o RBCs destroyed within blood vessels
o Examples:
Paroxysmal nocturnal haemoglobinuria (PNH)
Microangiopathic haemolytic anaemia (MAHA: TTP, HUS, DIC, HELLP)
Paroxysmal cold autoimmune haemolytic anaemia
Acute G6PD crisis
o RBCs destroyed in the spleen and liver by macrophages
o Examples:
Hereditary spherocytosis
Warm autoimmune haemolytic anaemia
Pyruvate kinase deficiency
Delayed haemolytic transfusion reactions
o Sickle cell disease
o β-thalassaemia major (transfusion-related haemolysis)
o Chronic low-grade G6PD deficiency
• Common to both intravascular and extravascular:
o Anaemia (↓ Hb)
o Reticulocytosis (↑ reticulocyte count)
o ↑ Lactate dehydrogenase (LDH)
o ↑ Unconjugated bilirubin
o ↓ or undetectable haptoglobin
o Haemoglobinaemia
o Haemoglobinuria (dark urine)
o Haemosiderinuria (several days after haemolysis)
o Splenomegaly
o Spherocytes on blood film
o Normal or only mildly reduced haptoglobin
o No haemoglobinuria
• Autosomal dominant inheritance
• Defect in RBC membrane proteins (spectrin, ankyrin)
• Features: jaundice, splenomegaly, gallstones
• Blood film: spherocytes, ↑ MCHC
• Diagnosis: EMA-binding test (preferred), osmotic fragility test (historical)
• Treatment: folate supplementation, splenectomy in severe cases
o X-linked recessive
o Triggered by infection, fava beans, drugs (sulfa, dapsone, nitrofurantoin, antimalarials)
o Episodic intravascular haemolysis
o Blood film: Heinz bodies (oxidised Hb), bite cells
o Autosomal recessive
o Chronic extravascular haemolysis
o Neonatal jaundice, splenomegaly
o ↑ 2,3-BPG → facilitates oxygen unloading
o IgG-mediated
o Extravascular (splenic macrophage clearance)
o Causes: idiopathic, SLE, CLL, drugs (penicillin, methyldopa)
o Blood film: spherocytes
o Positive direct Coombs’ test
o Treatment: steroids → immunosuppressants → splenectomy
o IgM-mediated with complement activation
o Intravascular haemolysis
o Triggered by cold exposure, Mycoplasma, EBV, lymphomas
o Features: acrocyanosis, haemoglobinuria in cold weather
o Treatment: keep warm, rituximab
o Detects antibodies (IgG or complement) on patient’s RBCs
o Positive in warm AIHA (IgG), cold AIHA (C3), haemolytic transfusion reactions
o Detects free antibodies in patient serum
o Used in crossmatching and antenatal screening
• Acquired mutation affecting GPI-anchored proteins (CD55, CD59) on RBCs
• Increased susceptibility to complement-mediated intravascular lysis
• Features:
o Episodic dark urine (haemoglobinuria, especially at night/morning)
o Pancytopenia
o Thrombosis (hepatic, cerebral veins)
• Diagnosis: flow cytometry (absent CD55/CD59 on blood cells)
• Treatment: eculizumab (C5 inhibitor), anticoagulation, stem cell transplant
• Intravascular haemolysis due to mechanical damage in microvasculature
• Causes:
o Thrombotic thrombocytopenic purpura (TTP): ↓ ADAMTS13
o Haemolytic uraemic syndrome (HUS): often E. coli O157:H7
o Disseminated intravascular coagulation (DIC)
o HELLP syndrome in pregnancy
• Blood film: schistocytes (fragmented RBCs)
• Treatment:
o TTP: urgent plasma exchange
o HUS: supportive care ± eculizumab
o DIC: treat underlying cause, give FFP/cryoprecipitate as needed
• Autosomal recessive β-globin mutation: glutamic acid → valine
• HbS polymerises when deoxygenated → sickling and vaso-occlusion
• Type of haemolysis: predominantly extravascular, some intravascular during crises
• Types of crises:
o Vaso-occlusive (pain)
o Aplastic (e.g. parvovirus B19)
o Sequestration (splenic pooling)
o Haemolytic
• Complications: autosplenectomy, osteomyelitis (Salmonella), stroke, priapism
• Diagnosis: haemoglobin electrophoresis
• Treatment: hydroxyurea, folic acid, vaccination, analgesia, transfusion as needed
• Check full blood count, reticulocyte count, LDH, bilirubin, haptoglobin
• Examine blood film for spherocytes, schistocytes, bite cells
• Use Coombs’ test to detect autoimmune cause
• Consider urine dip for haemoglobinuria (intravascular haemolysis)
• Look for splenomegaly on exam (suggests extravascular haemolysis)
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Author & Educational Disclaimer
Author:
Dr Phillip Cockrell BM FRCP DipClinEd
Dr Phillip Cockrell is a UK Consultant Physician in Internal Medicine, currently working at Queen Alexandra Hospital, Portsmouth University Hospitals NHS Trust. He has previously worked as a registrar across Intensive Care Medicine, Gastroenterology, Cardiology, Stroke Medicine, Acute Medicine, and Respiratory Medicine.
He has held senior leadership roles including Associate Clinical Director of the Acute Medical Unit, Clinical Director of Internal Medicine, and Chief of Medicine. Dr Cockrell has over 15 years’ experience in postgraduate medical education, having lectured extensively across the MRCP syllabus and contributed to MRCP revision teaching and course development.
Dr Cockrell holds a Bachelor of Medicine (BM), Fellowship of the Royal College of Physicians (FRCP), and a Diploma in Clinical Education (DipClinEd). His teaching approach is based on structured consolidation of complex medical topics to support efficient and effective revision for postgraduate examinations.
Purpose of this content:
The material on this page is intended solely for educational purposes to support revision for the MRCP (UK) Part 1 examination. It reflects examination-relevant principles of internal medicine and is designed to aid learning and pattern recognition.
Medical disclaimer:
This content is designed for postgraduate medical examination revision and does not constitute medical advice, diagnosis, or treatment guidance and must not be used as a substitute for professional clinical judgement, local guidelines, or specialist consultation. Clinical decisions should always be made in the context of individual patient circumstances and current national guidance.
