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