1 Current Status of Domestic and International Research on Aplastic Anemia

1 Current Status of Domestic and International Research on Aplastic Anemia

1.1 Modern Medical Understanding of Aplastic Anemia

1.1.1 Pathogenesis of Aplastic Anemia

Regarding the pathogenesis of aplastic anemia, medical scientists have conducted years of research and proposed various theories, including the seed theory, soil theory, insect theory, as well as theories related to constitutional or genetic factors.

1.1.1.1 Seed Theory (Deficiency or Defect in Hematopoietic Stem Cells)

Research has found that patients with aplastic anemia exhibit hypoproliferation of the bone marrow and pancytopenia, with reductions in red blood cells, granulocytes, and platelets. Since these three hematopoietic lineages all originate from the same hematopoietic stem cell, it can be inferred that aplastic anemia is caused by a deficiency or abnormality of hematopoietic stem cells. Experimental evidence shows that in vitro culture of bone marrow progenitor cells from patients reveals significant reductions in granulocyte–macrophage progenitor cells (CFU-GM and CFU-C) and erythroid progenitor cells (BFU-E and CFU-E), while successful bone marrow transplantation quickly restores normal hematopoietic function. In mice induced with aplastic anemia through injection of the drug mithramycin, observation of their bone marrow reveals a reduction in multipotent stem cells, which serves as supporting evidence. The underlying cause of the decrease in hematopoietic stem cell numbers is the presence of suppressive cells in the peripheral blood and bone marrow of aplastic anemia patients; these suppressive cells are primarily lymphocytes and macrophages. In recent years, research has focused on how suppressive T cells lead to impaired stem cell differentiation, resulting in bone marrow hypoproliferation and ultimately aplastic anemia. Scholars have metaphorically described hematopoietic stem cells as “seeds,” referring to this theory as the “seed theory.”

1.1.1.2 Soil Theory (Changes in the Bone Marrow Microenvironment)

The growth, development, and differentiation of hematopoietic stem cells depend on a favorable hematopoietic microenvironment within the bone marrow. This microenvironment comprises nerves, blood vessels, and stroma, whose functions include delivering nutrients to hematopoietic tissues and removing metabolic waste products, thereby facilitating the renewal of hematopoietic stem cells. Some pathogenic factors in aplastic anemia do not directly damage hematopoietic stem cells but instead first affect the hematopoietic microenvironment, causing microvascular spasm or damaging endothelial cells on the vessel walls, which subsequently leads to impaired blood perfusion and ultimately results in necrosis of multipotent stem cells. Additionally, defects in the stromal components of the bone marrow microenvironment also play a role. Scholars have metaphorically likened the hematopoietic microenvironment in the bone marrow to “soil,” hence the term “soil theory.”

1.1.1.3 Worm Theory (Immune Deficiency)

There are two mechanisms underlying immune deficiency in aplastic anemia: humoral immunity and cellular immunity, yet these two mechanisms are interconnected and mutually influential. Some aplastic anemia patients have inhibitory factors in their serum that can suppress GM-CFU colony formation, most commonly observed in primary aplastic anemia. Experiments have shown that this “aplastic anemia serum inhibitory factor” can inhibit hematopoiesis in vitro and exhibits certain characteristics of antibodies. Some studies indicate that lymphocytes in aplastic anemia patients can suppress bone marrow hematopoiesis, significantly reducing the proliferation of normal erythroid cells in healthy individuals, with occasional megaloblastic changes. T lymphocytes are the main effector cells in cellular immunity and constitute a highly heterogeneous population; they also play a crucial role in the immune dysregulation network associated with aplastic anemia. An imbalance between Th and Ts cells can lead to suppression of bone marrow hematopoietic function. In aplastic anemia patients, an imbalance in Th cell subsets—specifically an increase in the number and hyperactivity of Th1 cells—may be a key factor contributing to bone marrow failure. To date, dozens of cytokines involved in hematopoietic regulation have been identified, categorized into positive and negative regulators. Dysregulation of both positive and negative hematopoietic cytokine secretion also plays an important role in the pathogenesis of aplastic anemia. Some scholars believe that hematopoietic failure in aplastic anemia patients arises from weakened activity of positive regulators and abnormal activation of negative regulators. Various hematopoietic regulatory factors can induce Fas antigen expression on CD34⁺ cells, leading to apoptosis via FasL. IL-2 is primarily secreted by Th1 cells; increased IL-2 activity and elevated expression of IL-2 receptors (IL-2R) in Ts cells, NK cells, and monocytes/macrophages can promote T-cell proliferation and activation, enhance interferon production, and intensify suppression of hematopoietic stem cells. As a negative regulator of hematopoiesis, IL-2 plays a significant role in the development of aplastic anemia; moreover, IL-2 can boost NK-cell vitality, and NK cells themselves possess hematopoietic-suppressive activity. The C₃b receptor on the surface of red blood cells has the function of binding CIC and facilitating its clearance; approximately 80% of CIC adheres to red blood cells, which then transport them to the macrophage system in the liver and spleen for degradation, thereby preventing pathological damage caused by complement activation. In aplastic anemia patients, reduced red blood cell clearance function leads to increased levels of CIC in the bloodstream, which can deposit on the sinusoidal walls of the bone marrow, damaging the hematopoietic microenvironment and impairing the differentiation and maturation of hematopoietic cells. Studies examining pre- and post-treatment red blood cell immune function in chronic aplastic anemia patients have found that the rate of red blood cell immune complex rosettes (RICR) and complement C₃ levels were significantly higher after treatment, while CIC levels were markedly lower than before. Therefore, immune deficiency is also one of the mechanisms triggering aplastic anemia, a theory known as the “worm theory.”

1.1.2 Classification and Clinical Manifestations

Aplastic anemia can be clinically classified into congenital aplastic anemia and acquired aplastic anemia. Its clinical manifestations include anemia, bleeding, and infection. Chinese scholars further divide aplastic anemia into acute and chronic forms.

1.1.2.1 Acute Type

Characterized by sudden onset, severe illness, and rapid progression.

Anemia: Patients present with pallor, fatigue, dizziness, palpitations, and shortness of breath, often worsening progressively.

Infection: Most patients develop fever, with body temperatures exceeding 38°C; some remain in uncontrollable high fevers from onset to death. Respiratory tract infections are the most common, followed by gastrointestinal, genitourinary, and skin infections. The causative pathogens are predominantly Gram-negative bacilli, Staphylococcus aureus, and fungi, often complicated by sepsis.

Bleeding: All patients experience varying degrees of cutaneous, mucosal, and visceral bleeding, including epistaxis, gingival bleeding, conjunctival hemorrhage, small blood blisters on the oral mucosa, and petechiae or ecchymoses on the skin. Bleeding can occur in any organ, but only external openings are clinically detectable. Examples include hematemesis, hematochezia, hematuria, vaginal bleeding in women, retinal hemorrhage, and intracranial hemorrhage, the latter of which often poses a life-threatening risk.

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The severity of bleeding increases over time, progressing from superficial to visceral manifestations, often foreshadowing more serious hemorrhage.