Aplastic anemia: causes, symptoms, diagnosis, treatment

Aplastic anemia is a syndrome of bone marrow hypoplasia with pancytopenia (a decrease in red blood cells, white blood cells, and platelets) due to hematopoietic failure. Classically, acquired and hereditary forms are distinguished (e.g., Fanconi anemia, congenital dyskeratosis); in the "narrow" clinical sense, aplastic anemia most often refers to the acquired immune-mediated form in adolescents and adults. Without treatment, the disease is fraught with severe infection and bleeding, but with the introduction of immunosuppression, the thrombopoietin agonist eltrombopag, and hematopoietic stem cell transplantation, survival rates in many cohorts reach 80-85%. [1]

Hypoplastic anemia is a "milder" spectrum of the same process, where cytopenias are less pronounced and do not always meet the strict criteria for "severe aplastic anemia." An important clinical feature is the frequent association with clonal cell populations deficient in glycosylphosphatidylinositol (GPI) proteins (so-called paroxysmal nocturnal hemoglobinuria, PNH, clones), as well as the risk of "clonal evolution" to myelodysplasia. This influences the initial testing scope (highly sensitive PNH screening is mandatory) and the surveillance strategy. [2]

Severity threshold criteria (Camitta/modifications) determine the tactics: in the presence of a related compatible donor, early allogeneic transplantation is preferred in young patients; in the absence of a donor or in older age groups, combined immunosuppression based on equine anti-thymocyte globulin, cyclosporine, and eltrombopag has become the standard. For very severe forms (absolute neutrophils <0.2×10⁹/L), enhanced infection control and often more rapid routing to transplantation are necessary. [3]

Between 2017 and 2025, the evidence base has changed significantly: the addition of eltrombopag to standard immunosuppression increases the rate, speed, and depth of hematological responses in previously untreated patients; updates to the ASH/EBMT consensus statements have been released on the choice of first-line transplantation (matched related donor transplantation in young patients vs. immunosuppression + eltrombopag in other cases) and on the placement of haploidentical transplantation where there is no HLA-related donor. [4]

Code according to ICD-10 and ICD-11

According to ICD-10, aplastic anemia is coded in block D61 “Other aplastic anemias and other bone marrow failure syndromes”: D61.0 “Congenital aplastic anemia” (including D61.03 “Fanconi anemia”), D61.1 “Drug-induced aplastic anemia”, D61.2 “Aplastic anemia due to other external factors”, D61.3 “Idiopathic aplastic anemia”, D61.9 “Aplastic anemia, unspecified”. In reporting, it is important to simultaneously code concomitant/secondary factors (e.g., chemotherapy, infections). [5]

In ICD-11, aplastic anemia is listed in section 3A70 "Aplastic anemia" with the clarifying positions 3A70.0-3A70.4 (hereditary variants) and 3A70.Z "Aplastic anemia, unspecified." For clinically complex cases, post-coordination is used (e.g., 3A71.0 "Anemia in malignant neoplasms") and an indication of the factors that influenced the outcome. For an accurate selection of codes, the ICD-11 online browser and the WHO reference book (v2025-01) are recommended. [6]

Table 1. ICD codes for aplastic/hypoplastic anemia

Clinical situation	ICD-10	ICD-11	Comment
Idiopathic acquired aplastic anemia	D61.3	3A70.Z	Basic code for de-novo cases. [7]
Drug-induced aplastic anemia	D61.1	3A70.Z + factor	In ICD-11 - through post-coordination of the causal factor. [8]
Congenital forms (eg, Fanconi anemia)	D61.03	3A70.0-3A70.4	Encode syndrome + phenotype (according to local rules). [9]
Aplastic anemia, unspecified	D61.9	3A70.Z	Timestamp pending clarification of cause. [10]

Epidemiology

Aplastic anemia is a rare disease with a bimodal age distribution (peaks at 15–25 years and over 60 years). In Europe, the incidence is consistently estimated at around 2–3 cases per 1,000,000 per year; in a recently published ambispective study, the rate was 2.83 per 1,000,000 per year (median age 61 years). In East and Southeast Asian countries, the incidence is higher – approximately 4–6 per 1,000,000 per year, with regional variations. [11]

Systematic reviews confirm that in "Western" populations the expected frequency is 1.5-2.3 per 1,000,000, while in Asia it is 3.0-7.5 per 1,000,000. Differences are associated with environmental, infectious, and pharmacoexposure factors, as well as with differences in recording methods. Gender differences in frequency are usually not noted. [12]

Thanks to transplantation and modern immunosuppression, long-term survival has exceeded 80-85% in many series; however, outcomes are worse in older age groups, and the risk of clonal evolution and relapse is higher. As of March 2024, EBMT registries included tens of thousands of patients with acquired/hereditary bone marrow failure, of which more than 14,000 had acquired aplastic anemia. [13]

Table 2. Epidemiological landmarks

Region	Incidence (per 1,000,000/year)	Source
Europe (modern estimates)	≈2-3	[14]
Spain (multicenter, 2024)	2.83	[15]
Asia (generally)	4-6 (sometimes up to 7-8)	[16]
EBMT Registry (aplastic anemia, total)	>14,000 cases (cumulative)	[17]

Reasons

Approximately 60-70% of acquired cases are considered idiopathic; however, a significant proportion of patients have immune mechanisms associated with "small" PNH clones. Secondary causes include drug exposure (cytostatics, chloramphenicol—historically, anticonvulsants, etc.), toxic agents (benzene), viruses (seronegative hepatitis, parvovirus B19), and radiation. Hereditary causes—Fanconi anemia, telomeropathies (congenital dyskeratosis), Shwachman-Diamond, etc.—are critical to recognize early, especially in children and young adults. [18]

The PNH-associated pathway is important both as a diagnostic "beacon" (screening with high-sensitivity flow cytometry for FLAER/CD24/CD14/CD59 antigens) and as a prognostic and monitoring factor. PNH screening is recommended for patients with aplastic/hypoplastic anemia even in the absence of overt hemolysis, since "associated" clones are common. [19]

Risk factors

The risk is increased by exposure to benzene and solvents, certain medications, radiation, and possibly a number of viral infections. Certain population characteristics (higher incidence in Asian countries) are associated with environmental and genetic factors. In pediatrics, hereditary syndromes play a significant role (accounting for up to 30% of all cases of bone marrow failure in children). [20]

In adults, clinicians should be alert to signs of a congenital origin (short stature, skeletal/nail anomalies, pigmentation, family history of early cytopenias) – these are reasons for telomere length testing and panels for hereditary bone marrow failure syndromes. Correct identification changes the choice of therapy (e.g., contraindications to certain conditioning regimens) and monitoring strategy. [21]

Pathogenesis

The acquired form in most adults is based on a T-cell-mediated autoimmune attack on hematopoietic stem cells, resulting in their depletion and bone marrow hypocellularity. This is accompanied by the "survival" of rare clones with mutations and/or GPI deficiency (PNH clones), reflecting the selective pressure of the immune system. This immune nature explains the effectiveness of antithymocyte globulin and cyclosporine. [22]

Hereditary forms are associated with defects in DNA repair (Fanconi anemia), telomeropathies (telomere shortening, dyskeratosis), ribosomal/mitochondrial apparatus disorders, etc. These conditions phenocopy acquired aplasia, but require different approaches (genetic counseling, modification of conditioning during transplantation, different risk assessment). [23]

Symptoms

The clinical picture is explained by pancytopenia: weakness, shortness of breath, dizziness (anemia), frequent and/or severe infections (neutropenia), bleeding, petechiae, bruising, and mucosal bleeding (thrombocytopenia). The course can be acute (rapid drop in blood counts) or subacute/chronic. Splenomegaly is not characteristic of "pure" aplastic anemia and requires a search for an alternative or concomitant cause. [24]

Some patients experience precursors of infection, such as stomatitis and fever of unknown origin. Any bleeding in a person with platelet counts <20×10⁹/L is a reason for emergency measures. Visits to the dentist/surgery without correcting cytopenias are dangerous. [25]

Classification, forms and stages

The severity criteria used are (Camitta and modern modifications): "severe aplastic anemia" - bone marrow with cellularity <25% (or 25-50% with residual hematopoietic tissue <30%) and ≥2 of 3 indicators: absolute neutrophils <0.5×10⁹/l; platelets <20×10⁹/l; reticulocytes <20×10⁹/l (or <60×10⁹/l by automatic analyzer). "Very severe" - the same criteria, but neutrophils <0.2×10⁹/l. "NOT severe/hypoplastic" - hypocellular marrow without meeting the thresholds of severe form. [26]

Table 3. Criteria for the severity of aplastic anemia

Category	Neutrophils	Platelets	Reticulocytes	Cellularity of the CM
Very heavy	<0.2×10⁹/l	<20×10⁹/l	<20×10⁹/l (or <60×10⁹/l*)	<25% (or 25-50% with residual hematopoietic tissue <30%)
Heavy	<0.5×10⁹/l	<20×10⁹/l	<20×10⁹/l (or <60×10⁹/l*)	Same
Mild (hypoplastic)	≥0.5×10⁹/L (usually <1.0)	Often <50×10⁹/L	Demoted	Hypocellularity without "severe" thresholds
* automatic reticulocyte count. [27]

Complications and consequences

Key risks at onset include febrile neutropenia and bleeding, including intracranial bleeding. In the long term, relapse/incomplete response to immunosuppression and "clonal evolution" (myelodysplastic syndrome, acute myeloid leukemia) are possible, more often in older patients and with prolonged use of stimulants. The presence of PNH clones requires separate monitoring and, in the case of clinically significant hemolysis/thrombosis, specialized PNH therapy. [28]

Transfusion dependence leads to iron overload; ferritin monitoring and initiation of chelation therapy as indicated are necessary. An infection and vaccination profile are important when planning immunosuppression and transplantation. [29]

When to see a doctor

Immediately - fever ≥38.0 °C in the presence of neutropenia, any signs of bleeding (bloody vomiting/stool, nasal/gingival), severe weakness, dyspnea at rest, syncope. These conditions require urgent evaluation and empirical antibacterial therapy according to the febrile neutropenia protocol. [30]

Planned - persistent weakness, frequent infections, bruising without trauma, prolonged/heavy menstruation, and blood counts outside the reference range. Patients with familial/phenotypic features of hereditary syndromes require referral to a hematogeneticist. [31]

Diagnostics

Step 1. Confirm pancytopenia and hypoplasia. Complete blood count with reticulocytes; biochemistry (LDH, bilirubin) - usually without significant hemolysis; bone marrow puncture and trephine biopsy to assess cellularity and exclude infiltration/dysplasia. Histology sets the course for further investigation. [32]

Step 2. Rule out hereditary variants. If the patient is young or has phenotypic clues, perform a test for chromosomal fragility (Fanconi), telomere length (telomeropathies), and targeted and/or panel genetic testing for hereditary bone marrow failure syndromes. The results determine the transplant strategy and prognosis. [33]

Step 3. Conduct PNH screening. High-sensitivity flow cytometry (FLAER + granulocyte/monocyte/erythrocyte panels) is mandatory in all patients with aplastic/hypoplastic anemia, even without hemolysis. Clone detection aids in diagnosis and routing, and also forms a monitoring plan. [34]

Step 4. Stratify severity and select the primary treatment route. Use the criteria from Table 3; in parallel, minimal infectious screening before immunosuppression/transplantation and a vaccination plan. Young patients with a suitable related donor are candidates for primary transplantation; others are candidates for immunosuppression with eltrombopag. [35]

Table 4. Differential diagnosis of pancytopenia/hypocellular bone marrow

State	Smear/CM	Differences from aplastic anemia
Myelodysplastic syndrome (hypocellular)	Dysplasia, cytogenetic abnormalities	Often clonic anomalies; different prognosis/therapy.
Myelophthisis (infiltration/fibrosis)	Dry puncture, fibrosis, leukoerythroblastosis	See separate article; other tactics.
B12/folate deficiency	Macrocytosis, hypersegmentation	High LDH, respond to replacement therapy.
Hypersplenism	Splenomegaly	Bone marrow is not hypocellular.

Differential diagnosis

The key distinction is between "pure" aplasia and hypocellular myelodysplastic syndrome; morphology, cytogenetics/NGS panels, and immunosuppression dynamics are helpful. In young patients, it is essential to exclude hereditary syndromes (Fanconi anemia, telomeropathies), as standard conditioning regimens and even chemotherapy doses are different for them. [36]

Next comes the PNH assessment. A small clone indicates immune-mediated aplasia and does not necessarily indicate severe PNH; however, large clones with hemolysis and thrombosis require specific management (complement inhibitor therapy, as indicated, is beyond the scope of this article). Finally, toxic/drug-induced and infectious causes must be excluded, especially in the acute stage. [37]

Treatment

The basic logic is as follows: transplantation is the most curative treatment, but is optimal for young patients with a compatible relative; immunosuppression is standard for others, especially those older and/or without a donor; support is essential for everyone. The decision is made multidisciplinary, taking into account the severity, age, comorbidities, and availability of a donor/center. In the early days, infection and bleeding prevention, as-needed transfusions, and a vaccination plan prior to immunosuppression are important. [38]

First-line immunosuppression. The standard is equine anti-thymocyte globulin (ATG) and cyclosporine; the addition of eltrombopag (a thrombopoietin receptor agonist) improves the rate, speed, and depth of responses in previously untreated patients, without adding toxicity; this is supported by current guidelines and studies (including RACE). Eltrombopag is typically initiated simultaneously with the initiation of ATG and continued for months according to the center's protocol. Cyclosporine levels, liver function, and the risk of clonal evolution are monitored. [39]

Allogeneic stem cell transplantation. Patients younger than 40 years of age with an HLA-compatible related donor are priority candidates for first-line transplantation. In the absence of a related donor and unfavorable clinical conditions, an unrelated or haploidentical donor (with modern anti-rejection platforms, such as post-transplant cyclophosphamide) is actively considered, especially in very severe cases or in cases of non-response to immunosuppression. The choice of conditioning and graft-versus-host disease prophylaxis is based on the center's protocols and EBMT/ASTCT recommendations. [40]

Supportive care: transfusions. In stable hospitalized adults, "restrictive" red blood cell transfusion strategies are used (often Hb <7-8 g/dL, adjusted for clinical findings); 1 dose is transfused with reassessment. Platelets are given prophylactically at <10×10⁹/L in patients undergoing active treatment and below in the presence of bleeding/invasive procedures (guidelines 10-20×10⁹/L, higher - during punctures/surgeries). Strategies are specified according to current AABB/BSH guidelines and local protocols. [41]

Infection control. Febrile neutropenia is an indication for immediate empirical antibiotic therapy. In very severe cases, prophylaxis (antibacterial/antifungal/antiviral) is appropriate according to the local epidemiological situation; granulocyte colony-stimulating factors (G-CSF) can shorten the duration of neutropenia and hospitalization, but do not improve survival and require careful use (long-term use has been associated with a risk of late events in some series). Granulocyte transfusions are a niche option for life-threatening infections until the primary treatment response has been achieved. [42]

Second-line therapy and relapse. If there is no response after 3-6 months, a repeat course of ATG (usually rabbit) + cyclosporine, transfer to transplantation (if a donor is available), and the addition/continuation of eltrombopag if tolerated are possible. In the elderly, individualization is recommended, with an emphasis on safety and quality of life, and extended support. The decision is made by an expert panel. [43]

Haplo- and unrelated transplantation after immunosuppression. In cases of non-response/relapse and the absence of an HLA-related donor, haploHSCT is increasingly being used; the post-cyclophosphamide-based platform is comparable in early outcomes to alternatives but requires an experienced center. Careful assessment of infectious risks and late complications is important. [44]

Monitoring and prevention of clonal evolution. Regular clinical and laboratory visits, bone marrow morphology assessment as indicated, and periodic PNH screening are necessary. If the PNH clone grows and signs of hemolysis/thrombosis are present, referral to specialized PNH centers is necessary. [45]

Correction of iron deficiencies and iron chelation. In cases of transfusion dependence, ferritin is monitored; in cases of iron overload, deferasirox/deferoxamine is used as indicated. Nutritional support and correction of folate and vitamin B12 levels, if deficient, improve treatment tolerance and reduce the need for transfusions. [46]

Adolescence and pregnancy. In adolescents, special attention is paid to differentiating hereditary syndromes; in pregnant women, the approach is individualized, relying on supportive measures and cautious use of immunosuppression as indicated; transplant decisions are often postponed. (Detailed obstetric nuances are available in special recommendations.) [47]

Table 5. "Who - What": choosing the first line

Patient	First line	Alternative/escalation
<40 years old, HLA-matched relative	Allo-TGSC	For contraindications - ATG+CsA+CRT
No donor/older age	ATG (equine) + cyclosporine + eltrombopag	Unrelated/haplo-donor in case of non-response
Very severe form (neutrophils <0.2×10⁹/l)	Rapid routing to HSCT ± short-term G-CSF	Enhanced support, repeat IST if HSCT is unavailable

Prevention

There is no specific primary prevention for acquired aplastic anemia; general measures to reduce exposure to benzene/solvents and caution with potentially myelotoxic drugs are reasonable. Regarding secondary prevention, the key factors are: vaccination (inactivated vaccines before immunosuppression), education on "fever rules," infection prevention in profoundly neutropenic patients, careful transfusion strategies, and prevention of iron overload. [48]

For hereditary forms, prevention is individualized and includes genetic counseling of families, screening of donor relatives, fertility discussions, and early transplant planning in experienced centers. [49]

Forecast

Without treatment, "classic" severe aplastic anemia is life-threatening, but modern therapy has fundamentally changed outcomes: 5-year survival in some cohorts exceeds 80%. The best results are in young patients with early transplantation and in patients who received ATG + CsA + ELT with a complete/deep response. Age, comorbidities, infectious complications, and clonal evolution are the main risk factors. [50]

Supportive care impacts quality of life no less than etiotropic therapy: appropriate transfusion thresholds, infection prevention, and PNH clone and iron monitoring help reduce hospitalizations and complications. In the transplant field, access to donors (unrelated and haplogroup donors) is expanding, increasing the chances of a cure in the absence of an HLA-matched relative. [51]

FAQ

What is the incidence of aplastic anemia?
In Europe, it is about 2-3 cases per 1,000,000 per year; in East/Southeast Asia, it is 4-6 per 1,000,000. The disease is rare, with bimodal peaks by age. [52]

Who receives transplantation first?
Typically, patients are younger than 40 years of age with an HLA-compatible relative. If a donor is unavailable or if they are older, they start with ATG + CsA + Eltrombopag; haplo/unrelated HSCT is an option in case of non-response. [53]

Why should everyone be tested for PNH?
PNH clones are common in patients with aplastic/hypoplastic anemia and help confirm immune pathogenesis; large clones change monitoring and treatment strategies. Screening is performed using high-sensitivity flow cytometry (FLAER panels). [54]

Does everyone need G-CSF?
No. It may reduce the duration of neutropenia and hospitalization in some patients, but does not improve survival; long-term use is discussed with caution. [55]

Is eltrombopag a "mandatory" component?
Yes, for most previously untreated adults, it is part of first-line immunosuppression (ATG + CsA + ELT) - this is the current standard, increasing the frequency and depth of responses. [56]

Additional practical tables

Table 6. Minimum basic set of examinations

Direction	What to include	For what
Morphology	Trephine biopsy (cellularity, dysplasia/infiltration)	Confirm hypocellularity, exclude MDS/myelophthisis
Hereditary forms	Chromosome fragility (Fanconi), telomere length, IBMFS panels	Affects transplantation tactics
PNG screening	FLAER + CD24/CD14/CD59 (high sensitivity)	A frequent companion of aplasia, important for prognosis/monitoring
Infectious screening	HBV/HCV/HIV, parvovirus B19 as indicated	Safety of immunosuppression/HSCT

Table 7. Transfusion and prophylactic guidelines

Situation	Landmark	Note
Red blood cell transfusion	Often Hb <7-8 g/dL in stable	Always taking into account symptoms/comorbidities. [57]
Prevention of thrombocytopenia	<10×10⁹/l (higher - with risk of bleeding/procedures)	Follow local AABB/BSH protocols. [58]
Febrile neutropenia	Immediate empirical antibiotic therapy	According to local protocols; hospitalization is often indicated.
Prevention of iron overload	Ferritin monitoring; chelators as indicated	Especially with frequent transfusions. [59]