Drug-induced blood dyscrasias

Overview

•Direct toxicity - dose-dependent bone marrow suppression (e.g. methotrexate, cytotoxics)

•Immune-mediated - idiosyncratic, dose-independent (e.g. carbimazole agranulocytosis, penicillin thrombocytopenia)

•Redistribution - prednisolone causes neutrophilia by demarginating neutrophils from endovascular wall + releasing band neutrophils from marrow reserve; not a sign of toxicity

•TPMT pathway - azathioprine → 6-mercaptopurine → inactivated by TPMT; TPMT deficiency (~1 in 200-300) causes 6-TGN accumulation → pancytopenia

🎯
TPMT activity must be checked before starting azathioprine or mercaptopurine. Homozygous deficiency = contraindicated. Heterozygous (intermediate, ~10% population) = reduced dose + close monitoring.

Investigations

🥇 First-line

•FBC + blood film - identifies cell line affected; film shows morphology (hypersegmented neutrophils, spherocytes)

•Before azathioprine: TPMT activity assay

•Haemolysis screen: bilirubin, LDH, haptoglobin (low), reticulocyte count (high); Direct Coombs test for immune-mediated haemolysis

•Methaemoglobinaemia: co-oximetry on ABG - pulse oximetry unreliable (reads ~85%)

🏆 Gold standard

•bone marrow biopsy - reserved for unexplained pancytopenia / suspected aplastic anaemia

Management

🥇 First-line

•stop the causative drug immediately - most cytopenias improve on withdrawal; do not rechallenge

•Febrile neutropenia (neutrophils <0.5 x10⁹/L + fever): broad-spectrum IV antibiotics as oncological emergency

•Methaemoglobinaemia: methylthioninium chloride (methylene blue) 1-2 mg/kg IV - contraindicated in G6PD deficiency

•Methotrexate toxicity: folinic acid (calcium folinate) to rescue normal cells

🥈 Second-line

•platelet transfusion for active bleeding or platelets <10 x10⁹/L; note transfusion relatively contraindicated in HIT (thrombosis risk)

🥉 Third-line

•G-CSF (e.g. filgrastim) for severe agranulocytosis under haematology guidance

⚠️
Never restart carbimazole, clozapine, or co-trimoxazole after confirmed agranulocytosis - rechallenge risks more rapid, more severe recurrence.

🚨
Sore throat or mouth ulcers in a patient on carbimazole or clozapine = urgent FBC immediately. Do not wait for the next scheduled monitoring date.

Drug-dyscrasia associations

Key drug-dyscrasia pairings
DrugDyscrasiaKey detail
PrednisoloneNeutrophiliaDemargination - expected, reversible
AzathioprinePancytopeniaRisk greatly increased by TPMT deficiency
CarbimazoleAgranulocytosisOnset typically within weeks; sore throat = emergency FBC
ClozapineAgranulocytosisMandatory CPMS monitoring; stop if neutrophils <1.5 x10⁹/L
MethotrexateMegaloblastic anaemia / pancytopeniaFolate antagonism; rescue with folinic acid
Penicillin / furosemide / goldThrombocytopeniaImmune-mediated platelet destruction
Methyldopa / penicillinHaemolytic anaemiaDirect Coombs positive
Dapsone / nitratesMethaemoglobinaemiaCyanosis unresponsive to O₂; SpO₂ ~85% on pulse oximetry
NSAIDs (e.g. ibuprofen)Thrombocytopenia / interstitial nephritisNephritis: raised eosinophils + renal impairment

Drug	Dyscrasia	Key detail
Prednisolone	Neutrophilia	Demargination - expected, reversible
Azathioprine	Pancytopenia	Risk greatly increased by TPMT deficiency
Carbimazole	Agranulocytosis	Onset typically within weeks; sore throat = emergency FBC
Clozapine	Agranulocytosis	Mandatory CPMS monitoring; stop if neutrophils <1.5 x10⁹/L
Methotrexate	Megaloblastic anaemia / pancytopenia	Folate antagonism; rescue with folinic acid
Penicillin / furosemide / gold	Thrombocytopenia	Immune-mediated platelet destruction
Methyldopa / penicillin	Haemolytic anaemia	Direct Coombs positive
Dapsone / nitrates	Methaemoglobinaemia	Cyanosis unresponsive to O₂; SpO₂ ~85% on pulse oximetry
NSAIDs (e.g. ibuprofen)	Thrombocytopenia / interstitial nephritis	Nephritis: raised eosinophils + renal impairment