Hemolytic Anaemia
Hemolytic anaemia is a condition characterized by the premature destruction of red blood cells at a rate exceeding the bone marrow's compensatory production capacity, leading to reduced circulating erythrocytes.
Hemolytic Anaemia
Hemolytic anaemia is a group of anaemias resulting from an increased rate of destruction of circulating red blood cells, with a compensatory increase in red cell production from the bone marrow (provided marrow function is preserved). [1][2]
Think of it this way: the "factory" (bone marrow) is working fine — it's the "products" (RBCs) that are getting destroyed faster than they can be replaced. Normal RBC lifespan is ~120 days. When destruction outpaces production, the haemoglobin drops and you get anaemia.
The word itself breaks down as:
- Haemo- = blood
- -lytic = breaking/destruction (Greek: lysis)
- Anaemia = without blood (Greek: an- = without, haima = blood)
Key Conceptual Point
Hemolytic anaemia is NOT a diagnosis — it is a pathological process. You must always identify the underlying cause. The marrow's compensatory response (reticulocytosis) is a defining feature: if the marrow is also failing (e.g., parvovirus B19 aplastic crisis), you lose this compensation and the anaemia becomes catastrophically severe.
Epidemiology and Risk Factors
- Hemolytic anaemias are relatively uncommon compared to iron deficiency anaemia, but they carry significant morbidity
- Inherited forms (G6PD deficiency, thalassaemias, sickle cell disease) are among the most common genetic disorders worldwide — concentrated in malaria-endemic regions due to heterozygote advantage (balanced polymorphism)
- Autoimmune hemolytic anaemia (AIHA) has an estimated incidence of 1–3 per 100,000/year
- G6PD deficiency is the most clinically important inherited hemolytic anaemia in Hong Kong
- Prevalence: ~4.5% of males in Hong Kong (X-linked, so predominantly affects males)
- Universal neonatal screening programme in Hong Kong since 1984
- Common variants in Southern Chinese: Canton, Kaiping, Chinese-5
- Thalassaemias are extremely common in Southeast Asia and Southern China
- α-thalassaemia trait: ~3–5% carrier rate in Hong Kong
- β-thalassaemia trait: ~1–2% carrier rate
- HbH disease (--/- α) is encountered in clinical practice
- Sickle cell disease (HbS) is rare in Hong Kong (predominantly African/Mediterranean)
- Hereditary spherocytosis occurs but is less common than in Northern European populations
- Paroxysmal nocturnal haemoglobinuria (PNH): rare, but important acquired intrinsic RBC defect
- Autoimmune hemolytic anaemia: encountered in association with SLE, lymphoproliferative disorders
| Category | Risk Factors |
|---|---|
| Genetic/Inherited | Family history, ethnicity (Southern Chinese for G6PD/thalassaemia), consanguinity |
| Infections | Malaria (travel history — TOCC), C. perfringens, EBV, Mycoplasma |
| Drugs | Oxidant drugs in G6PD (dapsone, primaquine, sulfonamides), drug-induced immune haemolysis (penicillin, cephalosporins, methyldopa) |
| Autoimmune | SLE, lymphoproliferative neoplasms (CLL), other autoimmune conditions |
| Mechanical | Prosthetic heart valves, ECMO, DIC, TTP/HUS |
| Transfusion | ABO incompatibility, delayed transfusion reactions |
Anatomy and Function of the Red Blood Cell
Understanding hemolytic anaemia requires understanding the normal RBC and its components — because inherited hemolytic anaemias arise from defects in these components.
The adult haemoglobin A molecule consists of 2 alpha (α) globin chains and 2 beta (β) globin chains. Within each globin chain, there is one haem molecule. Within each haem molecule, there is one iron atom in the ferrous (Fe²⁺) state. [3]
RBC Components:
├── Membrane (lipid bilayer + skeletal proteins)
│ ├── Spectrin, ankyrin, band 3, protein 4.1, protein 4.2
│ └── GPI-anchored proteins (CD55, CD59) — relevant to PNH
├── Metabolism (enzyme systems)
│ ├── Glycolytic pathway (Embden-Meyerhof) → generates ATP
│ ├── Hexose monophosphate shunt (pentose phosphate pathway) → generates NADPH
│ │ └── G6PD is the rate-limiting enzyme here
│ └── Methemoglobin reductase pathway → keeps iron as Fe²⁺
└── Haemoglobin
├── HbA (α₂β₂) — 95–97% of adult Hb
├── HbA₂ (α₂δ₂) — 1.5–3.5%
└── HbF (α₂γ₂) — <1% in adults- RBCs are anucleate — they cannot synthesize new proteins or repair themselves
- They rely entirely on their existing enzyme stock and membrane integrity for their 120-day lifespan
- Any defect in the membrane skeleton, metabolic enzymes, or haemoglobin structure → premature destruction
- Extravascular haemolysis (majority): occurs in the reticuloendothelial system (RES), primarily the spleen (and liver)
- Macrophages in the splenic red pulp phagocytose abnormal/damaged/antibody-coated RBCs
- This is why splenomegaly is a hallmark of chronic extravascular haemolysis
- Intravascular haemolysis: occurs within the blood vessels themselves
- Free haemoglobin released directly into plasma → binds haptoglobin → when haptoglobin saturated → haemoglobinuria
- Causes: complement-mediated lysis (PNH, ABO mismatch), mechanical shear (TTP, prosthetic valves), severe infections (C. perfringens)
Etiology and Classification
Two main ways to classify hemolytic anaemias: (1) Hereditary/Inherited vs. Acquired, and (2) Intrinsic vs. Extrinsic. [1][2]
There is also an important clinical classification: Extravascular vs. Intravascular haemolysis — this guides your investigation strategy.
Classification Overlap
Almost all inherited causes are intrinsic RBC defects, and almost all acquired causes are extrinsic. The one major exception is Paroxysmal Nocturnal Haemoglobinuria (PNH): it is an acquired intrinsic RBC defect (somatic PIGA gene mutation in a haematopoietic stem cell). This is a classic exam question.
If inherited, think in terms of the components of the RBC, and how they can go wrong — either the membrane, the metabolism, or the haemoglobin. [1]
If acquired, most cases will be due to something outside that is attacking your red cells → only exception is the intrinsic red cell defect seen in PNH. [1][2]
| Category | Subcategory | Examples | Mechanism |
|---|---|---|---|
| INHERITED | Membrane defects | Hereditary spherocytosis | Deficiency of spectrin/ankyrin/band 3/protein 4.2 → loss of membrane surface area → spherocytes → trapped in splenic sinusoids |
| Hereditary elliptocytosis | Defective spectrin dimer self-association → elliptical shape | ||
| Enzyme defects | G6PD deficiency | Deficient NADPH → cannot regenerate reduced glutathione → oxidative damage to Hb → Heinz bodies → extravascular haemolysis (+ intravascular in severe cases) | |
| Pyruvate kinase deficiency | Deficient ATP production → rigid RBCs → extravascular haemolysis | ||
| Haemoglobin defects | HbS (Sickle cell disease) | Valine substitution for glutamate at position 6 of β-chain → HbS polymerizes when deoxygenated → sickle shape → vaso-occlusion + haemolysis | |
| HbH disease | 3 α-gene deletions (--/-α) → excess β-chains form β₄ tetramers (HbH) → unstable, precipitates → haemolysis | ||
| Unstable haemoglobins (e.g., Hb Köln) | Unstable Hb chains unfold and precipitate → Heinz bodies → extravascular haemolysis [3] | ||
| ACQUIRED (Intrinsic) | Paroxysmal nocturnal haemoglobinuria (PNH) | PIGA gene mutation → deficiency of glycophosphatidylinositol (GPI) → deficiency of CD55/CD59 → complement-mediated lysis [1][2] | |
| ACQUIRED (Extrinsic) | Immune | Autoimmune haemolytic anaemia (AIHA) | Autoantibodies (warm IgG or cold IgM) coat RBCs → extravascular destruction (warm) or complement-mediated intravascular lysis (cold) |
| Alloimmune: Transfusion reactions | Pre-formed or anamnestic antibodies against donor RBC antigens | ||
| Alloimmune: Haemolytic disease of the newborn (HDN) | Maternal IgG against fetal RBC antigens (e.g., anti-D, anti-Kell) crosses placenta | ||
| Drug-induced immune haemolysis | Drug acts as hapten, immune complex formation, or autoantibody induction | ||
| Non-immune | Heat, venoms, chemicals damaging RBC membrane | Direct membrane damage | |
| Drugs/chemicals oxidizing Hb | Oxidative stress (like G6PD but in normal individuals with massive exposure) | ||
| Red cell fragmentation syndromes | Microangiopathic haemolytic anaemia (MAHA): TTP, HUS, DIC | RBCs sheared by fibrin strands in damaged microvasculature → schistocytes | |
| Mechanical: prosthetic valves, ECMO | Turbulent flow shears RBCs [1][2] | ||
| Infectious | Bacterial infection of RBCs (C. perfringens) | Alpha-toxin (lecithinase) destroys RBC membrane | |
| Parasitic infection of RBCs (malaria) | Plasmodium invades and lyses RBCs during schizogony [1][2] | ||
| Hypersplenism | Portal hypertension, infiltrative splenomegaly | Increased sequestration and destruction in enlarged spleen [6] |
Pathophysiology
This is the most important pathophysiological distinction because it determines the clinical presentation and lab findings.
Where: Reticuloendothelial system — primarily the spleen (red pulp macrophages)
Why the spleen? The splenic sinusoids have narrow inter-endothelial slits (1–3 μm). Normal RBCs (7–8 μm) must deform to squeeze through. Abnormal RBCs (spherocytes, sickle cells, antibody-coated cells, rigid cells from enzyme deficiency) get trapped and phagocytosed.
Consequences:
- Splenomegaly — the spleen is working overtime
- Unconjugated (indirect) hyperbilirubinaemia — haem is broken down to unconjugated bilirubin within macrophages, overwhelming the liver's conjugation capacity
- Jaundice — but importantly, jaundice WITHOUT tea-coloured urine [1]. Why? Because unconjugated bilirubin is water-insoluble and bound to albumin → it cannot be filtered by the kidney. Tea-coloured urine = conjugated (direct) bilirubin in urine = suggests obstructive/hepatocellular jaundice, NOT haemolysis
- Increased urobilinogen — more bilirubin reaching the gut → more urobilinogen reabsorbed enterohepatic circulation → more excreted in urine (detected by dipstick)
- Pigment gallstones — Increase in the amount and concentration of unconjugated bilirubin in hepatic bile → promotion of stone formation within the gallbladder [1]. These are black pigment stones (calcium bilirubinate)
- Reticulocytosis — marrow compensatory response
- Raised LDH — released from destroyed RBCs (LDH-1 and LDH-2 isoforms)
Where: Within the blood vessels themselves
When: Complement-mediated lysis (PNH, ABO-incompatible transfusion, cold AIHA), mechanical shear (MAHA, prosthetic valves), severe infections (C. perfringens, malaria with massive parasitaemia)
Consequences:
- Free haemoglobin in plasma (plasma turns pink/red — "haemoglobinaemia")
- Haptoglobin depleted — haptoglobin is an α₂-globulin that binds free Hb in plasma; the Hb-haptoglobin complex is cleared by hepatocytes. In intravascular haemolysis, haptoglobin is rapidly consumed → serum haptoglobin drops to undetectable levels. This is one of the most sensitive markers.
- Haemoglobinuria — once haptoglobin is saturated, free Hb passes the glomerular filter → coca-cola coloured urine [1]
- Haemosiderinuria — renal tubular cells absorb filtered Hb, break it down, and store iron as haemosiderin. When these cells are shed into the urine → positive Prussian blue stain on urine sediment. This is a marker of chronic intravascular haemolysis (appears days after the acute event)
- Methaemalbuminaemia — haem released from oxidized Hb binds albumin → methaemalbumin (detected by Schumm's test — rarely done now)
- Renal injury — free Hb is directly nephrotoxic → can cause acute tubular necrosis (ATN). This is why massive intravascular haemolysis (e.g., ABO-incompatible transfusion) can lead to AKI [5]
High Yield: Extravascular vs. Intravascular Haemolysis
| Feature | Extravascular | Intravascular |
|---|---|---|
| Site | Spleen/liver (RES) | Blood vessels |
| Mechanism | Phagocytosis by macrophages | Direct lysis / mechanical shearing |
| Splenomegaly | Yes (hallmark) | Usually no (unless cause also affects spleen) |
| Jaundice | Yes (unconjugated) | Yes (unconjugated) |
| Haemoglobinuria | No | Yes — coca-cola urine |
| Haptoglobin | Mildly ↓ | Markedly ↓ to undetectable |
| Haemosiderinuria | No | Yes (chronic) |
| Urine colour | Normal | Dark/coca-cola |
| Tea-coloured urine | No (pre-hepatic jaundice) | No (pre-hepatic jaundice) |
| Classic causes | Hereditary spherocytosis, warm AIHA, G6PD (chronic), HbH | PNH, ABO mismatch, cold AIHA with complement, TTP/HUS, mechanical valves, G6PD (acute crisis) |
Specific Pathophysiology by Etiology
A. Inherited Membrane Defects
- Genetics: Autosomal dominant (75%) or recessive; most common inherited haemolytic anaemia in Northern Europeans (~1 in 2,000)
- Molecular defect: Deficiency of membrane skeletal proteins (spectrin, ankyrin, band 3, protein 4.2)
- Pathophysiology:
- Defective anchoring of the lipid bilayer to the cytoskeleton
- Progressive loss of unsupported membrane → surface area decreases but volume maintained
- Cell transitions from biconcave disc to sphere (spherocyte)
- Spherocytes are less deformable → cannot navigate the narrow splenic sinusoidal slits
- Trapped in the spleen → phagocytosed → extravascular haemolysis
- Lab hallmark: Raised MCHC (because cell volume ↓ but Hb remains the same), spherocytes on blood film, positive osmotic fragility test / EMA binding test
- Defective spectrin dimer self-association → cells adopt an elliptical shape
- Usually mild or asymptomatic; occasionally significant haemolysis in homozygous state (hereditary pyropoikilocytosis)
B. Inherited Enzyme Defects
- Genetics: X-linked recessive → predominantly affects males (hemizygous); females can be affected if homozygous or through lyonization
- Prevalence: ~400 million people worldwide; ~4.5% of males in HK
- Pathophysiology:
- G6PD catalyzes the first step of the hexose monophosphate shunt (pentose phosphate pathway)
- This pathway generates NADPH, which is essential for regenerating reduced glutathione (GSH)
- GSH protects RBC proteins (especially Hb) from oxidative damage
- With G6PD deficiency → ↓NADPH → ↓GSH → Hb and membrane proteins become oxidized
- Oxidized, denatured Hb precipitates as Heinz bodies (visible with supravital staining — crystal violet or methyl violet)
- Heinz bodies are "pitted" from RBCs by splenic macrophages → creates "bite cells" and "blister cells"
- Damaged RBCs → both extravascular (Heinz body pitting) and intravascular haemolysis (in severe crises)
- Triggers: The hallmark is episodic haemolysis triggered by oxidant stress:
- Drugs: primaquine, dapsone, sulfonamides, nitrofurantoin, rasburicase
- Infections (most common trigger — via oxidative burst by neutrophils)
- Fava beans ("favism" — more common with Mediterranean variant)
- Neonatal jaundice (important cause in HK — screened at birth)
Exam Trap: G6PD Testing
Do NOT test G6PD levels during an acute haemolytic crisis. The reticulocytes (young RBCs) that flood the circulation have higher G6PD levels than the old cells that were destroyed → can give a falsely normal result. Wait 2–3 months after the crisis to test.
- Genetics: Autosomal recessive
- Pathophysiology:
- PK catalyzes the last step of glycolysis (PEP → pyruvate)
- Deficiency → ↓ATP production → RBCs become rigid and dehydrated
- Rigid cells trapped in spleen → extravascular haemolysis
- Paradoxically, splenectomy is more effective here than in G6PD deficiency (because the main destruction site is the spleen)
- Lab: Blood film shows echinocytes (crenated cells), not spherocytes
C. Inherited Haemoglobin Defects (Haemoglobinopathies)
- Genetics: Point mutation in HBB gene → glutamic acid → valine at position 6 of the β-globin chain
- Pathophysiology:
- HbS polymerizes when deoxygenated → forms rigid polymers ("tactoids")
- These distort the RBC into a sickle/crescent shape
- Consequences: vaso-occlusion (sickled cells block microvasculature → ischaemia → pain crises, organ damage) + haemolysis (both extravascular and intravascular)
- Repeated sickling damages the membrane irreversibly → even reoxygenation cannot restore the shape ("irreversibly sickled cells")
- Not common in HK, but tested in exams
- Three α-globin gene deletions (--/-α)
- Excess unmatched β-chains form β₄ tetramers = HbH
- HbH is unstable → precipitates as inclusions → extravascular haemolysis
- HbH is identified by brilliant cresyl blue staining (golf-ball appearance) or Hb electrophoresis (fast-moving band)
- Clinically: moderate haemolytic anaemia, splenomegaly, jaundice
- Relevant in Hong Kong/Southeast Asia
- Haemoglobin Köln = unstable haemoglobin chains that unfold and precipitate → precipitated haemoglobin forms Heinz bodies within the RBC → these abnormal RBCs are tagged for destruction in the reticuloendothelial system → extravascular haemolysis, haemolytic anaemia [3]
- Infective episodes are a known trigger of haemolytic episodes in Hb Köln disease [3]
- Increased oxygen affinity haemoglobinopathies: less likely to release bound oxygen → chronic tissue hypoxia → secondary erythrocytosis (Hb may be elevated; may require venesection)
- Decreased oxygen affinity haemoglobinopathies: SpO₂/SiO₂ will be decreased on pulse oximetry → patient is relatively asymptomatic because tissues receive adequate O₂
- Methemoglobinaemia due to haemoglobinopathy (Hb M): mutations lead to iron in the haem ring being maintained in the ferric (Fe³⁺) state instead of ferrous (Fe²⁺) → prevents Hb from binding O₂ [3]
Paroxysmal Nocturnal Haemoglobinuria (PNH)
- PIGA gene mutation → deficiency of glycophosphatidylinositol (GPI) → deficiency of CD55/CD59 → complement-mediated lysis [1][2]
- Pathophysiology explained from first principles:
- PIGA gene (on X chromosome) encodes an enzyme required for GPI-anchor biosynthesis
- A somatic mutation in a haematopoietic stem cell → that clone cannot make GPI anchors
- CD55 (DAF — decay accelerating factor) and CD59 (MIRL — membrane inhibitor of reactive lysis) are GPI-anchored complement regulatory proteins on the RBC surface
- Without CD55: cannot accelerate decay of C3/C5 convertases → uncontrolled complement activation
- Without CD59: cannot prevent insertion of the membrane attack complex (MAC, C5b-9)
- Result: complement-mediated intravascular haemolysis
- The name "nocturnal" is because physiological mild respiratory acidosis during sleep slightly lowers pH → enhances complement activation → more lysis → morning haemoglobinuria. However, haemolysis is actually continuous, just classically noticed in the first morning void.
- Clinical triad: Intravascular haemolysis + thrombosis (thrombosis is the leading cause of death) + bone marrow failure (overlap with aplastic anaemia)
- Diagnosis: Flow cytometry — absence of GPI-anchored proteins (CD55, CD59) on RBCs and granulocytes (the most sensitive test; replaces the old Ham's test/acidified serum test)
- Treatment: Eculizumab (anti-C5 monoclonal antibody) — blocks terminal complement activation
E. Acquired Extrinsic — Immune Causes
Autoimmune Haemolytic Anaemia (AIHA)
- Autoantibodies (usually IgG) bind RBCs optimally at 37°C
- Mechanism: IgG-coated RBCs are partially phagocytosed by splenic macrophages (Fc receptor recognition) → loss of membrane → microspherocytes → further trapped in spleen → extravascular haemolysis
- Causes:
- Idiopathic (50%)
- Secondary: SLE, CLL, lymphomas, drugs (methyldopa, penicillin)
- Diagnosis: Positive Direct Antiglobulin Test (DAT / Direct Coombs Test) — detects IgG ± C3d on RBC surface
- Treatment: Steroids first line → rituximab → splenectomy → other immunosuppressants
- Cold agglutinin disease (CAD): IgM autoantibodies bind RBCs optimally at 4°C (but can react up to 30°C in pathological cases)
- Mechanism: IgM fixes complement (C3b) on RBCs in the cooler peripheral circulation → as blood returns to central circulation (37°C), IgM detaches but C3b remains → hepatic macrophages (C3b receptors) clear these cells → extravascular haemolysis (mainly hepatic, not splenic). If complement activation proceeds to MAC → intravascular haemolysis
- Causes:
- Primary CAD: Clonal B-cell lymphoproliferative disorder
- Secondary: Mycoplasma pneumoniae, EBV (infectious mononucleosis), lymphoma
- DAT: Positive for C3d only (IgM washes off during the test)
- Very rare subtype of cold AIHA [1]
- Donath-Landsteiner antibody: IgG that binds RBCs at cold temperatures and fixes complement → complement-mediated lysis at warm temperatures (biphasic haemolysin)
- More common in children, often post-viral
- Transfusion reactions: Recipient antibodies against donor RBC antigens → acute (ABO mismatch — intravascular, complement-mediated) or delayed (minor antigen mismatch — extravascular)
- Haemolytic disease of the newborn (HDN): Maternal IgG (anti-D, anti-Kell, anti-c) crosses placenta → attacks fetal RBCs [1][2]
- Three mechanisms:
- Drug adsorption (hapten): Drug binds to RBC surface → antibodies form against drug → complement activation or opsonization (e.g., penicillin)
- Immune complex: Drug-antibody complexes deposit on RBC → complement activation → lysis (e.g., quinine)
- Autoantibody induction: Drug induces true autoantibodies against RBC antigens (e.g., methyldopa — produces warm AIHA-like picture)
F. Acquired Extrinsic — Non-Immune Causes
- Microangiopathic haemolytic anaemia (MAHA): TTP, HUS, DIC [1][2]
- Pathophysiology: Fibrin strands deposited in damaged microvasculature act like "cheese wires" → shear RBCs as they pass through → schistocytes (fragmented RBCs) on blood film
- Classic causes:
- TTP (Thrombotic Thrombocytopenic Purpura): Deficiency of ADAMTS13 → ultra-large vWF multimers → platelet microthrombi
- HUS (Haemolytic Uraemic Syndrome): Shiga toxin (E. coli O157:H7) → endothelial damage → renal microthrombi
- DIC: Widespread coagulation activation → fibrin deposition
- HELLP syndrome: Hemolysis, Elevated Liver enzymes, Low Platelets — occurs in pre-eclampsia [4]
- Malignant hypertension, eclampsia, metastatic carcinoma
- Bacterial: Clostridium perfringens — alpha-toxin (phospholipase C / lecithinase) directly destroys the RBC phospholipid membrane → massive intravascular haemolysis (can be fulminant)
- Parasitic: Malaria (Plasmodium spp.) — merozoites invade RBCs, replicate, and lyse them during schizogony. P. falciparum can cause massive haemolysis ("blackwater fever") [1][2]
- Other infections triggering haemolysis: Babesiosis, Bartonella, Mycoplasma (via cold agglutinins), EBV
- Hypersplenism: Enlarged spleen sequesters and destroys excessive numbers of blood cells (not just RBCs) → pancytopenia with splenomegaly [6]
- Direct chemical/toxin damage: Snake venoms (phospholipases), arsine gas, copper (Wilson's disease — Coombs-negative haemolytic anaemia [7]), lead poisoning
- Burns: Thermal damage to RBCs in circulation
Wilson's Disease and Haemolysis
Fulminant hepatic failure due to Wilson's disease has a very specific feature: young patients with no reason for fulminant liver failure, exclusion of all other common causes → the only finding is low haemoglobin → Coombs-negative haemolytic anaemia. [7] The mechanism is copper directly damaging the RBC membrane. This is a classic exam scenario.
Clinical Features
Symptoms (with Pathophysiological Basis)
The symptoms can be divided into those from anaemia itself, those from the haemolytic process, and those from the underlying cause.
Depends on the onset and severity of anaemia [8]:
| Symptom | Pathophysiological Basis |
|---|---|
| Fatigue, decreased exercise tolerance | ↓O₂ delivery to tissues → ↓aerobic metabolism → ↓ATP production |
| Shortness of breath (dyspnoea on exertion) | Compensatory ↑ventilation to maintain O₂ delivery; in severe cases, high-output cardiac failure |
| Palpitations | Compensatory ↑heart rate (sympathetic activation) to maintain cardiac output and O₂ delivery |
| Dizziness / syncope | Cerebral hypoperfusion when compensatory mechanisms are overwhelmed |
| Symptoms of cardiac ischaemia (chest pain) | ↓O₂ supply to myocardium may unmask pre-existing coronary disease (demand ischaemia → MINOCA pattern) |
| Symptom | Pathophysiological Basis |
|---|---|
| Jaundice (yellow skin/scleral icterus) | ↑Unconjugated bilirubin from Hb breakdown exceeds hepatic conjugation capacity |
| Dark/coca-cola coloured urine (haemoglobinuria) | Intravascular haemolysis → free Hb filtered by kidneys → coca-cola urine [1] |
| Normal-coloured urine (no tea colour) | In extravascular haemolysis, unconjugated bilirubin is water-insoluble → does NOT enter urine → urine is normal [1] |
| Abdominal discomfort / fullness (LUQ) | Splenomegaly → splenic capsule stretch |
| Biliary colic / RUQ pain | Pigment gallstones from chronic ↑unconjugated bilirubin [1] |
| Back pain / loin pain | Acute intravascular haemolysis (e.g., ABO mismatch transfusion) → free Hb causing renal vasoconstriction and tubular injury |
| Episodic dark urine (paroxysmal) | PNH — classically first morning void is dark (nocturnal complement activation) |
Remember that anaemia is not a diagnosis — it reflects an underlying pathology. Always look for symptoms related to the cause. [8]
| Symptom | Suggested Cause |
|---|---|
| Fever, rigors | Infection (malaria, C. perfringens), transfusion reaction |
| Joint pain, skin rash (butterfly rash) | SLE → warm AIHA |
| Cold-induced acrocyanosis / Raynaud's-like symptoms | Cold agglutinin disease |
| Recent drug exposure | Drug-induced G6PD crisis, drug-induced immune haemolysis |
| Fava bean ingestion | G6PD deficiency (favism) |
| Recent blood transfusion | Transfusion reaction |
| Family history of anaemia, jaundice, splenectomy, gallstones | Inherited haemolytic anaemia |
Name important history to elicit from a patient with suspected haemolytic anaemia:
- Family history (inherited causes — autosomal dominant in HS, X-linked in G6PD, autosomal recessive in PK deficiency/sickle cell)
- Ethnicity (G6PD: Southern Chinese, Mediterranean, African; thalassaemia: Southeast Asian, Mediterranean; sickle cell: African)
- Infection (trigger for G6PD crisis; trigger for aplastic crisis with parvovirus B19; Mycoplasma → cold AIHA)
- Drugs (oxidant drugs for G6PD; immune haemolysis triggers)
- Transfusion history (transfusion reactions; alloimmunization)
- Co-existing illnesses such as autoimmune diseases / lymphoproliferative neoplasms (warm AIHA secondary to SLE or CLL) [1]
Signs (with Pathophysiological Basis)
| Sign | Pathophysiological Basis |
|---|---|
| Pallor (conjunctival, palmar crease, nail bed) | ↓Haemoglobin → ↓red colour of blood perfusing tissues [1][8] |
| Jaundice (scleral icterus — best detected here) | ↑Unconjugated bilirubin deposited in tissues with high elastin content (sclera has affinity for bilirubin) |
| Tachycardia | Compensatory ↑HR to maintain cardiac output |
| Bounding pulse / hyperdynamic precordium | High-output state from chronic anaemia → ↑stroke volume |
| Flow murmur | ↓Blood viscosity in anaemia → turbulent flow across normal valves |
| Koilonychia / angular stomatitis / glossitis | Suggests concomitant iron deficiency (chronic intravascular haemolysis can cause iron loss via haemosiderinuria) |
| Leg ulcers | Chronic haemolysis (especially sickle cell, HS) → microvascular ischaemia → poor wound healing in malleolar region |
| Sign | Pathophysiological Basis |
|---|---|
| Splenomegaly | Work hypertrophy of the spleen — the RES is working overtime to remove abnormal RBCs → splenic enlargement. This is a hallmark of extravascular haemolysis [1] |
| Hepatomegaly | RES expansion in the liver; extramedullary haematopoiesis in severe chronic cases |
| RUQ tenderness / Murphy's sign | Pigment gallstones → cholecystitis |
| Sign | Condition |
|---|---|
| Frontal bossing, maxillary hyperplasia ("chipmunk facies") | Thalassaemia major — chronic marrow expansion (erythroid hyperplasia) deforms membranous bones of the skull and face |
| Short stature, skeletal anomalies (absent thumbs, radial ray defects) | Fanconi's anaemia |
| Splenectomy scar | Previous splenectomy for hereditary spherocytosis, thalassaemia intermedia, or warm AIHA |
| Sickle cell dactylitis ("hand-foot syndrome") | Vaso-occlusion in small bones of hands/feet in children with SCD |
| Butterfly rash, arthritis | SLE → secondary warm AIHA |
| Kayser-Fleischer rings | Wilson's disease → copper deposition in Descemet's membrane → Coombs-negative haemolysis |
Laboratory Findings: Pattern Recognition
While a full diagnostic section will follow, understanding the expected lab pattern is integral to recognizing haemolysis clinically.
| Parameter | Expected Change | Why |
|---|---|---|
| Unconjugated (indirect) bilirubin | ↑ | Haem breakdown → bilirubin production exceeds hepatic conjugation |
| LDH | ↑ | Released from lysed RBCs (LDH-1, LDH-2) |
| Haptoglobin | ↓↓ (intravascular) or ↓ (extravascular) | Binds free Hb → complex cleared by liver → consumed. Most sensitive marker of intravascular haemolysis |
| Urine urobilinogen | ↑ | ↑Bilirubin → ↑gut conversion → ↑enterohepatic reabsorption → ↑urinary excretion |
| Urine haemosiderin | + (intravascular) | Renal tubular cells store iron from filtered Hb → shed into urine (Prussian blue positive) |
| Haemoglobinuria | + (intravascular) | Free Hb exceeds haptoglobin binding capacity → filtered by kidneys |
| Parameter | Expected Change | Why |
|---|---|---|
| Reticulocyte count | ↑↑ | Marrow responds to anaemia with ↑erythropoiesis → immature RBCs (reticulocytes) released early |
| MCV | Normal or ↑ | Reticulocytes are larger than mature RBCs → can raise MCV |
| Polychromasia on blood film | Present | Reticulocytes stain blue-grey with Wright's stain (residual RNA) |
| Erythroid hyperplasia on BM | Present | ↑Erythroid precursors; M:E ratio decreased (normally ~3:1, drops to <1:1) |
| Morphology | Condition |
|---|---|
| Spherocytes | Hereditary spherocytosis, warm AIHA |
| Schistocytes (fragmented cells) | MAHA — TTP, HUS, DIC, mechanical valves |
| Sickle cells | Sickle cell disease |
| Target cells | Thalassaemia, HbC disease, liver disease |
| Heinz bodies (supravital stain) | G6PD deficiency, unstable Hb (e.g., Hb Köln) |
| Bite cells / blister cells | G6PD deficiency (Heinz bodies pitted by spleen) |
| Elliptocytes | Hereditary elliptocytosis |
| Agglutination | Cold agglutinin disease |
| Nucleated RBCs (nRBCs) | Severe haemolysis, extramedullary haematopoiesis |
| HbH inclusions (golf-ball) | HbH disease (brilliant cresyl blue stain) |
| Howell-Jolly bodies | Post-splenectomy / hyposplenic (autosplenectomy in SCD) |
| Polychromasia | Reticulocytosis (any cause) |
The peripheral blood film is the single most informative investigation in haemolytic anaemia. Always look at it yourself.
Anatomical Pathology Considerations
- Erythroid hyperplasia with ↓M:E ratio
- In aplastic crisis (parvovirus B19): sudden cessation of erythropoiesis → giant pronormoblasts with nuclear inclusions, absent erythroblasts
- In megaloblastic crisis: folate deficiency (chronic haemolysis uses up folate stores) → megaloblastic changes
- Work hypertrophy → congested red pulp with expanded cords of Billroth
- In chronic haemolysis: haemosiderin-laden macrophages
- Pigment (bilirubin) gallstones — black stones composed of calcium bilirubinate
- Can develop as early as childhood in hereditary spherocytosis or SCD
- In intravascular haemolysis: haemosiderin deposition in renal tubular epithelial cells, ATN in severe cases
- In SCD: papillary necrosis (medullary ischaemia from sickling in the vasa recta — the medullary environment is hypoxic, acidotic, and hypertonic, all promoting sickling)
High Yield Summary
Definition: Hemolytic anaemia = increased rate of RBC destruction ± compensatory reticulocytosis
Classification:
- Inherited vs. Acquired
- Intrinsic vs. Extrinsic (PNH = acquired intrinsic — the exception!)
- Extravascular (spleen/liver — splenomegaly, jaundice, gallstones) vs. Intravascular (blood vessels — haemoglobinuria, ↓↓haptoglobin, renal injury)
Inherited causes — think RBC components:
- Membrane: Hereditary spherocytosis, elliptocytosis
- Enzyme: G6PD deficiency (X-linked, common in HK), pyruvate kinase deficiency
- Haemoglobin: SCD, HbH, unstable Hb (Köln), thalassaemias
Acquired causes — think what's attacking the RBC:
- Immune: Warm AIHA (IgG), Cold AIHA (IgM), alloimmune (transfusion/HDN), drug-induced
- Non-immune: MAHA (TTP/HUS/DIC), mechanical (valves/ECMO), infections (malaria, C. perfringens), hypersplenism, toxins
Key clinical features: Pallor + jaundice (WITHOUT tea-coloured urine) + splenomegaly = classic triad of extravascular haemolysis
Key labs: ↑Reticulocytes, ↑LDH, ↑unconjugated bilirubin, ↓haptoglobin, ±haemoglobinuria
History pearls: Family history, ethnicity, drug exposure, infections, transfusion history, autoimmune diseases
Hong Kong relevance: G6PD deficiency (neonatal screening), α/β-thalassaemia carrier states, HbH disease
Active Recall - Hemolytic Anaemia (Etiology, Pathophysiology, Clinical Features)
[1] GC Lecture Slides: "GC 047. Family history of anaemia.pdf" (Haemolytic anaemia classification slide) [2] GC Lecture Slides: "GC 097. Many members of the family have anaemia (MED).pdf" [3] Senior Notes: "Block A - Many members of the family have anaemia.pdf" (Haemoglobinopathies section) [4] Senior Notes: "Block A - A jaundiced and incoherent patient_ liver failure.pdf" (HELLP syndrome) [5] Senior Notes: "Block A - Nephrotology Teaching Clinic RTD.pdf" (ATN from haemoglobinaemia) [6] Senior Notes: "Block A - Splenomegaly_ common causes of splenomegaly; myeloproliferative diseases.pdf" [7] Senior Notes: "Block A - Patients with non-viral chronic liver diseases.pdf" (Wilson's disease and Coombs-negative haemolysis) [8] Senior Notes: "Block A - Pallor_ diagnosis of anaemia; nutritional anaemia; anaemia of systemic diseases.pdf" [9] Senior Notes: "Ryan Ho Chemical Path.pdf" (Iron metabolism, haemolysis biochemistry) [10] Senior Notes: "Maksim Medicine Notes.pdf" (Aplastic anaemia section with PNH overlap) [11] Senior Notes: "Block A - Family history of anaemia_ inherited causes of anaemia; haemolytic anaemia; aplastic anaemia.pdf" [12] GC Lecture Slides: "GC 076. Pallor_diagnosis of anaemia; nutritional anaemia; anaemia of systemic diseases.pdf" [13] Senior Notes: "Block A - Fever after a blood transfusion_ transfusion and related problems.pdf" [14] GC Lecture Slides: "Haematology Introduction to Haematological investigations (CBP, Clotting).pdf"
Differential Diagnosis of Hemolytic Anaemia
When you encounter a patient with features suggestive of haemolysis (anaemia + jaundice + ↑reticulocytes + ↑LDH + ↓haptoglobin), the differential diagnosis is essentially "What is destroying the red cells?" Your job is to systematically narrow down the cause using three layers of clinical reasoning:
- Is this really haemolysis? — Rule out mimics that share overlapping features
- If haemolysis, is it inherited or acquired? — History and blood film morphology are your best friends
- If acquired, what's the mechanism? — Immune vs. non-immune vs. infectious vs. mechanical
GC Lecture High Yield — Key History to Distinguish Causes
The following history points are critical in differentiating causes of haemolytic anaemia [1][2]:
- Family history — inherited causes (HS, G6PD, thalassaemia, SCD)
- Ethnicity — G6PD and thalassaemia in Southern Chinese/SE Asian; SCD in Africans
- Infection — trigger for G6PD crisis; Mycoplasma/EBV → cold AIHA; malaria
- Drugs — oxidant drugs for G6PD; immune haemolysis (penicillin, methyldopa)
- Transfusion history — acute or delayed transfusion reactions
- Co-existing illnesses such as autoimmune diseases and lymphoproliferative neoplasms — secondary warm AIHA
- History of gallstones — chronic haemolysis [1][2]
Several conditions can share individual features with haemolytic anaemia (e.g., jaundice, raised LDH, anaemia) but are NOT haemolysis. You must actively exclude these before proceeding.
| Condition | Shared Feature | How to Distinguish |
|---|---|---|
| Gilbert's syndrome | Unconjugated hyperbilirubinaemia + mild jaundice | Normal Hb, normal reticulocytes, normal LDH, normal haptoglobin. Bilirubin rises with fasting/stress. UGT1A1 promoter polymorphism |
| Ineffective erythropoiesis (megaloblastic anaemia, MDS, thalassaemia major) | ↑Unconjugated bilirubin, ↑LDH | Reticulocyte count is low/inappropriately normal (marrow precursors die before maturation). LDH can be very high in megaloblastic anaemia. Blood film: macro-ovalocytes, hypersegmented neutrophils (B12/folate deficiency) or dysplastic features (MDS) |
| Acute blood loss | Anaemia + tachycardia | No jaundice, no ↑LDH, normal haptoglobin initially, obvious source of bleeding, reticulocytosis only appears 3–5 days later |
| Myoglobinuria (rhabdomyolysis) | Dark "cola" urine | Urine dipstick positive for "blood" but microscopy shows no RBCs. Massively ↑CK (not just LDH). Myoglobin in urine, not haemoglobin |
| Hepatocellular jaundice | Jaundice + ↑bilirubin | Mixed conjugated + unconjugated bilirubin. ↑ALT/AST. Tea-coloured urine (conjugated bilirubin in urine) — which you would NOT expect in haemolysis [2][11] |
| Anaemia of chronic disease (ACD) | Normocytic anaemia, ↑ferritin | ↓Serum iron, ↓TIBC, ↑ferritin (positive acute phase reactant); iron is trapped in RES, not made available for erythropoiesis [9]. No reticulocytosis, no ↑LDH, normal haptoglobin |
Exam Pearl: Tea-Coloured Urine
Tea-coloured urine suggests obstructive jaundice, a consequence of conjugated bilirubin entering the urine. Hemolytic anaemia is a pre-hepatic cause of jaundice that results in unconjugated bilirubin, which is water-insoluble — so you would NOT expect the patient to have tea-coloured urine [2][11]. If someone with suspected haemolysis has tea-coloured urine, reconsider your diagnosis — think hepatocellular or obstructive cause.
Before diving into the specific causes, you need to confirm that haemolysis is occurring. The GC lecture slides explicitly list the laboratory features:
Laboratory features of haemolytic anaemia [1][14]:
- Anaemia (mildly macrocytic usually) with reticulocytosis
- Increase in unconjugated bilirubin, LDH
- Reduced serum haptoglobin
- Increased methaemalbumin
- Polychromasia
- Spherocytes (hereditary spherocytosis, immune haemolytic anaemia)
- RBC fragmentation (microangiopathic haemolysis)
- RBC agglutination (cold agglutinin disease)
Direct antiglobulin test — positive in immune haemolytic anaemia
Once haemolysis is confirmed, the next step is to determine the specific cause.
The master classification (from the previous section) now serves as your DDx framework. Here, we focus on how to differentiate between causes at the bedside and with initial investigations.
Diagnostic Algorithm — Mermaid Flowchart
Differential Diagnosis Organized by Key Discriminating Features
The Direct Antiglobulin Test (DAT / Direct Coombs Test) is the single most important first-line investigation to separate immune from non-immune haemolysis [1][14]. It detects antibodies (IgG) and/or complement (C3d) bound to the surface of the patient's RBCs.
| Condition | DAT Pattern | Key Distinguishing Features |
|---|---|---|
| Warm AIHA | IgG ± C3d | Spherocytes on film; splenomegaly; look for underlying SLE, CLL, lymphoma, drugs (methyldopa). Evans syndrome = warm AIHA + ITP [15] |
| Cold Agglutinin Disease (CAD) | C3d only | RBC agglutination on blood film [1][14]; symptoms worsen in cold; acrocyanosis; check cold agglutinin titre; look for Mycoplasma, EBV, lymphoma [15] |
| Drug-induced immune HA | Variable (IgG or C3d) | Temporal relationship with drug exposure; resolve on drug withdrawal |
| Delayed haemolytic transfusion reaction | Positive (new alloantibody) | 4–5 days after transfusion; minor blood group incompatibility (e.g., Kidd); fever, jaundice, rapid Hb drop; especially in thalassaemia patients [13] |
| Haemolytic disease of the newborn | Positive on baby's RBCs | Neonatal jaundice within 24h of birth; maternal anti-D or other alloantibodies |
High Yield: When DAT is Positive but NOT AIHA
A positive DAT does not always mean clinically significant immune haemolysis. Up to 10% of hospitalised patients may have a weakly positive DAT without haemolysis (e.g., from recent IV immunoglobulin, anti-CD38 therapy like daratumumab, or complement activation in infection). Always correlate with clinical and laboratory evidence of haemolysis.
If the DAT is negative but you see spherocytes on the film, the differential is much narrower:
| Condition | How to Distinguish |
|---|---|
| Hereditary Spherocytosis (HS) | AD inheritance (75%), sporadic (25%); chronic moderate haemolytic anaemia (Hb 8–12 g/dL, retics > 6%); MCHC ≥ 36 g/dL; flow cytometry: ↓EMA binding; osmotic fragility test [3][15][16] |
| Wilson's disease | Coombs-negative haemolytic anaemia in a young patient with fulminant liver failure; Kayser-Fleischer rings; ↓caeruloplasmin; ↑24h urine copper [7] |
| Clostridial sepsis | Acutely unwell, septic; recent abdominal surgery or trauma; C. perfringens alpha-toxin destroys membrane → massive intravascular haemolysis |
| Unstable Hb (Hb Köln) | Family history; episodic haemolysis triggered by infection; Heinz bodies on supravital stain [3] |
Key learning point: Both hereditary spherocytosis and warm AIHA produce spherocytes on the blood film. The DAT is what separates them. HS = DAT negative; warm AIHA = DAT positive [1][14][15].
RBC fragmentation on blood film = microangiopathic haemolysis [1][14]. This is a medical emergency in many cases.
| Condition | Key Features | How to Distinguish |
|---|---|---|
| TTP | Pentad: MAHA + thrombocytopenia + neurological symptoms + fever + renal impairment (full pentad present in < 10% of cases; do NOT wait for all 5) | ADAMTS13 activity < 10% is diagnostic [17] |
| HUS | MAHA + thrombocytopenia + AKI (predominant renal involvement) | Usually post-diarrhoeal illness (E. coli O157:H7 Shiga toxin); mainly children |
| DIC | MAHA + prolonged PT/APTT + ↑D-dimer + ↓fibrinogen | Underlying trigger: sepsis, malignancy, obstetric complications, trauma. Clotting profile should be NORMAL in TTP — if abnormal, think DIC [17] |
| HELLP | Hemolysis, Elevated Liver enzymes, Low Platelets in pregnancy/pre-eclampsia | Third trimester; hypertension; proteinuria [4] |
| Mechanical valve haemolysis | Chronic low-grade intravascular haemolysis | History of prosthetic valve; flow murmur; schistocytes may be few |
| Malignant hypertension | Severe hypertension + MAHA + AKI | BP > 180/120 with end-organ damage; retinal haemorrhages |
Critical Exam Point — TTP vs DIC
Both TTP and DIC produce schistocytes and thrombocytopenia. The key differentiator is the coagulation profile:
- TTP: clotting profile (PT, APTT, fibrinogen) should be NORMAL [17]
- DIC: prolonged PT/APTT, ↑D-dimer, ↓fibrinogen
This is because TTP involves platelet microthrombi (von Willebrand factor–mediated), NOT activation of the coagulation cascade, whereas DIC involves widespread thrombin generation consuming clotting factors.
| Condition | Key Features |
|---|---|
| G6PD deficiency | X-linked; 4.5% of males in HK; episodic haemolysis triggered by infection (most common), drugs (anti-malarials, dapsone, nitrofurantoin, sulfonamides, quinolones), fava beans, DKA; bite cells + Heinz bodies on film; G6PD assay (repeat after recovery if normal during crisis) [15] |
| Unstable haemoglobins (Hb Köln) | Heinz bodies; family history; episodic haemolysis triggered by infection [3] |
| Pyruvate kinase deficiency | Autosomal recessive; chronic haemolysis (not episodic); echinocytes on film (not bite cells); PK assay |
The key distinction between G6PD and PK deficiency: G6PD causes episodic haemolysis triggered by oxidant stress, whereas PK deficiency causes chronic haemolysis because ATP depletion is constant, not triggered.
| Blood Film Finding | Condition | Key Features |
|---|---|---|
| Sickle cells | Sickle cell disease | Vaso-occlusive crises; Hb electrophoresis shows HbS; rare in HK |
| Target cells + hypochromic microcytic | HbH disease / thalassaemia | HbH inclusions with brilliant cresyl blue (golf-ball appearance); Hb electrophoresis; common in HK/SE Asia [3] |
| Agglutination | Cold agglutinin disease | RBC agglutination on blood film; DAT positive for C3d [1][14]; spuriously ↑MCV on automated analyser (agglutinated cells counted as single large cell) |
| Elliptocytes | Hereditary elliptocytosis | Usually mild/asymptomatic; family history |
| Nucleated RBCs + polychromasia | Severe haemolysis of any cause | Normoblasts indicate very high demand for RBC production [17]; not specific to one cause |
The patient presents with haemoglobinuria. Top 2 differential diagnoses: [11]
- Paroxysmal nocturnal haemoglobinuria (PNH)
- Paroxysmal cold haemoglobinuria (PCH) — very rare subtype of cold AIHA [11]
Other causes of intravascular haemolysis with haemoglobinuria:
- ABO-incompatible transfusion reaction (coca-cola urine; abrupt onset of "sense of impending doom", flushing, fever, rigors, loin/back pain, vomiting, shock) [13]
- March haemoglobinuria (mechanical — prolonged marching/running)
- Severe G6PD crisis
- Severe falciparum malaria ("blackwater fever")
- C. perfringens sepsis
PNH — The Classic Acquired Intrinsic Cause
- PIGA gene mutation → GPI-anchor deficiency → loss of CD55/CD59 → complement-mediated intravascular haemolysis [1][2]
- Diagnosis: Flow cytometry on peripheral blood — deficiency of GPI-anchored proteins (CD55, CD59) on RBCs and granulocytes; MOST useful and accepted method [18]
- Must screen for PNH in all cases of aplastic anaemia and unexplained Coombs-negative haemolysis [18]
- Triad: haemolysis + thrombosis + cytopenias (marrow failure)
| Organism | Mechanism | Clinical Clue |
|---|---|---|
| Plasmodium spp. (malaria) | Parasitic invasion and lysis of RBCs during schizogony | Travel history (TOCC); fever with periodicity; thick and thin blood film; rapid diagnostic test (RDT) |
| C. perfringens | Alpha-toxin (lecithinase) destroys RBC membrane | Gas gangrene; post-surgical/trauma; acutely septic; massive intravascular haemolysis |
| Mycoplasma pneumoniae | Induces cold agglutinins (IgM) → cold AIHA | Atypical pneumonia; young adults; cold agglutinin titre |
| EBV | Cold agglutinins; splenic sequestration | Infectious mononucleosis; pharyngitis, lymphadenopathy, hepatosplenomegaly |
| Babesia | Intra-erythrocytic parasite → direct lysis | Tick-borne; resembles malaria on film; mainly immunocompromised |
H. Special Scenarios in the DDx
When haemolysis is accompanied by pancytopenia (not just anaemia), consider:
- Free Hb is directly nephrotoxic → ATN (endogenous nephrotoxin)
- Consider: ABO-incompatible transfusion, PNH crisis, G6PD crisis, TTP/HUS, rhabdomyolysis (myoglobin — the mimic)
- Under renal causes of AKI: haemoglobinaemia is listed as an endogenous nephrotoxin causing toxic ATN [5]
| Feature | Think of... |
|---|---|
| Positive DAT | AIHA (warm/cold), drug-induced immune, delayed transfusion reaction, HDN |
| Negative DAT + spherocytes | Hereditary spherocytosis, Wilson's disease |
| Schistocytes | TTP, HUS, DIC, HELLP, mechanical valves, malignant HTN |
| Bite cells / Heinz bodies | G6PD deficiency, unstable Hb |
| Sickle cells | Sickle cell disease |
| Agglutination | Cold agglutinin disease |
| Target cells + microcytic | Thalassaemia, HbH |
| Haemoglobinuria | PNH, ABO mismatch, PCH, severe G6PD, blackwater fever |
| Family history + chronic | HS, G6PD, PK deficiency, thalassaemia, SCD, unstable Hb |
| Recent transfusion | Acute haemolytic transfusion reaction (ABO), delayed haemolytic reaction |
| Travel to endemic area | Malaria, babesiosis |
| Drug exposure | G6PD crisis, drug-induced immune haemolysis |
| Autoimmune disease (SLE, CLL) | Secondary warm AIHA |
| Young patient + fulminant liver failure + Coombs-negative HA | Wilson's disease [7] |
| Pregnancy + hypertension | HELLP syndrome [4] |
High Yield Summary — DDx of Hemolytic Anaemia
Step 1: Confirm haemolysis — ↑reticulocytes, ↑LDH, ↑unconjugated bilirubin, ↓haptoglobin, polychromasia on film
Step 2: DAT (Direct Coombs Test) — the single most important branching investigation
- Positive → Immune (Warm AIHA, Cold AIHA, drug-induced, transfusion reaction)
- Negative → Non-immune (proceed to blood film morphology)
Step 3: Blood film morphology guides the rest
- Spherocytes + DAT neg → HS or Wilson's
- Schistocytes → MAHA (TTP/HUS/DIC/HELLP/mechanical)
- Bite cells → G6PD
- Sickle cells → SCD
- Agglutination → Cold agglutinin disease
Step 4: Haemoglobinuria?
- Yes → PNH (flow cytometry for CD55/CD59), ABO mismatch, severe G6PD, malaria
Don't forget: TOCC for malaria; drugs for G6PD and immune haemolysis; family history for inherited causes; SLE/CLL for secondary AIHA
Active Recall - Differential Diagnosis of Hemolytic Anaemia
References
[1] Lecture slides: GC 047. Family history of anaemia.pdf (Haemolytic anaemia — classification, clinical features, laboratory features slides) [2] Lecture slides: GC 097. Many members of the family have anaemia (File 2).pdf (Laboratory diagnosis of haemoglobinopathy) [3] Senior notes: Block A - Many members of the family have anaemia.pdf (Haemoglobinopathies, Hb Köln, oxygen affinity) [4] Senior notes: Block A - A jaundiced and incoherent patient_ liver failure.pdf (HELLP syndrome) [5] Senior notes: Block A - Nephrotology Teaching Clinic RTD.pdf (ATN from haemoglobinaemia) [6] Senior notes: Block A - Splenomegaly_ common causes of splenomegaly; myeloproliferative diseases.pdf (Splenomegaly sizes and causes) [7] Senior notes: Block A - Patients with non-viral chronic liver diseases.pdf (Wilson's disease, Coombs-negative haemolytic anaemia) [9] Senior notes: Ryan Ho Chemical Path.pdf (Anaemia of chronic disease, iron metabolism) [11] Senior notes: Block A - Family history of anaemia_ inherited causes of anaemia; haemolytic anaemia; aplastic anaemia.pdf (Clinical features, haemoglobinuria DDx) [13] Senior notes: Block A - Fever after a blood transfusion_ transfusion and related problems.pdf (ABO-incompatible transfusion, delayed haemolytic reaction) [14] Lecture slides: Haematology Introduction to Haematological investigations (CBP, Clotting).pdf (Haemolytic anaemia laboratory features) [15] Senior notes: Maksim Medicine Notes.pdf (Haemolytic anaemia overview, AIHA, G6PD, HS tables) [16] Senior notes: Ryan Ho Haemtology.pdf (Hereditary spherocytosis, elliptocytosis) [17] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (TTP diagnosis — MAHA, ADAMTS13, clotting profile normal) [18] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (PNH — flow cytometry for CD55/CD59; aplastic anaemia workup)
Diagnostic Criteria, Algorithm, and Investigations for Hemolytic Anaemia
Unlike conditions such as heart failure or rheumatoid arthritis, hemolytic anaemia does not have a single universally accepted "diagnostic criteria" checklist. Instead, the diagnostic process is a two-step approach:
- Confirm that haemolysis is occurring — using a constellation of laboratory markers
- Determine the specific cause — using targeted investigations guided by clinical context and blood film morphology
This is because "hemolytic anaemia" is a pathological process, not a single disease. Your job is to prove destruction is happening, then find out why.
There is no single test that alone confirms haemolysis. Instead, you need a constellation of findings that together prove accelerated RBC destruction with compensatory marrow response.
The "Haemolysis Screen" — Core Markers
Laboratory features of haemolytic anaemia [1][14]:
- Anaemia (mildly macrocytic usually) with reticulocytosis
- Increase in unconjugated bilirubin, LDH
- Reduced serum haptoglobin
- Increased methaemalbumin
These can be separated into two categories:
A. Evidence of Increased RBC Destruction
| Marker | Expected Change | Why / Mechanism | Interpretation Pearls |
|---|---|---|---|
| Unconjugated (indirect) bilirubin | ↑ | Haem from destroyed RBCs → broken down by haem oxygenase in macrophages → biliverdin → unconjugated bilirubin. Exceeds hepatic conjugation capacity | Typically < 85 μmol/L in haemolysis alone. If much higher, consider concomitant liver disease or Gilbert's. Remember: no tea-coloured urine because unconjugated bilirubin is water-insoluble [11] |
| LDH (lactate dehydrogenase) | ↑ | LDH is abundant in RBC cytoplasm (isoforms LDH-1 and LDH-2). Released when RBCs lyse | Non-specific — also elevated in tissue ischaemia, liver disease, malignancy. According to Prof Anskar Leung, LDH is the immediate parameter to look at to differentiate whether anaemia is due to haemolysis [11] |
| Serum haptoglobin | ↓ or undetectable | Haptoglobin (an α₂-globulin) binds free Hb in plasma → the Hb-haptoglobin complex is cleared by hepatocytes → haptoglobin consumed and not recycled | Most sensitive marker of intravascular haemolysis (undetectable). Also mildly ↓ in extravascular. Caveat: haptoglobin deficiency is common in Chinese — 1:1000 [13]. Also a positive acute-phase reactant — can be falsely normal during concurrent infection/inflammation |
| Methaemalbumin | ↑ | Once haptoglobin is fully saturated, free haem binds to albumin → forming methaemalbumin [13] | Indicates severe intravascular haemolysis (haptoglobin already depleted). Detected by Schumm's test (rarely performed clinically) |
| Urine haemoglobin (haemoglobinuria) | + (intravascular) | Free Hb exceeds haptoglobin binding capacity → filtered by glomerulus → appears in urine (coca-cola colour) | Specific for intravascular haemolysis. Dipstick positive for "blood" but microscopy shows no RBCs |
| Urine haemosiderin | + (intravascular, chronic) | Renal tubular cells absorb filtered Hb → break it down → store iron as haemosiderin → when cells shed → haemosiderinuria | Prussian blue stain on urine sediment. Appears days after acute event; marker of chronic intravascular haemolysis |
B. Evidence of Compensatory Increased RBC Production
| Marker | Expected Change | Why / Mechanism | Interpretation Pearls |
|---|---|---|---|
| Reticulocyte count | ↑↑ ( > 2%; absolute reticulocyte count > 100 × 10⁹/L) | Erythropoietin-driven marrow response → release of immature RBCs (reticulocytes still containing residual RNA) into circulation | If reticulocyte count is NOT elevated in the setting of haemolysis, consider: (1) aplastic crisis (parvovirus B19), (2) marrow failure (MDS, aplastic anaemia), (3) nutritional deficiency (folate/B12) limiting the compensatory response |
| MCV | Normal or mildly ↑ | Reticulocytes are generally larger than mature RBCs, so they drag up the average MCV [11] | Can be ↓ if underlying cause is thalassaemia; can be ↓ if spherocytes predominate (HS) |
| Polychromasia on blood film | Present | Reticulocytes stain blue-grey with Wright's stain due to residual RNA → polychromatic appearance [1][11][14] | |
| Nucleated RBCs (normoblasts) | May be present | Severe marrow stress → premature release of nucleated RBC precursors | Indicates high demand for bone marrow to produce RBCs such that immature RBCs are released into circulation [17] |
| Bone marrow (if examined) | Erythroid hyperplasia; ↓M:E ratio | ↑Erythroid precursors in response to ↑EPO drive | Not routinely needed to confirm haemolysis; reserved for specific indications |
Minimal Criteria to Confirm Haemolysis (Practical Summary)
You need at least 3 concordant findings from the following to confidently diagnose a haemolytic process:
- Anaemia (↓Hb)
- ↑Reticulocyte count (compensatory)
- ↑LDH
- ↑Unconjugated bilirubin
- ↓Haptoglobin
If all 5 are present, haemolysis is virtually certain. If only 1 or 2 are abnormal, consider other diagnoses or early/compensated haemolysis.
Once haemolysis is confirmed, the algorithm branches based on DAT (Direct Coombs Test) → then blood film morphology → then targeted investigations.
After confirming a patient has haemolysis, the next step to determine whether the patient is undergoing autoimmune-mediated destruction is the Direct Antiglobulin Test [11].
Recall that some portion of the healthy population will have positive DAT but no haemolysis, so you can't blindly do this test for everyone — the pre-test probability must be good, must ensure that patient has a form of haemolysis first [11].
Investigation Modalities: Detailed Guide
Tier 1: Initial Investigations (Order for Every Suspected Haemolysis Case)
| Parameter | Expected Finding | Interpretation |
|---|---|---|
| Haemoglobin | ↓ (variable severity) | Degree depends on rate of destruction vs. marrow compensation |
| MCV | Normal or mildly macrocytic | Reticulocytes are larger → drag up MCV [11]. However, MCV can be ↓ if thalassaemia or HS; or ↑ if concurrent B12/folate deficiency. MCV can be N/↓/↑ depending on amount of reticulocytes (↑MCV) and spherocytes (↓MCV) [15] |
| MCHC | ↑ in HS (≥ 36 g/dL) | Spherocytes have lost membrane surface area but retained Hb → concentrated. MCHC ≥ 36 g/dL is a hallmark of hereditary spherocytosis [3][16] |
| RDW | Usually ↑ | Mixed population of reticulocytes + mature RBCs → increased variation in size |
| Reticulocyte count | ↑↑ (> 2%, often > 5%) | Compensatory erythroid hyperplasia: retics > 2%, polychromasia and nucleated RBC on PBS [15]. If retics are LOW in the setting of haemolysis → aplastic crisis (parvovirus B19) or marrow failure |
| WBC, platelets | Variable | ↓Platelets → TTP/HUS, DIC, Evans syndrome, hypersplenism. ↑WBC → infection. Pancytopenia → PNH with marrow failure, hypersplenism |
Blood film findings in haemolytic anaemia [1][14]:
- Polychromasia — reticulocytes (blue-grey staining due to residual RNA)
- Spherocytes — hereditary spherocytosis, warm AIHA
- RBC fragmentation — microangiopathic haemolysis (TTP/HUS/DIC)
- RBC agglutination — cold agglutinin disease
| Morphology | Condition Implied | Why This Shape? |
|---|---|---|
| Spherocytes (small, dense, no central pallor) | HS, warm AIHA, Wilson's | Loss of membrane → ↓surface area:volume ratio → sphere |
| Schistocytes (fragmented cells, helmet cells) | MAHA — TTP, HUS, DIC, prosthetic valve | Fibrin strands in damaged microvasculature shear RBCs |
| Bite cells | G6PD deficiency | Splenic macrophages "bite out" Heinz body inclusions |
| Heinz bodies (supravital stain: crystal violet) | G6PD deficiency, unstable Hb (Hb Köln) | Precipitated denatured Hb from oxidative damage |
| Target cells | Thalassaemia, HbC, liver disease, post-splenectomy | Relative excess of membrane to Hb content → central pallor with central dot of Hb |
| Sickle cells (crescent/sickle) | Sickle cell disease | HbS polymerises when deoxygenated → rigid polymers distort cell |
| Elliptocytes | Hereditary elliptocytosis | Defective spectrin self-association → permanent elliptical deformation |
| Agglutination (clumps of RBCs) | Cold agglutinin disease | IgM cross-links RBCs at cold temperatures. Spuriously ↑MCV on automated counter |
| Nucleated RBCs | Severe haemolysis, extramedullary haematopoiesis | Premature release from stressed marrow [17] |
| Basophilic stippling | Thalassaemia, lead poisoning | Aggregates of ribosomes (residual RNA) |
| Howell-Jolly bodies | Post-splenectomy, hyposplenism | Nuclear remnants not removed by spleen |
| HbH inclusions (brilliant cresyl blue: "golf-ball") | HbH disease | β₄ tetramers precipitate with supravital staining |
| Test | Expected | Notes |
|---|---|---|
| Unconjugated bilirubin | ↑ | Fractionation essential — total bilirubin alone is insufficient |
| LDH | ↑ | Most readily available marker. The immediate parameter to differentiate haemolysis [11] |
| Serum haptoglobin | ↓ or absent | Most sensitive for intravascular haemolysis. Remember: 1:1000 Chinese have haptoglobin deficiency [13] — a baseline value is useful before interpreting |
| Methaemalbumin | ↑ (intravascular) | Detected by Schumm's test; indicates haptoglobin-saturating levels of free Hb [13] |
| Test | Finding | Significance |
|---|---|---|
| Dipstick for blood | Positive | In haemoglobinuria: dipstick positive but microscopy shows NO red cells (because it's free Hb, not intact RBCs). Also positive in myoglobinuria — distinguished by clinical context and CK |
| Urine haemosiderin | Prussian blue positive | Chronic intravascular haemolysis — haemosiderin-laden renal tubular cells shed into urine |
| Urine urobilinogen | ↑ | ↑Bilirubin → ↑gut conversion → ↑enterohepatic reabsorption |
| Urine colour | Coca-cola (haemoglobinuria); normal (extravascular) | No tea-coloured urine in haemolysis — that suggests obstructive/hepatocellular jaundice [1][11] |
Tier 2: Establishing the Mechanism — The Key Branching Investigation
This is the pivotal branching point in the algorithm.
Principle: The patient's washed RBCs are incubated with anti-human globulin reagent (Coombs reagent). If IgG or C3d is already bound to the RBC surface, the reagent will cause visible agglutination.
Direct antiglobulin test — positive in immune haemolytic anaemia [1][14]
| DAT Result | Interpretation | Next Steps |
|---|---|---|
| Positive: IgG ± C3d | Warm AIHA (IgG autoantibody at 37°C) | Screen for secondary causes: SLE (ANA, anti-dsDNA), CLL (flow cytometry), lymphoma (CT), drugs (methyldopa, penicillin) [15] |
| Positive: C3d only | Cold AIHA / Cold Agglutinin Disease (IgM dissociates at 37°C during wash, but C3d remains) | Cold agglutinin titre; screen for Mycoplasma (serology, cold agglutinins), EBV (Paul-Bunnell/monospot), lymphoma [15] |
| Positive: IgG + C3d | Mixed pattern — can be warm AIHA or drug-induced | Correlate with drug history; consider mixed AIHA |
| Negative | Non-immune haemolysis OR: low-level antibody below detection, PNH, hereditary causes | Proceed to blood film morphology and targeted investigations |
GC Lecture Case: Classic Warm AIHA Presentation
A thirty-five year old woman presents with symptoms of anaemia. Investigations show: Haemoglobin 7.5 g/dL, WCC 9.5 × 10⁹/L, Platelet 200 × 10⁹/L, Peripheral blood: spherocytes ++, Reticulocyte count: 10%, Total bilirubin: 55 μmol/L, LDH: 950 IU/L, Direct antiglobulin test: positive for immunoglobulin G and complement [14]
This is the classic exam case for warm AIHA: anaemia + spherocytes + high retics + high bilirubin + high LDH + DAT positive for IgG and complement. The next step would be to identify the cause (primary vs. secondary).
- Detects free antibodies in the patient's serum (not bound to RBCs)
- Used in: pre-transfusion crossmatch ("type and screen"), identifying alloantibodies (e.g., anti-D, anti-Kell)
- Relevant in: delayed haemolytic transfusion reactions, HDN workup
Tier 3: Targeted Investigations — Based on Suspected Cause
| Investigation | Finding | Notes |
|---|---|---|
| Flow cytometry: ↓Eosin-5-Maleimide (EMA) binding | ↓EMA binding on RBC membrane proteins | EMA binds to band 3 and related proteins; reduced binding = reduced membrane protein content = spherocytosis. This is the preferred diagnostic test [3][15][16] |
| Osmotic fragility test (± pre-incubation at 37°C for 24h) | ↑Fragility compared to normal RBCs in hypotonic solutions | Pre-incubation at 37°C for 24h increases diagnostic yield. Low sensitivity/specificity compared to flow cytometry — use when EMA binding is not available [3][16] |
| SDS-PAGE of membrane proteins | Identifies specific protein deficiency (spectrin, ankyrin, band 3, protein 4.2) | Research/specialised labs; not routine |
| Family screening | CBC + blood film of family members | AD inheritance in 75%; 25% sporadic |
| Investigation | Finding | Notes |
|---|---|---|
| Blood film | Bite cells, Heinz bodies (supravital stain) [15] | Heinz bodies = precipitated denatured Hb |
| G6PD enzyme assay | Reduced enzyme activity | May be normal during acute haemolysis — reticulocytes have higher G6PD activity → falsely normal result. Repeat after recovery (2–3 months) [15] |
| Methaemoglobin reductase assay | If considering other causes of oxidative haemolysis |
| Investigation | Finding | Notes |
|---|---|---|
| Hb electrophoresis / HPLC | Identifies abnormal Hb variants (HbS, HbC, HbH, HbE) and quantifies HbA₂, HbF | HbA₂ > 3.5% → β-thalassaemia trait. HbH band (fast-moving) → HbH disease |
| HbH inclusions (brilliant cresyl blue stain) | Golf-ball appearance | Specific for HbH disease [3] |
| DNA analysis / genetic testing | α-globin gene deletions (MLPA, gap-PCR), β-globin mutations | Definitive for thalassaemia genotyping; essential for genetic counselling and prenatal diagnosis [3] |
| Iron studies | Thalassaemia trait: normal serum iron, normal TIBC, normal transferrin saturation. IDA: ↓serum iron, ↑TIBC, ↓transferrin saturation [3] | Critical to differentiate these two common causes of hypochromic microcytic anaemia in HK |
| Ferritin | Normal or ↑ in thalassaemia (iron loading); ↓ in IDA | Ferritin is a surrogate marker for iron stores. In thalassaemia intermedia, risk of iron overload from ↑absorption due to ineffective erythropoiesis ± transfusions [3] |
High Yield: Differentiating Thalassaemia Trait from IDA in Hong Kong
Both are the two most common causes of hypochromic microcytic anaemia in our locality [3][14a]:
| Feature | Thalassaemia Trait | Iron Deficiency Anaemia |
|---|---|---|
| Haemoglobin | 10–13 g/dL | Any level |
| RBC count | Normal or increased | Decreased |
| MCV | ↓ but usually not < 65 fL | Any level |
| Serum iron | Normal | Decreased |
| TIBC | Normal | Increased |
| % transferrin saturation | Normal | Decreased |
| RDW | Usually normal (uniform microcytes) | ↑ (variable cell sizes) |
| HbA₂ | ↑ > 3.5% (β-thal trait) | Normal or ↓ |
| Investigation | Finding | Purpose |
|---|---|---|
| DAT (already done) | Positive IgG ± C3d (warm) or C3d only (cold) | Confirms immune mechanism [1][14] |
| Cold agglutinin titre | ↑ (> 1:64 significant, > 1:512 highly significant) | For cold AIHA — titre correlates with clinical severity |
| Thermal amplitude testing | Determines the temperature range at which the antibody is active | Higher thermal amplitude (closer to 37°C) → more clinically significant |
| ANA, anti-dsDNA | Positive in SLE | Screen for secondary warm AIHA |
| Flow cytometry for lymphocyte markers | Clonal B-cell population (e.g., CD5+, CD23+) | Screen for CLL (common cause of secondary warm AIHA) |
| CT chest/abdomen/pelvis | Lymphadenopathy, splenomegaly | Screen for lymphoma |
| Serology | Mycoplasma IgM, EBV (VCA IgM, monospot) | Secondary cold AIHA |
| Investigation | Finding | Notes |
|---|---|---|
| Flow cytometry on peripheral blood | Deficiency of GPI-anchored proteins including CD55 and CD59 on RBCs and granulocytes | MOST useful and accepted method to confirm diagnosis of PNH [18]. Identifies the PNH clone size. Also tests granulocytes (more reliable than RBCs because transfused RBCs can dilute the PNH clone) |
| FLAER (fluorescent aerolysin) | Binds directly to GPI anchors — absent on PNH granulocytes/monocytes | More sensitive than CD55/CD59 for small PNH clones; does not work on RBCs |
| Urine haemosiderin | Positive | Chronic intravascular haemolysis |
| LDH, haptoglobin, reticulocytes | Classic haemolysis pattern | Monitor disease activity |
| BM biopsy | May show hypocellularity | To assess for concurrent aplastic anaemia (PNH-AA overlap syndrome) |
When to Screen for PNH
Screen for PNH in all patients with: [18]
- Unexplained Coombs-negative intravascular haemolysis
- Aplastic anaemia (overlap syndrome)
- Unexplained thrombosis at unusual sites (hepatic vein → Budd-Chiari, cerebral venous sinuses)
- Unexplained cytopenias with haemolysis
| Investigation | Finding | Purpose |
|---|---|---|
| Blood film | Schistocytes (fragmented RBCs) [1][14][17] | Confirms MAHA |
| Platelet count | ↓↓ | Platelets consumed in microthrombi |
| Coagulation profile (PT, APTT, fibrinogen, D-dimer) | Normal in TTP; Abnormal in DIC (prolonged PT/APTT, ↓fibrinogen, ↑D-dimer) | Key differentiator between TTP and DIC [17] |
| ADAMTS13 activity | < 10% = diagnostic of TTP | Severely reduced ADAMTS13 activity < 10% during an acute episode is a hallmark of acquired TTP [17] |
| ADAMTS13 inhibitor | Presence of autoantibodies against ADAMTS13 [17] | Confirms acquired (autoimmune) TTP vs. congenital (hereditary ADAMTS13 deficiency) |
| RFT (serum creatinine) | ↑ in HUS (predominant renal involvement); mildly ↑ in TTP | |
| Stool culture / Shiga toxin PCR | Positive for E. coli O157:H7 in typical HUS | |
| Pregnancy test, LFT | For HELLP syndrome exclusion | Hemolysis, Elevated Liver enzymes, Low Platelets |
Investigations for delayed haemolytic transfusion reaction [13]:
- CBP, reticulocyte count, manual film
- Haptoglobin, methaemalbumin, direct/indirect bilirubin, LDH
- Direct antiglobulin test, Indirect antiglobulin test
- Extended red cell phenotype (of pre-transfusion sample)
For acute haemolytic transfusion reaction (ABO incompatibility):
- Stop transfusion immediately
- Check patient identity against the blood product label
- Blood bank: repeat ABO group and crossmatch on pre- and post-transfusion samples
- Urine: inspect for haemoglobinuria (coca-cola urine)
- Blood cultures (to exclude bacterial contamination)
| Investigation | Organism | Notes |
|---|---|---|
| Thick and thin blood film | Plasmodium spp. (malaria) | Thick film = screening (higher sensitivity); thin film = species identification. TOCC (travel, occupation, contact, clustering) is essential |
| Rapid diagnostic test (RDT) | Malaria antigen | Quick bedside test; less sensitive than microscopy for low parasitaemia |
| Blood cultures | C. perfringens, other bacteria | If septic + haemolysis |
| Mycoplasma serology | Mycoplasma pneumoniae | Cold agglutinins; atypical pneumonia |
| EBV serology (VCA IgM, monospot) | EBV | Infectious mononucleosis + cold AIHA |
Fulminant hepatic failure due to Wilson's has a very specific feature: young patients with no reason for fulminant liver failure, exclusion of all other common causes → only finding is low haemoglobin → Coombs-negative haemolytic anaemia [7]
| Investigation | Finding | Notes |
|---|---|---|
| Serum caeruloplasmin | ↓ | Copper-carrying protein; low in Wilson's |
| 24h urine copper | ↑ | Increased renal copper excretion |
| Slit-lamp examination | Kayser-Fleischer rings | Copper deposition in Descemet's membrane |
| Liver biopsy (hepatic copper content) | ↑↑ | Gold standard for tissue copper quantification |
| Genetic testing (ATP7B) | Mutations identified | Genetic test does not have to be positive to reach a diagnosis — with compatible clinical and history, you can still diagnose. Wilson's hereditary pathway is very heterogeneous [7] |
Bone marrow aspiration and trephine biopsy is NOT routinely needed to confirm haemolysis or diagnose its cause. It is reserved for specific situations:
| Indication | What You're Looking For |
|---|---|
| Suspected aplastic anaemia / PNH overlap | Hypocellular marrow, fat replacement, no malignant infiltration [16][18] |
| Suspected marrow infiltration | Leukaemia, lymphoma, myeloma, myelofibrosis, metastatic carcinoma |
| Suspected MDS | Dysplastic features, ring sideroblasts, cytogenetics |
| Unexplained pancytopenia | To differentiate aplastic anaemia from hypocellular MDS |
| Suspected megaloblastic anaemia with atypical features | If doesn't respond to B12/folate replacement → consider MDS |
| Assess erythropoietic response | Erythroid hyperplasia with ↓M:E ratio confirms marrow compensation |
| Suspected pure red cell aplasia | Absent erythroid precursors; may see giant pronormoblasts (parvovirus B19) |
| Tier | Investigations | Purpose |
|---|---|---|
| Tier 1 (All patients) | CBC + retics, PBS, LDH, unconjugated bilirubin, haptoglobin, urinalysis | Confirm haemolysis; initial morphological clues |
| Tier 2 (Branching) | DAT (Direct Coombs) | Immune vs. non-immune |
| Tier 3 (Targeted) | EMA / osmotic fragility (HS); G6PD assay; Hb electrophoresis; cold agglutinin titre; flow cytometry for CD55/CD59 (PNH); ADAMTS13 (TTP); coagulation profile (DIC); malaria film; Wilson's workup | Specific aetiological diagnosis |
| Tier 4 (Selected) | Bone marrow aspiration + trephine | Aplastic anaemia, MDS, infiltration, unexplained pancytopenia |
High Yield Summary — Diagnostics
- Confirm haemolysis with: ↑reticulocytes + ↑LDH + ↑unconjugated bilirubin + ↓haptoglobin + polychromasia on film
- DAT is the pivotal test: Positive = immune; Negative = non-immune
- Blood film morphology guides targeted Ix: spherocytes → HS/AIHA; schistocytes → MAHA; bite cells → G6PD; agglutination → cold AIHA
- PNH diagnosis: Flow cytometry for CD55/CD59 (replaces Ham's test)
- TTP vs DIC: Clotting profile normal in TTP; abnormal in DIC. ADAMTS13 < 10% = TTP
- G6PD testing trap: Don't test during crisis — wait 2–3 months
- HS diagnosis: EMA binding (preferred) > osmotic fragility test
- Haptoglobin caveats: 1:1000 Chinese have congenital deficiency; positive acute-phase reactant can mask ↓ in inflammation
- Thalassaemia vs IDA (HK high yield): Iron studies, RDW, HbA₂ are key discriminators
Active Recall - Diagnostics of Hemolytic Anaemia
References
[1] Lecture slides: GC 047. Family history of anaemia.pdf (Laboratory features of haemolytic anaemia, blood film findings, DAT) [3] Senior notes: Block A - Many members of the family have anaemia.pdf (Thalassaemia trait vs IDA table, HbH, Hb Köln, haemoglobinopathy triggers) [7] Senior notes: Block A - Patients with non-viral chronic liver diseases.pdf (Wilson's disease, Coombs-negative HA, genetic testing) [11] Senior notes: Block A - Family history of anaemia_ inherited causes of anaemia; haemolytic anaemia; aplastic anaemia.pdf (Clinical features, lab features, DAT algorithm, LDH as immediate parameter) [13] Senior notes: Block A - Fever after a blood transfusion_ transfusion and related problems.pdf (Delayed haemolytic transfusion reaction investigations, haptoglobin deficiency in Chinese, methaemalbumin) [14] Lecture slides: Haematology Introduction to Haematological investigations (CBP, Clotting).pdf (Haemolytic anaemia lab features, blood film findings, DAT, Case 6 warm AIHA) [15] Senior notes: Maksim Medicine Notes.pdf (Haemolytic anaemia overview, AIHA warm/cold, G6PD, HS investigation tables) [16] Senior notes: Ryan Ho Haemtology.pdf (Hereditary spherocytosis diagnosis — EMA, osmotic fragility, MCHC) [17] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (TTP diagnosis — ADAMTS13, schistocytes, clotting profile normal, nucleated RBCs) [18] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (PNH — flow cytometry CD55/CD59, aplastic anaemia exclusion)
Management of Hemolytic Anaemia
The management of hemolytic anaemia follows a logical, layered approach. Think of it as addressing three questions simultaneously:
- Is the patient haemodynamically stable? → Resuscitation and supportive care first
- Can I stop the destruction? → Remove the cause or suppress the mechanism
- Can I support the system while it recovers? → Transfusion, folate, monitoring for complications
The specific treatment depends entirely on the underlying cause — there is no single "treatment for haemolysis." However, certain principles are universal across all causes.
Universal Management Principles (All Causes)
These apply regardless of aetiology:
Folate supplementation is generally recommended for any form of haemolysis — replenish the raw material [11]
- Why: Chronic haemolysis → ↑RBC turnover → ↑folate demand for DNA synthesis during compensatory erythropoiesis. If folate stores are depleted, the marrow cannot mount an adequate reticulocyte response → megaloblastic crisis superimposed on haemolysis
- Dose: Folic acid 1–2 mg/day for moderate/severe haemolysis; 5 mg/day if pregnant [3][16]
- Exception: Once a patient is on regular transfusion (e.g., thalassaemia major on hypertransfusion), folate supplementation is NOT required — because the marrow is suppressed and not actively producing RBCs [19]
Transfusion if necessary [11] — indicated for:
- Symptomatic anaemia (dyspnoea, chest pain, haemodynamic compromise)
- Critically low Hb (especially acute drops)
- Aplastic crisis (parvovirus B19) where reticulocytes are absent
Transfusion considerations in haemolytic anaemia:
- In warm AIHA, crossmatching is extremely difficult because the autoantibody reacts with virtually all donor RBCs → the blood bank must find the "least incompatible" unit. Transfusion should NOT be withheld in life-threatening anaemia just because of crossmatch difficulty — transfuse and accept some additional haemolysis
- In thalassaemia major, use pre-filtered products that are leukocyte-depleted and matched for at least D, C, c, E, e and Kell antigens to minimize WBC-induced febrile reaction [19]
- In cold AIHA, use pre-warmed IV fluids and a blood warmer during transfusion [15]
- Pre-medications for transfusion: IV/PO chlorpheniramine 30 mins before transfusion; IV furosemide at the start of transfusion [19]
- AKI from free Hb nephrotoxicity (intravascular haemolysis) → monitor RFT, ensure adequate hydration, aggressive fluid resuscitation [13]
- Pigment gallstones → USS abdomen; cholecystectomy if symptomatic
- Aplastic crisis → if sudden severe drop in Hb with absent reticulocytes, test for parvovirus B19
- Iron overload (transfusion-dependent patients) → monitor ferritin, start chelation when indicated
Cause-Specific Management
A. Autoimmune Haemolytic Anaemia (AIHA)
The 4 principles of treatment in AIHA [11]:
- Transfusion if necessary
- Folate supplementation
- Decrease further haemolysis:
- Steroids/immunosuppression in WARM AIHA
- Avoidance of certain drugs in drug-induced haemolytic anaemia
- Keep warm in cold haemagglutinin disease
- Splenectomy
- Treat the underlying cause if present → i.e., AIHA due to underlying lymphoproliferative disorders
| Line | Treatment | Mechanism | Notes |
|---|---|---|---|
| 1st line | Corticosteroids (oral prednisolone 1 mg/kg/day) | Suppress autoantibody production; reduce Fc receptor expression on splenic macrophages → ↓phagocytosis of antibody-coated RBCs | Response rate ~80%. Taper gradually over weeks–months once Hb stabilises. Do NOT stop abruptly — risk of rebound haemolysis and adrenal crisis [15] |
| 2nd line | Rituximab (anti-CD20 monoclonal antibody) | Depletes B-lymphocytes → ↓autoantibody production | Used for steroid-refractory or steroid-dependent patients. Increasingly used as early 2nd line. Response rate ~80% |
| 2nd line | IVIG | Blocks Fc receptors on splenic macrophages → ↓phagocytosis; also modulates complement | Rapid but temporary effect. Useful as a bridge in severe, acute haemolysis |
| 2nd line | Splenectomy | Removes the primary site of extravascular haemolysis (splenic macrophages phagocytose IgG-coated RBCs) | Refractory AIHA [6]. Response rate ~60–70%. Must vaccinate pre-splenectomy (see below) |
| 3rd line | Azathioprine, cyclophosphamide, mycophenolate mofetil (MMF) | Broader immunosuppression | For refractory cases after steroids + rituximab ± splenectomy [15] |
Important: Evans Syndrome
Evans syndrome = warm AIHA + ITP [15]. Both are autoimmune cytopenias. Management is similar (steroids → rituximab → splenectomy) but more refractory. Must also screen for underlying SLE or CVID.
Primary chronic cold agglutinin disease has been considered more difficult to treat than warm AIHA. This is because of the lack of efficacy of therapy with corticosteroids or other non-specific immunosuppressive agents in cold AIHA [11]
| Treatment | Mechanism | Notes |
|---|---|---|
| Avoid cold exposure | IgM binds RBCs in cold peripheral circulation → preventing cold exposure reduces antibody binding | First-line non-pharmacological measure. Pre-warmed IV fluids during hospitalisation [15] |
| Rituximab | Depletes the clonal B-cells producing pathological IgM cold agglutinin | First-line pharmacological therapy for CAD. Corticosteroids are NOT effective in cold AIHA (unlike warm AIHA) |
| Rituximab + bendamustine | Combination chemo-immunotherapy for refractory CAD | Higher response rates than rituximab alone |
| Sutimlimab (anti-C1s) | Inhibits the classical complement pathway at C1s → blocks complement-mediated haemolysis | FDA-approved 2022 for CAD. Specifically targets the complement pathway without broad immunosuppression |
| Plasmapheresis / IVIG | Removes circulating IgM (which is mostly intravascular due to large molecular size) | Useful for acute severe haemolysis as a temporising measure [15] |
| Splenectomy | Generally NOT effective in cold AIHA | Because hepatic macrophages (not splenic) are the primary clearance site for C3b-coated RBCs in cold AIHA |
Why Steroids Don't Work in Cold AIHA
In warm AIHA, steroids reduce Fc receptor expression on splenic macrophages (reducing IgG-mediated phagocytosis) and suppress autoantibody production. In cold AIHA, destruction is primarily complement-mediated (C3b → hepatic macrophages) and the pathological IgM is produced by a clonal B-cell population that is relatively steroid-resistant. Hence the emphasis on rituximab (anti-B cell) and complement inhibitors.
- Stop and avoid the offending agent — this is the most important step [11]
- Haemolysis usually resolves within days–weeks of drug cessation
- Supportive care: folate, transfusion if needed
- Steroids may be used if methyldopa-induced (autoantibody type persists longer)
Hereditary Spherocytosis (HS)
No specific treatment can target the underlying membrane defect [3][16]
| Treatment | Details | Rationale |
|---|---|---|
| Folic acid supplementation | 1–2 mg/day; 5 mg/day if pregnant | Compensate for ↑folate requirement from chronic haemolysis [3][16] |
| Transfusion | If severe anaemia | Particularly during aplastic crisis (parvovirus B19) or haemolytic crisis |
| EPO | May be useful in some infants < 9 months to ↓transfusion requirement [3][16] | Bridge before spleen matures |
| Splenectomy | At > 6–7 years old for severe haemolysis | Indications: transfusion-dependence or severely symptomatic anaemia beyond 1 year. Timing: usually deferred till > 6–7 years to ↓risk of sepsis [3][16] |
| Cholecystectomy | If symptomatic pigment gallstones | Can be done concurrently with splenectomy. 50% of adult HS patients develop pigmented gallstones [16] |
| Allogeneic HSCT | NOT used due to unfavourable risk-benefit ratio [3][16] | Risk of GVHD and transplant mortality outweighs benefit in a condition manageable with splenectomy |
Why splenectomy works in HS: The spleen is where spherocytes are trapped and destroyed. Removing the spleen eliminates the primary site of extravascular haemolysis → Hb normalises (though spherocytes persist on the blood film). The cells are still abnormal — they just have nowhere to be destroyed.
C. Enzyme Defects
Treatment for G6PD deficiency [11]:
- Supportive
- Blood transfusion
- Folic acid → as in any cause of haemolysis
- Stop and avoid offending agents
| Treatment | Details |
|---|---|
| Avoidance of triggers | Avoid drugs: anti-malarials (primaquine), analgesics, dapsone, nitrofurantoin, quinolones, sulfonamides (e.g., Septrin) [15]. Avoid mothballs (naphthalene), fava beans [15] |
| Supportive during acute crisis | IV fluids, transfusion if Hb critically low, monitor for AKI (intravascular haemolysis → haemoglobinuria → ATN) |
| Folate supplementation | For any chronic or recurrent haemolysis |
| Patient education | Provide list of drugs/foods to avoid; MedicAlert bracelet; inform all prescribers |
| Neonatal management | Phototherapy ± exchange transfusion for neonatal jaundice; all newborns screened in HK |
Key point: G6PD deficiency does NOT require splenectomy (unlike HS). Why? Because acute G6PD crises are self-limiting — only the older, G6PD-depleted RBCs are destroyed. The younger reticulocytes have sufficient G6PD to survive. Once the trigger is removed, the haemolysis stops spontaneously.
| Treatment | Details |
|---|---|
| Folate supplementation | Chronic haemolysis → ↑folate requirement |
| Transfusion ± iron chelation | For severe anaemia; monitor for transfusional iron overload [16] |
| Splenectomy | More effective than in G6PD deficiency because PK deficiency causes chronic extravascular haemolysis in the spleen. Reduces anaemia severity and transfusion requirement |
| Mitapivat (2022 approval) | Oral allosteric activator of pyruvate kinase → increases PK enzyme activity even in the mutant enzyme → ↑ATP production → ↓haemolysis. First targeted therapy for PK deficiency |
D. Thalassaemia
| Treatment | Details | Rationale |
|---|---|---|
| Regular transfusion (hypertransfusion) | Maintain pre-transfusion Hb 9.5–10.5 g/dL; post-transfusion Hb 14 g/dL (to suppress BM hyperactivity). Avoid post-transfusion Hb > 15 g/dL due to increased risk of viscosity and thrombosis [19] | Suppress ineffective erythropoiesis → ↓marrow expansion → ↓bony deformities, ↓extramedullary haematopoiesis, ↓iron absorption |
| Iron chelation therapy | Start when: ≥ 3 years old, serum ferritin > 2000 ng/mL, or transfused > 20 units. Target ferritin 1000–2000 ng/mL [16][19] | Prevent iron overload from chronic transfusions → iron deposits in heart (cardiomyopathy), liver (cirrhosis), endocrine organs (DM, hypothyroidism, hypogonadism) |
| Folate supplementation | For thal intermedia with chronic haemolysis. NOT required once on regular transfusion | Marrow suppressed by hypertransfusion → no ↑folate demand [16][19] |
| Low iron diet | Avoid red meat, spinach [16] | Reduce dietary iron absorption |
| Splenectomy | Generally deferred till ≥ 4 years. Indications: ↑transfusion requirement or cytopenias due to hypersplenism; symptomatic splenomegaly [16] | ↓Anaemia, ↓transfusion requirement (and therefore ↓iron overload) |
| Allogeneic HSCT | Potentially curative but NOT gold standard yet. Considerations: need HLA-matched sibling (not common in HK); ↑rejection risk due to hyperplastic BM; GVHD risk [16] | Only curative option. Reserved for severe disease with matched donors |
| Luspatercept (SC) | Newly approved for β-thal major (2019) [16] | Modified activin receptor IIA ligand trap → promotes late-stage erythroid maturation → ↓transfusion burden |
| Agent | Route | Key Features | Side Effects |
|---|---|---|---|
| Deferoxamine (Desferal) | SC/IV | Most studied iron chelator with excellent safety and efficacy. SC 5–6 days/week, 20–50 mg/kg/day. Give Vitamin C to augment renal excretion of chelated iron but do NOT give without Desferal — it will increase iron absorption in the gut alone [19] | Ototoxicity, retinal damage, bone dysplasia with truncal shortening [19] |
| Deferiprone | PO | Good cardiac iron removal; can be combined with deferoxamine | Agranulocytosis (idiosyncratic — monitor FBC), arthropathy, GI upset |
| Deferasirox (Exjade) | PO | Once-daily oral tablet; convenient | Nephrotoxicity, hepatotoxicity, GI upset; requires monitoring of RFT/LFT |
Monitoring of iron overload: serum ferritin is useful as a screening tool but may be inaccurate in predicting quantitative iron stores. Quantitative liver iron and cardiac iron measurement by MRI is the standard indicator of total-body iron stores [19]
| Treatment | Mechanism | Notes |
|---|---|---|
| Eculizumab (anti-C5 mAb) | Binds C5 → prevents cleavage to C5a + C5b → blocks formation of the membrane attack complex (MAC, C5b-9) → stops complement-mediated intravascular haemolysis | First-in-class; given IV Q2 weeks. Dramatically reduces haemolysis, transfusion requirements, and thrombotic risk. Must vaccinate against meningococcus (Neisseria meningitidis) before starting — terminal complement inhibition increases risk of meningococcal infection |
| Ravulizumab (next-gen anti-C5) | Same mechanism as eculizumab but engineered for longer half-life | Given IV Q8 weeks — better convenience |
| Iptacopan (oral factor B inhibitor) | Inhibits alternative complement pathway at factor B → prevents C3 opsonisation (addresses both intravascular and extravascular haemolysis) | 2023 approval. Oral agent; addresses residual extravascular haemolysis seen with C5 inhibitors |
| Danicopan (oral factor D inhibitor) | Inhibits factor D of alternative pathway → ↓C3 convertase activity | Used as add-on to C5 inhibitors |
| Supportive | Folate supplementation; iron supplementation (if intravascular haemolysis → iron lost via haemoglobinuria/haemosiderinuria); anticoagulation for thrombosis; transfusion PRN | PNH patients can become iron-deficient despite haemolysis — because iron is lost in urine |
| HSCT | Only curative option; reserved for severe PNH with bone marrow failure or refractory disease | Same principles as HSCT for aplastic anaemia — allogeneic HSCT is an indication for aplastic anaemia (which overlaps with PNH) [11][20] |
F. Microangiopathic Haemolytic Anaemia (MAHA)
| Treatment | Mechanism | Notes |
|---|---|---|
| Therapeutic plasma exchange (TPE) | Removes autoantibodies against ADAMTS13 and ultra-large vWF multimers; replaces functional ADAMTS13 | Must be started urgently — TTP is a medical emergency with > 90% mortality if untreated. Daily until platelet normalisation |
| Corticosteroids | Suppress autoantibody production | Given concurrently with TPE |
| Caplacizumab (anti-vWF nanobody) | Blocks interaction between vWF and platelet GPIb → prevents platelet microthrombus formation | 2019 approval. Reduces time to platelet recovery and recurrence risk. Given alongside TPE + steroids |
| Rituximab | Depletes B-cells producing anti-ADAMTS13 autoantibodies | For refractory or relapsing TTP |
- Typical (Shiga toxin-associated) HUS: Mainly supportive — IV fluids, electrolyte management, dialysis if needed. Do NOT give antibiotics for E. coli O157:H7 diarrhoea — may increase Shiga toxin release and worsen HUS
- Atypical HUS (complement-mediated): Eculizumab (anti-C5) — targets uncontrolled complement activation that causes endothelial damage
- Treat the underlying cause (sepsis, malignancy, obstetric emergency) — this is the most important intervention
- Supportive: transfusion with platelets, FFP, cryoprecipitate [20]
- Anticoagulation (heparin) only in specific situations (e.g., chronic DIC with thrombotic predominance)
G. Transfusion Reactions
Management [13]:
- Stop the transfusion
- Intensive care often indicated — consult ICU
- Aggressive fluid resuscitation
- Alkaline diuresis — maintain urine pH > 6.5 to prevent haem precipitation in renal tubules
- Dopamine infusion to preserve renal perfusion (low dose for renal vasodilation) [13]
- Verify patient identity and blood product compatibility
- Send remaining blood product and patient samples to blood bank
Cannot shift blame — ABO-incompatible transfusion will always be a medical error → can be FATAL [13]
- Always do type and screen properly
- Always give group-specific blood
- Bedside identity check before every transfusion
H. Splenectomy — Shared Considerations
Splenectomy is relevant in multiple haemolytic anaemias. Whenever splenectomy is considered, the following principles apply:
- Refractory ITP or AIHA (less common)
- Decrease transfusion requirement in thalassaemia major (but try to delay in children)
- Hereditary spherocytosis — severe disease with transfusion-dependence
- Pyruvate kinase deficiency — chronic extravascular haemolysis
- Symptomatic relief in massive splenomegaly (e.g., myelofibrosis)
Post-splenectomy patients are at risk of life-threatening infection from encapsulated bacteria → overwhelming post-splenectomy infection (OPSI) [6][21]
| Measure | Details |
|---|---|
| Vaccination (at least 2 weeks before elective splenectomy) | Pneumococcal (PCV13 + PPSV23), Meningococcal (MenACWY + MenB), Haemophilus influenzae type b (Hib) |
| Post-splenectomy prophylactic antibiotics | Oral penicillin V daily — lifelong (or at least 5 years post-splenectomy, lifelong in children). Alternative: amoxicillin |
| Patient education | MedicAlert bracelet; seek urgent medical attention with any fever; carry standby antibiotics for travel |
| Annual influenza vaccination | ↓Risk of secondary bacterial pneumonia |
Features that may appear alarming on CBC but are consequences of splenectomy:
- Spurious leukocytosis — WBCs no longer pooled in spleen
- Increase in platelet counts — platelets no longer sequestered (risk of thrombosis, especially portal vein)
- Howell-Jolly bodies on PBS — nuclear remnants no longer removed by splenic macrophages
- Target cells, acanthocytes may appear
Penicillamine causes worsened neurological symptoms in the first few days — patient is used to copper in brain; once penicillamine is given, they lose copper, the body is not used to it, may exacerbate neurological symptoms [7]
| Treatment | Mechanism | Notes |
|---|---|---|
| D-Penicillamine | Copper chelation → promotes urinary copper excretion | First-line; start at low dose and increase gradually. Monitor FBC (risk of aplastic anaemia), urinalysis (proteinuria) |
| Trientine | Alternative copper chelator | Used if penicillamine intolerant |
| Zinc acetate | Blocks intestinal copper absorption by inducing metallothionein in enterocytes | Used for maintenance therapy |
| Liver transplant | Definitive cure for hepatic Wilson's | Indicated for fulminant liver failure or decompensated cirrhosis unresponsive to medical therapy |
For the acute haemolytic crisis in Wilson's: supportive (transfusion, dialysis if AKI), urgent liver transplant assessment.
| Cause | Treatment | Notes |
|---|---|---|
| Malaria | Antimalarials based on species and severity: artesunate (severe P. falciparum), ACTs (uncomplicated P. falciparum), chloroquine (P. vivax/ovale) + primaquine for radical cure | Must check G6PD status before giving primaquine (oxidant drug → can trigger G6PD crisis) |
| C. perfringens | High-dose IV penicillin + clindamycin ± surgical debridement | Gas gangrene with haemolysis is a surgical + medical emergency |
| Condition | Key Treatment | What NOT to Do |
|---|---|---|
| Warm AIHA | Steroids → rituximab → splenectomy | Don't withhold transfusion just because crossmatch is difficult |
| Cold AIHA | Avoid cold; rituximab; sutimlimab | Steroids are NOT effective [11]; splenectomy generally not helpful |
| G6PD deficiency | Avoid triggers; supportive in crisis | Don't test G6PD during crisis; don't give primaquine/rasburicase |
| HS | Folate; splenectomy if severe | Don't do HSCT — unfavourable risk-benefit [3][16] |
| Thalassaemia major | Transfusion + iron chelation ± HSCT | Don't give Vitamin C without Desferal [19]; don't ignore iron overload |
| PNH | Eculizumab/ravulizumab | Must vaccinate against meningococcus before anti-C5 therapy |
| TTP | Plasma exchange + steroids + caplacizumab | Don't give platelet transfusion (can worsen microthrombi); don't delay TPE |
| ABO mismatch | Stop transfusion; resuscitation; alkaline diuresis | Prevention is key — always verify identity |
High Yield Summary — Management
Universal principles for ALL haemolytic anaemias:
- Folate supplementation (except if on regular transfusion)
- Transfusion when clinically indicated
- Identify and treat the specific cause
- Monitor for AKI, gallstones, aplastic crisis, iron overload
Key cause-specific points:
- Warm AIHA: Steroids first → rituximab → splenectomy; treat underlying SLE/CLL
- Cold AIHA: Steroids DON'T work; rituximab ± complement inhibitors; avoid cold
- G6PD: Remove trigger; self-limiting in most cases; no splenectomy needed
- HS: Splenectomy curative but defer till > 6–7 years; vaccinate pre-splenectomy
- Thalassaemia major: Hypertransfusion + iron chelation; HSCT if matched sibling
- PNH: Eculizumab/ravulizumab; vaccinate against Neisseria meningitidis
- TTP: Emergency plasma exchange; caplacizumab; DO NOT give platelets
- ABO mismatch: Stop transfusion; aggressive resuscitation; alkaline diuresis
- Post-splenectomy: Lifelong penicillin prophylaxis; encapsulated organism vaccines
Active Recall - Management of Hemolytic Anaemia
References
[3] Senior notes: Block A - Many members of the family have anaemia.pdf (Thalassaemia management, folate, HbH, haemoglobinopathies) [6] Senior notes: Block A - Splenomegaly_ common causes of splenomegaly; myeloproliferative diseases.pdf (Indications for splenectomy, post-splenectomy complications) [7] Senior notes: Block A - Patients with non-viral chronic liver diseases.pdf (Wilson's disease management, penicillamine side effects) [11] Senior notes: Block A - Family history of anaemia_ inherited causes of anaemia; haemolytic anaemia; aplastic anaemia.pdf (AIHA 4 principles of treatment, G6PD treatment, severe AA treatment) [13] Senior notes: Block A - Fever after a blood transfusion_ transfusion and related problems.pdf (ABO-incompatible transfusion management, prevention) [15] Senior notes: Maksim Medicine Notes.pdf (Warm/Cold AIHA management tables, G6PD drugs, Evans syndrome) [16] Senior notes: Ryan Ho Haemtology.pdf (HS management, PK deficiency, thalassaemia iron chelation, splenectomy timing) [19] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (Thalassaemia transfusion targets, pre-medications, iron chelation indications, deferoxamine dosing) [20] Senior notes: Block A - High white cell count_ acute and chronic leukaemia; bone marrow transplantation; immunogenetics.pdf (HSCT indications, DIC in APL management, supportive treatment) [21] Senior notes: Gen Clerk Anaes + Microbiology Summary.pdf (Post-splenectomy infection organisms, prophylaxis)
Complications of Hemolytic Anaemia
The complications of hemolytic anaemia arise from three interconnected processes:
- Consequences of RBC destruction itself — the breakdown products (free Hb, unconjugated bilirubin, iron) are toxic or create downstream problems
- Consequences of the compensatory marrow response — erythroid hyperplasia can exhaust nutrient reserves or, when it fails, cause catastrophic decompensation
- Consequences of the underlying disease or its treatment — splenectomy, chronic transfusion, and immunosuppression each carry their own complication profiles
Think of it as a chain reaction: haemolysis → bilirubin and iron → gallstones, iron overload, jaundice; haemolysis → free Hb → AKI, pulmonary hypertension; haemolysis → marrow drive → folate depletion → megaloblastic crisis; haemolysis + parvovirus B19 → aplastic crisis.
1. Complications Directly from Haemolysis
Mechanism: increase in the amount and concentration of unconjugated bilirubin in hepatic bile → promotion of stone formation within the gallbladder [11]
- Type: Black pigment stones (calcium bilirubinate) — distinct from the cholesterol stones of metabolic syndrome
- Incidence: Very common in chronic haemolysis — 50% of adults with hereditary spherocytosis develop pigmented gallstones [16]
- Clinical consequence: Biliary colic, acute cholecystitis, choledocholithiasis with obstructive jaundice (now conjugated bilirubin → tea-coloured urine, which can confuse the clinical picture in someone with pre-existing haemolytic jaundice), ascending cholangitis, gallstone pancreatitis
- Management: Cholecystectomy (often performed at the same time as splenectomy in HS)
- Why does this happen from first principles? Chronic haemolysis → ↑haem breakdown → ↑unconjugated bilirubin produced → liver conjugates more bilirubin than normal → higher concentration of conjugated bilirubin excreted in bile → in the gallbladder, bacterial β-glucuronidase deconjugates some of it → the insoluble unconjugated bilirubin precipitates with calcium → black pigment stones
- Pre-hepatic (unconjugated) hyperbilirubinaemia — typically mild, fluctuating, scleral icterus
- Jaundice WITHOUT tea-coloured urine — unconjugated bilirubin is water-insoluble → not filtered by kidneys [11]
- Usually well-tolerated in adults but in neonates → unconjugated bilirubin crosses the immature blood-brain barrier → kernicterus (bilirubin encephalopathy)
Predominantly a complication of intravascular haemolysis (but can occur in severe extravascular haemolysis too):
Free haemoglobin from haemolysed RBCs can cause AKI through multiple mechanisms [13]:
| Mechanism | Explanation |
|---|---|
| Direct nephrotoxicity | Free Hb is an endogenous nephrotoxin → causes toxic acute tubular necrosis (ATN). Haemoglobinaemia is listed as an endogenous toxin causing ATN [5] |
| Renal vasoconstriction | Free haemoglobin binds nitric oxide (NO) → less NO means less relaxation → smooth muscle dystonia → if occurring in renal vasculature → AKI [13] |
| Tubular obstruction | Haem pigment precipitates in renal tubules, especially in acidic urine → tubular obstruction |
| Complement and inflammation | Activated complement system releases anaphylatoxins → degranulation of mast cells → phagocytes release cytokines (TNF, IL-6, IL-8) → activation of coagulation system → DIC → thrombus formed in renal vasculature → AKI [13] |
- Prevention: Aggressive IV fluid resuscitation, maintain urine output, alkaline diuresis (to prevent Hb precipitation in acidic tubular lumen)
- Classic scenarios: ABO-incompatible transfusion, severe G6PD crisis, PNH crisis, massive falciparum malaria
- Chronic intravascular haemolysis → chronic depletion of NO by free Hb → endothelial dysfunction → vasoconstriction and remodelling of pulmonary vasculature → pulmonary hypertension
- Particularly important in: sickle cell disease, thalassaemia intermedia, PNH
- Screen with echocardiography (tricuspid regurgitant jet velocity)
- PNH: Thrombosis is the leading cause of death — venous thrombosis at unusual sites (hepatic veins → Budd-Chiari syndrome, cerebral venous sinuses, mesenteric veins)
- Mechanism: free Hb scavenges NO → platelet activation; complement activation on platelets; release of procoagulant microvesicles from lysed RBCs
- Sickle cell disease: Vaso-occlusion is the hallmark complication (see below)
- Post-splenectomy thrombocytosis → risk of portal vein thrombosis and other venous thromboembolism [6][16]
- Splenectomy risks: ↑thromboembolism, ↑life-threatening infection, ↑pulmonary hypertension [16]
- Occurs in severe acute intravascular haemolysis (ABO-incompatible transfusion, C. perfringens sepsis)
- Mechanism: activated complement system → platelet activation + cytokine release (TNF, IL-6, IL-8) → activation of coagulation system → DIC [13]
- DIC causes consumption of clotting factors and platelets → paradoxical bleeding
- DIC can cause further MAHA (fibrin strands in vessels shear more RBCs) → vicious cycle
Iron complications arise from two sources:
| Source | Mechanism | Conditions |
|---|---|---|
| Transfusional iron overload | Each unit of packed RBCs contains ~200–250 mg iron. The body has no active excretion mechanism for iron | Thalassaemia major, other transfusion-dependent anaemias |
| Increased intestinal iron absorption | Ineffective erythropoiesis → suppressed hepcidin → ↑ferroportin activity → ↑iron absorption from gut | Thalassaemia intermedia (even without transfusions), sickle cell disease, congenital dyserythropoietic anaemia |
| Chronic intravascular haemolysis → iron loss | Paradoxically, iron can be LOST via haemoglobinuria and haemosiderinuria | PNH — can develop iron deficiency despite haemolysis |
Consequences of iron overload:
| Organ | Consequence | Mechanism |
|---|---|---|
| Heart | Dilated cardiomyopathy, arrhythmias, heart failure | Iron-catalysed free radical (Fenton reaction) damages cardiomyocytes |
| Liver | Hepatic fibrosis → cirrhosis → hepatocellular carcinoma | Iron deposited in hepatocytes and Kupffer cells → oxidative damage |
| Endocrine | Diabetes mellitus, hypothyroidism, hypogonadism (delayed puberty, infertility), hypoparathyroidism | Iron deposited in pancreatic β-cells, thyroid, pituitary/gonads, parathyroid |
| Skin | Bronze discolouration | Iron deposited in dermis |
Monitoring of iron overload: serum ferritin useful as screening but quantitative liver iron and cardiac iron measurement by MRI is the standard indicator of total-body iron stores [16]
Long-term complications of transfusion include haemosiderosis [13]
Iron Paradox in PNH
PNH patients lose iron in their urine through chronic haemoglobinuria and haemosiderinuria. Unlike thalassaemia patients who develop iron overload, PNH patients often develop iron deficiency and may actually need iron supplementation. This is counter-intuitive for a haemolytic condition and is a classic exam point.
2. Complications of the Compensatory Marrow Response
Transient aplastic crisis in patients with underlying haemolytic anaemia — following primary parvovirus B19 infection [11]
- Mechanism: Parvovirus B19 has tropism for erythroid progenitor cells (binds to globoside / P antigen on erythroblasts) → directly lyses erythroid precursors → sudden cessation of red cell production
- Normal individuals: Barely notice this because their RBCs survive 120 days — a transient 7–10 day halt in production causes minimal Hb drop
- Patients with chronic haemolysis: Already depend on compensatory reticulocytosis to maintain Hb. When production stops, Hb plummets catastrophically over days (because destruction continues unabated while production has ceased)
- Lab hallmark: Severe anaemia with absent reticulocytes (reticulocyte count near zero) — this is the clue
- Duration: Self-limiting over 7–14 days (once viral clearance occurs, marrow recovers)
- Management: Transfusion support during the nadir; IVIG for immunocompromised patients who cannot clear the virus
- Complications of parvovirus B19 infection [11]:
- Transient aplastic crisis in patients with underlying haemolytic anaemia (e.g., hereditary spherocytosis)
- Chronic hypoplastic anaemia
- Pure red cell aplasia in immunocompromised patients
- Hydrops fetalis in pregnant women
Exam Scenario: Sudden Severe Anaemia in HS
A child with known hereditary spherocytosis presents with sudden severe pallor, Hb 3 g/dL, and a reticulocyte count of 0.1%. What happened?
Answer: Parvovirus B19 aplastic crisis. The virus killed the erythroid precursors, and without compensatory reticulocytosis, the chronic haemolysis causes rapid Hb decline. Treatment: urgent transfusion.
- Megaloblastic crisis due to folate deficiency, usually occurring during pregnancy when there is increased folate need [3][16]
- Mechanism: Chronic haemolysis → ↑RBC turnover → ↑folate consumption for DNA synthesis in erythroid precursors → folate stores depleted → megaloblastic change in the marrow → ineffective erythropoiesis
- Risk factors: Pregnancy (↑folate demand), poor dietary intake, alcoholism
- Prevention: Folic acid supplementation 1–2 mg/day for chronic haemolysis; 5 mg/day if pregnant [3][16]
- Distinct from aplastic crisis: in megaloblastic crisis, the marrow is present but dysfunctional (megaloblastic precursors); in aplastic crisis, the erythroid precursors are absent
- Haemolytic crisis due to increased severity of haemolysis, uncommon, usually associated with infections [3][16]
- An acute exacerbation of the baseline haemolysis → sudden ↓Hb with ↑reticulocytes (unlike aplastic crisis where reticulocytes are absent)
- Triggers: intercurrent infections, drugs (in G6PD), oxidant stress
- Management: supportive, transfusion if needed, treat the trigger
- Chronic compensatory erythroid hyperplasia → marrow cavity expands → cortical bone thinning
- Relevant in: thalassaemia major (if undertransfused), sickle cell disease
- Skeletal complications:
- Frontal bossing, maxillary hyperplasia ("chipmunk facies") — expansion of the diploic space in the skull
- "Hair-on-end" appearance on skull X-ray — perpendicular trabecular striations from marrow expansion
- Pathological fractures — cortical thinning weakens bones
- Extramedullary haematopoiesis — marrow function "spills over" into spleen, liver, paravertebral masses → hepatosplenomegaly, cord compression
Chronic extravascular haemolysis → work hypertrophy of the spleen → splenomegaly:
| Complication | Mechanism |
|---|---|
| Hypersplenism (pancytopenia) | Enlarged spleen pools and destroys excessive amounts of all blood cells (not just RBCs) → anaemia worsens, thrombocytopenia (↑bleeding risk), leukopenia (↑infection risk) [6] |
| Splenic infarction | Vascular supply cannot keep up with enlarged parenchyma (especially in SCD — sickled cells occlude splenic vessels) |
| Splenic rupture | Rare; risk increases with massive splenomegaly or concurrent infection (e.g., EBV mononucleosis with splenomegaly — avoid exercise to prevent splenic rupture until 21 days after onset [22]) |
| Autosplenectomy (functional hyposplenism) | In sickle cell disease: repeated splenic infarction → fibrosis → small, non-functional spleen by childhood → same infection risk as surgical splenectomy |
4. Complications of Treatment
A. Post-Splenectomy Complications
Why don't we just liberally do splenectomies? [6]:
Rare but life-threatening complication in post-splenectomy patients. Caused by invasive infections of encapsulated bacteria. > 50% of infections are due to Streptococcus pneumoniae. Lifetime risk of OPSI is estimated to be 5% but most (50%) occur within the first two years of splenectomy [6]
- Why encapsulated organisms? The spleen is the primary site for opsonisation and clearance of encapsulated bacteria. Splenic marginal zone B-cells produce natural IgM antibodies against polysaccharide capsular antigens. Without the spleen, the body cannot mount an effective immune response against these organisms.
- Classic pathogens:
- Clinical presentation: Rapid onset of sepsis with DIC → can progress from mild febrile illness to death within 12–24 hours
- Prevention: Pre-splenectomy vaccination + lifelong prophylactic antibiotics + patient education (discussed in Management section)
Features that may appear alarming on CBC but are just consequences of splenectomy [6]:
- Spurious leukocytosis
- Increase in platelet counts
- Howell-Jolly bodies (nuclear remnants no longer pitted by spleen)
- Target cells, acanthocytes, nucleated RBCs may appear
Patients with chronic haemolytic anaemias (especially thalassaemia major, SCD, warm AIHA) require repeated transfusions, exposing them to:
| Complication | Mechanism | Notes |
|---|---|---|
| Iron overload (haemosiderosis) | Each unit of packed RBCs ≈ 200–250 mg iron; no excretion mechanism | See iron overload section above. Long-term complication of transfusion [13] |
| Alloimmunisation | Exposure to foreign RBC antigens → development of alloantibodies | Especially in thalassaemia patients — more prone to delayed haemolytic transfusion reactions [13]. Makes future crossmatching progressively more difficult |
| Febrile non-haemolytic reactions | Leucoagglutinins in recipient react with transfused leukocytes → cytokine release | Prevented by leukocyte-depleted products |
| Transfusion-associated infections | Viral (HBV, HCV, HIV — now extremely rare with screening), bacterial contamination | Long-term complications: infectious risks [13] |
| Transfusion-associated circulatory overload (TACO) | Volume overload in patients with impaired cardiac function | Prevent with slow transfusion rate, furosemide |
| Transfusion-associated acute lung injury (TRALI) | Donor antibodies against recipient leukocyte antigens → neutrophil activation in pulmonary vasculature | Acute respiratory distress during/after transfusion |
Long-term steroid use (warm AIHA), rituximab, and other immunosuppressants carry their own complications:
- Steroids: Cushingoid features, osteoporosis, diabetes, adrenal suppression, infection susceptibility, avascular necrosis, cataracts
- Rituximab: Hepatitis B reactivation (must screen HBsAg/anti-HBc before starting), progressive multifocal leukoencephalopathy (very rare), late-onset neutropenia
- Splenectomy complications: As detailed above
5. Disease-Specific Complications
Sickle Cell Disease
Complications of sickle cell disease [3]:
| Complication | Mechanism |
|---|---|
| Vaso-occlusive pain crisis | Sickled cells obstruct microvasculature → ischaemia → severe pain (bones, abdomen, chest) |
| Acute chest syndrome | Vaso-occlusion in pulmonary vasculature ± fat embolism from infarcted bone marrow ± infection → fever, chest pain, new pulmonary infiltrate, hypoxia. Leading cause of death in SCD |
| Renal papillary necrosis | Medullary environment (hypoxic, acidotic, hypertonic) promotes sickling in vasa recta → papillary ischaemia → necrosis |
| Priapism | Sickled cells block penile venous outflow → prolonged erection → emergency (risk of permanent impotence) |
| Osteonecrosis (avascular necrosis) | Vaso-occlusion in bone → infarction (femoral head, humeral head most common) |
| Dactylitis ("hand-foot syndrome") | Vaso-occlusion in small bones of hands/feet → swelling, pain (earliest presentation in young children) |
| Splenic sequestration crisis | Massive pooling of sickled cells in spleen → acute splenomegaly → hypovolaemic shock (paediatric emergency) |
| Complication | Mechanism |
|---|---|
| Ischaemic stroke | Large vessel vasculopathy → stenosis of internal carotid/middle cerebral artery → cerebral infarction |
| Pulmonary hypertension | Chronic intravascular haemolysis → NO scavenging → endothelial dysfunction → pulmonary vascular remodelling |
| Complication | Mechanism |
|---|---|
| Overwhelming infection | Functional asplenia from autosplenectomy → susceptibility to encapsulated organisms (same risk as surgical splenectomy) |
- Thrombosis (leading cause of death): hepatic vein (Budd-Chiari), cerebral venous sinuses, mesenteric veins, dermal veins
- Bone marrow failure (overlap with aplastic anaemia): PNH clones arise from the aplastic marrow; ~15–20% of aplastic anaemia patients develop PNH
- Chronic kidney disease from recurrent AKI episodes and haemosiderin deposition in renal tubules
- Smooth muscle dystonia (dysphagia, abdominal pain, erectile dysfunction) — due to NO depletion by free Hb
An underappreciated but clinically important complication of haemolytic anaemia:
HbA1c is inaccurate in haemolytic anaemia [24]:
- HbA1c measures glycated haemoglobin accumulated over the ~120-day RBC lifespan
- In haemolytic anaemia, RBC lifespan is shortened → less time for glycation → HbA1c is falsely DECREASED
- Conversely, HbA1c is falsely increased in: iron deficiency anaemia, post-splenectomy, HbH disease (older cells with more glycation are preferentially retained) [24]
- Clinical implication: Do not rely on HbA1c for diabetes screening or monitoring in patients with haemolytic anaemia — use fructosamine or continuous glucose monitoring instead
| Category | Complications |
|---|---|
| From RBC destruction products | Pigment gallstones, jaundice (± neonatal kernicterus), AKI (free Hb toxicity), pulmonary hypertension, thrombosis, DIC |
| From compensatory marrow response | Aplastic crisis (parvovirus B19), megaloblastic crisis (folate depletion), haemolytic crisis, skeletal deformities (marrow expansion), extramedullary haematopoiesis |
| From splenomegaly | Hypersplenism (pancytopenia), splenic infarction, splenic rupture, autosplenectomy (SCD) |
| From treatment (splenectomy) | OPSI, thrombocytosis/thromboembolism, Howell-Jolly bodies |
| From treatment (transfusion) | Iron overload (haemosiderosis), alloimmunisation, transfusion reactions, infections, TACO, TRALI |
| From treatment (immunosuppression) | Steroid side effects, HBV reactivation (rituximab), infection |
| Disease-specific (SCD) | Vaso-occlusive crises, acute chest syndrome, stroke, renal papillary necrosis, priapism, osteonecrosis, splenic sequestration |
| Disease-specific (PNH) | Thrombosis (unusual sites), marrow failure, CKD, smooth muscle dystonia |
| Metabolic | Falsely low HbA1c (shortened RBC lifespan) |
High Yield Summary — Complications
Must-know complications for exams:
- Pigment gallstones — from chronic ↑unconjugated bilirubin (50% of adult HS patients)
- Aplastic crisis — parvovirus B19 → absent reticulocytes → Hb crashes
- AKI — free Hb nephrotoxicity (intravascular haemolysis); NO scavenging → renal vasoconstriction
- Iron overload — from transfusions (heart, liver, endocrine) OR increased gut absorption (thalassaemia intermedia). Paradoxically, PNH can cause iron deficiency
- OPSI — post-splenectomy, encapsulated organisms (pneumococcus #1), lifetime risk ~5%, can kill in 12–24h
- Falsely low HbA1c — shortened RBC lifespan → less glycation → underestimates true glucose levels
- SCD vaso-occlusion — pain crisis, acute chest syndrome, stroke, priapism, osteonecrosis
- PNH thrombosis — leading cause of death; unusual sites (hepatic, cerebral veins)
Active Recall - Complications of Hemolytic Anaemia
References
[3] Senior notes: Block A - Many members of the family have anaemia.pdf (Sickle cell complications, thalassaemia clinical syndromes, megaloblastic crisis) [5] Senior notes: Block A - Nephrotology Teaching Clinic RTD.pdf (ATN from haemoglobinaemia) [6] Senior notes: Block A - Splenomegaly_ common causes of splenomegaly; myeloproliferative diseases.pdf (Splenectomy complications, OPSI, post-splenectomy haematological changes, vaccination) [11] Senior notes: Block A - Family history of anaemia_ inherited causes of anaemia; haemolytic anaemia; aplastic anaemia.pdf (Gallstone mechanism, parvovirus B19 complications, HS complications, aplastic crisis) [13] Senior notes: Block A - Fever after a blood transfusion_ transfusion and related problems.pdf (AKI mechanism in ABO mismatch, DIC mechanism, haemosiderosis, transfusion complications) [16] Senior notes: Ryan Ho Haemtology.pdf (HS complications — NNJ, gallstones, aplastic crisis; splenectomy risks; iron chelation monitoring; thalassaemia monitoring) [21] Senior notes: Gen Clerk Anaes + Microbiology Summary.pdf (Post-splenectomy encapsulated organisms, Capnocytophaga) [22] Senior notes: Ryan Ho Respiratory.pdf (EBV complications — avoid exercise for splenic rupture, haemolytic anaemia) [23] Senior notes: Maksim Surgery Notes.pdf (Splenectomy complications, prophylactic aspirin for thrombocytosis, OPSI pathogens mnemonic) [24] Senior notes: Ryan Ho Endocrine.pdf (HbA1c inaccuracy in haemolytic anaemia — decreased; increased in HbH, post-splenectomy)
High Yield Summary
Definition: Hemolytic anaemia = increased rate of RBC destruction ± compensatory reticulocytosis
Classification:
- Inherited vs. Acquired
- Intrinsic vs. Extrinsic (PNH = acquired intrinsic — the exception!)
- Extravascular (spleen/liver — splenomegaly, jaundice, gallstones) vs. Intravascular (blood vessels — haemoglobinuria, ↓↓haptoglobin, renal injury)
Inherited causes — think RBC components:
- Membrane: Hereditary spherocytosis, elliptocytosis
- Enzyme: G6PD deficiency (X-linked, common in HK), pyruvate kinase deficiency
- Haemoglobin: SCD, HbH, unstable Hb (Köln), thalassaemias
Acquired causes — think what's attacking the RBC:
- Immune: Warm AIHA (IgG), Cold AIHA (IgM), alloimmune (transfusion/HDN), drug-induced
- Non-immune: MAHA (TTP/HUS/DIC), mechanical (valves/ECMO), infections (malaria, C. perfringens), hypersplenism, toxins
Key clinical features: Pallor + jaundice (WITHOUT tea-coloured urine) + splenomegaly = classic triad of extravascular haemolysis
Key labs: ↑Reticulocytes, ↑LDH, ↑unconjugated bilirubin, ↓haptoglobin, ±haemoglobinuria
History pearls: Family history, ethnicity, drug exposure, infections, transfusion history, autoimmune diseases
Hong Kong relevance: G6PD deficiency (neonatal screening), α/β-thalassaemia carrier states, HbH disease
High Yield Summary — DDx of Hemolytic Anaemia
Step 1: Confirm haemolysis — ↑reticulocytes, ↑LDH, ↑unconjugated bilirubin, ↓haptoglobin, polychromasia on film
Step 2: DAT (Direct Coombs Test) — the single most important branching investigation
- Positive → Immune (Warm AIHA, Cold AIHA, drug-induced, transfusion reaction)
- Negative → Non-immune (proceed to blood film morphology)
Step 3: Blood film morphology guides the rest
- Spherocytes + DAT neg → HS or Wilson's
- Schistocytes → MAHA (TTP/HUS/DIC/HELLP/mechanical)
- Bite cells → G6PD
- Sickle cells → SCD
- Agglutination → Cold agglutinin disease
Step 4: Haemoglobinuria?
- Yes → PNH (flow cytometry for CD55/CD59), ABO mismatch, severe G6PD, malaria
Don't forget: TOCC for malaria; drugs for G6PD and immune haemolysis; family history for inherited causes; SLE/CLL for secondary AIHA
High Yield Summary — Diagnostics
- Confirm haemolysis with: ↑reticulocytes + ↑LDH + ↑unconjugated bilirubin + ↓haptoglobin + polychromasia on film
- DAT is the pivotal test: Positive = immune; Negative = non-immune
- Blood film morphology guides targeted Ix: spherocytes → HS/AIHA; schistocytes → MAHA; bite cells → G6PD; agglutination → cold AIHA
- PNH diagnosis: Flow cytometry for CD55/CD59 (replaces Ham's test)
- TTP vs DIC: Clotting profile normal in TTP; abnormal in DIC. ADAMTS13 < 10% = TTP
- G6PD testing trap: Don't test during crisis — wait 2–3 months
- HS diagnosis: EMA binding (preferred) > osmotic fragility test
- Haptoglobin caveats: 1:1000 Chinese have congenital deficiency; positive acute-phase reactant can mask ↓ in inflammation
- Thalassaemia vs IDA (HK high yield): Iron studies, RDW, HbA₂ are key discriminators
High Yield Summary — Management
Universal principles for ALL haemolytic anaemias:
- Folate supplementation (except if on regular transfusion)
- Transfusion when clinically indicated
- Identify and treat the specific cause
- Monitor for AKI, gallstones, aplastic crisis, iron overload
Key cause-specific points:
- Warm AIHA: Steroids first → rituximab → splenectomy; treat underlying SLE/CLL
- Cold AIHA: Steroids DON'T work; rituximab ± complement inhibitors; avoid cold
- G6PD: Remove trigger; self-limiting in most cases; no splenectomy needed
- HS: Splenectomy curative but defer till > 6–7 years; vaccinate pre-splenectomy
- Thalassaemia major: Hypertransfusion + iron chelation; HSCT if matched sibling
- PNH: Eculizumab/ravulizumab; vaccinate against Neisseria meningitidis
- TTP: Emergency plasma exchange; caplacizumab; DO NOT give platelets
- ABO mismatch: Stop transfusion; aggressive resuscitation; alkaline diuresis
- Post-splenectomy: Lifelong penicillin prophylaxis; encapsulated organism vaccines
High Yield Summary — Complications
Must-know complications for exams:
- Pigment gallstones — from chronic ↑unconjugated bilirubin (50% of adult HS patients)
- Aplastic crisis — parvovirus B19 → absent reticulocytes → Hb crashes
- AKI — free Hb nephrotoxicity (intravascular haemolysis); NO scavenging → renal vasoconstriction
- Iron overload — from transfusions (heart, liver, endocrine) OR increased gut absorption (thalassaemia intermedia). Paradoxically, PNH can cause iron deficiency
- OPSI — post-splenectomy, encapsulated organisms (pneumococcus #1), lifetime risk ~5%, can kill in 12–24h
- Falsely low HbA1c — shortened RBC lifespan → less glycation → underestimates true glucose levels
- SCD vaso-occlusion — pain crisis, acute chest syndrome, stroke, priapism, osteonecrosis
- PNH thrombosis — leading cause of death; unusual sites (hepatic, cerebral veins)
Aplastic Anaemia
Aplastic anaemia is a bone marrow failure syndrome characterized by pancytopenia and hypocellular marrow resulting from destruction or suppression of haematopoietic stem cells.
Megaloblastic Anaemia
Megaloblastic anaemia is a type of macrocytic anaemia caused by impaired DNA synthesis, most commonly due to vitamin B12 or folate deficiency, resulting in large, abnormal erythroid precursors (megaloblasts) in the bone marrow.