Pathophysiology refers to the fundamental operations or mechanisms that trigger the development of various diseases or disorders (Sharifi-Rad et al., 2020). For healthcare professionals, the study of pathophysiology is one of the most important, providing deeper knowledge on the causes, clinical manifestations, and possible treatment of diseases and medical conditions. Aplastic anemia is a rare and fatal disorder where the bone marrow stops making enough new blood cells. The disease is not peculiar to any age group and may seriously affect individuals’ health and social lives. Therefore, the full molecular comprehension of the etiology of aplastic anemia, on the one hand, is a critical element in the research process. However, it also provides the means to improve diagnostics and develop more efficient treatments. Nonetheless, the etiology of aplastic anemia is crucial to its pathophysiology. The parallel decoding of the complex genetic, immune, and environmental factors involved in this disease’s development and deterioration can provide us with the causes, early detection, and enhanced patient outcomes in general.
Aplastic anemia is a disorder of the bone marrow that causes a decrease in the production of all blood cells, including red blood cells (RBCs), white blood cells (WBCs), and platelets. In these cases, the production of blood cells is absent (Furlong & Carter, 2020). Therefore, it can be seen in clinically diverse symptoms and the most severe forms of anemia.
The basic molecular pathways of bone marrow failure in aplastic anemia are a multi-factorial process, which makes the participation of genetic, environmental, and immunologic factors more complicated. The reasons that can be attributed to the disorder in the normal status of HSC survival, proliferation, and differentiation are the causes of such occurrences.
Genetic variables are a vital part of developing aplastic anemia. One example is genetic changes or alterations that could cause the disorders. Several genetic factors have been extensively studied, and the presence of mutations in the TERT and TERC genes, those coding for telomere maintenance, is the most important contribution (Fernández-Varas et al., 2024). The telomeres (the tips or caps of the chromosomes) act as the protective mechanism; if impaired, they may cause early cell senescence and marrow failure.
Likewise, the joint appearance of these other gene abnormalities, the RUNX1, GATA2, and CEBPA gene mutations is associated with a higher chance of developing aplastic anemia. This gene’s expression is important in hematopoietic stem cell activity control and differentiation.
Additionally, there is evidence that it may be due to certain circumstances and exposure to specific chemicals, radiation, and viral infections. The toxicants may be able to directly interact with the stem cells or trigger inappropriate responses from the immune system, ultimately destroying the hematopoietic system.
It is well known that long-term exposure to chemical substances such as benzene, pesticides, and especially chemotherapeutic drugs increases aplastic anemia risk substantially. Such an initiation can result in oxidative stress, DNA damage, or apoptosis (programmed cell death) of hematopoietic stem cells and, consequently, bone marrow failure.
Medical imaging and environmental radioactivity are the two major ionization sources that could also affect the bone marrow. Radiation damages the synthesis of normal DNA and the re-population and differentiation of hematopoietic stem cells.
Hepatitis viruses and Epstein-Barr virus (EBV) all have the potential to be involved in aplastic anemia development, while HIV is associated with this disease (Sheta, n.d). These viruses might either assume a direct pathway by infecting and killing bone marrow cells or indirectly incite an abnormal immune response against the blood system.
Immunological causes form a fundamental part of the pathophysiology of aplastic anemia. In some cases, an autoimmunity mechanism is believed to be involved, and the hematopoietic stem cells and precursor cells in the bone marrow are mistakenly identified and destroyed by the body’s immune system (Van der Valk, 2020).
The autoimmune response is still a cause of bewilderment to the medical community among the probable causes that have been raised. These conditions can occur due to virus infections, drug and chemical exposure, or genetic variations of the immune system, leading to mislabeling the body’s antigens as foreign.
In aplastic anemia, these T-lymphocytes and autoantibodies are thought to target antigens expressed on hematopoietic stem cells and progenitor cells (Van der Valk, 2020). This assault is sometimes triggered by the dysfunction or failure of these cells, resulting in a lack of bone marrow and blood cell production.
Along with the alterations of cytokine regulation, abnormal Treg function, and dysregulation of pro-inflammatory-anti-inflammatory signaling pathways, the immune system is also involved in the mechanisms of aplastic anemia development.
In aplastic anemia, the molecular manifestations occur through different mechanisms and are later responsible for several clinical manifestations and complications. The severity of these symptoms generally follows the depth of the bone marrow failure and the ensuing problems with blood cell production.
Common clinical manifestations of aplastic anemia include: The clinical manifestations of aplastic anemia are prevalent and frequently include the following:
Fatigue and weakness: Anemia, another common symptom, is a familiar problem among patients with RA. It is characterized by drowsiness, paleness, and breathlessness (Furlong & Carter, 2020).
Increased susceptibility to infections: Being leukopenic means the body lacks the required amount of white blood cells, so the immune system cannot fight pathogens represented by bacteria, viruses, and fungi, so patients are more likely to have infectious diseases.
Bleeding and bruising: The low thrombocyte level (thrombocytopenia) will result in damage to the skin (easy bruising), open wounds, bleeding for a long time (nicks and injuries), and the possibility of severe hemorrhages.
The treatment aims to get to the molecular level, correct the defect at its root cause, and normalize the process of blood cell production. The major concerns determining the type of treatment are the disease severity, the age of patients, and the presence of any genetic or immunological factors.
Immunosuppressive therapy represents the first line of treatment employed in aplastic anemia, where immunological factors cause the disease. The treatment here employs drugs like cyclosporine, ATG, or anti-thymocyte globulin (ATG), famous for reducing abnormal immune responses and returning the bone marrow to health (Furlong, E., & Carter, 2020).
Autologous stem cell transplantation, bone marrow transplant, or hematopoietic stem cell transplant (HSCT) is another therapy used in severe aplastic anemia. This would mean that healthy stem cells would be transplanted into a match donor’s body, where the patient’s bone marrow would start functioning properly.
When the genetic cause has been established, treatments would likely be directed at the molecular pathways or gene editing targeting the genetic defects. Another example is telomerase activation or gene therapy treatment for aplastic anemia due to telomere biology disorders.
Aplastic anemia, a severe disease, is responsible for a marrow defect and the production of insufficient numbers of blood cells. Its pathophysiology results from the complex interplay among genetic, environmental, and immunological factors, thus disrupting the normal function of the hematopoietic stem cells. Discovering the molecular mechanisms behind the disease is the most important phase to help us proceed further into disease knowledge, diagnostic accuracy, and developing therapy. Genetic mutations, environmental factors, and immunity/immunogenetics can be the culprits for autism. Such factors are the causes, risk possibilities, and therapeutic targets. In the long term, researchers are synthesizing a multi-disciplinary approach to develop more efficient diagnostic tools, individualized treatment methods, and better overall aplastic anemia results.
Fernández-Varas, B., Manguan-García, C., Rodriguez-Centeno, J., Mendoza-Lupiáñez, L., Calatayud, J., Perona, R., … & Sastre, L. (2024). Clinical mutations in the TERT and TERC genes coding for telomerase components induced oxidative stress, DNA damage at telomeres, cell apoptosis, and decreased telomerase activity. Human Molecular Genetics, ddae015. https://academic.oup.com/hmg/advance-article-abstract/doi/10.1093/hmg/ddae015/7600382
Furlong, E., & Carter, T. (2020). Aplastic anemia: Current concepts in diagnosis and management. Journal of pediatrics and child health, 56(7), 1023–1028.
Sharifi-Rad, M., Anil Kumar, N. V., Varoni, E. M., Dini, L., Panzarini, E., Rajkovic, J., … & Sharifi-Rad, J. (2020). Lifestyle, oxidative stress, and antioxidants: back and forth in the pathophysiology of chronic diseases. Frontiers in physiology, 11, 552535. https://www.frontiersin.org/journals/physiology/articles/10.3389/fphys.2020.00694
Sheta, E. A., El-Hawary, E. E. S., Elbendary, A. S., & Shebl, S. S. The Role of Certain Congenital Infections in Aplastic Anemia and Prognostic Value of Fetal Hemoglobin as a Follow-Up Marker.
Van der Valk, P. (2020). The lymphoreticular system and bone marrow. In Muir’s Textbook of Pathology (pp. 199-229). CRC Press. https://www.taylorfrancis.com/chapters/edit/10.1201/9780429053016-9/lymphoreticular-system-bone-marrow-paul-van-der-valk