Acquired Pancytopenia

Classification by Bone Marrow Findings (Harrison's 22e)

1. Pancytopenia with Hypocellular (Aplastic) Marrow

• Acquired (immune) aplastic anemia
• Hypoplastic myelodysplastic syndrome (MDS)
• Aleukemic leukemia (rare)
• Some acute lymphoid leukemia
• Copper deficiency

2. Pancytopenia with Cellular Marrow

3. Hypocellular Marrow without Full Pancytopenia

• Q fever, Legionnaires' disease, Anorexia nervosa/starvation, Mycobacterium

Acquired Aplastic Anemia (Primary Focus)

Epidemiology

• Incidence: 2 per million/year in Europe and Israel; 5-7 per million/year in Thailand and China
• Bimodal age distribution: major peak in teens/twenties, second peak in older adults
• Equal sex distribution

Etiology

• Definite (dose-dependent): Cytotoxic chemotherapy agents (antimetabolites, antimitotics, some antibiotics), benzene
• Idiosyncratic reactions (unpredictable): Chloramphenicol, NSAIDs (phenylbutazone, indomethacin, ibuprofen), anticonvulsants (hydantoins, carbamazepine), heavy metals (gold, arsenic), sulfonamides, antithyroid drugs (methimazole, PTU), antihistamines (cimetidine), d-penicillamine, antidiabetics (tolbutamide), allopurinol, methyldopa, quinidine, carbamazepine, lithium, phenothiazines

• Seronegative hepatitis (non-A, B, C): Accounts for ~5% of AA cases; typically young men, severe aplasia 1-2 months after hepatitis; likely immune-mediated
• EBV (infectious mononucleosis): Rarely causes AA
• Parvovirus B19: Causes pure red cell aplasia (transient aplastic crisis in chronic hemolytic anemias); rarely generalized marrow failure
• HIV-1: Pancytopenia via marrow infiltration and immunosuppression

• Eosinophilic fasciitis (rare collagen vascular syndrome)
• Thymoma and hypoimmunoglobulinemia
• SLE
• Transfusion-associated GVHD (nonirradiated blood products to immunodeficient recipient)
• Large granular lymphocytosis (LGL syndrome)
• CTLA4 deficiency

• PNH clones are detectable by flow cytometry in ≥50% of AA patients at presentation
• Up to 50% of PNH patients develop AA; conversely, ~50% of AA patients have small PNH clones
• Classic triad: hemolysis (Coombs-negative), thrombosis, and pancytopenia/marrow failure
• Thrombosis is a major cause of morbidity (Budd-Chiari, portal/splenic vein, cerebral)

Pathophysiology of Acquired AA (Immune-Mediated)

1. Activated cytotoxic T-cell clones (oligoclonal, expanded) are found in blood and marrow - they decline with successful immunosuppression
2. Type 1 cytokines are produced: interferon-gamma (IFN-γ) induces Fas (CD95) expression on CD34+ stem cells, triggering apoptosis
3. CD34+ cells are reduced to ≤1% of normal in severe disease
4. HLA loss on HSCs allows immune escape and PNH clone expansion
5. Genetically determined features (HLA polymorphisms, cytokine gene variants, T-cell regulatory gene variants) determine why only some individuals exposed to a trigger develop AA

Other Acquired Causes

Myelodysplastic Syndromes (MDS)

Bone Marrow Infiltration (Myelophthisis)

• Malignancy: acute leukemia, lymphoma, multiple myeloma, metastatic carcinoma (breast, prostate, lung, stomach)
• Infection: miliary tuberculosis (caseating granulomas on biopsy; pancytopenia mostly in HIV+ patients), fungi, brucellosis
• Fibrosis: primary myelofibrosis, or secondary (myelophthisis) from above conditions
• Storage diseases: Gaucher disease
• Classic finding: "dry tap" on aspiration; leukoerythroblastic blood picture (tear-drop cells, nucleated RBCs, immature myeloid cells)

Hypersplenism

• Splenomegaly causing sequestration and premature destruction of blood cells
• Massive spleens can sequester up to 90% of platelets, 65% of granulocytes, and 30% of RBCs
• Bone marrow is normo- or hypercellular (reactive)
• Causes: cirrhosis/portal hypertension, myeloproliferative disease, lymphoma, infections, storage diseases
• Splenectomy can be curative when hypersplenism is the sole driver

Vitamin B12/Folate Deficiency

Drug-Induced Marrow Suppression

Other Toxins

• Alcohol: direct marrow toxicity + folate deficiency; may persist despite cessation
• Arsenic poisoning
• Benzene (industrial solvent exposure)

Severity Classification of Aplastic Anemia

Clinical Features

• Bleeding: Most common early symptom - easy bruising, gum oozing, epistaxis, heavy menses, petechiae; risk of intracranial hemorrhage with severe thrombocytopenia
• Anemia symptoms: Lassitude, weakness, dyspnea, palpitations
• Infection: Not the usual first symptom (unlike agranulocytosis), but neutropenic fever becomes a major complication
• Absent organomegaly: Patients often look surprisingly well despite very low counts; absence of lymphadenopathy and hepatosplenomegaly helps distinguish from malignancy
• Seronegative hepatitis AA: abrupt presentation in young male following recent hepatitis

Diagnosis

• CBC: Pancytopenia; macrocytosis common; absolute reticulocyte count low
• Peripheral smear: No dysplastic cells (unlike MDS), no blasts (unlike leukemia), no schistocytes
• Bone marrow biopsy (required): Hypocellular marrow with fat replacement; residual lymphocytes and plasma cells; no fibrosis or infiltration
• Bone marrow aspirate: May be "dry tap" in severe cases
• Chromosomal analysis: Normal karyotype in immune AA (abnormalities suggest MDS/leukemia); chromosomal breakage studies if Fanconi anemia is suspected
• Flow cytometry: PNH clone detection (GPI-anchor-deficient RBCs and granulocytes) - should be performed in all patients
• LFTs/hepatitis serology: Relevant if seronegative hepatitis suspected
• Vitamin B12, folate, copper levels
• Autoimmune workup (ANA, dsDNA) if SLE suspected

Treatment

Definitive Therapy

• Treatment of choice for young patients (<40 years, or up to 50 if suitable) with severe/very severe AA and a matched sibling donor
• Cures marrow failure; eliminates risk of clonal evolution
• Preferred over immunosuppression if profound neutropenia in younger patients
• Patients who fail immunosuppression can be salvaged with SCT later

• Overall response rate 70-80%; complete response ~50%
• Horse ATG is significantly superior to rabbit ATG
• Mechanism of ATG: depletes autoreactive T-cells; early serendipitous observation of immune pathophysiology
• Cyclosporine: oral, titrated by blood levels; side effects include nephrotoxicity, hypertension, seizures
• Eltrombopag (TPO mimetic): once daily for 6 months; likely stimulates HSC directly; side effect is hepatotoxicity
• Serum sickness (~day 10 of ATG): flu-like illness with skin eruption and arthralgias - treated with methylprednisolone
• Relapse is common (as cyclosporine/eltrombopag tapered); most patients respond to reinstitution
• Clonal evolution to MDS or leukemia occurs in ~10-15% over a decade

• Unverified in controlled trials but some patients respond
• Upregulate telomerase activity (useful in telomere biology disorders)
• 3-4 month trial appropriate for moderate disease, especially if telomere defect present

Supportive Care

• Infections: Prompt empirical broad-spectrum IV antibiotics for neutropenic fever; anti-fungal therapy for persistent fever (Candida, Aspergillus); granulocyte transfusions for refractory bacterial/fungal infections
• Platelet transfusions: Maintain >10,000/μL prophylactically; use single-donor platelets; HLA-matched for alloimmunized patients; suppress menstruation with estrogens
• Red cell transfusions: Maintain Hb ≥70 g/L (~2 units every 2 weeks); iron chelation (deferoxamine or deferasirox) after ~50th transfusion
• Growth factors (G-CSF, EPO): Generally NOT effective in immune aplastic anemia
• Avoid aspirin and NSAIDs (thrombocytopenia)

Pediatric Perspective (Nelson 2024)

• Acquired aplastic anemia (immune-mediated)
• Acute leukemia (blasts on smear/marrow - key diagnostic distinction)
• Myelodysplastic syndrome
• PNH (Chapter 510 Nelson 2024 - rare in children; classic presentation includes pancytopenia/aplastic anemia preceding or following PNH diagnosis)
• Hemophagocytic lymphohistiocytosis (HLH)
• Vitamin B12/folate deficiency
• Infections (EBV, CMV, parvovirus B19, HIV, TB, visceral leishmaniasis)
• SLE

Key References

• Harrison's Principles of Internal Medicine 22E (2025), Chapter 107, pp. 850-856
• Nelson Textbook of Pediatrics 2024 (Part XIX - Diseases of the Blood), Chapters 496, 510, 517
• Frameworks for Internal Medicine, Chapter 27 (Pancytopenia), pp. 358-365
• Robbins, Cotran & Kumar: Pathologic Basis of Disease (aplastic anemia section)