive therapy with improved progression-free survival and overall survival. Other mutations associated with a poor response to immunosuppressive therapy include: DNMT3A, ASXL1, JAK3, RUNX1, TP53, CSMD1 [99].…”