1.2 Pathogenesis

1.2 Pathogenesis

The pathogenesis of aplasia is complex, with immune-mediated suppression of hematopoiesis being the most common mechanism [1]. Some patients have stem cell defects, some have damage to the hematopoietic microenvironment, and some have inhibitory factors in the blood or suppressive effects of cells. Regarding the underlying principles of aplasia, medical scientists have conducted research and proposed several theories, mainly the seed theory, soil theory, bug theory, as well as constitutional or genetic factors.

1.2.1 Seed Theory (Deficiency or Abnormality of Hematopoietic Stem Cells)

Research has found that aplastic anemia patients have low bone marrow proliferation and reduced total blood cells, with fewer red blood cells, granulocytes, and platelets. Since these three blood cell lines all differentiate from the same hematopoietic stem cell, it can be inferred that aplasia is caused by a deficiency or abnormality in hematopoietic stem cells. Experimental evidence shows that in vitro culture of bone marrow progenitor cells from patients reveals a significant reduction in granulocyte-macrophage lineage progenitors and red blood cell lineage progenitors, while bone marrow transplantation restores normal hematopoietic function shortly thereafter [2]. Injecting the drug myleran into mice to induce aplasia and observing their bone marrow shows a reduction in multipotent stem cells, providing supporting evidence [1]. The reason for the reduction in hematopoietic stem cells is the presence of inhibitory cells in the peripheral blood and bone marrow of aplastic anemia patients. These inhibitory cells are mainly lymphocytes and macrophages. In recent years, research has focused on how inhibitory T-cells interfere with stem cell differentiation, leading to reduced bone marrow proliferation and causing aplastic anemia. Scholars metaphorically compare hematopoietic stem cells to "seeds," calling this theory the "seed theory."

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Research on Pei Zhengxue's series of prescriptions

1.2.2 Soil Theory (Changes in the Bone Marrow Microenvironment)

For hematopoietic stem cells to grow, develop, and differentiate, they need a good hematopoietic microenvironment in the bone marrow. This environment consists of nerves, blood vessels, and matrix, and its function is to deliver nutrients to hematopoietic tissues and remove metabolic waste, facilitating the renewal of hematopoietic stem cells. Some causative factors of aplasia do not directly damage hematopoietic stem cells, but first affect the hematopoietic microenvironment, causing microvascular spasm or damaging endothelial cells on the vessel walls, leading to impaired blood perfusion and ultimately resulting in the death of multipotent stem cells [14]. In addition, defects in the matrix components of the bone marrow microenvironment also have a certain impact. Scholars metaphorically compare the hematopoietic microenvironment in the bone marrow to "soil," calling this theory the "soil theory."

1.2.3 Bug Theory (Immune Deficiency)

There are two mechanisms of immune deficiency in aplasia: humoral immunity and cellular immunity.

① Humoral Immunity Mechanism: Some aplastic anemia patients have inhibitory factors in their serum that can suppress GM-CFU colony formation, most commonly seen in primary aplasia. Experiments have shown that this "aplasic serum inhibitory factor" can suppress hematopoiesis in vitro and exhibits some characteristics of antibodies, indicating that certain aplastic anemia patients have a specific humoral immune state. ② Cellular Immune Mechanism: The occurrence of certain cases of aplastic anemia is associated with cellular immunity. Some studies have shown that lymphocytes in patients with aplastic anemia can suppress bone marrow hematopoiesis, leading to a significant proliferation of erythroid cells in normal individuals; in a few cases, megaloblastic changes may also appear. There is an increase in hemosiderin granules and a marked increase and enlargement of sideroblasts, with many late-stage proerythroblasts showing a ring-like distribution around the nucleus, and numerous coarse iron granules (siderocytes) can also be seen within mature red blood cells. Serum iron concentration and serum iron saturation are mostly significantly elevated. Dynamic iron metabolism tests indicate accelerated serum iron clearance and reduced iron utilization. The content of free protoporphyrin in red blood cells is mostly decreased, while free fecoporphyrin is mostly normal. In cases that are unresponsive to vitamin B6 treatment, free fecoporphyrin levels can be very high, whereas free protoporphyrin is markedly reduced [15].

1.2.4 Constitutional or Genetic Factors

Aplastic anemia is not a hereditary disease, but clinical data show that patients with certain HLA-II antigens respond better to immunosuppressive therapy, and some patients with aplastic anemia are susceptible to chloramphenicol and certain viruses, all of which suggest that the onset of aplastic anemia may be related to genetic factors.

2 Clinical Manifestations, Diagnostic Criteria, and Differential Diagnosis