Aplastic anemia. Agranulocytosis

01Definition and overview

Aplastic anaemia (AA) is failure of the bone marrow: pancytopenia with a hypocellular marrow, without an abnormal infiltrate or marrow fibrosis. The diagnosis needs at least two of a haemoglobin below 100 g/L, platelets below 50 × 10⁹/L and neutrophils below 1.5 × 10⁹/L. The name misleads: anaemia is only one of three cytopenias, and patients die of infection and bleeding.

Agranulocytosis is a near absence of neutrophils, a count below 0.5 × 10⁹/L, usually from an idiosyncratic reaction to a drug, with the other cell lines spared. The two conditions share a title because both are failures of blood cell production that drugs and immune attack can cause, and both kill through infection.

02Etiology and pathophysiology

Acquired aplastic anaemia

1. 1

   A trigger, usually unseen

   No cause is found in 70 to 80 per cent of all aplastic anaemia, and most of the rest is inherited. A few acquired cases follow a drug, a seronegative hepatitis, or pregnancy, which may expose new antigens or activate T cells.
2. 2

   T cells attack the stem cells

   Oligoclonal cytotoxic T cells release interferon-γ and tumour necrosis factor, which drive haemopoietic stem and progenitor cells into apoptosis. The marrow empties and fat takes its place; levels of growth factors such as erythropoietin and thrombopoietin are already high.
3. 3

   Escape clones

   Stem cells the attack spares can expand: PNH clones lacking GPI-anchored proteins, cells that have lost an HLA allele, and cells with myeloid mutations (DNMT3A, ASXL1, BCOR), found in 20 to 30 per cent. Most stay small, but some evolve into PNH, myelodysplasia or acute myeloid leukaemia.

Inherited marrow failure

Inherited syndromes can first appear in adults, sometimes as aplastic anaemia alone. Missing them matters: immunosuppression does not work, a sibling donor may carry the same disease, standard transplant conditioning is too toxic, and patients need cancer surveillance.

Others include Diamond–Blackfan anaemia (red cells only) and congenital amegakaryocytic thrombocytopenia. Next-generation sequencing panels now test for all of them together.

PNH and aplastic anaemia

Aplastic anaemia and paroxysmal nocturnal haemoglobinuria are linked: the stem cells that lack GPI-anchored proteins seem to escape the immune attack, so small PNH clones turn up in about half of patients, and some grow into haemolytic PNH over the years. A clone does not change the treatment of the aplasia, but it argues against an inherited cause, and it is followed with flow cytometry: every 3 months for a year if present, then yearly.

Agranulocytosis and other neutropenias

Drugs are thought to damage neutrophils in two ways: by immune destruction of mature neutrophils, often with the drug as a hapten, which can drop the count within days; or by toxicity to the precursors, slower, over weeks. The reactions are idiosyncratic and mostly not dose-related, and typically begin weeks to a few months after the first dose.

Other causes of neutropenia, by mechanism:

• Less production: chemotherapy and radiotherapy (predictable), marrow failure or infiltration, B12 or folate deficiency, inherited syndromes (severe congenital neutropenia and cyclic neutropenia, both often from ELANE mutations).
• More destruction or pooling: viral infections (the commonest cause of a transient neutropenia), severe sepsis and typhoid, autoimmune neutropenia, Felty syndrome in rheumatoid arthritis, large granular lymphocyte leukaemia, hypersplenism.
• A normal variant: the Duffy-null associated neutrophil count. People who lack the Duffy antigen (ACKR1) on their red cells, a trait selected because it protects against vivax malaria, have lower blood neutrophil counts with no excess infection. In one US study of healthy Black adults, two thirds were Duffy-null; their median neutrophil count was 2.8 × 10⁹/L, against 5.0 in those who were not, and about a quarter of them had counts below 2.0, against none of the others. The term replaces the older "benign ethnic neutropenia", which tied a normal trait to ethnicity rather than to a gene.

03Clinical features

The symptoms come from the three cytopenias:

• Thrombocytopenia: bruising, petechiae, nosebleeds, gum bleeding, blood blisters in the mouth and heavy periods; bleeding is often what brings the patient in.
• Neutropenia: bacterial and fungal infections, mouth ulcers and gum infection; invasive aspergillosis is a feared complication of long, severe neutropenia.
• Anaemia: tiredness, breathlessness and pallor.

There are no enlarged lymph nodes, liver or spleen in aplastic anaemia: a palpable spleen, lymphadenopathy or blasts on the film in a patient with pancytopenia point to another diagnosis, such as leukaemia, lymphoma or hairy cell leukaemia. The history asks about drugs and chemicals in the preceding months, jaundice two to three months before (post-hepatitic AA), and a family history of cytopenias, early grey hair, lung fibrosis or cancer; examination looks for the stigmata of inherited syndromes.

Agranulocytosis usually starts abruptly in a patient who has been taking a drug for weeks: fever, chills, sore throat, painful mouth or anal ulcers, myalgia. Pneumonia and sepsis can follow within hours.

04Diagnosis and management

Making the diagnosis

• Blood count with reticulocytes (very low) and a film by an experienced eye (no blasts or dysplasia; macrocytosis is common).
• Bone marrow aspirate and trephine biopsy: the trephine, of good length, is essential to judge cellularity; cytogenetics and a myeloid gene panel look for the clones of myelodysplasia.
• Flow cytometry for a PNH clone, using FLAER.
• B12 and folate, liver tests, viral studies (hepatitis A, B, C and E, Epstein–Barr virus, cytomegalovirus, HIV, parvovirus B19), autoantibodies.
• Tests for inherited marrow failure in younger patients and whenever clues exist: chromosome breakage, telomere length, gene panels.
• HLA typing of the patient and siblings at diagnosis, so that a transplant is not delayed.

Severity is graded by the Camitta criteria, modified for automated reticulocyte counts:

Supportive care

• Red cells to keep the haemoglobin at about 70 to 80 g/L, guided by symptoms; platelets prophylactically below 10 × 10⁹/L during treatment, or below 20 × 10⁹/L during ATG, but not routinely in stable outpatients.
• Leucodepleted blood for all; irradiated components around ATG and transplantation, to prevent transfusion-associated graft-versus-host disease; no blood from family members before a possible transplant, to avoid sensitisation.
• With severe neutropenia, a quinolone such as ciprofloxacin and a mould-active azole as prophylaxis, and aciclovir during ATG and ciclosporin. Irradiated granulocyte transfusions are considered for life-threatening infection.
• Iron chelation for overload, with deferasirox (watching the kidneys alongside ciclosporin); deferiprone is avoided because it causes agranulocytosis.
• G-CSF and erythropoietin do not work in aplastic anaemia and do not replace definitive treatment.
• Any drug that might be the cause is stopped for good, never given again and reported.

Definitive treatment

1. 1

   Severe, aged under 40, with a matched sibling

   Allogeneic stem cell transplantation from the HLA-identical sibling, using bone marrow rather than blood stem cells to limit graft-versus-host disease. Patients aged 40 to 50 are considered by fitness.
2. 2

   Severe, no sibling donor, or older

   Immunosuppression: horse antithymocyte globulin (ATG) 40 mg/kg a day for 4 days as an inpatient, with prednisolone only to prevent serum sickness; ciclosporin from day 1, continued for at least 12 months after the response and tapered slowly; and eltrombopag 150 mg a day from day 14 to 6 months.
3. 3

   No response or relapse

   A transplant from a matched unrelated donor after one failed course, or upfront in a young adult with severe infection and a donor ready; a haploidentical donor with cyclophosphamide after the transplant when none is matched; or a second course of ATG.
4. 4

   Non-severe disease

   Many need only watching. Those who become transfusion-dependent, bleed or keep getting infections are treated with ATG and ciclosporin.

Horse ATG beat rabbit ATG in a randomised trial (response at 6 months 68 against 37 per cent, survival at 3 years 96 against 76 per cent). In the RACE trial, adding eltrombopag raised complete responses at 3 months from 10 to 22 per cent and overall responses at 6 months from 41 to 68 per cent, and shortened the median time to a first response from 8.8 to 3 months, without more serious side effects; survival at 2 years was similar. The British guideline recommends the triple combination for severe disease, and so does American guidance of 2026, which also prefers a first transplant from a matched sibling or a matched unrelated donor for younger patients. In the EU, however, eltrombopag is licensed in aplastic anaemia only for adults with severe disease that is refractory to immunosuppression or heavily pretreated and who are unsuitable for transplantation, so its first-line use is off-label (it is approved for it in the USA). Monosomy 7 emerges in some patients given eltrombopag, so the marrow is rechecked during treatment.

Responses to ATG start after 3 to 4 months. Ciclosporin needs its trough level, blood pressure and kidney function checked, and interacts with the azoles. In older patients immunosuppression is the treatment of choice, with care over the heart risks of ATG beyond 60. In pregnancy the platelets are kept above 20 × 10⁹/L and ciclosporin can be used; ATG, transplantation and eltrombopag are not.

neutrophils: the line for agranulocytosis and neutropenic sepsis

0.5× 10⁹/Lneutrophils: the line for agranulocytosis and neutropenic sepsis

to the first intravenous antibiotic in febrile neutropenia

1hourto the first intravenous antibiotic in febrile neutropenia

the marrow cellularity below which, with two low counts, aplasia is severe

25per centthe marrow cellularity below which, with two low counts, aplasia is severe

the usual age limit for upfront sibling transplantation

40yearsthe usual age limit for upfront sibling transplantation

Drug-induced agranulocytosis

The suspected drug is stopped at once, and all other non-essential drugs with it; the neutrophils usually recover within one to two weeks. A well patient without fever can be watched closely; a febrile patient is treated as neutropenic sepsis. G-CSF shortens the neutropenia a little and is given to selected patients with severe infection or a very low count. The drug, and drugs that cross-react with it, are never given again, and the reaction is reported.

Prevention rests on warning patients rather than on routine counts, which miss most cases:

• Metamizole: since the EMA review of 2024, routine blood counts are no longer recommended. Patients are told to stop the drug and seek help at once if fever, chills, sore throat or painful sores in the mouth, nose, throat, genital or anal area appear during or shortly after treatment; a blood count with a differential is done immediately. It must not be given after agranulocytosis from it or another pyrazolone or pyrazolidine, or to anyone with marrow disease.
• Carbimazole and other thionamides: before starting, the patient is told to stop and have an urgent count if a sore throat, mouth ulcers or fever develop.
• Clozapine: blood counts are mandatory, weekly for the first 18 weeks and then monthly. Since a 2025 EU review, monitoring is based on the absolute neutrophil count alone, and in patients who have had no neutropenia it drops to every 12 weeks after the first year and to once a year after two years.

Febrile neutropenia

Definitions vary. UK guidance diagnoses neutropenic sepsis in a patient on anticancer treatment with neutrophils at or below 0.5 × 10⁹/L and a temperature above 38 °C or other signs of sepsis; ESMO uses an oral temperature above 38.3 °C, or above 38.0 °C on two readings over 2 hours, with neutrophils below 0.5 × 10⁹/L or expected to fall below it. In-hospital mortality is about 10 per cent.

1. 1

   Suspect it

   Anyone unwell within weeks of chemotherapy, or on a drug known to cause agranulocytosis, is treated as neutropenic until the count is known.
2. 2

   Antibiotics within the hour

   Blood cultures (from a central line and a vein), then intravenous empirical antibiotics at once: in the UK piperacillin with tazobactam alone, without an aminoglycoside or a glycopeptide unless there is a specific reason. Resuscitation follows the sepsis pathway.
3. 3

   Find the source

   Examination of the mouth, skin, line sites and perianal area (no rectal examination); urine, chest X-ray and cultures as indicated.
4. 4

   Grade the risk

   Within 24 hours a risk score such as MASCC separates low-risk patients, who may switch to oral antibiotics or go home, from high-risk ones. Persistent fever after a few days prompts a search for fungal infection, and empirical antibiotics stop once the infection has responded, whatever the neutrophil count.

G-CSF is not given routinely for febrile neutropenia; it is used to prevent it with chemotherapy regimens that carry a high risk.

05Epidemiology

• Aplastic anaemia: about 2 to 3 new cases per million people a year in Europe, more in East Asia. It has two age peaks, at 10 to 25 and over 60, and affects men and women about equally.
• Drug-induced agranulocytosis: about 2 to 15 cases per million people a year, more often in older people, who take more drugs.
• Duffy-null associated neutrophil count: common in people of African ancestry and in some groups in the Middle East; it explains many of the low counts found in well people of these origins.
• Febrile neutropenia: among the commonest reasons a patient on chemotherapy comes to the emergency department.

06Prognosis

• Untreated, severe aplastic anaemia is usually fatal, from infection and bleeding. In a 1976 prospective study of severe disease, 24 of 36 patients given an early marrow transplant were alive after a median of 9 months, against 12 of 31 treated conventionally.
• After immunosuppression, 50 to 70 per cent of patients with severe disease respond by 6 months (fewer in very severe disease), but relapse and dependence on ciclosporin are common. Survival at 15 years depends on age: about 89 per cent under 20, 81 per cent at 20 to 39, 55 per cent at 40 to 60, and 32 per cent over 60.
• Late clonal disease follows immunosuppression: myelodysplasia or acute myeloid leukaemia in about 15 to 25 per cent at 10 years in older series (lower in recent ones), and haemolytic PNH in about 10 per cent, so counts are followed for life.
• After a sibling transplant most young patients are cured; in adults aged 30 to 50, survival is about 70 to 90 per cent, with graft failure and chronic graft-versus-host disease as the main risks.
• Drug-induced agranulocytosis is fatal in about 5 per cent, most often in older patients, those with sepsis, and those whose count falls below 0.1 × 10⁹/L (in published case reports, 10 per cent of these died, against 3 per cent of the rest).