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Drug & Haemolysis

Unique Features of Erythrocytes (RBC) Coomb’s Test (DAT – Direct Antiglobulin Test)
Deformability
No Nucleus
No Ribosome
No Mitochondria
Oxygen delivery – Haemoglobin

Haemolysis
Rupture or Breakage of RBC membrane
Release of Hb & internal cellular components into surrounding fluid
Drug Induced Haemolysis
Haemolytic Anaemia (HA) Drug Induced Haemolysis of Drug Induced Haemolysis of
A type of Anaemia due to Haemolysis Normal RBC RBC with pre-existing abnormality
Abnormal breakdown of RBC in G6PD Deficiency
Blood vessels (Intravascular) Drugs actively provoke RBC
Spleen (Extravascular) destruction
Due to ↑ rates of blood cell destruction Characterized by
Blood cells have abnormally ↓ Life Span +ve Coomb’s test (DAT)
Destroyed Faster than BM can produce them Blood disorder, drug tells immune
system to attack RBC (“foreign”)
Symptoms of HA
Pallor
Jaundice
Confusi on
Dark Coloured Urine
Dizziness, Weakness, Intolerance to Physical activity
Enlarged Spleen, Liver
Fever
Heart Murmur
↑ Heart Rate

Classification of Haemolytic Anaemia

Inherited/ Genetic & Acquired classification
Immune & N on-i mmune classi fication
Intra-vascular & Extra-vascular classification

Inherited/ Genetic & Acquire d Classification

Genetic/ Inherited Acquired
Lifelong conditions May go away if cause is found &
Require ongoing treatment corrected
Genetic conditions of RBC Membrane Characterized by Coomb’s Test
Defects in RBC Membrane (DAT – Direct Antiglobulin Test)
Hereditary Hereditary
Spherocytosis Elliptocytosis Immune Non-Immune
Mediated Mediated
Autoimmune Toxins
HA Snake venom
Warm Antibody
Autoimmune
HA
Genetic conditions of RBC Metabolism Alloimmune Trauma
(enzyme defects) HA
Defects in Anaerobic Glycolysis & Haemolytic
Glutathione Metabolism Disease of
(Eg. G6PD Deficiency) Newborn
Genetic conditions of Haemoglobin Drug induced Infections
Defects in Globin structure & synthesis immune Malaria,
(Eg. Sickle Cell Anaemia) mediated HA Septicaemia
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Mechanisms of Drug Induce d Haemolytic Anaemia

Immune Complex (= Drug-Dependent Antibody) Drug Adsorption (Hapten) Methyldopa Induced (=Autoimmune Ind uction)

Drug form Complex with Plasma Protein Drug firmly binds to RBC surface Antibody produced cause Autoimmune Haemolysis
Complex b ound loosely to Red Cell Membrane Induce for mation of Antibody against RBC-Drug Mechanism unknown. Possibly
Drug-Protein Complex will stimulate Antibody complex • Alteration of Red Cell antigens or interference
production Produce agglutination & ↑ RBC destruction with immune system regulation allowing
Drug-Plasma Protein Antibody complex settles on RBC production of red cell autoantibodies
will trigger Complement Activation • Drug induces antibody production which cross
RBC Lysis (formation of MAC) react with RBC
Since Antibody & Drug are not firmly attached to Red
Cell Membrane, they are free to interact with other
RBC & repeat the process
Clinical Characteristics Clinical Characteristics Clinical Characteristics
IgM, IgG can be involved ↑ Drug dose required (10 million units or more/day) Onset – usually gradual at ↑ dose
Antibodies not directed against cell itself, red cell Onset - ↓ acute (7-10 days after start treatment) Haemolytic anaemia may not be seen until few
destroyed as an innocent bystander (usually ↓ severe than Immune Complex) months start drug
(Innoce nt Bystander reaction) +ve Coombs Test
↓ Drug dose – cause significant haemolysis (without clinical evidence of haemolysis)
Onset – sudden, shortly after drug 1st given Haemolysis takes place 1° in Spleen
Intravascular/ Extravascular Haemolysis (Extravascular Haemolysis)
Evidence of Intravascular Haemolysis Haemoglobinuria, Renal Failure rarely occur
Haemoglobinemia
Haemoglobinuria
(can progress to Anuria, Renal Failure)
Less common than other Haemolysis Mechanisms
Can cause Drug Induced Thrombocytopenia
(↓ Platelet count)
Laboratory Laboratory Laboratory
+ve DAT/ Coombs test +ve DAT/ Coombs test +ve DAT
(Complement on RBC) (due to IgG coating of RBC)(compleme nt may present) (IgG seen up to 10% patients receiving Methyldopa)
Generally Mild → Moderate
Only Minority ( <1%) gets significant Haemolysis
Management Management Management
Stop drug immediately Stop drug Stop drug
Steroid if necessary (haemolysis ceases when drug cleared from plasma) Haemolysis gradually disappear often within 3 weeks
(antibody usually disappear within few weeks) (can last 4-8 weeks after stopping)
Drugs Drugs Drugs
2nd , 3rd generation Cephalosporin Penicillins (when given in massive doses IV) Methyldopa (antihypertensive)
(Cefatetan, Cefotaxime, Ce ftazidime) Antibiotics Levodopa (parkinson’s disease)
Antibiotics (Sulfonamides) (rarely Cephalosphorin – eg. Cefazolin, Cephaloridine) Procainamide (antiarrhythmic agent)
NSAIDs (Diclofenac, Sulindac, Tolmetin) (Tetracycline, Erythromycin) Mefanamic acid (NSAID)
Antimalaria (Quinidine, Quinine, Primaquine) Cisplatin (anti cancer drug)
Analgesic (Phenacetin) Tolbutamide (oral hypoglycaemic drug)
AntiTB (Isoniazid)
Antipsychotic (Chlorpromazine )
Hypoglycemic (Chlorpropamide )
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Drug Induced Haemolysis of RBC with Pre-existing Abnormality
(G6PD Deficiency)

Definition G6PD Deficiency

G6PD Deficiency – X-linked Recessive Hereditary disease
Characteristic When Oxidant drug/ substance is taken
Abnormally ↓ levels of G6PD Oxidant Drugs/ Fava Beans → Superoxide & H2 O2
Common enzyme deficie ncy (400 million people have G6PD Deficiency) ↓
Most prevalent – African, Mediterranean, Asian origins Both substances can Oxidise Hb & RBC Membrane
G6PD Enzyme – Located on Sex Chromosome X at q28 locus (X-Linked Gene ) Results in Oxidation of Sulfhydryl groups, Precipitation of Hb, Lysis of RBC
(eg. Haemolysis)
↓
Multiple haemolysis episodes in short time span
(lead to Haemolytic Anaemia)
↓
GSH is required to Detoxify substances

G6PD Deficiency
Exhibit Nonimmu ne Haemolytic Anaemia in response to a number of causes
Common causes
Infection
Medication
Chemicals

G6PD
Defects in PPP
Glucose-6 -phosphate dehydrogenase
Ineffective NADPH generation
Enzyme in Pentose Phosphate Pathway (PPP) ↓ production of GSH from GSSG
(supplies reducing energy to cells)
Important in Red Blood Cell Metabolism
Drugs
Function of pathway
Antimalarials
Produce NADPH (nicotinamide adenine din ucleotide phos phate)
(Primaquine, Pyrimethamine, Quinine, Chloroquine, Mepacrine,
From NADP
Hydroxychloroquine)
NADPH is required to produce Reduced Glutathione (GSH) from Oxidised
Analgesics
Glutathione (GSSG)
(Phenacetin, Acetylsalicylic acid (aspirin))
Normally GSH prevent sulfhydryl groups (-SH) on Hb & RBC Membrane from
Antibiotics
oxidation by Reactive Oxygen Species (ROS) (Oxygen radical)
(Sulphonamides, Dapsone, Nitrofurantoin, Isoniazid, Streptomycin,
Chloramphenicol)
Vitamin K, Vitamin C (↑ dose), Methyldopa, some anti cancer drugs
Chemicals – Napthalene balls
Food – Fava Beans (Favism)
Henna (cause haemolytic crisis in G6PD Deficient Infants)

Clinical
Haemolytic crisis – may manifest within hours of expos ure to oxidant stress
Diagnosis confirmed by G6PD assay
Deficiency usually Asymptomatic
Between Crises, Blood count often Nor mal when older & defective RBCs are
replaced by younger cells (test has to be repeated)
Newborns with G6PD Deficiency are about 1.5X likely to get Neonatal Jaundice
(compared with newborns without G6PD Deficiency)
Complete Blood Count/ Screening Test
(Test, Measure G6PD enzyme activity – suspected in newborn child)
Attacks of haemolytic anaemia (serious for infant)
Brain Damage, Death (Possible, but Preventable)
Malaysia – Newborns screened for G6PD Deficiency

Management
Stop offending drug
Maintain ↑ Urine Output
Transfusion (for severe anaemia)
Preventive action (Avoid substances known to induce haemolysis)