bubble_chart Overview

Aplastic anemia (AA), also known as pancytopenia, is a syndrome characterized by a reduction in all blood cell types due to bone marrow hematopoietic failure. It is relatively common in children. Between 1956 and 1993, Beijing Children's Hospital treated a total of 746 cases of this disease. The main symptoms include anemia, bleeding, and recurrent infections. The condition involves a simultaneous decrease in all three types of blood cells, without hepatosplenomegaly or lymphadenopathy.

bubble_chart Etiology

Acquired aplastic anemia is further divided into idiopathic and secondary types.

Idiopathic aplastic anemia accounts for about 50% of cases, with no identifiable cause in the medical history. Although the cause remains unknown, in some cases, the possibility of exposure to harmful chemical or physical factors cannot be completely ruled out, as such exposures may have been forgotten by parents or patients due to the passage of time.

Regarding secondary cases, substances that can cause bone marrow suppression can be divided into two categories. The first category includes substances that, with sufficient exposure, can cause bone marrow damage in anyone. Examples of such substances are X-rays, radioactive materials, or ionizing radiation from nuclear explosions, as well as high doses of chloramphenicol, various cytotoxic drugs (such as those used to treat malignant tumors and leukemia, including nitrogen mustard, cyclophosphamide, 6-mercaptopurine, cytarabine, methotrexate, and doxorubicin). Some organic solvents like benzene can also lead to hematopoietic disorders in the bone marrow. The second category involves substances related to individual idiosyncratic reactions, where certain items only affect a small subset of people, and the dose does not correlate with the degree of bone marrow suppression. Most of these items are drugs, with chloramphenicol being the most common. Statistics show that approximately 1 in 30,000 patients taking chloramphenicol develop bone marrow suppression, with nearly all cases resulting from oral administration. A few cases have been linked to chloramphenicol eye drops, while intravenous administration rarely causes the condition. This type of bone marrow suppression is "irreversible" and occurs independently of the dose of chloramphenicol, manifesting within four days of administration. It is speculated that such patients may have a genetic predisposition to hypersensitivity to chloramphenicol. Other drugs that can cause aplastic anemia in susceptible individuals include certain pain relievers like phenylbutazone (in these patients, the metabolism of phenylbutazone is unusually slow) and aminopyrine, antiepileptic drugs like phenytoin sodium and trimethadione, antimalarial drugs like quinacrine, as well as fertilizers, dyes, and insecticides.

Cases of aplastic anemia secondary to viral hepatitis have been increasingly reported since 1955. Beijing Children's Hospital's hepatitis ward observed 21 such cases, with a median diagnosis time of only 11 weeks from the onset of hepatitis to the detection of aplastic anemia. The occurrence of aplastic anemia does not correlate with the severity of hepatitis (grade III or otherwise). While other severe infections can also cause bone marrow suppression, it is necessary to determine whether the infection is primary or secondary. There have been reports of bone marrow suppression occurring during the peak phase of infectious mononucleosis and infections caused by viruses similar to the dengue Rebing virus.

Patients with paroxysmal nocturnal hemoglobinuria may also develop secondary aplastic anemia.

bubble_chart Pathogenesis

The exact mechanism is not yet fully understood. According to recent research, the occurrence of aplastic anemia is primarily due to changes in the bone marrow hematopoietic microenvironment and damage to stem cells. The production of blood cells requires the surrounding cells to supply hematopoietic raw materials. The red marrow contains a capillary bed with many dilated segments, known as sinusoids, which are the functional units of the capillary bed. When ⁶⁰Co irradiation was applied to mouse bone marrow, severe damage to the basement membrane of the sinusoids and the outer membrane cells was observed during the radiation reaction period, along with destruction of hematopoietic cells. During the stage of convalescence, the recovery of sinusoids and a small number of hematopoietic cells appeared first, followed by the restoration of sinusoids and a small number of hematopoietic cells, and then the recovery of hematopoietic cells around the sinusoids. Therefore, it was once believed that damage to the bone marrow microenvironment was the root cause of aplastic anemia, while damage to hematopoietic stem cells was secondary. Recent experiments have shown that normal pluripotent stem cells can proliferate in the bone marrow of aplastic anemia patients, indicating that the cause of aplastic anemia is not solely due to damage to the bone marrow microenvironment but may also be related to damage to the host stem cells. In summary, the pathogenesis of aplastic anemia is not yet fully understood. Known factors include damage to the bone marrow pluripotent stem cells and microenvironment, leading to a series of functional and morphological changes, which further result in pancytopenia. Recently, it has been discovered that aplastic anemia patients may have a decrease in total lymphocyte count, absolute values of E-Rose Flower formation, skin hypersensitivity reactions, and varying degrees of impairment in macrophage function. In acute cases, there is also a reduction in properdin and γ-globulin levels, suggesting that immune factors may also contribute to the development of aplastic anemia.

bubble_chart Pathological Changes

The red marrow is replaced by adipose tissue, and reticulated cells, lymphocytes, plasma cells, and basophilic histiocytes can be observed in its parenchyma. Megakaryocytes are difficult to detect, and both the granulocytic and erythroblastic series are significantly reduced.

bubble_chart Clinical Manifestations

Aplastic anemia is generally classified into two major categories: congenital and acquired.

(1) Congenital Aplastic Anemia

Also known as Fanconi's anemia, it is an autosomal recessive genetic disorder characterized by pancytopenia along with multiple congenital malformations. These include microcephaly, microphthalmia, strabismus; approximately 3/4 of patients exhibit skeletal deformities, most commonly absence or malformation of the radius and thumb, followed by hypoplasia of the first metacarpal bone, ulnar deformities, patchy brown skin pigmentation, café-au-lait spots, auricle malformations, or deafness. Some patients experience intellectual disability. Over half of affected males have underdeveloped genitalia. Family history often reveals similar cases.

(2) Acquired Aplastic Anemia

Acquired aplastic anemia is one of the more common anemias in childhood, though it can occur at any age, with higher prevalence in children and adolescents. There is generally no gender difference, except in hepatitis-associated cases where males are more frequently affected.

Onset is usually gradual. Symptoms often first attract attention due to subcutaneous petechiae, ecchymoses, or epistaxis. The severity of symptoms varies depending on the degree of anemia and the speed of disease progression. Common anemia symptoms include pallor, fatigue, and shortness of breath. Recurrent oral mucosal ulcers, necrotic stomatitis, and pharyngitis due to granulocytopenia may occur, sometimes progressing to sepsis that is difficult to control even with antibiotics. As the disease advances, bleeding symptoms worsen, potentially leading to hematochezia and hematuria. The liver, spleen, and lymph nodes are typically not enlarged, though grade I hepatosplenomegaly may develop after repeated blood transfusions.

In acute cases, the course is shorter with rapid progression of bleeding and infections. Chronic cases often have an insidious onset, persisting for years, with anemia and bleeding potentially becoming less apparent during remission stages.

bubble_chart Auxiliary Examination

Changes in blood parameters can occur between the ages of 1.5 and 22, with an average of approximately 6 to 8 years, more commonly in males than females, and often drawing attention due to bleeding. Whether or not bleeding is present, anemia is usually the primary manifestation, with macrocytic normochromic red blood cells accompanied by a decrease in nucleated cells and platelets. Due to the slow progression of the disease, the bone marrow changes resemble those of acquired aplastic anemia. At the onset, there are often no signs of bone marrow failure, and erythroid hyperplasia or megaloblastic changes may even be observed. Subsequently, the bone marrow shows increased fat deposition, markedly reduced cellularity, and only scattered hematopoietic islands. Hemoglobin F is often elevated to 5–15%, and decreased G-6PD may also be observed.

Chromosomal analysis typically reveals no numerical abnormalities, but a higher frequency of chromosomal breaks, partial translocations, ring chromosomes, or multiple centromeres may be seen. Similar abnormalities are observed in cultured skin or fibroblast cells. Approximately 25% of patients exhibit renal malformations, such as horseshoe kidney or unilateral renal agenesis. Bone marrow culture demonstrates hypoplasia of erythroid and granulocyte progenitor cells.

bubble_chart Diagnosis

For typical cases of aplastic anemia, diagnosis is not difficult based on clinical manifestations and laboratory findings.

Congenital aplastic anemia presents with multiple malformations, making it distinguishable from acquired aplastic anemia, but differentiation is required from congenital pure red cell aplasia with malformations and thrombocytopenia associated with bone defects.

In acquired aplastic anemia, cases with only one or two types of cytopenia or residual hematopoietic islands in the bone marrow are difficult to diagnose definitively with a single bone marrow aspiration. If the bone marrow aspiration is unsatisfactory and the specimen is heavily diluted with blood, the bone marrow smear may show very few cells, potentially leading to a misdiagnosis of aplastic anemia. However, such specimens typically lack abundant fat droplets and do not show an increase in non-hematopoietic cells. In both scenarios, multiple bone marrow aspirations from different sites should be performed, and a bone marrow biopsy may be necessary if needed.

The primary condition to exclude is leukemia, as pediatric leukemia often presents with pancytopenia. If immature cells are absent in the peripheral blood, bone marrow aspiration is essential for differentiation. For cases with good bone marrow hyperplasia and splenomegaly, cervical malignancy with cachexia and hypersplenism should be ruled out. These two conditions often show elevated reticulocyte counts, and repeated bone marrow aspirations typically reveal hyperplastic marrow. Paroxysmal nocturnal hemoglobinuria may also present with pancytopenia, and repeated urine tests may detect hemoglobinuria. Although reticulocyte counts may be significantly reduced, they tend to fluctuate widely.

bubble_chart Treatment Measures

Treatment of congenital aplastic anemia:

The approach is the same as for general aplastic anemia. The combined use of corticosteroids and testosterone can improve blood counts, and bone marrow may also show signs of hyperplasia. However, relapse is common after discontinuation, necessitating long-term maintenance with small doses. In cases of severe anemia, concentrated red blood cell transfusions should be administered. White blood cell or platelet transfusions may also be given as needed. If a compatible bone marrow donor is available, a bone marrow transplant can be performed. The 5-year survival rate is approximately 50%, higher than that for acquired aplastic anemia. After anemia remission, significant improvements in height, weight, and intelligence are also observed.

Treatment of acquired aplastic anemia:

The first step is to identify and eliminate the disease cause. A detailed medical history should be taken, including any medications taken within the six months prior to onset, exposure to chemical or physical factors, and any infections. Immediately remove any potential causes of bone marrow damage.

The principles of treatment for aplastic anemia are as follows: ① Supportive therapy, including transfusions of red blood cells, platelets, and white blood cells to maintain blood function, and the use of effective antibiotics in case of infection. ② Stimulation of bone marrow hematopoietic function with drugs such as androgens and glucocorticoids to induce anemia remission. ③ Immunosuppressants. ④ Bone marrow transplantation. ⑤ Cryopreserved fetal liver infusion. Additionally, splenectomy may be considered if indicated. The various treatment methods are briefly described below:

⑴ Supportive therapy: Prevent bleeding caused by trauma and encourage appropriate outdoor activity. Strict isolation is required for patients with granulocyte counts below 500/mm³. For patients without obvious infection, antibiotics should not be used prophylactically to avoid microbial imbalance and fungal infections. Infected patients should undergo blood cultures and other tests (e.g., nasopharyngeal secretions, sputum, or urine cultures) to guide appropriate antibiotic selection. Bactericidal antibiotics are preferable to bacteriostatic ones.

Blood transfusions should be minimized, as prolonged illness and frequent transfusions can sensitize patients to red blood cell subtypes, white blood cells, and platelets, leading to severe reactions. Transfusions are only indicated for severe anemia (hemoglobin below 6g/dl) with hypoxic symptoms. Concentrated red blood cell transfusions are preferred. Platelet transfusions may be considered for severe bleeding. Repeated whole blood or platelet transfusions can lead to antiplatelet antibodies, reducing hemostatic efficacy; in such cases, platelet typing should be performed, and histocompatible platelets should be used.

⑵ Androgens: Androgens stimulate erythropoiesis, likely by increasing renal erythropoietin production and directly sensitizing bone marrow stem cells to erythropoietin. They are more effective in children than in adults and are suitable for chronic mild to moderate (grade II) anemia. Commonly used agents include testosterone propionate (1–2mg/(kg·d)), administered via daily intramuscular injection for 3–6 months, with an efficacy rate of 50–65%. Other options include oxymetholone (1–3mg/(kg·d), oral), methandrostenolone (5mg, three times daily, oral), or stanozolol (1–2mg, three times daily, oral). The latter three androgens have milder masculinizing side effects and no fluid retention but are slightly less effective and carry a higher risk of liver toxicity, including potential hepatocellular carcinoma. Androgens accelerate bone marrow maturation, leading to premature fusion of the epiphyses and diaphyses, which may affect longitudinal growth.

In responsive cases, reticulocyte counts rise first, followed by hemoglobin, then white blood cells, with platelets being the slowest to recover. If no response is observed after six months of treatment, the therapy should be discontinued as ineffective. The best outcomes are seen in mild cases, though spontaneous remission is possible in such patients.

(3) Adrenal cortex hormones: Their effect on bone marrow hematopoietic function is still uncertain, but they can provide temporary symptom relief. When combined with androgens, they can reduce the latter's side effects on bone growth and delay epiphyseal closure. Small doses of steroids can alleviate bleeding symptoms caused by thrombocytopenia. Prednisone at 10mg/(m²·d) or 0.5mg/(kg·d) can achieve the above objectives. Higher doses may easily lead to immunosuppression and increase the risk of infection.

(4) Immunosuppressants: In recent years, promising results have been achieved in the treatment of acute and severe aplastic anemia using high-dose methylprednisolone (HD-MP), antithymocyte globulin (ATG), or antilymphocyte globulin (ALG). ① HD-MP involves intravenous bolus administration of methylprednisolone at 20 mg/kg once daily for 14 days, followed by abrupt discontinuation; ② ATG is administered at 10 mg/kg via continuous intravenous infusion over 12–18 hours for 5 consecutive days; ③ ALG is given at 40 mg/kg via intravenous infusion for 4 consecutive days. Both ATG and ALG should be used in combination with HD-MP.

(5) Bone marrow transplantation: This has become the most effective treatment for acute and severe cases. For matched bone marrow transplants, approximately 50–80% of pediatric patients achieve long-term remission. However, due to unresolved issues such as bone marrow sourcing, its application remains limited domestically. Umbilical bleeding and placental blood stem cell transplantation may eventually replace bone marrow transplantation.

(6) Cyclosporin A: Recent reports suggest that this drug, either alone or in combination with ATG, offers a new therapeutic approach for severe refractory aplastic anemia. However, attention must be paid to its side effects, such as renal impairment, and further observation is still required.

bubble_chart Prognosis

Congenital aplastic anemia progresses to acute leukemia in about 5–10% of cases, mostly of the myelomonocytic type. Patients with significant skin changes typically do not have renal malformations but may eventually develop squamous cell carcinoma or other malignancies.

The prognosis of acquired aplastic anemia varies depending on the disease cause. Cases with specific reactions to chloramphenicol or those caused by hepatitis have an extremely poor prognosis, whereas those induced by chloramphenicol overdose often recover.

High-risk indicators include acute onset, severe bleeding, platelets <20,000/mm³, granulocytes <500/mm³, and very low or absent reticulocytes. Severe bone marrow hypoplasia dominated by lymphocytes and non-hematopoietic cells is also a marker; over 50% of such patients die within months from infections like staphylococcal sepsis or Pneumocystis pneumonia or from bleeding. Cases with slow progression, less severe granulocytopenia and thrombocytopenia, milder bone marrow involvement, and responsiveness to androgen therapy have a better prognosis. Long-term survival after bone marrow transplantation can reach 30–60%.