Pancytopenia

Pancytopenia is a simultaneous reduction of all three blood cell lines: haemoglobin under 130 g/L in men or 120 g/L in women, neutrophils under 1.5 x 10^9/L, and platelets under 150 x 10^9/L. It signals bone marrow failure, marrow infiltration, ineffective haematopoiesis, or peripheral destruction, and always needs a cause.

• Reduced production: aplastic anaemia (idiopathic, drugs, viral hepatitis associated, post-viral), myelodysplastic syndrome, acute leukaemia, hairy cell leukaemia, marrow infiltration (lymphoma, myeloma, metastatic cancer, tuberculosis, fungal infection, myelofibrosis, Gaucher disease), megaloblastic anaemia (B12 and folate deficiency), copper deficiency, paroxysmal nocturnal haemoglobinuria, congenital marrow failure (Fanconi anaemia), and radiotherapy.
• Increased destruction or sequestration: hypersplenism (portal hypertension, cirrhosis, malaria, kala azar, schistosomiasis, sarcoidosis, lymphoma), haemophagocytic lymphohistiocytosis, systemic lupus erythematosus, and sepsis.
• Infection: HIV, hepatitis, parvovirus B19, EBV, CMV, dengue, brucellosis, typhoid, visceral leishmaniasis, and miliary tuberculosis.
• Drugs and toxins: chemotherapy, chloramphenicol, antiepileptics (carbamazepine, phenytoin), co-trimoxazole, sulfonamides, antithyroid drugs, gold, NSAIDs, zidovudine, benzene, pesticides, and alcohol.
• Megaloblastic anaemia is the commonest treatable cause in primary care.

• Anaemia: fatigue, pallor, breathlessness, palpitations.
• Thrombocytopenia: bruising, petechiae, gum and nose bleeding, heavy periods.
• Neutropenia: fever, mouth ulcers, recurrent infections.
• Features of the cause: lymphadenopathy, splenomegaly (hypersplenism, lymphoma, leishmaniasis), hepatomegaly, jaundice, bone pain (leukaemia, myeloma), neuropathy (B12 deficiency), rash and arthralgia (lupus), weight loss, night sweats, and drug, chemical and radiation exposure.
• Geography and travel for malaria, schistosomiasis, leishmaniasis, and TB; HIV risk.
• Red flags: fever, bleeding, platelets under 20 x 10^9/L, neutrophils under 0.5 x 10^9/L, haemoglobin under 70 g/L, blasts on film, severe sepsis, or haemodynamic instability.

• FBC with indices, reticulocyte count, and blood film (blasts, dysplasia, schistocytes, parasites, hypersegmented neutrophils, leucoerythroblastic picture, teardrop cells).
• Tests: urea, electrolytes, liver function, lactate dehydrogenase, urate, vitamin B12, folate, ferritin, copper, thyroid function, glucose, ESR, CRP, clotting, direct antiglobulin test, antinuclear antibodies, HIV, hepatitis B and C, EBV, CMV, parvovirus B19, malaria film, blood cultures, TB tests, and Brucella serology.
• Imaging: abdominal ultrasound for spleen and liver, chest X-ray, CT if lymphoma suspected.
• Bone marrow aspirate and trephine biopsy with cytogenetics, flow cytometry, reticulin stain, and culture for TB and fungi, which separates hypocellular aplastic marrow (aplastic anaemia, with fatty replacement) from hypercellular marrow with dysplasia, infiltration, or hypersplenism.
• PNH flow cytometry; chromosomal breakage testing for Fanconi anaemia in young patients; leishmaniasis by marrow or spleen aspirate and rK39 test.
• Severity of aplastic anaemia: severe when marrow cellularity is under 25 percent with two of neutrophils under 0.5, platelets under 20, reticulocytes under 20 x 10^9/L; very severe when neutrophils are under 0.2 x 10^9/L.

Immediate stabilisation

• Admit for severe pancytopenia, fever, bleeding, or unexplained cause; protective measures and haematology referral at once.
• Stop all non-essential drugs, especially suspected marrow toxins.
• Transfusion with irradiated, leucodepleted products: red cells for haemoglobin under 70 g/L (under 80 g/L with cardiovascular disease), platelets for counts under 10 x 10^9/L (under 20 with fever or sepsis, under 50 with active bleeding), and avoid family donors in transplant candidates.
• Febrile neutropenia: piperacillin tazobactam 4.5 g intravenously every 6 hours within 1 hour of presentation, escalating to meropenem 1 g every 8 hours, with antifungal cover if fever persists beyond 4 to 7 days.
• Prophylaxis in severe disease under haematology: aciclovir 400 mg twice daily, levofloxacin 500 mg daily, fluconazole 200 mg daily.

Treat the cause

• Megaloblastic anaemia: hydroxocobalamin 1 mg intramuscularly on alternate days for 2 weeks, then every 3 months, with folic acid 5 mg daily for 4 months; counts recover within 2 to 8 weeks.
• Infection: specific treatment; malaria (artemether lumefantrine or intravenous artesunate), leishmaniasis (liposomal amphotericin B 3 mg/kg daily on days 1 to 5, 14 and 21), tuberculosis (multidrug antituberculous therapy under specialist care), brucellosis (doxycycline 100 mg twice daily with rifampicin 600 to 900 mg daily for 6 weeks), HIV (antiretroviral therapy).
• Hypersplenism: treat portal hypertension or the infiltration; splenectomy or partial embolisation only in selected cases (with vaccination against pneumococcus, meningococcus and Haemophilus influenzae at least 2 weeks before, and lifelong penicillin V 250 mg twice daily).
• Copper deficiency: copper replacement and removal of excess zinc.
• Lupus: prednisolone 0.5 to 1 mg/kg daily with hydroxychloroquine 200 mg twice daily.
• Haemophagocytic lymphohistiocytosis: dexamethasone 10 mg/m2 daily, etoposide, and specialist care.

Aplastic anaemia (specialist)

• Age under 40 with an HLA-matched sibling donor: haematopoietic stem cell transplantation.
• Others: horse antithymocyte globulin 40 mg/kg daily for 4 days with ciclosporin 5 mg/kg daily in two doses (target trough 150 to 250 micrograms/L) plus eltrombopag 150 mg daily; prednisolone 1 mg/kg to prevent serum sickness; avoid live vaccines.

Malignancy and myelodysplasia

• Acute leukaemia, lymphoma, myeloma, and myelodysplasia: specialist treatment (induction chemotherapy, hypomethylating agents such as azacitidine 75 mg/m2 subcutaneously for 7 days every 28 days, transplantation).

Follow up

• Frequent FBCs (weekly or more often in unstable patients); transfusion support; infection precautions; psychosocial support; fertility advice; review in a haematology clinic.