Aplastic Anemia

Aplastic anemia (AA) is bone marrow failure in which the hematopoietic stem cell pool is severely and diffusely reduced, leaving a hypocellular marrow that can no longer adequately produce red cells, white cells, and platelets — the result is pancytopenia with a hypocellular, fatty marrow that contains no malignant infiltrate, no significant fibrosis, and no dysplasia sufficient to diagnose myelodysplastic syndrome (MDS) instead. In the great majority of acquired cases the cause is a T-cell-mediated autoimmune attack on the patient's own hematopoietic stem cells, not a primary disease of the marrow stroma itself — a mechanistic point that is what makes immunosuppressive therapy, rather than marrow-stimulating drugs, the pharmacologic backbone of treatment for patients who are not transplant candidates.^[1] AA is rare, and can be acquired (idiopathic in most cases, or attributable to a drug, virus, toxin, or pregnancy) or inherited (Fanconi anemia, dyskeratosis congenita, and other constitutional bone marrow failure syndromes, which can first present in a way that looks identical to acquired AA, especially in a young patient). AA is a diagnosis of exclusion: a bone marrow aspirate and trephine biopsy are both mandatory before treatment begins, both to confirm hypocellularity and to exclude the mimics that would otherwise change management entirely — hypocellular MDS, hypoplastic acute leukemia, and an inherited bone marrow failure syndrome.^[2] Once confirmed, disease severity (non-severe, severe, or very severe, by blood-count thresholds) together with the patient's age and HLA-matched donor availability determine both the urgency and the choice of first-line treatment.

Presentation reflects the specific cell lines affected and can be insidious or abrupt — there is no single "typical" AA patient. Presentation ranges from an incidental abnormal CBC in an otherwise well patient to life-threatening infection or hemorrhage at first presentation.

• No identifiable cause (idiopathic) — the majority of acquired cases; presumed autoimmune T-cell-mediated destruction of hematopoietic stem cells.^[1]
• Drug exposure — a genuine, reportable medication-safety event. Classic culprits include chloramphenicol (the prototype idiosyncratic cause), NSAIDs, antithyroid drugs (methimazole, carbimazole, propylthiouracil), carbamazepine and certain other antiepileptics, sulfonamide antibiotics, and gold salts.^[1]
• Seronegative hepatitis-associated aplastic anemia — AA developing weeks after an episode of acute hepatitis in which no causative hepatitis virus is ever identified; disproportionately affects young men.
• Other viral associations — Epstein-Barr virus, HIV; parvovirus B19 more typically causes isolated pure red cell aplasia rather than trilineage AA, but can occasionally contribute in an already-compromised marrow.
• Ionizing radiation and myelotoxic chemical exposure (benzene and related industrial solvents).
• Pregnancy — a rare but recognized association, with cytopenias that can worsen further as pregnancy progresses.
• Inherited bone marrow failure syndromes — Fanconi anemia, dyskeratosis congenita, Shwachman-Diamond syndrome, and others — can present indistinguishably from acquired AA, especially in a younger patient; look for short stature, abnormal skin pigmentation, nail dystrophy, oral leukoplakia, skeletal or renal anomalies, and a relevant family history.^[2]
• A concurrent paroxysmal nocturnal hemoglobinuria (PNH) clone is detectable in roughly half to two-thirds of patients with acquired AA at diagnosis — it is tested for as a routine part of the AA workup, not searched for separately.^[2]

Confirming the diagnosis

• CBC with differential and reticulocyte count — pancytopenia with an inappropriately low (not compensatory-elevated) reticulocyte count; this is what separates AA from a peripheral-destruction process such as hemolysis or ITP, where the marrow is trying, and often succeeding, to compensate.
• Peripheral blood smear — to exclude blasts, dysplastic forms, and a leukoerythroblastic picture, none of which are expected in AA.
• Bone marrow aspirate AND trephine biopsy — both are mandatory, not either alone: the biopsy should be an adequate length (roughly 1.5-2 cm) to reliably assess overall cellularity and exclude a patchy abnormal infiltrate, fibrosis, or dysplasia that a small or hemodiluted aspirate alone could miss.^[2]
• Cytogenetics (karyotype), FISH for chromosomes 5, 7, 8, and 13, and SNP array — to exclude MDS. Up to about 12% of otherwise typical AA cases show an abnormal clone (for example, del(13q) or trisomy 8) at diagnosis without this by itself indicating MDS — but any degree of monosomy 7 or a complex karyotype changes both prognosis and, later, eltrombopag eligibility.^[2]
• Flow cytometry for a PNH clone (6-colour methodology including fluorescent aerolysin, FLAER) is mandatory at diagnosis — present in roughly 50-60% of patients; a large PNH clone across all lineages makes an inherited cause unlikely.^[2]
• DEB (diepoxybutane) chromosomal breakage testing for Fanconi anemia — perform in every patient under 50, or at any age with clinically suggestive features, before a sibling is considered as a stem cell donor (see Common Errors to Avoid).^[2]
• Telomere length testing (flow-FISH or multiplex qPCR) to screen for dyskeratosis congenita, and next-generation sequencing gene panels for constitutional marrow failure when an inherited cause remains a real possibility after the above.
• Vitamin B12, folate, and liver function tests; hepatitis A/B/C/E, EBV, CMV, HIV, and parvovirus B19 serology; ANA and anti-dsDNA.
• Full medication history covering the preceding several months, specifically looking for a known culprit drug (see Risk Factors).

Distinguishing acquired AA from hypocellular MDS

This distinction genuinely changes management and is not always straightforward on morphology alone. Features favouring MDS over AA include dysplastic granulocyte or megakaryocyte morphology, an increased blast proportion, increased marrow reticulin, and elevated CD34+ cells (roughly 5% or more); features favouring AA include the absence of dysplasia, prominent residual lymphocytes and macrophages, and normal reticulin. Low-level somatic mutations (for example, in DNMT3A, ASXL1, PIGA, or BCOR/BCORL1) are found in roughly 20-30% of otherwise typical idiopathic AA and do not, on their own, indicate transformation to MDS — an integrated cyto-histological and genetic assessment by an experienced hematopathologist resolves genuinely ambiguous cases, not any single test.^[2]

Severity classification (Camitta criteria)

Severity, not the presence of AA alone, is what determines urgency and drives the first-line treatment decision in Choose Initial Treatment.^[2]

• Confirm the diagnosis and exclude MDS, hypoplastic acute leukemia, and an inherited bone marrow failure syndrome before committing to AA-directed therapy.
• Select curative therapy — allogeneic HSCT — for every patient young enough and fit enough with a suitably matched donor, rather than defaulting every patient to immunosuppression regardless of eligibility.
• For patients who are not immediate transplant candidates, restore adequate blood counts with immunosuppressive therapy to prevent death or disability from infection and bleeding.
• Support the patient safely through the neutropenic, thrombocytopenic window that IST or conditioning itself creates before it can work.
• Preserve future transplant eligibility throughout — irradiated, leukoreduced transfusion support and avoidance of unnecessary alloimmunization matter from the very first transfusion, not only once a transplant is imminent.
• Detect and permanently remove any causative drug.
• Maintain long-term surveillance for relapse and late clonal evolution to MDS or acute leukemia.

• Use irradiated and leukoreduced blood products for every transfusion — irradiation prevents transfusion-associated graft-versus-host disease and leukoreduction reduces HLA alloimmunization; both specifically preserve the patient's future transplant eligibility, not just reduce a generic transfusion reaction risk.^[2]
• Avoid transfusion from a potential related stem cell donor (a sibling being worked up as a possible match) wherever clinically avoidable, since it can sensitize the patient against that donor's HLA antigens before transplant.
• Nurse a severely neutropenic patient (ANC under 0.5 ×10⁹/L) in protective isolation during hospitalization, with strict hand hygiene for all contacts.
• Maintain careful oral hygiene with a soft toothbrush; avoid invasive dental work during severe neutropenia or thrombocytopenia where it can reasonably be deferred.
• Avoid intramuscular injections, contact sports, and other high bleeding-risk activities during significant thrombocytopenia.
• Refer early to a transplant-capable expert hematology centre — AA is rare enough, and management complex enough, that outcomes are better with early specialist involvement rather than prolonged management at a general centre.^[2]
• Complete any needed non-live vaccination before starting IST or conditioning where timing allows; avoid live vaccines during and for a defined period after ATG, cyclosporine, or HSCT conditioning.
• Discuss fertility preservation before ATG-based conditioning or HSCT wherever feasible, given the gonadotoxic potential of conditioning regimens.
• If an inherited bone marrow failure syndrome is confirmed or still suspected, arrange genetic counselling for the patient and any potential related donor before that relative is used as a stem cell source — see Common Errors to Avoid.

Pregnancy

Breastfeeding

Eltrombopag and cyclosporine both require individualized specialist-directed decisions given limited breastfeeding data; ATG is not a maintenance drug and this question does not typically arise for it directly.

Pediatrics

Allogeneic HSCT outcomes are excellent in children and are favoured over IST even with a well-matched, non-sibling donor more readily than in adults, given how well children tolerate transplant and the durability of a cure over prolonged immunosuppression. The added benefit of eltrombopag on top of standard IST is less clearly established in children than in adults.^[2] ATG and cyclosporine are dosed on the same mg/kg basis as in adults; monitor growth throughout treatment.

Older adults (over 60 years)

IST is generally preferred over up-front HSCT given higher conditioning-related toxicity at this age. ATG itself carries increased toxicity risk in older patients — infection, bleeding, arrhythmia, myocardial ischemia, and heart failure — so weigh this carefully before committing to a full ATG course in a frail patient. Reasonable alternatives in an unfit patient include cyclosporine monotherapy, eltrombopag, an androgen (danazol), single-agent alemtuzumab, or best supportive care alone in a patient too frail for any of the above.^[2][3]

Hepatic impairment

Reduce the eltrombopag starting dose in hepatic impairment and monitor liver function tests closely throughout — consult the current product monograph for the specific adjustment, since the aplastic anemia dosing regimen differs from the lower dose used in immune thrombocytopenia.

Renal impairment

Cyclosporine is itself nephrotoxic — dose and trough-level adjustment, avoidance of other nephrotoxic drugs, and close renal function monitoring are essential throughout therapy. In a patient whose renal impairment genuinely limits cyclosporine use, alemtuzumab monotherapy is a reasonable alternative under specialist direction.

Suspected or confirmed inherited bone marrow failure syndrome

Standard-intensity ATG-based conditioning is not appropriate for a patient with an inherited bone marrow failure syndrome such as Fanconi anemia — these patients are markedly more sensitive to alkylating agents and radiation, and require a specifically reduced-intensity, fludarabine-based conditioning regimen if HSCT is undertaken. Confirm or exclude an inherited cause with DEB testing before finalizing the conditioning plan, and see Common Errors to Avoid for the related donor-testing point.

During IST induction: CBC with differential and reticulocyte count at least weekly initially, spacing out as counts recover; cyclosporine trough level, renal function, blood pressure, and magnesium/potassium regularly throughout therapy; liver function tests regularly while on eltrombopag. Assess hematologic response formally at 3 and 6 months of IST — this is the point at which treatment failure or an inadequate response should prompt escalation rather than simply continuing the same regimen (see Treatment Failure / Next Step).^[2]

Periodic bone marrow examination with cytogenetics — per hematology direction, and always if a new cytopenia, an unexplained change in blood counts, or a clinical concern for transformation arises — to monitor for late clonal evolution to MDS or acute myeloid leukemia, a real long-term risk of AA itself and of eltrombopag exposure specifically; discontinue eltrombopag and refer urgently for transplant evaluation if a new monosomy 7 or complex karyotype appears, regardless of prior assumptions about donor eligibility.^[2]

Periodic flow cytometry to track PNH clone size, since it can expand over time in a subset of patients. In a transfusion-dependent patient: serial ferritin, and periodic cardiac/liver T2* MRI where iron burden is a concern, to guide chelation therapy rather than relying on ferritin alone. Review vaccination status, growth and development in children, and fertility follow-up where relevant at routine visits. Confirm the causative drug, where one was identified, remains clearly documented in the patient's allergy/intolerance record indefinitely.

1. Confirm the diagnosis is still correct — repeat the bone marrow examination and cytogenetics — before concluding that IST itself has failed, particularly if the clinical picture has changed.
2. Confirm adherence and that cyclosporine trough levels have genuinely been in the target therapeutic range throughout, not just at the most recent visit, before labeling the regimen a true treatment failure.
3. For no response by 3-6 months, or relapse after an initial response: re-evaluate transplant candidacy and donor availability first — a suitable candidate with an available donor (matched unrelated, haploidentical, or cord blood) should proceed to allogeneic HSCT rather than repeating IST indefinitely.^[2][3]
4. For a patient who is not a transplant candidate, or has no donor yet identified: a second IST course is reasonable in a fitter patient, particularly for a late relapse (rabbit ATG is typically used for this second course, since horse ATG was already used first-line); for a patient unfit for further ATG, use a lower-intensity option instead — cyclosporine monotherapy, eltrombopag, an androgen, or alemtuzumab, under specialist direction.^[2]
5. Do not add mycophenolate mofetil or sirolimus to standard IST expecting a better response — neither has been shown to improve outcomes over ATG plus cyclosporine alone, and moderate/high-dose cyclophosphamide is specifically not recommended given a high fungal-infection mortality despite a reported response.^[2]
6. For new cytogenetic evolution (particularly a new monosomy 7 or complex karyotype) during eltrombopag treatment: discontinue eltrombopag and refer urgently for transplant evaluation.
7. For a life-threatening infection during severe neutropenia that is not responding to appropriate antimicrobial therapy: consider irradiated granulocyte transfusion under specialist direction — evidence is limited, but it can be lifesaving in this specific situation.^[2]

• Diagnosing or starting treatment for AA based on a bone marrow aspirate alone, without a trephine biopsy — both are mandatory, since a biopsy is what reliably excludes a patchy infiltrate, fibrosis, or dysplasia that a small or hemodiluted aspirate can miss.
• Treating lymphadenopathy, splenomegaly, or hepatomegaly as an incidental finding alongside a presumed AA diagnosis — none of these are features of AA and their presence should prompt reconsideration of the diagnosis instead.
• Selecting a sibling as an HSCT donor without DEB testing when Fanconi anemia has not been excluded — an affected sibling can carry the identical underlying genetic defect, and using an unrecognized Fanconi anemia carrier or affected sibling as a stem cell donor can be catastrophic for both the recipient and, if affected, the donor.
• Using standard-intensity ATG/cyclophosphamide-based conditioning in a patient with an unrecognized inherited bone marrow failure syndrome — these patients are markedly more sensitive to alkylating agents and radiation and need a specifically reduced-intensity regimen.
• Giving non-irradiated or non-leukoreduced blood products — this risks transfusion-associated graft-versus-host disease and HLA alloimmunization that can jeopardize the patient's own future transplant eligibility, not just cause a generic transfusion reaction.
• Transfusing a patient from a potential related stem cell donor before that donor's status is settled, risking HLA sensitization against them.
• Using rabbit ATG as first-line therapy instead of horse ATG — horse ATG has superior response and survival in randomized comparison for first-line treatment.
• Using ATG without cyclosporine, or cyclosporine without ATG, as first-line therapy for severe AA — the combination, not either agent alone, is the standard of care.
• Starting eltrombopag without baseline and serial cytogenetic monitoring — clonal evolution is a real, described risk, particularly in a patient with pre-existing monosomy 7 or a complex karyotype.
• Missing the empty-stomach and polyvalent-cation-separation counselling point for eltrombopag, leading to reduced absorption and an apparent treatment failure that is really an absorption problem.
• Giving G-CSF routinely to correct neutropenia in AA — it is essentially ineffective in this disease and is not indicated outside a specific severe-infection situation under specialist direction.
• Missing a culprit drug (chloramphenicol, an antithyroid drug, carbamazepine, an NSAID, a sulfonamide, or a gold salt) as the actual cause, and failing to stop and permanently document it before assuming the case is idiopathic.
• Delaying referral to a transplant-capable hematology centre while repeating supportive-care-only management of severe or very severe AA — the extended cytopenia interval itself is what carries most of the risk, and outcomes are genuinely better the earlier definitive therapy starts.

How to use this table: doses are adult doses and require patient-specific confirmation, including renal/hepatic adjustment. Conditioning regimens for allogeneic HSCT itself are transplant-centre-specific and not reproduced here — this table covers the medical/immunosuppressive management pathway. Select any drug name to open its complete Pharmasist Drug Database page.

Immunosuppressive therapy (IST) — first-line backbone for severe/very severe AA

Horse ATG and cyclosporine are always given together as first-line IST, never as monotherapy; give a short corticosteroid course alongside ATG specifically to prevent or treat serum sickness.

Thrombopoietin receptor agonist — added to IST in eligible adults

Adds a real, randomized-trial-demonstrated increase in complete response when combined with standard ATG plus cyclosporine in adults with treatment-naive severe AA.

Second-line / refractory disease

Reserved for non-response to first-line IST, relapse, or a patient unfit for a full ATG course — always under specialist direction.

Not indicated for routine use

Infection prophylaxis during severe neutropenia

Follow local antimicrobial stewardship protocol for exact agent selection; the classes below reflect BSH-cited UK practice and are broadly consistent with Canadian tertiary-centre practice for a severely neutropenic patient.

Iron chelation (transfusion-dependent patients)

Reserve for confirmed transfusional iron overload, guided by serial ferritin and periodic cardiac/liver T2* MRI rather than ferritin alone. Use deferasirox cautiously alongside cyclosporine given additive renal risk; avoid deferiprone in a neutropenic patient given its own agranulocytosis risk.

Evidence note: drug inventory, dosing, and comments reflect the 2024 British Society for Haematology guideline for adult aplastic anaemia, cross-checked against the Babushok et al. Modified Delphi panel consensus recommendations and the RACE trial evidence for eltrombopag.^[2]