Aplastic anaemia

01OverviewDefinition, clinical context and the essential points that orientate the chapter.

Acquired aplastic anaemia usually reflects cytotoxic T-cell attack on haematopoietic stem cells, leaving fatty hypocellular marrow and reduced production across erythroid, myeloid and megakaryocytic lineages. Peripheral destruction is not the primary mechanism, so reticulocytes are low rather than compensatorily raised. The clinical picture depends on which line reaches danger first. Profound neutropenia drives bacterial and fungal infection, thrombocytopenia drives mucosal or internal bleeding, and anaemia develops with fatigue, tachycardia and cardiac strain.

Aplastic anaemia is a diagnosis of mechanism and exclusion. Repeat a credible count and examine the film for blasts, dysplasia, fragments or megaloblastosis. Assess B12, folate, liver disease, viral infection, pregnancy and drug or occupational exposure. Bone-marrow trephine is essential because an aspirate alone may be dilute and misleading. Cytogenetic and molecular findings, dysplasia or fibrosis may favour hypoplastic myelodysplastic syndrome. In younger people, physical features and family history guide testing for Fanconi anaemia, telomere biology disorders and other inherited syndromes before transplant conditioning.

Definitive treatment is individualised early rather than after months of transfusion. Donor search, transplant fitness and inherited-failure evaluation run alongside stabilisation. Matched-sibling transplantation offers curative potential in appropriately selected younger patients. Horse antithymocyte globulin with ciclosporin, often with eltrombopag under specialist protocols, aims to remove immune suppression of residual stem cells when transplant is unsuitable or unavailable. Response takes time; relapse, refractory disease, PNH evolution and myeloid clonal evolution require long-term surveillance.

Key points

Aplastic anaemia is pancytopenia caused by failure of haematopoietic stem and progenitor cells in a hypocellular marrow without malignant replacement or substantial fibrosis.
Most acquired cases are immune mediated and idiopathic; implicated exposures include medicines, toxins, hepatitis and other infections, while inherited marrow-failure syndromes require active consideration.
Patients present through consequences of low cell lines: fatigue and dyspnoea, infection or mouth ulceration, petechiae, bruising and mucosal bleeding.
Splenomegaly, lymphadenopathy, marked dysplasia or constitutional bone pain is atypical and should broaden assessment to malignancy, infiltration, hypersplenism or another diagnosis.
The blood count, reticulocytes and film identify pancytopenia with an inappropriately low reticulocyte response; marrow aspirate and trephine establish hypocellularity and exclude clonal disease.
Severity classification uses marrow cellularity plus neutrophil, platelet and reticulocyte thresholds and must be calculated from validated local measurements by haematology.
Flow cytometry for a PNH clone and cytogenetic or molecular studies help define overlap and exclude hypoplastic myelodysplasia, but a small PNH clone does not itself mean classical haemolytic PNH.
Younger fit patients with severe disease and a matched sibling donor may proceed to allogeneic stem-cell transplantation; others commonly receive antithymocyte globulin plus ciclosporin-based immunosuppression.
Eltrombopag may be combined with specialist immunosuppression or used in selected refractory disease under current NHS pathways, with liver and clonal monitoring.
Supportive care includes infection treatment, carefully selected transfusion, bleeding prevention and avoidance of unnecessary marrow-toxic medicines while definitive therapy is arranged.

02AetiologyUnderlying causes, associations and risk factors, with why each one matters.

Acquired immune injury

Autoreactive T cells and inhibitory cytokines suppress or destroy haematopoietic stem cells. A specific trigger is often not found despite careful medicine, infection and exposure review.

Secondary exposures

Rare medicine reactions, benzene, radiation and hepatitis-associated syndromes can precede marrow failure; temporal association requires specialist causality assessment rather than assuming every concurrent medicine is responsible.

Inherited marrow failure

Fanconi-pathway, telomere and other germline disorders may first appear in adolescence or adulthood and materially change donor choice, conditioning intensity and family counselling.

03PathophysiologyThe causal sequence from the underlying abnormality to symptoms and harm.

1
Stem-cell depletion
Loss of multipotent progenitors reduces production of red cells, granulocytes and platelets together, producing a fatty hypocellular marrow and low circulating reticulocytes.
2
Neutrophil deficit
Reduced innate cellular defence permits rapidly progressive bacterial infection and, when prolonged, invasive fungal disease, sometimes with little inflammatory response or localising pus.
3
Platelet-production failure
Insufficient megakaryopoiesis produces petechiae and mucosal bleeding and can progress to retinal, gastrointestinal or intracranial haemorrhage at very low counts.
4
Clonal selection
Surviving stem-cell clones may acquire growth advantages, explaining PNH populations and later myelodysplastic or leukaemic evolution in a minority of patients.

04Clinical features and red flagsSymptoms, examination findings, patterns of presentation and time-critical warnings.

Production pancytopenia

Anaemia, neutropenia and thrombocytopenia occur with an inappropriately low absolute reticulocyte count and without a crowded leucoerythroblastic film.

Infection phenotype

Fever, oral ulceration or perianal pain may be the only evidence of severe neutropenic infection and deserves immediate assessment.

Bleeding phenotype

Petechiae, gum bleeding, epistaxis or menorrhagia reflect thrombocytopenia; headache or focal neurology raises critical intracranial bleeding.

Septic deteriorationRed flag

Hypotension, confusion, hypoxia or fever with profound neutropenia requires empirical antibiotics and resuscitation before diagnostic completion.

Atypical organ findings

Substantial nodes, splenomegaly or bone tenderness argues against uncomplicated aplasia and prompts investigation for malignant or systemic disease.

05InvestigationsWhat to request, why it matters and how to interpret it.

Investigation order

Read from the initial assessment onwards. Tests may run in parallel in urgent care; first-line, preferred, confirmatory, definitive and gold-standard labels appear only when the chapter explicitly states them.

01
Repeat full blood count and reticulocytesFirst step
Why
Confirm cytopenias and quantify marrow output.
Interpretation and limitations
A low absolute reticulocyte count supports production failure; review old results for tempo and exclude sampling artefact or dilution.
02
Expert blood film
Why
Look for blasts, dysplasia, fragments and deficiency patterns.
Interpretation and limitations
A bland pancytopenic film fits aplasia, whereas blasts, marked dysgranulopoiesis or schistocytes demand alternate urgent pathways.
03
Bone-marrow aspirate and trephine
Why
Establish cellularity and exclude infiltration or fibrosis.
Interpretation and limitations
A markedly hypocellular trephine with reduced haematopoiesis supports aplastic anaemia; sampling quality and patchiness require expert correlation.
04
Cytogenetic and molecular studies
Why
Assess clonal myeloid disease and inherited predisposition.
Interpretation and limitations
Some abnormalities strongly support myelodysplasia, while small age-related clones need interpretation with morphology and serial behaviour.
05
PNH flow cytometry
Why
Detect GPI-deficient granulocyte and monocyte populations.
Interpretation and limitations
Small clones are common in immune aplasia and can support biology without causing haemolysis; larger symptomatic clones alter thrombosis and treatment review.
06
Viral, nutritional and organ screen
Why
Identify associated or reversible contributors and treatment constraints.
Interpretation and limitations
Test hepatitis, HIV, parvovirus, B12, folate, liver and renal function according to context; serology alone rarely proves causal aplasia.

06Differential diagnosisRealistic alternatives and the features that help distinguish them.

Hypoplastic myelodysplasia

Cytopenias with hypocellularity can arise from myelodysplastic neoplasia; convincing dysplasia, abnormal cytogenetics, somatic mutation patterns and age-dependent context guide specialist distinction.

Acute leukaemia

Leukaemia may present with pancytopenia even without circulating blasts; marrow morphology, immunophenotyping and genetics identify malignant replacement requiring an entirely different urgent pathway.

Megaloblastic anaemia

Severe B12 or folate deficiency can cause pancytopenia, macro-ovalocytes, hypersegmented neutrophils and biochemical ineffective erythropoiesis but usually produces a cellular megaloblastic marrow.

Peripheral consumption

Sepsis, hypersplenism and thrombotic microangiopathy lower circulating cells through sequestration or destruction; examination, film, coagulation and haemolysis findings differ from pure production failure.

07ManagementImmediate care, first-line treatment, alternatives and escalation.

01Immediate safetyProtect against infection and bleedingFirst stepNew pancytopenia includes severe neutropenia, thrombocytopenia or symptomatic anaemia.

1Admit unstable or severely cytopenic patients, culture suspected infection and deliver the local neutropenic-sepsis antibiotic regimen without waiting for marrow biopsy.
2Discuss platelet and red-cell support with haematology and transfusion medicine, using appropriately selected components and minimising avoidable donor exposure before transplant.
3Stop plausible marrow-toxic exposure after senior review, institute bleeding and infection precautions and avoid rectal procedures or intramuscular injections when unsafe.

02Diagnostic definitionProve hypocellularity and exclude mimicsCounts and reticulocytes suggest global production failure.

1Review medicine, toxin, infection, pregnancy, autoimmune and family history and examine for congenital features, nodes, liver and spleen enlargement.
2Obtain expert film plus marrow aspirate and trephine with flow, cytogenetic and molecular analysis, and calculate severity using validated haematology criteria.
3Test for a PNH clone and select germline or telomere investigations before donor or conditioning decisions when age or phenotype raises inherited failure.

03Definitive therapyChoose donor treatment earlyDefinitiveSevere or very severe acquired aplastic anaemia is confirmed.

1Begin HLA typing and donor search at diagnosis while assessing fitness, infection, inherited syndromes and patient priorities with a transplant centre.
2Offer matched-sibling allogeneic transplantation to appropriate younger fit patients; otherwise use specialist antithymocyte-globulin and ciclosporin-based immunosuppression with commissioned adjuncts.
3Monitor response over months and plan salvage transplant, further immunosuppression or supportive care for refractory disease without overlooking relapse or clonal evolution.

Key medicines and prescribing safety3 treatments · regimens, roles and cautions

Depletes pathogenic T lymphocytes to permit recovery of residual haematopoietic stem cells.

Horse antithymocyte globulin

A common adult severe-aplastic-anaemia regimen is 40 mg/kg intravenously once daily for 4 days, given in a specialist centre with corticosteroid reaction prophylaxis and ciclosporin when indicated.

Infusion reactions, serum sickness, anaphylaxis, infection and worsening cytopenias require monitored administration; product selection and viral screening follow the centre protocol.

Suppresses T-cell-mediated stem-cell injury and maintains response after antithymocyte globulin.

Ciclosporin

A specialist commonly starts about 5 mg/kg/day orally in 2 divided doses, then adjusts to the centre's trough target, renal function, blood pressure and interactions. Taper only after a sustained haematological response.

Nephrotoxicity, hypertension, magnesium loss, neurotoxicity, infection and numerous CYP3A interactions require laboratory and clinical surveillance; abrupt early withdrawal promotes relapse.

Stimulates residual haematopoiesis as part of selected initial or refractory aplastic-anaemia regimens.

Eltrombopag

The marrow-failure service titrates the licensed oral dose under the applicable NHS pathway, accounting for ancestry, liver function, polyvalent-cation separation and response.

Monitor liver tests, marrow morphology, cytogenetics and thrombosis; it is not a substitute for urgent antibiotics or transfusion support during dangerous cytopenia.

08ComplicationsImportant consequences, why they occur and why they matter clinically.

Neutropenic sepsis

Profound neutropenia can turn minor mucosal or line-associated infection into shock rapidly, while fever or inflammatory markers may be muted and treatment cannot await culture confirmation.

Major haemorrhage

Severe thrombocytopenia may cause gastrointestinal, retinal, pulmonary or intracranial bleeding, with risk modified by fever, medicines, trauma and platelet function.

Transfusion complications

Repeated support can produce alloimmunisation, iron loading and reactions; component selection also matters for future transplantation and prevention of transfusion-associated graft-versus-host disease.

Clonal evolution

A PNH clone, myelodysplastic change or acute myeloid leukaemia can emerge during follow-up, signalled by new count patterns, haemolysis, dysplasia or cytogenetic abnormalities.

09Monitoring and follow-upTreatment response, safety checks and longer-term review.

Repeat full counts and reticulocytes frequently during severe disease and after therapy, tracking lineage recovery rather than haemoglobin in isolation.
Monitor temperature, oral and perianal symptoms, lines and fungal-risk duration during neutropenia, investigating small clinical changes promptly.
During ciclosporin measure trough concentrations, creatinine, potassium, magnesium, liver tests and blood pressure and reconcile interacting medicines.
Record all red-cell and platelet exposure, alloantibodies and reactions and evaluate iron loading when cumulative transfusion becomes substantial.
Reassess marrow morphology, cytogenetics, PNH clone and molecular findings when counts worsen, haemolysis emerges or response is lost.
After transplant or immunosuppression follow infection, graft complications, relapse, fertility, secondary cancer and psychosocial recovery through the specialist programme.

10Special situationsVariants, exceptions and circumstances that change the usual approach.

Reticulocytes define production

A very low absolute reticulocyte count distinguishes marrow output failure from the compensatory response expected in peripheral haemolysis.

Trephine carries the diagnosis

A dilute aspirate may look empty for technical reasons; architectural cellularity and exclusion of infiltration require an adequate core biopsy.

Small PNH clones differ

A tiny clone in immune aplasia can mark pathobiology without producing classical haemolysis or automatically requiring complement inhibition.

Donor planning starts early

Transfusion choices, germline testing and HLA search can influence curative options long before supportive care becomes difficult.

11Common pitfallsFrequent interpretation and management errors.

01
Waiting for marrow biopsy before treating neutropenic sepsis.
02
Calling a dilute aspirate diagnostic without trephine architecture.
03
Missing inherited failure in a young adult.
04
Equating a small PNH clone with classical PNH.
05
Giving unselected blood components before transplant discussion.