Pathogenesis of aplastic anemia

According to modern concepts based on numerous cultural, electron microscopic, histological, biochemical, enzymatic methods of investigation, three main mechanisms are important in the pathogenesis of aplastic anemia: direct damage to polypotent stem cells (PCN), changes in the microenvironment of the stem cell and, as a result, inhibition or disturbance its functions; immunopathological condition.

According to modern ideas, the cause of pantoptopenia at the cellular and kinetic level is a significant decrease in the number of PUK and more mature committed erythro-, myelo- and thrombocytopoiesis progenitors. A certain role is played by the qualitative defect of residual stem cells, expressed in their inability to produce an adequate number of mature offspring. Defect of CPM is a primary disorder that is manifested or enhanced by exposure to various etiological factors. The primary defect of CPM as the leading factor in the pathogenesis of aplastic anemia is based on the detection in patients of a sharp decrease in the colony-forming ability of bone marrow cells that persists even during the period of clinical-hematologic remission and the detection of morphologically defective hematopoietic cells indicative of functional inferiority of CPM. It was found that with a decrease in the level of CPM by more than 10% of the norm, there is an imbalance in the processes of differentiation and proliferation with a predominance of differentiation than, most likely, the decrease in the colony-forming ability of the bone marrow. Primacy of the CPM defect in aplastic anemia is confirmed by the following facts:

• the development of aplastic anemia is possible with the use of chloramphenicol (levomycete), irreversibly inhibiting the incorporation of amino acids into mitochondrial proteins and the synthesis of RNA in bone marrow precursor cells, which leads to a violation of their proliferation and differentiation;
• radiation exposure causes the death of part of the CPM and the changes in the trunk system of irradiated changes may be the cause of aplastic anemia;
• effectiveness of allogeneic bone marrow transplantation in aplastic anemia;
• confirmed the relationship of aplastic anemia with clonal diseases - it is possible to transform aplastic anemia into paroxysmal nocturnal hemoglobinuria, myelodysplastic syndrome, acute myeloblastic leukemia.

Currently, it is believed that the reduction of the pool of hematopoietic progenitors is mediated by the mechanism of programmed cell death (apoptosis). The cause of development of aplasia of hematopoiesis is probably an increased apoptosis of stem cells. The increased propensity of stem cells to apoptosis can be congenital (such a mechanism is postulated for congenital aplasia) or induced overexpression of proapoptotic genes by activated participants of the immune response (idiopathic aplasia, aplasia after infusions of donor lymphocytes) or myelotoxic effects (y-radiation). It has been established that the rates of reduction of the precursor pool and specific effector mechanisms of apoptosis differ for different variants of A.

An important aspect of the pathogenesis of aplastic anemia is the pathology of the hematopoietic microenvironment. A primary defect in the cells of the hematopoietic microenvironment is possible, as evidenced by a decrease in the colony-forming function of bone marrow fibroblasts and a change in the ultrastructural and ultracytochemical parameters of bone marrow cells of the stromal microenvironment. Thus, in patients with aplastic anemia, along with total fatty degeneration, changes common for all stromal cells are noted, regardless of their location in the parenchyma of the bone marrow. In addition, an increase in the content of mitochondria, ribosomes and polysomes in the cytoplasm of cells was observed. A defect in the function of the stroma of the bone marrow is possible, which leads to a decrease in the ability of stromal cells to isolate hematopoietic growth factors. A significant role in changing the hematopoietic microenvironment is assigned to the viruses. It is known that there is a group of viruses capable of affecting bone marrow cells - hepatitis C virus, Dengue virus, Epstein-Barr virus, cytomegalovirus, parvovirus B19, human immunodeficiency virus. Viruses can affect hematopoietic cells either directly or through a change in the hematopoietic microenvironment, as evidenced by the detection of multiple pathological inclusions in the nuclei of virtually all stromal cells according to electron microscopy. Persistent viral particles are able to affect the genetic apparatus of cells, thereby distorting the adequacy of the transfer of genetic information to other cells and disrupting the intercellular interaction, which can be inherited.

Significant immunological mechanisms of development of aplastic anemia. Various immune phenomena have been described, the target of which may be hematopoietic tissue: the increase in T-lymphocyte activity (mainly with the CD8 phenotype) with an increase in interleukin-2 production and interleukin-1 depression, depression of natural killer activity, disruption of monocyte maturation in macrophages, of the production of interferon, possibly the presence of antibodies that inhibit the activity of colony-forming cells. An increase in the expression of histocompatibility antigens DR 2 and an increased level of tumor necrosis factor, which is a potential inhibitor of hematopoiesis, is reported. These immunological shifts lead to inhibition of hemopoiesis and promote the development of hematopoiesis aplasia.

Thus, multifactorial pathological mechanisms lie at the basis of the development of aplastic anemia.

As a result of the damaging effect, the bone marrow of patients with aplastic anemia undergoes a number of significant changes. It is inevitable to reduce the content of proliferating hematopoietic cells in it, which leads to a marked decrease in the cellularity (nuclearity) of the bone marrow, as well as bone replacement with adipose tissue (fatty infiltration), an increase in the number of lymphoid elements and stromal cells. In severe cases, almost complete disappearance of the hematopoietic tissue occurs. It is known that the life span of erythrocytes in aplastic anemia is shortened, which is usually due to a decrease in the activity of individual erythroid enzymes, concomitantly with an increase in the level of fetal hemoglobin in the period of exacerbation of the disease. In addition, it has been established that intra-cerebral disruption of erythroid cells occurs.

The pathology of leukopoiesis is manifested by a decrease in the number of granulocytes and a violation of their function, there are structural changes in the lymphoid pool in combination with a violation of the kinetics of lymphocytes. Reduced values of humoral immunity (concentration of immunoglobins G and A) and nonspecific protective factors (beta-lysines, lysozyme). Violation of thrombocytopoiesis is expressed in thrombocytopenia, a sharp decrease in the number of megakaryocytes in the bone marrow, various morphological changes. The life span of platelets is moderately shortened.

In the pathogenesis of hereditary aplastic anemia, great importance is attached to genetic defects and the influence of adverse effects in the early stages of embryogenesis. It has now been established that the onset of hereditary aplastic anemias is associated with an increased inherent predilection of the CPM to apoptosis. Perhaps the inheritance of Fanconi anemia by autosomal recessive type; about 10-20% of patients are born from closely related marriages. Cytogenetic studies performed in children with Fanconi anemia revealed distinct changes in the structure of chromosomes in the form of various chromosomal aberrations (chromatid breaks, gaps, changes, exchanges, endoreduplications) due to changes in chromosomes 1 and 7 (complete or partial deletion or transformation). It was previously believed that the pathogenesis of Fanconi anemia is due to a defect in DNA repair, since many agents called clastogens are used to diagnose Fanconi anemia, pointing to the above mechanism. These agents (mitomycin C, diepoxybutane, nitrogen mustard) damage DNA, causing crosslinks between its chains, inside the chains and their ruptures. Currently, an alternative hypothesis may be the assumption that the increased sensitivity of the cells of Fanconi anemia to mitomycin C is associated with damage caused by oxygen radicals, rather than violations in the cross-links of DNA strands. Free oxygen radicals include a superoxide anion, hydrogen peroxide and hydroxyl radical. They are mutagens, and the hydroxyl ion, in particular, can cause chromosomal abnormalities and DNA breaks. There are various detoxification mechanisms for removing oxygen free radicals and protecting cells from damage. These include the enzymatic systems of superoxide dismutase (SOD) and catalase. Adding SOD or catalase to lymphocytes in Fanconi anemia patients reduces chromosome damage. Clinical studies using recombinant SOD have shown that when it is prescribed in a number of cases, the number of failures decreases. The obtained data served as a basis for reviewing the role of free oxygen radicals in the existence of hypersensitivity of cells of Fanconi anemia patients to mitomycin C and for studying the role of apoptosis in this situation. Mitomycin C exists in the inactivated state and in the form of an oxide. A lot of enzymes in the cell can catalyze the loss of one electron in the molecule of mitomycin C, which becomes highly active. With a low oxygen concentration that exists in the cells of the hypoxic cell lines, mitomycin C reacts with DNA and leads to cross-linking. However, at a high concentration of oxygen, which is typical for a normal cell culture, mitomycin C is re-oxidized by oxygen to form free oxygen radicals, and its ability to form crosslinks with DNA is significantly reduced. The study of apoptosis, carried out with the help of special research systems, showed that at a low (5%) concentration of oxygen, there is no difference in the expression of apoptosis in normal cells and cells of Fanconi anemia patients. However, with a high concentration of oxygen (20%), which promotes the formation of free radicals under the influence of mitomycin C, apoptosis in cells of Fanconi anemia is more pronounced and qualitatively different than in normal cells.

With Blackfen-Diamond anemia, it is established that the disease is not associated with either the loss of the ability of the microenvironment to maintain erythropoiesis or the immune system response against erythroid progenitors (studies supporting this hypothesis have shown transfusion-dependent alloimmunization). The most likely hypothesis of the appearance of Blackfen-Diamond anemia is the intracellular defect of the mechanisms of signal transduction or transcription factors at the early hemopoiesis stage (the earliest erythroid precursor or pluripotent stem cell). Such changes may lead to an increase in the sensitivity of erythroid cells to apoptosis: when cultured in vitro without erythropoietin, such cells enter a programmed cell death faster than normal cells from individuals in the control group.

Genetics of Blackfang-Diamond anemia: more than 75% of cases are sporadic, in 25% of patients a mutation of a gene located on chromosomes 19ql3, encoding the ribosomal protein S19, is found. A consequence of this mutation is the occurrence of Blackfang-Diamond anemia. Mutation of the gene is found in sporadic and family cases of anemia, when several patients with this anemia are observed in one family. Family cases include an explicit dominant inheritance of anemia in the proband and one of the parents, or the occurrence of anomalies in the siblings born after each other; the possibility of autosomal recessive and X-linked chromosome inheritance is not ruled out. Random anomalies were found in most patients with Blackfang-Diamond anemia, for example, chromosome 1 and 16 anomalies.

[1], [2], [3], [4], [5], [6]