Hereditary elliptocytosis is a group of inherited red blood cell membrane disorders, primarily due to defects in spectrin or other cytoskeletal proteins, resulting in elliptical-shaped erythrocytes and variable degrees of hemolytic anemia.

Hereditary Elliptocytosis (HE)

Hereditary elliptocytosis (HE) is a group of inherited disorders of the red blood cell (RBC) membrane skeleton characterised by the presence of elliptical (oval-shaped) erythrocytes on peripheral blood smear ^[1]^[2]. The name itself tells you the condition: "hereditary" = inherited/genetic, "elliptocytosis" = elliptical cells ("elliptos" Greek = oval, "cyto" = cell, "-osis" = condition of).

Like its more commonly discussed cousin hereditary spherocytosis (HS), HE is fundamentally a disease of the cytoskeletal-membrane interaction. The difference is in which structural proteins are affected and how the membrane fails:

In HS, there is vertical membrane–cytoskeleton uncoupling → membrane loss → spherocytes.
In HE, there is horizontal cytoskeletal network disruption → failure to maintain the normal biconcave disc shape after deformation → permanent elliptical deformation ^[1]^[3].

HE is a disorder of red cell membrane due to mutations in cytoskeletal proteins, resulting in elliptocytes on blood film and a clinical spectrum ranging from asymptomatic carrier state to severe haemolytic anaemia ^[1]^[2].

The clinical severity is highly variable — most patients are asymptomatic with the diagnosis made incidentally on a blood film, while a minority (especially those with compound heterozygosity or the hereditary pyropoikilocytosis subtype) develop significant chronic haemolysis ^[1]^[2].

Feature	Detail
Prevalence	~1 in 2,000–4,000 worldwide ^[1]
Geographic enrichment	Most common in Africa, Mediterranean region, and Southeast Asia — areas historically endemic for Plasmodium falciparum malaria ^[1]^[2]
Inheritance	Predominantly autosomal dominant (AD) for common HE; autosomal recessive (AR) for hereditary pyropoikilocytosis (HPP) and some severe forms ^[1]^[3]
Sex	Equal sex distribution (gene is autosomal)
Ethnic relevance to HK	Relatively uncommon in the Hong Kong Chinese population compared to HS-predominant northern European populations; however, Southeast Asian ovalocytosis (SAO), a subtype, is relevant in the SE Asian context ^[1]^[2]

Why is HE maintained in the population?

The geographic overlap with malaria-endemic regions is not a coincidence. Elliptocytic RBCs confer a selective survival advantage against P. falciparum malaria — the altered membrane makes it harder for the merozoite to invade or for the parasitised cell to sustain its normal intracellular development. This is analogous to the heterozygote advantage seen with sickle cell trait, thalassaemia trait, and G6PD deficiency ^[2]^[4].

The thalassaemia/HE gene is maintained in the human population because it confers greater immunity in heterozygous individuals against malaria ^[4].

3. Anatomy and Function of the RBC Membrane Skeleton

Understanding HE requires understanding normal RBC membrane architecture. This is the foundation.

A mature RBC has:

No nucleus, no mitochondria, no ribosomes — cannot synthesise new proteins.
A biconcave disc shape (7–8 μm diameter, ~2 μm thick at the edge, ~1 μm at the centre).
An incredibly deformable membrane — it must squeeze through splenic sinusoidal slits that are only ~2–3 μm wide and then spring back to its original shape.

3.2 Membrane Skeleton Components

The RBC membrane has two major structural layers:

Standard phospholipid bilayer with embedded transmembrane proteins (Band 3, Glycophorin C).

This is a two-dimensional meshwork of proteins that gives the RBC its shape and deformability. The key proteins are:

Protein	Role	Relevant to HE?
α-Spectrin	Forms heterodimers with β-spectrin; the fundamental building block	Yes — most common mutation in HE
β-Spectrin	Partners with α-spectrin to form heterodimers; most common mutation in HS	Yes — less commonly mutated in HE
Protein 4.1 (Band 4.1)	Stabilises the spectrin–actin junction	Yes — mutations cause a subtype of HE
Actin (short filaments)	Junction complex — links spectrin heterodimers together	Rarely mutated in HE
Ankyrin	Vertical linkage (membrane → cytoskeleton)	More relevant to HS
Band 3	Transmembrane protein; vertical anchor	More relevant to HS
Glycophorin C	Transmembrane protein; links to protein 4.1	Relevant to SAO subtype

The cytoskeletal network is stabilised by two types of protein-protein interactions:

Vertical vs Horizontal — The Exam Classic

Vertical interaction defects → Hereditary Spherocytosis (HS): membrane uncouples from the skeleton, lipid bilayer is lost as microvesicles → surface area decreases → cell becomes a sphere (spherocyte).
Horizontal interaction defects → Hereditary Elliptocytosis (HE): the cytoskeletal meshwork itself is mechanically weak → when RBCs are sheared in the circulation, they cannot spring back to a disc → they remain permanently elongated/elliptical.

The spectrin heterodimer (α + β) self-associates head-to-head to form tetramers.
These tetramers are cross-linked at junctional complexes (actin + protein 4.1 + other proteins).
This creates a hexagonal lattice under the lipid bilayer — like a geodesic dome.
When the RBC is deformed (e.g., squeezing through the spleen), the spectrin tetramers can unfold, stretch, and then re-fold — restoring the disc shape.

In HE, spectrin dimer self-association is impaired → the tetramers are unstable → under shear stress, the meshwork cannot reassemble → the cell stays elongated → elliptocyte ^[1]^[3].

4. Aetiology

HE is caused by mutations in genes encoding red cell membrane skeletal proteins involved in horizontal interactions:

Gene	Protein	Proportion of HE cases	Mechanism
SPTA1	α-Spectrin	~65% (most common)	Impaired α-β spectrin dimer self-association into tetramers
SPTB	β-Spectrin	~30%	Impaired dimer self-association
EPB41	Protein 4.1 (Band 4.1)	~5%	Disrupted junctional complex (spectrin–actin–4.1)
SLC4A1	Band 3	Rare (mainly SAO)	Altered transmembrane protein → rigidity

Autosomal dominant for common HE — a single mutant allele is sufficient to produce elliptocytes on blood film, although usually insufficient to cause significant haemolysis ^[1]^[3].
Autosomal recessive for HPP and severe HE — typically compound heterozygosity (two different spectrin mutations) or homozygosity → severe mechanical instability → marked haemolysis even in neonatal period.
~25% may have negative family history due to de novo mutations or low-expressivity alleles in parents ^[1].

In Hong Kong, hereditary elliptocytosis is uncommon relative to the more prevalent inherited haemolytic anaemias seen in the local Chinese/SE Asian population:

G6PD deficiency — most common inherited red cell enzyme defect in HK (~4.5% of males).
α-Thalassaemia trait (~5% of HK population).
β-Thalassaemia trait (~3% of HK population) ^[4].
Hereditary spherocytosis — more commonly discussed in the HK curriculum than HE.

However, Southeast Asian ovalocytosis (SAO), a specific HE subtype caused by a 27-bp deletion in the SLC4A1 gene (Band 3), is relevant in patients of Malaysian, Indonesian, Filipino, or Papua New Guinean descent who present in Hong Kong ^[1]^[2].

5. Pathophysiology

Let us trace the pathophysiology from gene to bedside:

This is a question students always ask. The key difference:

In HS, membrane lipid is lost (vertical defect) → surface-area-to-volume ratio decreases → the only geometrically possible shape with reduced surface area enclosing the same volume is a sphere.
In HE, the cytoskeletal meshwork is weak but the membrane itself is intact (no significant lipid loss initially). The RBC gets deformed by shear forces in the circulation and simply fails to recoil → it stays elongated. Think of it like a rubber band that has lost its elasticity — it stretches but doesn't snap back.

When haemolysis occurs in HE, it is predominantly extravascular:

Elliptocytes (and especially the more severely deformed cells — poikilocytes, fragments) have reduced deformability.
They cannot traverse the narrow (~2–3 μm) fenestrations of the splenic sinusoidal endothelium.
They are trapped in the splenic cords of Billroth → phagocytosed by splenic macrophages.
This is extravascular haemolysis → unconjugated hyperbilirubinaemia, ↑LDH, ↓haptoglobin, reticulocytosis.

In very severe forms (HPP), there may also be some degree of intravascular fragmentation because the membrane is so unstable it physically fragments under circulatory shear.

In common HE (AD, single heterozygous mutation), the spectrin tetramer instability is mild enough that:

The bone marrow can compensate by increasing erythropoiesis (reticulocyte count may be mildly elevated).
The RBC lifespan is only mildly shortened or even near-normal.
Elliptocytes are present on the film but do not cause significant splenic trapping.

The patient has compensated haemolysis — increased destruction balanced by increased production → normal or near-normal Hb ^[1]^[2].

Subtypes of HE: common HE, hereditary pyropoikilocytosis (HPP), Southeast Asian ovalocytosis (SAO), spherocytic elliptocytosis (HSE) ^[1].

Subtype	Inheritance	Key Mutation	Blood Film	Clinical Severity
Common HE	AD	α-spectrin (most), β-spectrin, protein 4.1	Elliptocytes 15–100% of all RBCs	Usually asymptomatic or mild haemolysis; ~90% of all HE cases
Hereditary Pyropoikilocytosis (HPP)	AR (compound heterozygous)	Severe α-spectrin defects (two alleles)	Poikilocytes, fragments, microspherocytes, budding cells; RBCs thermally unstable (fragment at 45–46°C vs 49°C normal — "pyro" = heat, "poikilo" = varied shape)	Severe haemolytic anaemia, often presents in neonatal period; transfusion-dependent
Southeast Asian Ovalocytosis (SAO)	AD (homozygosity is lethal in utero)	27-bp deletion in SLC4A1 (Band 3)	Stomatocytes (mouth-shaped central pallor) and large, round ovalocytes; RBCs are rigid (opposite of deformable)	Usually asymptomatic despite rigid cells; heterozygotes have almost no haemolysis; confers malaria resistance
Spherocytic HE (HSE)	AD	Combined horizontal + mild vertical defect	Spherocytes and elliptocytes	Moderate haemolysis; phenotypically overlaps with HS

HPP — The Severe End of the HE Spectrum

HPP is NOT a separate disease — it is the severe homozygous/compound heterozygous end of the HE spectrum. A patient with HPP typically has:

One parent with common (mild) HE.
Inherited a second spectrin mutation (often a low-expression polymorphic allele of α-spectrin called αLELY).
The combined effect produces a catastrophically unstable cytoskeleton.

The name "pyropoikilocytosis" comes from the observation that these RBCs fragment when heated to 45–46°C (normal RBCs fragment at ~49°C). "Pyro" = fire/heat.

7. Clinical Features

Clinical features of HE are variable depending on subtypes ^[1].

The clinical spectrum ranges from:

Silent carrier → no anaemia, no symptoms, elliptocytes found incidentally.
Mild common HE → compensated haemolysis, normal Hb, mild reticulocytosis.
Moderate HE → chronic haemolytic anaemia with complications.
Severe HPP → transfusion-dependent from infancy ^[1]^[2].

Symptom	Pathophysiological Basis
Asymptomatic / incidental finding	Most common presentation (~90%). The mild membrane defect causes elliptocytes but insufficient haemolysis to overwhelm marrow compensation → normal Hb.
Fatigue, exercise intolerance, pallor	When haemolysis exceeds marrow compensatory capacity → anaemia → reduced oxygen-carrying capacity → tissue hypoxia → fatigue.
Jaundice (intermittent or chronic)	Extravascular haemolysis → macrophages break down haemoglobin → unconjugated bilirubin released into plasma → exceeds hepatic conjugation capacity → jaundice (scleral icterus before skin icterus because bilirubin has affinity for elastin).
Dark urine	Excess urobilinogen (from increased bilirubin metabolism in the gut, reabsorbed and excreted renally) causes darkened urine. In severe intravascular haemolysis (rare in HE, more in HPP), free haemoglobin/haemosiderin in urine.
Right upper quadrant / biliary colic	Chronic unconjugated hyperbilirubinaemia → pigmented (calcium bilirubinate) gallstones → cholecystitis / biliary colic.
Neonatal jaundice (NNJ)	Particularly in HPP and moderate-severe HE. Neonatal liver has immature UDP-glucuronosyltransferase → cannot conjugate the increased bilirubin load from haemolysis → severe NNJ, risk of kernicterus ^[1].
Symptoms of aplastic crisis (acute severe pallor, lethargy, tachycardia)	Parvovirus B19 infects erythroid precursors → temporary red cell aplasia → reticulocyte count drops to near zero → because RBC lifespan is already shortened in HE, Hb falls precipitously over 7–10 days → acute severe anaemia.
Symptoms of megaloblastic crisis	Chronic haemolysis → increased erythropoiesis → increased folate consumption → if dietary folate is borderline, develop folate deficiency → megaloblastic change → worsening anaemia.

Sign	Pathophysiological Basis
Pallor	Reduced Hb → decreased perfusion of skin and mucous membranes ^[5].
Jaundice (scleral icterus)	Unconjugated hyperbilirubinaemia from extravascular haemolysis ^[5].
Splenomegaly	The spleen is the primary site of extravascular haemolysis in HE. Chronic work hypertrophy of the reticuloendothelial system (macrophages in the red pulp) → splenomegaly. Also, increased trapping of abnormal RBCs expands the red pulp ^[1]^[5].
Hepatomegaly (less common)	Compensatory extramedullary haemopoiesis in the liver if marrow is overwhelmed; also from increased RES workload.
Pigmented gallstones (Murphy's sign if cholecystitis)	Gallstones develop in ~50% of adults with significant haemolysis — chronic excess unconjugated bilirubin → calcium bilirubinate stones ^[1].
Leg ulcers (rare, in severe cases)	Chronic haemolysis → impaired microvascular oxygen delivery → ischaemic skin breakdown, typically over the malleoli. More associated with sickle cell disease and severe HS but can occur in severe HE.
Skeletal deformities (rare, only in severe cases)	If severe chronic anaemia from infancy → marrow expansion to compensate → cortical thinning, frontal bossing, maxillary hypertrophy ("chipmunk facies"). This is the same mechanism as in thalassaemia major but much rarer in HE ^[5].
No abnormalities	Most common finding — the majority of HE patients have a completely normal physical examination ^[1]^[2].

Clinical Evaluation of Inherited Anaemia — History and PE Checklist

From the lecture slides ^[5]:

History:

Family history — pattern of inheritance
Age of onset
Drug history (e.g., oxidising drugs in G6PD deficiency — not directly relevant to HE but important in the differential)
Symptoms of haemolysis (jaundice, gallstone, dark urine)
Transfusion requirement
Complications, including those due to long-term red cell transfusion

Physical Examination:

Pallor
Jaundice
Splenomegaly
Skin complexion
Skeletal deformities (in inherited BM failure syndromes, severe thalassaemia, or severe chronic haemolysis)

Like all chronic haemolytic anaemias, HE patients are susceptible to acute crises that cause sudden worsening:

Crisis	Trigger	Mechanism	Key Feature
Haemolytic crisis	Infections, fever	Increased splenic activity + further membrane damage by fever/inflammatory mediators → accelerated haemolysis	Worsening jaundice, falling Hb, reticulocytes INCREASED
Aplastic crisis	Parvovirus B19	Virus has tropism for erythroid precursors (binds globoside/P antigen) → temporary red cell aplasia for ~7–10 days	Acute severe anaemia, reticulocytes DECREASED/ABSENT — this is the distinguishing feature
Megaloblastic crisis	Folate deficiency (increased folate demand from chronic haemolysis)	Impaired DNA synthesis in erythroid precursors → ineffective erythropoiesis	Macrocytic change, hypersegmented neutrophils, worsening anaemia
Sequestration crisis	Massive splenomegaly	Pooling of blood in the spleen → acute drop in circulating Hb	Acute splenic enlargement, hypovolaemia — more associated with sickle cell disease

Aplastic crisis is due to parvovirus B19 infection → severe anaemia with decreased reticulocyte count ^[1].

7.5 Special Considerations by Subtype

Neonates: May present with transient haemolytic anaemia and poikilocytosis in the first few months of life (because neonatal RBCs have higher levels of free 2,3-DPG and fetal haemoglobin which affect membrane stability). This typically resolves by 6–12 months as adult haemoglobin predominates and RBC membrane matures.
Adults: Usually asymptomatic. The diagnosis is often made when a blood film is done for another reason.

Presents at birth or early infancy with severe haemolytic anaemia, NNJ, and transfusion dependence.
Blood film shows dramatic poikilocytosis, fragmentation, budding, and microspherocytes — not just simple elliptocytes.
MCV is characteristically very low (50–60 fL) due to membrane fragmentation → tiny cells.

Almost always asymptomatic despite markedly rigid RBCs.
Paradoxically, SAO RBCs are so rigid they resist invasion by P. falciparum — this is the strongest malaria-protective effect of any red cell membrane disorder.
Homozygous SAO is lethal (hydrops fetalis) — only heterozygotes survive.

Feature	Hereditary Spherocytosis (HS)	Hereditary Elliptocytosis (HE)
Defect	Vertical interactions	Horizontal interactions
Key proteins	Ankyrin, Band 3, β-spectrin, Band 4.2	α-Spectrin, β-spectrin, Protein 4.1
Inheritance	AD (75%), AR, de novo	AD (common HE), AR (HPP)
RBC morphology	Spherocytes	Elliptocytes (15–100% of RBCs)
Mechanism of shape change	Membrane lipid loss → ↓SA:V → sphere	Mechanical weakness → failure to recoil → ellipse
Haemolysis	Almost always present (variable severity)	Usually absent or mild; severe only in HPP/compound heterozygotes
Osmotic fragility	Increased (spherocytes lyse easily in hypotonic solutions)	Usually normal (except in HSE/HPP where spherocytic forms exist)
Prevalence in HK	Uncommon	Rare
Management	Same principles	Same as HS ^[1]

High Yield Summary

HE = horizontal cytoskeletal defect (α-spectrin most common mutation) → mechanically weak meshwork → RBCs permanently deformed into ellipses after circulatory shear stress.
HS = vertical membrane-cytoskeleton defect → membrane lipid loss → spherocytes. This is the key conceptual distinction.
Subtypes: Common HE, HPP, SAO, HSE — varying in severity from asymptomatic to transfusion-dependent.
Most HE patients are asymptomatic — incidental elliptocytes on blood film. ~90% have compensated haemolysis with normal Hb.
When haemolysis occurs, it is extravascular (splenic) → jaundice, splenomegaly, pigmented gallstones.
Clinical features are variable depending on subtypes — key signs include pallor, jaundice, splenomegaly, and gallstones.
Crises: haemolytic (infections), aplastic (Parvovirus B19 — ↓reticulocytes), megaloblastic (folate deficiency).
Prevalence ~1/2,000–4,000; enriched in Africa, Mediterranean, SE Asia due to malaria selection pressure.
Management: same as HS (supportive, folate supplementation, splenectomy for severe cases).
Disorders of red cell membrane causing inherited anaemia: Hereditary spherocytosis, hereditary elliptocytosis and hereditary pyropoikilocytosis, Southeast Asian ovalocytosis, hereditary acanthocytosis, hereditary stomatocytosis ^[2].

Active Recall - Hereditary Elliptocytosis

Differential Diagnosis of Hereditary Elliptocytosis

The differential diagnosis of hereditary elliptocytosis (HE) is really the differential diagnosis of two clinical presentations:

Elliptocytes on a peripheral blood smear — What else causes elliptical RBCs?
Chronic haemolytic anaemia with a positive family history — What other inherited conditions cause haemolysis?

These are distinct diagnostic problems, and you need to think through both. Let's tackle each systematically.

This is the scenario you are most likely to encounter in an exam: you see elliptocytes on a blood film and need to decide whether this is truly HE or something else. The key teaching point is:

Elliptocytes ≠ Hereditary Elliptocytosis

Elliptocytes on a blood film are NOT pathognomonic for HE. Up to 10–15% elliptocytes can be seen in normal individuals and various acquired conditions. In HE, the proportion is typically 15–100% of all RBCs ^[1]. The clinical context and percentage of elliptocytes are essential.

Elliptocytes: Hereditary elliptocytosis – Ask about history of chronic haemolysis including personal and family history of gallstones ^[6]^[7].

Condition	Why Elliptocytes?	Distinguishing Features
Hereditary Elliptocytosis	Intrinsic horizontal cytoskeletal defect → permanent elliptical deformation	15–100% elliptocytes; positive family history (AD); usually asymptomatic; lifelong; DAT negative ^[1]
Iron Deficiency Anaemia (IDA)	Impaired haemoglobin synthesis → insufficient filling of cell → the cell becomes thin and floppy → elongates under shear. These are often called "pencil cells" rather than true elliptocytes	Microcytic hypochromic elliptocytes of different sizes ("pencil cells"); high RDW; low ferritin, low iron, high TIBC; reactive thrombocytosis ^[8]^[9]
Megaloblastic anaemia (B12/folate deficiency)	Impaired DNA synthesis → nuclear-cytoplasmic dyssynchrony → abnormally large, oval erythrocytes (macro-ovalocytes)	Macroovalocytes (not true thin elliptocytes); hypersegmented neutrophils; low B12 or folate; high MCV ^[6]^[7]
Thalassaemia (especially β-thalassaemia trait)	Abnormal haemoglobin polymerisation and membrane damage → some elliptocytic forms among target cells and other abnormal shapes	Target cells, basophilic stippling; microcytic hypochromic; low RDW (uniform small cells); abnormal Hb electrophoresis (raised HbA2 in β-thal trait) ^[9]
Myelodysplastic syndrome (MDS)	Dysplastic erythropoiesis → abnormal cell shapes including elliptocytes	Elderly patient; pancytopenia; dysplastic features in multiple lineages; blast cells; ring sideroblasts on marrow
Myelofibrosis	Extramedullary haemopoiesis produces distorted cells	Teardrop cells (dacrocytes) are the hallmark; leukoerythroblastic picture; splenomegaly; dry tap on bone marrow aspirate ^[6]^[7]
Normal variant	Up to ~10–15% elliptocytes can be seen in healthy individuals	No anaemia, no haemolysis markers, no family history

Key pearl from the Haematology Interactive Tutorial: When you see microcytic hypochromic elliptocytes of different sizes on peripheral blood smear, can confidently diagnose iron-deficiency anaemia ^[8]. These "pencil cells" are acquired elliptocytes from iron deficiency, NOT hereditary elliptocytosis.

IDA 'Pencil Cells' vs HE Elliptocytes — High Yield Distinction

IDA pencil cells: Hypochromic, microcytic, variable size (high RDW), accompanied by target cells and reactive thrombocytosis. The elliptocytes are a consequence of the cell being "too thin" — not enough haemoglobin to fill the cell, so it flattens and elongates.
HE elliptocytes: Normochromic, normocytic (unless concurrent haemolysis shifts MCV), uniform ellipses, high proportion ( > 15%), with markers of haemolysis if clinically significant.

3. Differential Diagnosis of Inherited Haemolytic Anaemia

When a patient presents with chronic haemolysis + positive family history + anaemia, the real question is: which inherited haemolytic anaemia is this? The approach taught in the GC lectures is to think in terms of which RBC component is defective ^[2]^[10]:

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 ^[2].

Disorders of red cell membrane: Hereditary spherocytosis, Hereditary elliptocytosis and hereditary pyropoikilocytosis, Southeast Asian ovalocytosis, Hereditary acanthocytosis, Hereditary stomatocytosis ^[2]^[10].

Below is a detailed comparison of each major inherited haemolytic anaemia against HE:

Feature	Hereditary Elliptocytosis (HE)	Hereditary Spherocytosis (HS)	Southeast Asian Ovalocytosis (SAO)
Defect type	Horizontal cytoskeletal	Vertical membrane-cytoskeletal	Band 3 transmembrane rigidity
Key proteins	α-spectrin, β-spectrin, protein 4.1	β-spectrin (most common), α-spectrin, ankyrin, Band 3, protein 4.2 ^[1]^[5]	Band 3 (SLC4A1 27-bp deletion)
Inheritance	AD (common HE); AR (HPP)	AD (75%); 25% sporadic ^[1]^[5]	AD (homozygous = lethal)
Blood film	Elliptocytes 15–100%	Spherocytes (small, round, dense, reduced/absent central pallor) ^[10]	Stomatocytes, large rigid ovalocytes
MCHC	Usually normal	Often raised ( > 36 g/dL — because sphere has minimum SA:volume) ^[5]^[11]	Normal
Osmotic fragility	Usually normal	Increased (spherocytes lyse earlier in hypotonic solutions) ^[5]^[11]	Decreased (rigid cells resist osmotic lysis)
EMA binding	Normal or mildly reduced	Reduced (flow cytometric test for membrane protein deficiency) ^[5]^[11]	Variable
DAT	Negative	Negative	Negative
Severity	Usually asymptomatic	Variable — majority mild to moderate (Hb 8–12 g/dL, RET > 6%) ^[1]	Usually asymptomatic
Haemolysis type	Extravascular (splenic)	Extravascular (splenic) — spherocytes cannot traverse splenic microcirculation ^[5]	Usually no significant haemolysis

HS is the Most Important DDx — and the Most Common Cause of Spherocytes is NOT HS

The most common cause of spherocytes → haemolysis is warm autoimmune haemolytic anaemia (AIHA), not hereditary spherocytosis ^[12]. This is a classic exam trap. The way to distinguish:

HS: DAT negative, lifelong, positive family history
Warm AIHA: DAT positive (IgG ± C3 on RBC surface), acquired, often associated with lymphoproliferative disease or autoimmune conditions

Feature	HE	G6PD Deficiency	Pyruvate Kinase (PK) Deficiency
Inheritance	AD	X-linked recessive	AR
Mechanism	Membrane skeleton defect	Deficient NADPH for glutathione reduction → oxidative damage → Heinz bodies → bite cells	Deficient ATP production → rigid cells → extravascular haemolysis
Trigger	Constant (no trigger needed)	Episodic — triggered by oxidising drugs (primaquine, dapsone, sulphonamides), fava beans, infections	Constant (chronic haemolysis)
Blood film	Elliptocytes	Bite cells, blister cells, Heinz bodies (supravital stain) ^[6]^[7]	Echinocytes, acanthocytes
Haemolysis pattern	Chronic, compensated	Acute, episodic (intravascular + extravascular)	Chronic extravascular
G6PD assay	Normal	Low (may be falsely normal during acute episode because reticulocytes have higher G6PD — repeat after recovery) ^[5]	Normal
Relevance in HK	Rare	Very common (~4.5% of males) — the most common inherited RBC enzyme defect in HK ^[5]	Rare

G6PD assay: may be normal during acute haemolysis → consider repeating test a few weeks after recovery ^[5].

Feature	HE	α-Thalassaemia trait	β-Thalassaemia trait	Sickle Cell Disease
MCV	Normal (unless HPP)	Low	Low	Normal/mildly ↓
Blood film	Elliptocytes	Target cells, microcytic hypochromic	Target cells, basophilic stippling, microcytic hypochromic ^[9]	Sickle cells, target cells, Howell-Jolly bodies
Haemolysis	Usually mild	Minimal	Minimal (trait only)	Chronic + vaso-occlusive crises
Hb electrophoresis	Normal	Normal (need gene testing)	HbA2 raised ( > 3.5%)	HbS present
Relevance in HK	Rare	5% prevalence ^[4]	3% prevalence ^[4]	Very rare in HK Chinese
RDW	Normal	Low (uniform small cells)	Low	Normal/↑

In Hong Kong, the two most common causes of hypochromic microcytic anaemia: Iron deficiency anaemia and Thalassaemia ^[9].

If the patient has haemolytic anaemia but no family history, consider acquired causes. These are not HE but must be excluded:

Category	Condition	Key Distinguishing Feature from HE
Immune-mediated	Warm AIHA	DAT positive (IgG ± C3); spherocytes; associated with SLE, CLL, drugs ^[12]
Immune-mediated	Cold AIHA / Cold agglutinin disease	DAT positive (C3); RBC agglutination on film; associated with infections (Mycoplasma, EBV), lymphoma
Microangiopathic	TTP, HUS, DIC	Schistocytes (fragmented RBCs) on film; thrombocytopenia; elevated LDH; coagulopathy in DIC ^[6]^[7]
Mechanical	Prosthetic heart valve haemolysis	History of valve replacement; schistocytes
Infection	Malaria	Travel history; thick and thin film shows parasites ^[5]^[6]
Paroxysmal	Paroxysmal nocturnal haemoglobinuria (PNH)	Flow cytometry: reduced CD55/CD59 expression; intravascular haemolysis; haemoglobinuria; thrombosis ^[5]

Laboratory features of haemolytic anaemia: Anaemia (mildly macrocytic usually) with reticulocytosis, increase in unconjugated bilirubin, LDH, reduced serum haptoglobin, increased methaemalbumin ^[13].

Blood film in haemolytic anaemia: Polychromasia, Spherocytes (hereditary spherocytosis, immune haemolytic anaemia), RBC fragmentation (microangiopathic haemolysis), RBC agglutination (cold agglutinin disease) ^[13].

Direct antiglobulin test – positive in immune haemolytic anaemia ^[13].

Investigation	What it differentiates
Peripheral blood film	The single most important initial test — morphology points you to the diagnosis
DAT (Direct Antiglobulin / Coombs' Test)	Positive = immune haemolysis (AIHA); Negative in all inherited RBC defects (HS, HE, G6PD, PK, thalassaemia) ^[5]^[13]
Osmotic fragility test	Increased in HS (spherocytes lyse easily); usually normal in HE ^[5]^[11]
EMA binding (flow cytometry)	Reduced in HS (decreased membrane proteins); normal or mildly reduced in HE ^[5]^[11]
G6PD assay	Low in G6PD deficiency; normal in HE
Hb electrophoresis / HPLC	Detects thalassaemia (raised HbA2, HbF) and haemoglobinopathies (HbS, HbC, etc.)
Iron studies	Low ferritin, low iron, high TIBC in IDA
Flow cytometry for CD55/CD59	Absent/reduced in PNH ^[5]
LDH	Most important parameter for working up and ruling out haemolysis — if normal, it is not haemolysis ^[12]

LDH — The Haemolysis Gatekeeper

LDH is the most important parameter for working up and ruling out haemolysis. If LDH is normal, it is not haemolysis ^[12]. LDH is released from RBCs when they are destroyed. A normal LDH effectively excludes significant ongoing haemolysis — regardless of the blood film findings.

Diagnosis	Inheritance	Film	MCV	DAT	Key Test	HK Relevance
Hereditary Elliptocytosis	AD	Elliptocytes > 15%	N	Neg	Clinical + film + FHx	Rare
Hereditary Spherocytosis	AD	Spherocytes	N/↑	Neg	EMA binding, osmotic fragility	Uncommon
G6PD Deficiency	X-linked	Bite cells, Heinz bodies	N	Neg	G6PD assay	Very common
α-Thal trait	AR	Target cells, microcytic	↓	Neg	Gene testing	5% prevalence
β-Thal trait	AR	Target cells, basophilic stippling	↓	Neg	HbA2 raised	3% prevalence
Warm AIHA	Acquired	Spherocytes	N/↑	Pos	DAT positive	Moderate
IDA	Acquired	Pencil cells, target cells	↓	Neg	Iron studies	Very common
PNH	Acquired	Non-specific	N	Neg	CD55/CD59 flow	Rare

High Yield Summary

Elliptocytes on film ≠ HE. The DDx includes IDA (pencil cells), megaloblastic anaemia (macro-ovalocytes), thalassaemia, MDS, myelofibrosis, and normal variant ( < 15%).
For inherited haemolytic anaemia, think: Membrane (HS, HE, SAO, acanthocytosis, stomatocytosis), Metabolism (G6PD, PK), Haemoglobin (thalassaemia, sickle cell, unstable Hb) ^[2]^[10].
DAT is the key test to separate inherited from immune-mediated haemolysis — negative in HS/HE/G6PD, positive in AIHA ^[5]^[13].
Most common cause of spherocytes on film is warm AIHA, not HS ^[12].
LDH is the most important parameter — if normal, it is not haemolysis ^[12].
In HK, the most relevant DDx conditions for inherited anaemia are G6PD deficiency, α-thal trait, and β-thal trait, all of which are far more common than HE.
IDA pencil cells: microcytic, hypochromic, variable size (high RDW) — distinct from HE elliptocytes which are normochromic, normocytic, uniform ^[8]^[9].
EMA binding and osmotic fragility distinguish HS from HE (both abnormal in HS, usually normal in HE) ^[5]^[11].
Hb electrophoresis/HPLC is essential to exclude thalassaemia and haemoglobinopathies in the HK setting.

Active Recall - Differential Diagnosis of Hereditary Elliptocytosis

References

^[1] Senior notes: Ryan Ho Haemtology.pdf (Section 2.5 — Hereditary Elliptocytosis, p.38) ^[2] Senior notes: Block A - Family history of anaemia_ inherited causes of anaemia; haemolytic anaemia; aplastic anaemia.pdf (Disorders of red cell membrane section, p.14; Haemolytic anaemia classification, p.1) ^[4] Senior notes: MBBS Final MB (Pediatrics) (Felix PY Lai).pdf (Thalassaemia epidemiology, p.578) ^[5] Senior notes: Adrian Lui Pediatrics Notes.pdf (Red cell membrane defects table p.374; HS diagnosis p.375; Haemolytic anaemia investigations p.374) ^[6] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (Peripheral blood smear morphology, p.1314) ^[7] Senior notes: MBBS Final MB (Pediatrics) (Felix PY Lai).pdf (Peripheral blood smear morphology, p.557) ^[8] Senior notes: Block A - Hematology Interactive Tutorial.pdf (IDA pencil cells, p.5) ^[9] Senior notes: Block A - Introduction to Haematological investigations (CBP, Clotting).pdf (IDA vs Thalassaemia film, p.5) ^[10] Lecture slides: GC 047. Family history of anaemia.pdf (Disorders of red cell membranes, p.23) ^[11] Senior notes: Block A - Family history of anaemia_ inherited causes of anaemia; haemolytic anaemia; aplastic anaemia.pdf (HS diagnosis — osmotic fragility and EMA binding, p.16) ^[12] Senior notes: Block A - Hematology Data Interpretation.pdf (LDH most important for haemolysis; warm AIHA most common cause of spherocytes, p.2) ^[13] Lecture slides: Haematology Introduction to Haematological investigations (CBP, Clotting).pdf (Haemolytic anaemia laboratory features, p.32)

Diagnostic Criteria, Diagnostic Algorithm and Investigations for Hereditary Elliptocytosis

Unlike conditions such as rheumatoid arthritis or SLE, there are no formal international diagnostic criteria with a validated scoring system for hereditary elliptocytosis. The diagnosis is instead made through a constellation of clinical, haematological, and family history findings. This is important to understand — HE is a clinical-morphological diagnosis, not a criteria-based one.

The diagnosis of HE rests on three pillars:

Pillar	What you need	Why
1. Characteristic blood film	Elliptocytes comprising > 15–25% of all RBCs on peripheral blood smear ^[1]^[6]^[7]	This is the morphological hallmark. < 15% elliptocytes can be normal or acquired. In common HE, elliptocytes range from 15–100% of all RBCs ^[1].
2. Evidence of haemolysis (if clinically significant)	Reticulocytosis, ↑LDH, ↑unconjugated bilirubin, ↓haptoglobin	Confirms that the abnormal morphology is causing functional RBC destruction. Note: many HE patients have no haemolysis — the diagnosis can still be made on film + family history alone.
3. Exclusion of acquired causes of elliptocytosis and other haemolytic anaemias	Negative DAT (rules out immune haemolysis); normal iron studies (rules out IDA pencil cells); normal Hb electrophoresis (rules out thalassaemia/haemoglobinopathy)	You cannot call it "hereditary" until you have excluded the common acquired mimics ^[1]^[5].

A positive family history with autosomal dominant inheritance pattern strongly supports the diagnosis but is absent in ~25% of cases (de novo mutations or low-penetrance alleles in parents) ^[1].

The Diagnosis of HE in Practice

In the real world (and in exams), the diagnosis of common HE is usually straightforward:

You see lots of elliptocytes on a blood film.
The patient is well (no/minimal anaemia).
A family member has the same finding.
DAT is negative.
You are done.

The challenge arises in the severe subtypes (HPP, spherocytic HE) or when there is no family history, where more extensive workup is needed.

The algorithm below walks through the logical sequence of investigations when elliptocytes are identified on a blood film or when a patient presents with chronic haemolytic anaemia and a positive family history.

Key Principle — The Diagnostic Approach is Stepwise

The approach follows a logical hierarchy:

See it — identify elliptocytes on film.
Prove haemolysis — reticulocyte count + haemolysis markers.
Exclude immune — DAT.
Exclude other inherited causes — Hb electrophoresis, G6PD, iron studies.
Confirm hereditary pattern — family screening.
Specialised tests — only if atypical or severe.

Most common HE patients are diagnosed at steps 1–5 without needing step 6.

3. Investigation Modalities — Detailed Interpretation

3.1 First-Line Investigations

Parameter	Expected in Common HE	Expected in HPP	Why
Haemoglobin	Normal or mildly reduced (compensated haemolysis)	Significantly reduced (severe haemolysis, may be < 8 g/dL)	Marrow can usually compensate in common HE; overwhelmed in HPP
MCV	Normal (normocytic)	Very low (50–70 fL — characteristically microcytic)	In HPP, membrane fragments → tiny cells; in common HE, no significant membrane loss
MCHC	Usually normal (compare with HS where MCHC often raised ≥ 36 g/dL ^[1]^[5])	May be elevated	In HS, sphere has minimum SA:V → high Hb concentration per cell; in common HE, cell shape is elliptical but volume relatively preserved
RDW	Normal to mildly elevated	Elevated (heterogeneous fragments)	Useful to distinguish from thalassaemia trait (low RDW) ^[9]
Reticulocyte count	Normal to mildly elevated ( < 6% in mild HE)	Markedly elevated ( > 10%)	Reflects marrow compensatory erythropoiesis; in HPP the drive is massive

CBC in HS: anaemia, MCV variable (decreased in neonate, normal or increased in children/adults due to reticulocytosis), MCHC ≥ 36 g/dL ^[5]. In HE, MCHC is typically NOT elevated — this is a useful distinguishing point.

This is the single most important investigation for diagnosing HE.

Finding	Interpretation	Subtype Correlation
Elliptocytes 15–100% of all RBCs ^[1]	Hallmark of HE. Elongated, oval-shaped RBCs. Must be > 15% to suggest HE (up to 10–15% can be normal)	Common HE
Poikilocytes, fragmented cells, budding cells	Extreme membrane instability → cells fragment under shear stress	HPP ^[1]^[10]
Stomatocytes (mouth-shaped central pallor)	Rigid ovalocytes with transverse slit	SAO ^[10]
Spherocytes mixed with elliptocytes	Combined horizontal + vertical defect	Spherocytic HE (HSE) ^[1]
Polychromasia (blue-tinged larger cells)	Reticulocytes released early from marrow → indicates active compensatory erythropoiesis	Any HE with haemolysis
Target cells	NOT a feature of HE — think thalassaemia or liver disease	Rules against HE

Elliptocytes: Hereditary elliptocytosis – Ask about history of chronic haemolysis including personal and family history of gallstones ^[6]^[7].

Blood-film images show: Numerous elongated, oval/elliptical red cells (elliptocytes). Marked red-cell shape variation (poikilocytosis), including irregularly shaped and fragmented forms, consistent with hereditary pyropoikilocytosis ^[10].

Neonatal HE — A Film Trap

In neonates with HE, the blood film may show poikilocytes and fragments rather than classic elliptocytes. This can mimic HPP or even microangiopathic haemolytic anaemia. Why? Neonatal RBCs contain high levels of fetal haemoglobin (HbF) and free 2,3-DPG, which destabilise the spectrin network. By 6–12 months of age, as HbA replaces HbF, the film typically transitions to showing classic elliptocytes and the haemolysis settles. Don't diagnose HPP prematurely in a neonate — wait and repeat the film.

These are not specific to HE — they confirm that haemolysis is occurring, regardless of cause.

Marker	Expected Result	Pathophysiological Basis
LDH	Elevated	LDH is an intracellular enzyme in RBCs. When RBCs are destroyed (intra- or extravascularly), LDH is released. LDH is the most important parameter for working up and ruling out haemolysis — if normal, it is not haemolysis ^[12].
Unconjugated (indirect) bilirubin	Elevated	Haem from haemoglobin is converted to unconjugated bilirubin by macrophages. Overwhelms hepatic conjugation → unconjugated hyperbilirubinaemia → jaundice ^[2]^[5]
Haptoglobin	Reduced	Haptoglobin is a plasma protein that scavenges free haemoglobin. In haemolysis (especially intravascular, but also to some extent in extravascular), free Hb consumes haptoglobin → levels drop ^[1]^[5]
Methaemalbumin	Elevated (mainly intravascular)	Once haptoglobin is saturated, free haem binds to albumin → forms methaemalbumin. More relevant to intravascular haemolysis ^[1]^[5]
Reticulocyte count	Elevated	Marrow compensatory response → increased release of young RBCs (reticulocytes). These are larger and blue-tinged (polychromasia on film)

Markers of extravascular haemolysis: ↑LDH, ↑unconjugated bilirubin ^[5].

Markers of intravascular haemolysis: ↓haptoglobin (also occurs albeit to a lesser extent in extravascular haemolysis), ↑methaemalbumin, haemosiderinuria and haemoglobinuria ^[1]^[5].

Result	Interpretation
Negative	Expected in HE (and all inherited red cell defects — HS, G6PD, PK, thalassaemia). Rules out immune-mediated haemolysis ^[1]^[5]^[13]
Positive	Immune haemolytic anaemia (warm AIHA, cold AIHA, drug-induced). NOT HE.

Direct antiglobulin test (DAT): use of anti-human Ab on patient's RBCs — tests for prior Ab sensitization on patient RBC ^[1]^[5].

Why does this test work? The DAT uses anti-human immunoglobulin (Coombs' reagent) added to washed patient RBCs. If IgG or complement (C3d) is already coating the RBCs (as in autoimmune haemolysis), the Coombs' reagent will cross-link them → agglutination = positive test. In HE, the RBC defect is structural (cytoskeletal), not immunological, so no antibodies are bound → negative DAT.

3.2 Second-Line Investigations (Exclusion of Other Inherited Causes)

These are ordered to exclude the important differential diagnoses before confirming HE.

Finding	Interpretation
Normal HbA2, HbF, no abnormal bands	Expected in HE — rules out thalassaemia and haemoglobinopathies
HbA2 raised ( > 3.5%)	β-thalassaemia trait
Abnormal band (HbS, HbC, HbE, etc.)	Haemoglobinopathy

Hemoglobin pattern and analysis in thalassemia — this is the key investigation for excluding thalassaemia ^[1]^[5].

Finding	Interpretation
Normal	Expected in HE
Low	G6PD deficiency

G6PD assay: may be normal during acute haemolysis → consider repeating test a few weeks after recovery ^[5]. This is because reticulocytes (which are increased during acute haemolysis) have higher G6PD activity than mature RBCs, giving a falsely normal result.

Parameter	IDA	HE
Serum iron	↓	Normal
Ferritin	↓	Normal
TIBC	↑	Normal
Transferrin saturation	↓	Normal

This excludes iron deficiency anaemia, which is the commonest acquired cause of elliptocytes (pencil cells) ^[8]^[9]^[14].

3.3 Confirmatory / Specialised Investigations

These are used in atypical cases, severe presentations, or when a definitive diagnosis is required (e.g., for genetic counselling).

Principle	Expected in HE	Expected in HS
RBCs are exposed to increasingly hypotonic saline solutions. Cells that have decreased SA:V ratio (e.g., spherocytes) lyse at higher tonicities because they cannot swell as much before bursting.	Usually NORMAL — elliptocytes have relatively preserved SA:V ratio; they are elongated, not spherical	Increased fragility — spherocytes lyse prematurely ^[5]^[11]

Osmotic fragility test (± pre-incubation at 37°C for 24h to increase diagnostic yield): finding is increased fragility compared to normal RBC when exposed to hypotonic solutions of decreasing tonicities. Performance: low sensitivity/specificity compared to flow cytometry ^[5].

The OFT is useful for distinguishing HE from HS — it is abnormal in HS but typically normal in common HE. In spherocytic HE (HSE) or HPP, there may be some increase in osmotic fragility due to the presence of spherocytic forms.

Principle	Expected in HE	Expected in HS
EMA binds to Band 3 and related membrane proteins. Reduced binding indicates decreased membrane protein content (membrane loss). Measured by flow cytometry.	Usually NORMAL or only mildly reduced — membrane loss is not the primary defect in HE (horizontal, not vertical defect)	Reduced binding — the vertical defect causes membrane loss, so there are fewer membrane proteins to bind EMA ^[5]^[11]

Flow cytometric analysis showing ↓eosin-5-maleimide (EMA) binding on red cell skeletal proteins — this is the preferred confirmatory test for HS, not HE ^[5].

OFT and EMA — Normal in HE, Abnormal in HS

This is a high-yield distinction. Both tests detect membrane loss (the vertical defect in HS). Since HE is a horizontal defect (cytoskeletal weakness, not membrane loss), both tests are typically normal in common HE:

Osmotic fragility test → Normal in HE, Increased in HS
EMA binding → Normal in HE, Decreased in HS

This makes these tests useful for differentiating HE from HS in cases with mixed morphology (spherocytic HE) or when the film is ambiguous.

Principle	Finding in HPP	Finding in Common HE
RBCs are heated in a water bath and the temperature at which they fragment is measured	Fragment at 45–46°C (normal RBCs fragment at ~49°C). This is the defining test for HPP ("pyro" = fire/heat)	Fragment at normal temperature (~49°C)

This test is specific for HPP and is not routinely performed — reserved for suspected HPP with severe neonatal haemolysis and bizarre poikilocytes on film.

Principle	Finding
Separates RBC membrane proteins by molecular weight. Identifies which specific cytoskeletal protein is deficient or abnormal	Can demonstrate reduced or abnormal α-spectrin, β-spectrin, or protein 4.1 bands

This is a research/specialised laboratory test, not routinely available. It is used when precise protein characterisation is needed (e.g., for genetic counselling or research).

Test	Purpose
DNA sequencing of SPTA1, SPTB, EPB41, SLC4A1	Identifies the precise causative mutation. Important for: genetic counselling, prenatal diagnosis in severe subtypes (HPP), confirming diagnosis when phenotype is atypical

Genetic testing is increasingly accessible with next-generation sequencing panels but remains a specialised investigation, not first-line.

Finding	Interpretation
Erythroid hyperplasia	Compensatory response to chronic haemolysis — the marrow is working overtime to replace destroyed RBCs. Myeloid:erythroid ratio shifts from normal (~3:1) to closer to 1:1 or even reversed

Bone marrow examination is NOT routinely needed for the diagnosis of HE. It is only indicated if:

There is unexplained pancytopenia suggesting an alternative diagnosis (aplastic anaemia, MDS).
There is diagnostic uncertainty.
An aplastic crisis is suspected (to confirm red cell aplasia).

Marrow examination: indicated in unexplained cytopaenias/leukocytosis. Site: typically posterior iliac crest ^[15].

Principle	Use
Patient RBCs are labelled with radioactive 51Cr and re-injected. The rate of disappearance from the circulation is measured → gives RBC lifespan. Surface counting over the spleen and liver identifies the predominant site of haemolysis	Reserved for difficult cases where evidence of true decreased RBC lifespan is needed, or to confirm splenic destruction prior to considering splenectomy

51Cr labelled RBC study in difficult cases to document evidence of true ↓RBC lifespan + surface counting for predominant site of haemolysis ^[1].

Once HE is diagnosed, certain investigations are ordered to screen for and monitor complications of chronic haemolysis:

Complication	Investigation	Expected Finding
Pigmented gallstones	Abdominal ultrasound	Echogenic foci with acoustic shadowing in gallbladder. ~50% of adults with significant haemolysis develop gallstones ^[1]^[5]
Folate deficiency (megaloblastic crisis)	Serum folate, red cell folate	Low — chronic haemolysis ↑ folate consumption
Iron overload (if transfusion-dependent)	Serum ferritin, transferrin saturation; cardiac MRI T2* if concern for cardiac iron loading	Elevated ferritin → iron overloading macrophages → ferritin leaks into serum ^[14]
Aplastic crisis	Reticulocyte count, Parvovirus B19 IgM serology	Reticulocyte count near zero + positive B19 IgM = acute aplastic crisis ^[1]^[5]
Splenomegaly	Physical examination, abdominal ultrasound	Enlarged spleen from chronic RES work hypertrophy

Investigation Tier	Tests	Purpose
First-line	CBC, reticulocyte count, peripheral blood film	Identify elliptocytes, quantify anaemia, assess marrow response
First-line	LDH, unconjugated bilirubin, haptoglobin	Confirm and quantify haemolysis
First-line	DAT	Exclude immune-mediated haemolysis
Second-line	Hb electrophoresis / HPLC	Exclude thalassaemia and haemoglobinopathies
Second-line	G6PD assay, iron studies	Exclude G6PD deficiency and IDA
Second-line	Family screening (blood film of relatives)	Confirm AD inheritance pattern
Specialised	Osmotic fragility test, EMA binding	Differentiate from HS (both normal in HE, abnormal in HS)
Specialised	Thermal sensitivity test	Diagnose HPP (fragments at 45–46°C)
Specialised	SDS-PAGE, molecular/genetic testing	Identify specific protein/gene defect
Specialised	51Cr labelled RBC study	Document shortened RBC lifespan and site of haemolysis
Complication screening	USS abdomen, serum folate, ferritin, B19 serology	Gallstones, folate deficiency, iron overload, aplastic crisis

GC Lecture Slide — Key Proteins Table: ^[10]

Protein Function Associated disorders
α-spectrin Cytoskeleton network Hereditary spherocytosis, hereditary elliptocytosis
β-spectrin Cytoskeleton network Hereditary pyropoikilocytosis, HS, HE
Ankyrin Vertical contact Hereditary spherocytosis
Band 3 Anion exchange channel HS, SEA ovalocytosis, hereditary acanthocytosis
Protein 4.1 Spectrin–actin contact HE
Protein 4.2 Spectrin–ankyrin interaction HS (Japan)

Protein	Function	Associated disorders
α-spectrin	Cytoskeleton network	Hereditary spherocytosis, hereditary elliptocytosis
β-spectrin	Cytoskeleton network	Hereditary pyropoikilocytosis, HS, HE
Ankyrin	Vertical contact	Hereditary spherocytosis
Band 3	Anion exchange channel	HS, SEA ovalocytosis, hereditary acanthocytosis
Protein 4.1	Spectrin–actin contact	HE
Protein 4.2	Spectrin–ankyrin interaction	HS (Japan)

High Yield Summary

HE is a clinical-morphological diagnosis — no formal scoring criteria. Diagnosis = characteristic blood film (elliptocytes > 15%) + exclusion of acquired causes + negative DAT ± positive family history.
Blood film is the single most important investigation — look for elliptocytes (common HE), poikilocytes/fragments (HPP), stomatocytes (SAO), or mixed spherocytes + elliptocytes (HSE).
Haemolysis markers (LDH, unconjugated bilirubin, haptoglobin, reticulocyte count) confirm functional significance. If LDH is normal, it is not haemolysis ^[12].
DAT must be negative — a positive DAT points to immune haemolysis (AIHA), not HE.
Osmotic fragility test and EMA binding are normal in HE but abnormal in HS — key differentiating point. Both tests detect membrane loss (vertical defect), which is not the mechanism in HE (horizontal defect).
MCHC is elevated in HS (≥ 36 g/dL) but usually normal in HE — another useful distinguishing parameter.
Specialised tests (thermal sensitivity, SDS-PAGE, genetic testing) are reserved for atypical/severe cases (HPP, diagnostic uncertainty, genetic counselling).
Screen for complications: USS abdomen (gallstones), folate levels, ferritin (if transfused), Parvovirus B19 serology (if aplastic crisis suspected).
Key protein–disease associations for exam: α-spectrin → HS + HE; β-spectrin → HPP + HS + HE; Protein 4.1 → HE; Ankyrin → HS; Band 3 → HS + SAO ^[10].

Active Recall - Diagnosis and Investigation of Hereditary Elliptocytosis

References

^[1] Senior notes: Ryan Ho Haemtology.pdf (Section 2.5.1 — Red Cell Membrane Defects and HE, p.37–38) ^[2] Senior notes: Block A - Family history of anaemia_ inherited causes of anaemia; haemolytic anaemia; aplastic anaemia.pdf (Haemolytic anaemia clinical features, p.3) ^[5] Senior notes: Adrian Lui Pediatrics Notes.pdf (HS diagnosis p.375; Haemolytic anaemia investigations p.374; Red cell membrane defects table p.374) ^[6] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (Peripheral blood smear morphology — elliptocytes, p.1314) ^[7] Senior notes: MBBS Final MB (Pediatrics) (Felix PY Lai).pdf (Peripheral blood smear morphology — elliptocytes, p.557) ^[8] Senior notes: Block A - Hematology Interactive Tutorial.pdf (IDA pencil cells, p.5) ^[9] Senior notes: Block A - Introduction to Haematological investigations (CBP, Clotting).pdf (IDA vs Thalassaemia film, RDW, Mentzer index, p.5–6) ^[10] Lecture slides: GC 047. Family history of anaemia.pdf (Disorders of red cell membranes, protein table, p.23–24) ^[11] Senior notes: Block A - Family history of anaemia_ inherited causes of anaemia; haemolytic anaemia; aplastic anaemia.pdf (HS diagnosis — osmotic fragility and EMA binding, p.16) ^[12] Senior notes: Block A - Hematology Data Interpretation.pdf (LDH most important for haemolysis, p.2) ^[13] Lecture slides: Haematology Introduction to Haematological investigations (CBP, Clotting).pdf (Haemolytic anaemia laboratory features, p.32) ^[14] Senior notes: Block A - Many members of the family have anaemia.pdf (Ferritin rationale in thalassaemia; thalassaemia vs IDA differentiation, p.6, p.30) ^[15] Senior notes: Ryan Ho Fundamentals.pdf (Marrow examination indications and technique, p.391)

Management of Hereditary Elliptocytosis

The most important concept to grasp before diving into specifics:

No specific treatment can target the underlying membrane defect ^[1]^[5].

This makes intuitive sense when you think from first principles. The defect in HE is a structural mutation in a cytoskeletal protein (α-spectrin, β-spectrin, or protein 4.1). Every single RBC the patient produces will carry this defect — you cannot "fix" a germline mutation with a drug. The mutant protein folds incorrectly or fails to self-associate, and no pharmacological agent currently reverses this.

Therefore, management is entirely supportive and complication-directed:

Support erythropoiesis (folate supplementation).
Replace blood when needed (transfusion).
Remove the site of destruction if haemolysis is severe (splenectomy).
Manage complications (gallstones, iron overload, crises).

Management of HE: same as HS ^[1].

Treatment for hereditary spherocytosis: Folic acid supplementation (as in all cases of haemolysis), if compensated haemolysis → no specific treatment, cholecystectomy if symptomatic gallstones, splenectomy in severe haemolysis ^[11].

3. Treatment Modalities — Detailed

3.1 General Measures (All Patients)

Folic acid supplementation: 1–2 mg/day for moderate/severe haemolysis, 5 mg/day if pregnant ^[1]^[5].

Aspect	Detail
Why?	Chronic haemolysis → increased erythropoietic drive → bone marrow is turning over RBCs faster than normal → increased folate consumption for DNA synthesis in rapidly dividing erythroid precursors. If folate is not replenished, the patient develops megaloblastic crisis — worsening anaemia with macrocytic change and hypersegmented neutrophils.
Dose	1–2 mg/day for patients with moderate-to-severe haemolysis ^[1]^[5]
Pregnancy dose	5 mg/day — pregnancy already increases folate demand (for the developing fetus), and in a patient with chronic haemolysis, the demand is additive → higher dose needed ^[1]^[5]
Who needs it?	All patients with evidence of chronic haemolysis (elevated reticulocytes, LDH, etc.). Asymptomatic carriers with no haemolysis may not strictly need supplementation but many clinicians prescribe it prophylactically.
Contraindications	None significant. Ensure B12 is checked before starting folate — folate supplementation in the presence of undiagnosed B12 deficiency can mask the haematological features while neurological damage progresses ("folate trap").

Why Folic Acid in All Chronic Haemolysis — First Principles

Folate (vitamin B9) is essential for thymidylate synthesis (conversion of deoxyuridylate to thymidylate) — i.e., making the "T" base for DNA. When the marrow is working at 5–10× normal capacity to replace haemolysed RBCs, folate is consumed at a proportionally higher rate. Run out of folate → impaired DNA synthesis → megaloblastic erythropoiesis → megaloblastic crisis superimposed on the baseline haemolytic anaemia. Supplementation prevents this.

Topic	Rationale
Nature of the condition	Explain that this is a lifelong inherited condition, not curable, but usually benign. Most patients live completely normal lives.
Warning signs of crises	Teach patients/parents to recognise: sudden pallor, worsening jaundice, fever with anaemia (haemolytic crisis), extreme fatigue with pale colour (aplastic crisis from Parvovirus B19).
Avoidance of Parvovirus B19 exposure	Particularly important for patients with moderate/severe haemolysis. Pregnant family members should be warned about B19 exposure risk (can cause hydrops fetalis).
Genetic counselling	Autosomal dominant — 50% chance of transmission to offspring. Family screening with blood films of parents/siblings recommended.

Parameter	Frequency	Purpose
CBC + reticulocyte count	Annually (more frequently if symptomatic)	Monitor anaemia severity and marrow compensation
LFT (bilirubin)	Annually	Monitor degree of haemolysis
Serum folate	Annually	Ensure adequacy of supplementation
Serum ferritin	If receiving transfusions	Monitor for iron overload
Abdominal ultrasound	Periodically (every 3–5 years in moderate haemolysis, or when symptomatic)	Screen for pigmented gallstones

3.2 Transfusion Therapy

Scenario	When to Transfuse
Acute aplastic crisis	Severe anaemia with reticulocyte count near zero (Parvovirus B19) → may need urgent packed RBC transfusion to bridge the 7–10 day aplastic period until marrow recovers
Severe haemolytic crisis	Haemoglobin dropping faster than marrow can compensate (e.g., during acute infection)
Symptomatic chronic anaemia	In HPP or severe HE where Hb is chronically low despite marrow compensation
Neonatal period	Severe neonatal haemolysis (HPP) may require exchange transfusion or top-up transfusions

Transfusion if severe anaemia ^[1]^[5].

Issue	Detail
Iron overload	Each unit of blood (~500 mL) contains ~250 mg of iron. The body has no physiological mechanism for excreting iron — it accumulates. Chronic transfusion → iron deposition in heart (cardiomyopathy), liver (cirrhosis), and endocrine organs (diabetes, hypogonadism) ^[8].
Iron chelation	Required when serum ferritin rises above ~1,000 μg/L or after ~10–20 units of blood. Agents: Desferrioxamine (DFO — subcutaneous/IV infusion), Deferiprone (DFP — oral), Deferasirox (oral). They bind iron and promote excretion via urine and faeces ^[8].
Alloimmunisation	Repeated transfusions → risk of developing RBC alloantibodies → future cross-matching difficulties. Extended phenotype matching reduces this risk.

EPO: may be useful in some infants < 9 months to decrease transfusion requirement ^[1]^[5].

Aspect	Detail
Why?	In the first few months of life, endogenous EPO production is low (physiological nadir). Supplemental EPO can stimulate the marrow to produce more RBCs, reducing the need for transfusion.
Age limit	Useful mainly in infants < 9 months. After this age, endogenous EPO is adequate and the main issue is peripheral destruction (haemolysis), not inadequate production.
Not a long-term solution	EPO does not fix the membrane defect — it just pushes the marrow harder. It is a bridge measure for severely anaemic infants who are too young for splenectomy.

3.3 Splenectomy — The Definitive Intervention

The spleen is the primary site of extravascular haemolysis in HE. Deformed elliptocytes (and especially poikilocytes/fragments in HPP) are trapped in the narrow (~2–3 μm) fenestrations of the splenic sinusoidal endothelium and phagocytosed by splenic macrophages. Removing the spleen removes the site of destruction → RBC lifespan improves dramatically → haemolysis decreases → Hb rises → transfusion requirements decrease or cease.

Important: splenectomy does not cure the membrane defect. The elliptocytes will still be present on the blood film. But without the spleen to destroy them, they survive longer in the circulation.

Splenectomy at > 6 years old for severe haemolysis to decrease transfusion requirement ^[1].

Indications: transfusion-dependence or severely symptomatic anaemia beyond 1 year of age ^[1]^[5].

Indication	Detail
Transfusion-dependent anaemia	Patient requires regular transfusions to maintain an acceptable Hb → splenectomy should reduce/eliminate this need
Severely symptomatic anaemia	Significant symptoms (fatigue, exercise limitation, growth retardation in children) despite maximal supportive therapy
Recurrent haemolytic crises	Frequent exacerbations requiring hospitalisation

Therapeutic splenectomy indications: symptomatic relief in massive splenomegaly, refractory ITP or AIHA, decrease transfusion requirement in thalassaemia major ^[16]. The same principle applies to HE — removing the site of destruction.

Guideline	Rationale
Usually deferred till > 6–7 years old ^[1]^[5]	The spleen is a critical immunological organ, especially in young children. It is the main site of opsonisation and clearance of encapsulated bacteria. Young children have an immature adaptive immune system and rely heavily on splenic function. Splenectomy in a child < 6 years carries a significantly higher risk of overwhelming post-splenectomy infection (OPSI) — a fulminant, often fatal septicaemia caused by encapsulated organisms.

Guideline

Rationale

Usually deferred till > 6–7 years old ^[1]^[5]

The spleen is a critical immunological organ, especially in young children. It is the main site of opsonisation and clearance of encapsulated bacteria. Young children have an immature adaptive immune system and rely heavily on splenic function. Splenectomy in a child < 6 years carries a significantly higher risk of overwhelming post-splenectomy infection (OPSI) — a fulminant, often fatal septicaemia caused by encapsulated organisms.

Approach	Advantage	Disadvantage
Total splenectomy	Maximum haemolysis reduction; definitive	Complete loss of splenic immune function; lifelong infection risk
Partial (subtotal) splenectomy	Preserves some splenic immune function (especially valuable in children); reduces but does not eliminate haemolysis	Splenic remnant may regrow and haemolysis may recur over time; technically more challenging

Current practice increasingly favours partial splenectomy in children with moderate HE/HS, especially if the primary goal is to reduce (not eliminate) transfusion burden while preserving some splenic immune function. Total splenectomy is reserved for the most severe cases.

These are critical and commonly examined:

Measure	Detail	Why
Vaccination against encapsulated organisms	Pneumococcus (PCV13 + PPSV23), Meningococcus (MenACWY + MenB), Haemophilus influenzae type b (Hib)	The spleen is the primary organ for opsonising and clearing encapsulated bacteria. Without it, these organisms can cause OPSI — a rapidly fatal septicaemia. Vaccines should be given at least 2 weeks before elective splenectomy to allow time for antibody response.
Confirm need	Ensure that the patient truly meets criteria for splenectomy; document the site of haemolysis (51Cr scan if needed)	Avoid unnecessary splenectomy

Encapsulated Organisms — The SHiNE Mnemonic

The encapsulated bacteria that pose the greatest risk post-splenectomy:

S — Streptococcus pneumoniae (most important)
H — Haemophilus influenzae type b
N — Neisseria meningitidis
E — Escherichia coli (K1 capsule, especially neonatal)

Also: Salmonella species, Capnocytophaga canimorsus (from dog bites), and malaria parasites (the spleen clears parasitised RBCs).

Measure	Detail	Rationale
Lifelong prophylactic penicillin V	Oral penicillin V 250–500 mg BD (children: 125–250 mg BD). Lifelong in children; at least 5 years in adults, though many centres recommend lifelong ^[1]	Prevents OPSI by providing baseline cover against S. pneumoniae
MedicAlert bracelet / card	Patient must carry identification stating asplenic status	Ensures emergency physicians know to give empirical broad-spectrum antibiotics immediately for any febrile illness
Annual influenza vaccination	Yearly	Influenza can predispose to secondary bacterial pneumonia, which is particularly dangerous in asplenic patients
Booster vaccinations	Pneumococcal booster every 5 years	Maintains protective antibody titres
Malaria prophylaxis	If travelling to endemic areas — heightened vigilance	Asplenic patients are at increased risk of severe malaria because the spleen normally removes parasitised RBCs
Monitoring for post-splenectomy blood film changes	Expect: Howell-Jolly bodies (nuclear remnants normally removed by the spleen), target cells, occasional spurious leukocytosis and increased platelet count ^[16]	These are expected findings, not pathological. Howell-Jolly bodies on film confirm functional asplenia.
Thrombosis prophylaxis	Monitor platelet count post-splenectomy	Reactive thrombocytosis is common post-splenectomy (loss of splenic platelet pooling). Usually self-limiting but in extreme cases ( > 1,000 × 10⁹/L) may require aspirin.

Post-splenectomy blood findings: spurious leukocytosis, increase in platelet counts, abnormal nucleated RBC / Howell-Jolly bodies may be seen on blood film ^[16].

Risk of infection post-splenectomy: life-threatening infection from encapsulated bacteria → overwhelming post-splenectomy infection (OPSI) ^[16].

Contraindication	Rationale
Age < 6 years (relative)	Unacceptably high OPSI risk. Defer unless transfusion requirements are truly life-threatening and no alternatives exist.
Mild/asymptomatic HE	Risk of splenectomy outweighs benefit in a patient with compensated haemolysis and normal Hb. This is the vast majority of HE patients.
Hereditary stomatocytosis	Absolute contraindication in this specific membrane disorder — splenectomy paradoxically increases thrombotic risk dramatically. Not directly relevant to HE, but an important exam fact when discussing splenectomy for membrane disorders.

Complication	Management
Pigmented gallstones	Cholecystectomy if symptomatic ^[11]. Often performed at the same time as splenectomy to avoid two separate operations.
Aplastic crisis (Parvovirus B19)	Supportive — packed RBC transfusion to bridge the 7–10 day aplastic period. B19 is self-limiting in immunocompetent patients. IV immunoglobulin may be considered in immunocompromised patients with persistent B19 viraemia.
Megaloblastic crisis	High-dose folate replacement; ensure B12 is also adequate.
Haemolytic crisis	Treat the precipitant (usually infection); supportive with transfusion if Hb drops significantly.
Neonatal jaundice	Phototherapy ± exchange transfusion depending on bilirubin levels and gestational age. Standard neonatal hyperbilirubinaemia protocols.
Iron overload (if chronically transfused)	Iron chelation: Desferrioxamine (DFO), Deferiprone (DFP), Deferasirox — bind iron and excrete via urine and faeces ^[8]. Target serum ferritin < 1,000 μg/L. Cardiac MRI T2* to assess cardiac iron loading.

Treatment	Why NOT
Allogeneic HSCT (haematopoietic stem cell transplantation)	NOT used due to unfavourable risk-benefit ratio ^[1]^[5]. HSCT carries significant transplant-related mortality and morbidity (graft-vs-host disease, infection, graft failure). Since most HE patients have mild disease manageable with supportive measures ± splenectomy, the risks of HSCT far outweigh the benefits.
Corticosteroids	No role — this is not an immune-mediated haemolysis. The defect is structural, not immunological.
Gene therapy	Not yet clinically available for HE, though theoretically possible in the future.

Severity	Clinical Picture	Management
Asymptomatic / Silent carrier	Normal Hb, no haemolysis, incidental elliptocytes	No specific treatment ^[11]. Reassurance. Genetic counselling. Family screening.
Mild (compensated haemolysis)	Mildly elevated reticulocytes/LDH, normal Hb	Folic acid 1–2 mg/day. Annual monitoring. Genetic counselling.
Moderate	Hb 8–12 g/dL, reticulocytosis, splenomegaly, gallstones	Folic acid 1–2 mg/day (5 mg/day if pregnant). Transfusion for acute crises. USS for gallstones. Consider splenectomy if symptoms significantly impair quality of life.
Severe (HPP / compound heterozygous)	Hb < 8 g/dL, transfusion-dependent, neonatal onset	Chronic transfusion + iron chelation. EPO for infants < 9 months. Splenectomy at > 6 years (partial preferred in children). Pre- and post-splenectomy vaccination and penicillin prophylaxis.

High Yield Summary

No specific treatment can target the underlying membrane defect — management is entirely supportive ^[1]^[5].
Management of HE is the same as HS ^[1].
Folic acid supplementation: 1–2 mg/day (5 mg/day if pregnant) — prevents megaloblastic crisis from increased folate consumption ^[1]^[5].
Splenectomy indications: transfusion-dependence or severely symptomatic anaemia beyond 1 year of age. Usually deferred till > 6–7 years to decrease risk of sepsis ^[1]^[5].
Pre-splenectomy vaccines against encapsulated organisms: Pneumococcus, Meningococcus, Haemophilus influenzae type b.
Post-splenectomy: lifelong penicillin prophylaxis, MedicAlert bracelet, annual influenza vaccine, booster vaccines.
Allogeneic HSCT is NOT used — unfavourable risk-benefit ratio ^[1]^[5].
EPO may be useful in infants < 9 months to reduce transfusion requirement ^[1]^[5].
Cholecystectomy for symptomatic gallstones ^[11].
Iron chelation (DFO, DFP, Deferasirox) for chronically transfused patients to prevent iron overload ^[8].
Most HE patients (common HE) need no treatment — observation, folate, and reassurance only.

Active Recall - Management of Hereditary Elliptocytosis

References

^[1] Senior notes: Ryan Ho Haemtology.pdf (Section 2.5 — Red Cell Membrane Defects, HE and HS management, p.38–39) ^[5] Senior notes: Adrian Lui Pediatrics Notes.pdf (HS/HE management p.375; Red cell membrane defects p.374) ^[8] Senior notes: Block A - Hematology Interactive Tutorial.pdf (Iron in transfusion, chelation agents, p.5) ^[11] Senior notes: Block A - Family history of anaemia_ inherited causes of anaemia; haemolytic anaemia; aplastic anaemia.pdf (HS treatment — folic acid, cholecystectomy, splenectomy, p.17) ^[16] Senior notes: Block A - Splenomegaly_ common causes of splenomegaly; myeloproliferative diseases.pdf (Splenectomy indications, post-splenectomy findings, OPSI risk, p.19)

Complications of Hereditary Elliptocytosis

The complications of HE are fundamentally the consequences of chronic haemolysis and its downstream effects. Since most patients with common HE have minimal or compensated haemolysis, complications are correspondingly mild or absent. However, patients at the severe end of the spectrum (HPP, compound heterozygotes, spherocytic HE) can develop the full range of haemolytic complications.

The key framework is to think of complications in four categories:

Direct consequences of chronic RBC destruction (bilirubin overload, splenomegaly).
Acute crises that punctuate the chronic course.
Consequences of chronic anaemia (if uncompensated).
Complications of treatment (splenectomy, chronic transfusion).

Complications of haemolysis: NNJ, splenomegaly and pigmented gallstones (50% adults) ^[1]^[5].

Crises of anaemia exacerbation complicating typical course of chronic haemolysis: haemolytic crisis, megaloblastic crisis, aplastic crisis ^[1]^[5].

2. Complications of Chronic Haemolysis

Aspect	Detail
Prevalence	~50% of adults with significant chronic haemolysis ^[1]^[5]
Pathophysiology	Chronic extravascular haemolysis → macrophages break down haemoglobin → haem is converted to unconjugated bilirubin → transported to liver → conjugated and excreted in bile. When the bilirubin load chronically exceeds the normal bile solubility threshold, the excess unconjugated bilirubin precipitates with calcium in the gallbladder → calcium bilirubinate (pigmented) gallstones. These are dark, small, multiple stones — distinct from the large, pale cholesterol stones of metabolic syndrome.
Clinical presentation	May be asymptomatic (found incidentally on ultrasound) or present with biliary colic (RUQ pain after fatty meals), acute cholecystitis (persistent RUQ pain + fever + Murphy's sign), or choledocholithiasis (obstructive jaundice, cholangitis).
Management	Cholecystectomy if symptomatic ^[11]. Often performed simultaneously with splenectomy to avoid two operations.

Gallstone Type Matters

In chronic haemolysis, the stones are pigmented (calcium bilirubinate) — black, radio-opaque on X-ray. This is different from cholesterol stones (pale, radiolucent, associated with obesity/metabolic syndrome) and mixed stones. If an exam question describes a young patient with chronic haemolysis and gallstones, they are almost certainly pigmented stones.

Aspect	Detail
Pathophysiology	The spleen is the primary site of extravascular haemolysis in HE. Deformed elliptocytes are trapped in the splenic cords of Billroth and phagocytosed by macrophages in the red pulp. Chronic work hypertrophy of the reticuloendothelial macrophages + pooling of trapped RBCs → progressive splenic enlargement.
Consequences	(1) Hypersplenism: the enlarged spleen pools and destroys not just RBCs but also platelets and white cells → can cause pancytopenia (anaemia worsened, thrombocytopenia, leukopenia). (2) Mechanical symptoms: abdominal fullness, early satiety (stomach compression), LUQ discomfort. (3) Splenic sequestration crisis (rare in HE, more characteristic of sickle cell disease): acute massive pooling of blood in the spleen → hypovolaemia and cardiovascular collapse.

Aspect

Detail

Pathophysiology

The spleen is the primary site of extravascular haemolysis in HE. Deformed elliptocytes are trapped in the splenic cords of Billroth and phagocytosed by macrophages in the red pulp. Chronic work hypertrophy of the reticuloendothelial macrophages + pooling of trapped RBCs → progressive splenic enlargement.

Consequences

(1) Hypersplenism: the enlarged spleen pools and destroys not just RBCs but also platelets and white cells → can cause pancytopenia (anaemia worsened, thrombocytopenia, leukopenia). (2) Mechanical symptoms: abdominal fullness, early satiety (stomach compression), LUQ discomfort. (3) Splenic sequestration crisis (rare in HE, more characteristic of sickle cell disease): acute massive pooling of blood in the spleen → hypovolaemia and cardiovascular collapse.

Clinical features of splenomegaly: pressure symptoms (abdominal fullness, early satiety), symptoms related to pancytopenia (due to greater blood pooling in spleen), features due to the underlying disease ^[16].

Aspect	Detail
Why neonates are vulnerable	The neonatal liver has immature UDP-glucuronosyltransferase (the enzyme that conjugates bilirubin). A normal neonate already has physiological jaundice because of this. Add chronic haemolysis from HE on top → bilirubin production overwhelms the already limited conjugation capacity → severe unconjugated hyperbilirubinaemia.
Risk	Kernicterus — unconjugated bilirubin is lipid-soluble and crosses the immature blood-brain barrier → deposits in the basal ganglia and brainstem nuclei → irreversible neurological damage (choreoathetosis, sensorineural deafness, gaze palsy).
Subtypes most affected	HPP (hereditary pyropoikilocytosis) and moderate-to-severe HE. Common HE may cause only mild NNJ.
Management	Phototherapy (isomerises unconjugated bilirubin to a water-soluble form that can be excreted without conjugation) ± exchange transfusion if bilirubin exceeds treatment thresholds.

Complications of haemolysis: NNJ ^[1]^[5].

3. Acute Crises

These are acute episodes that punctuate the chronic course of HE. They are shared with all chronic haemolytic anaemias (HS, sickle cell disease, thalassaemia intermedia, PK deficiency, etc.).

Aspect	Detail
Cause	Parvovirus B19 infection ^[1]^[5]
Pathophysiology	Parvovirus B19 has tropism for erythroid precursors in the bone marrow — it binds to the P antigen (globoside) on the surface of early erythroid progenitors → enters the cell → replicates → lyses the erythroid precursor. This causes temporary pure red cell aplasia lasting ~7–10 days (the time it takes for the immune system to clear the virus). In a normal person, this is barely noticeable because normal RBCs live ~120 days — losing 7–10 days of production is trivial. But in HE (especially HPP), where RBC lifespan may be shortened to 10–30 days, losing even one week of production causes a precipitous drop in Hb.
Key distinguishing feature	Severe anaemia with ↓reticulocyte count ^[1]^[5]. This is the critical distinction from a haemolytic crisis (where reticulocytes are INCREASED). The marrow is temporarily "switched off" for the red cell line.
Clinical presentation	Acute onset of severe pallor, fatigue, tachycardia, dizziness, possible high-output cardiac failure. May have a preceding viral prodrome (fever, rash — "slapped cheek" rash in children with erythema infectiosum / fifth disease).
Management	Supportive — packed RBC transfusion to bridge the aplastic period. B19 is self-limiting in immunocompetent patients; marrow recovers spontaneously in ~7–10 days. The reticulocyte count will rebound sharply when the marrow recovers.
Important note	One episode of B19 confers lifelong immunity → aplastic crisis from B19 is usually a one-time event.

Aplastic Crisis — The Most Dangerous Acute Complication

This is the complication that can kill an HE patient. A haemolytic crisis rarely drops Hb fast enough to be life-threatening because the marrow is still compensating. But in an aplastic crisis, the marrow is shut down while haemolysis continues unabated → Hb can fall to dangerously low levels within days. Always check the reticulocyte count — a near-zero reticulocyte count in a patient with known chronic haemolysis = aplastic crisis until proven otherwise.

Aspect	Detail
Cause	Usually associated with infections (viral or bacterial) ^[1]^[5]
Pathophysiology	Infections → fever → increased splenic activity (macrophage activation) + inflammatory cytokines further damage already fragile RBC membranes → accelerated extravascular haemolysis → Hb drops faster than marrow can compensate.
Key feature	Worsening jaundice, falling Hb, but reticulocyte count is INCREASED (the marrow is working harder, unlike in aplastic crisis).
Management	Treat the underlying infection. Transfuse if symptomatic anaemia. Usually self-limiting.

Haemolytic crisis due to ↑severity of haemolysis, uncommon, usually associated with infections ^[1]^[5].

Aspect	Detail
Cause	Folate deficiency (occasionally B12) ^[1]^[5]
Pathophysiology	Chronic haemolysis → increased erythropoietic drive → bone marrow consumes folate at 5–10× normal rate for DNA synthesis in rapidly dividing erythroid precursors. If dietary folate intake is borderline or supplementation is inadequate → folate stores deplete → impaired DNA synthesis → megaloblastic change in erythroid precursors → ineffective erythropoiesis (precursors die in the marrow) + macro-ovalocytes in peripheral blood → worsening anaemia superimposed on baseline haemolysis.
Key feature	Rising MCV, oval macrocytes, hypersegmented neutrophils on film, low serum/red cell folate.
When it typically occurs	Usually occurring during pregnancy when there is ↑folate need — may be the first presentation of HE if previously undiagnosed ^[1]^[5].
Management	High-dose folate replacement. Prevention with daily folic acid supplementation (1–2 mg/day, 5 mg/day in pregnancy).

These complications are relevant mainly to HPP or poorly managed severe HE where Hb is chronically low.

Complication	Pathophysiology
High-output cardiac failure	Chronic anaemia → reduced oxygen-carrying capacity → heart compensates by increasing cardiac output (increased heart rate + stroke volume) → over time, the heart cannot sustain this demand → dilated cardiomyopathy → heart failure.
Growth retardation (in children)	Chronic tissue hypoxia + increased metabolic demands of constant compensatory erythropoiesis → calories diverted from growth to haemopoiesis → poor growth and delayed puberty.
Skeletal changes / Marrow expansion	Severe chronic anaemia from infancy → maximal bone marrow expansion to compensate → cortical thinning, widened diploe of skull (hair-on-end appearance on skull X-ray), frontal bossing, maxillary hypertrophy ("chipmunk facies"). This is the same mechanism as in thalassaemia major but is rare in HE — only seen in the most severe HPP cases.
Leg ulcers	Chronic haemolysis → impaired microvascular oxygen delivery + free haemoglobin-mediated nitric oxide scavenging → endothelial dysfunction → ischaemic skin breakdown, typically over the malleoli. More commonly associated with sickle cell disease and severe HS.
Folate deficiency (if unsupplemented)	As described above — the precursor to megaloblastic crisis.

5. Complications of Treatment

Complication	Pathophysiology	Prevention/Management
Overwhelming post-splenectomy infection (OPSI)	The spleen is the primary site for opsonisation and phagocytosis of encapsulated bacteria. Without it, these organisms proliferate unchecked in the bloodstream → fulminant septicaemia with DIC, multi-organ failure. Mortality can exceed 50% once established. Pathogens: Streptococcus pneumoniae (most common), Neisseria meningitidis, Haemophilus influenzae ^[16]^[17]	Pre-splenectomy vaccination (Pneumococcal, Meningococcal, Hib) at least 2 weeks before surgery; lifelong prophylactic penicillin V; MedicAlert bracelet; patient education to seek immediate medical attention for any febrile illness ^[16]^[17]
Post-splenectomy thrombocytosis	Loss of splenic platelet pooling (normally the spleen sequesters ~30% of circulating platelets) → acute rise in platelet count. May also reflect a reactive acute-phase response post-surgery.	Prophylactic aspirin if platelet > 1,000 × 10⁹/L ^[17]. Usually self-limiting.
Venous thromboembolism	Post-splenectomy patients have a chronically increased risk of VTE — multifactorial: thrombocytosis, loss of splenic filtration of procoagulant microparticles, altered RBC deformability → endothelial damage.	Vigilance for DVT/PE symptoms. Thromboprophylaxis perioperatively.
Portal / splenic vein thrombosis	Postoperative complication — altered flow dynamics in the splenic vein stump.	USS Doppler monitoring if symptomatic (abdominal pain, fever). Anticoagulation if confirmed.

Risk of infection post-splenectomy: life-threatening infection from encapsulated bacteria → overwhelming post-splenectomy infection ^[16].

Post-splenectomy blood findings: spurious leukocytosis, increase in platelet counts, Howell-Jolly bodies on PBS ^[16].

Post-splenectomy septicaemia: Risk factors — young, immunocompromised. Pathogens — Strep pneumoniae, N meningitidis, H influenzae ^[17].

OPSI — The Exam Favourite Post-Splenectomy Complication

OPSI can occur at any time after splenectomy — even decades later. The risk is highest in the first 2 years and in children < 6 years. It classically presents as a fulminant, rapidly progressive sepsis — the patient may go from well to dead within 12–24 hours. The organisms are almost always encapsulated bacteria because the spleen is essential for complement-mediated opsonisation and phagocytosis of these organisms. Without the spleen, even vaccinated patients remain at increased risk, hence the need for lifelong penicillin prophylaxis (at least in children and many centres recommend it lifelong in adults too) and immediate empirical antibiotics for any febrile episode.

Complication	Pathophysiology	Prevention/Management
Transfusional iron overload	Each unit of blood contains ~250 mg of iron. The body has no physiological excretion mechanism for iron. After ~10–20 units, iron accumulates in parenchymal organs → cardiac (restrictive/dilated cardiomyopathy, arrhythmias — the leading cause of death in transfusion-dependent patients), hepatic (fibrosis → cirrhosis), endocrine (diabetes mellitus from pancreatic iron deposition, hypogonadism from pituitary iron deposition, hypothyroidism) ^[8]	Iron chelation therapy: Desferrioxamine (DFO), Deferiprone (DFP), Deferasirox. Target serum ferritin < 1,000 μg/L. Cardiac MRI T2* for cardiac iron assessment ^[8]
Alloimmunisation	Repeated exposure to foreign RBC antigens → patient develops alloantibodies against minor blood group antigens (e.g., Kidd, Duffy, Kell, Rh subtypes) → makes future cross-matching increasingly difficult → risk of delayed haemolytic transfusion reactions	Extended phenotype matching; leucodepletion of blood products
Transfusion-transmitted infections	Risk of bloodborne pathogens (HBV, HCV, HIV — now extremely rare with screening; bacterial contamination of stored products)	Stringent blood bank screening; leucodepleted, irradiated products when indicated
Transfusion reactions	Febrile non-haemolytic (most common), allergic, acute haemolytic (ABO incompatibility), TRALI	Standard transfusion safety protocols; washed RBCs for patients with known reactions

Complication	Detail
Worsening anaemia	Pregnancy increases plasma volume (physiological dilution) + increases folate demand → can unmask previously compensated HE or precipitate a megaloblastic crisis
First presentation of HE	Megaloblastic crisis due to folate deficiency, usually occurring during pregnancy when there is ↑folate need (if HE/HS first presents in pregnancy) ^[1]^[5] — the increased folate demand of pregnancy tips a previously compensated patient into clinical anaemia
Fetal considerations	If both parents carry spectrin mutations, offspring may be homozygous/compound heterozygous → HPP phenotype. SAO homozygosity is lethal (hydrops fetalis). Genetic counselling pre-conception is important.

Category	Complication	Key Mechanism	Key Feature
Chronic haemolysis	Pigmented gallstones	↑Unconjugated bilirubin → calcium bilirubinate precipitation	RUQ pain; USS shows stones; ~50% of adults
	Splenomegaly	RES work hypertrophy + RBC trapping	LUQ mass; early satiety; hypersplenism
	NNJ	Immature hepatic conjugation + haemolysis	Neonatal jaundice; kernicterus risk
Acute crises	Aplastic crisis	Parvovirus B19 → erythroid precursor lysis	↓↓ Reticulocytes; severe acute anaemia
	Haemolytic crisis	Infection → accelerated splenic destruction	↑ Reticulocytes; worsening jaundice
	Megaloblastic crisis	Folate depletion from chronic marrow hyperactivity	↑ MCV; hypersegmented neutrophils
Chronic anaemia	Cardiac failure, growth retardation, skeletal changes	Tissue hypoxia; marrow expansion	Severe/HPP only
Post-splenectomy	OPSI	Loss of splenic clearance of encapsulated bacteria	Fulminant sepsis
	Thrombocytosis / VTE	Loss of platelet pooling	Reactive ↑platelets
Transfusion	Iron overload	No physiological iron excretion	Cardiomyopathy, cirrhosis, endocrinopathy
	Alloimmunisation	Antibodies against minor blood groups	Difficult cross-matching

High Yield Summary

Complications of haemolysis: NNJ, splenomegaly, and pigmented gallstones (~50% of adults) ^[1]^[5].
Three acute crises: Aplastic (Parvovirus B19 — reticulocytes ↓↓), Haemolytic (infections — reticulocytes ↑), Megaloblastic (folate deficiency — ↑MCV).
Aplastic crisis is the most dangerous — marrow stops producing RBCs while haemolysis continues unabated → precipitous Hb drop. The key diagnostic clue is a near-zero reticulocyte count.
OPSI is the most feared post-splenectomy complication — fulminant sepsis from encapsulated bacteria (S. pneumoniae, N. meningitidis, H. influenzae). Prevented by vaccination + lifelong penicillin.
Iron overload from chronic transfusion is the leading cause of mortality in transfusion-dependent patients — cardiac iron deposition causing cardiomyopathy. Managed with chelation therapy.
Most complications are shared across all chronic haemolytic anaemias — the same framework applies to HS, HE, thalassaemia intermedia/major, PK deficiency, and sickle cell disease.
Most common HE patients (common HE) develop no significant complications because haemolysis is compensated.

Active Recall - Complications of Hereditary Elliptocytosis

References

^[1] Senior notes: Ryan Ho Haemtology.pdf (Section 2.5 — HE and HS complications and crises, p.38–39) ^[5] Senior notes: Adrian Lui Pediatrics Notes.pdf (HS complications and crises, p.375) ^[8] Senior notes: Block A - Hematology Interactive Tutorial.pdf (Iron in transfusion, chelation agents, p.5) ^[11] Senior notes: Block A - Family history of anaemia_ inherited causes of anaemia; haemolytic anaemia; aplastic anaemia.pdf (HS treatment — cholecystectomy, p.17) ^[16] Senior notes: Block A - Splenomegaly_ common causes of splenomegaly; myeloproliferative diseases.pdf (Splenectomy complications, OPSI, post-splenectomy CBC changes, p.19) ^[17] Senior notes: Maksim Surgery Notes.pdf (Splenectomy indications, complications, OPSI prevention, p.152–153)

High Yield Summary

HE = horizontal cytoskeletal defect (α-spectrin most common mutation) → mechanically weak meshwork → RBCs permanently deformed into ellipses after circulatory shear stress.
HS = vertical membrane-cytoskeleton defect → membrane lipid loss → spherocytes. This is the key conceptual distinction.
Subtypes: Common HE, HPP, SAO, HSE — varying in severity from asymptomatic to transfusion-dependent.
Most HE patients are asymptomatic — incidental elliptocytes on blood film. ~90% have compensated haemolysis with normal Hb.
When haemolysis occurs, it is extravascular (splenic) → jaundice, splenomegaly, pigmented gallstones.
Clinical features are variable depending on subtypes — key signs include pallor, jaundice, splenomegaly, and gallstones.
Crises: haemolytic (infections), aplastic (Parvovirus B19 — ↓reticulocytes), megaloblastic (folate deficiency).
Prevalence ~1/2,000–4,000; enriched in Africa, Mediterranean, SE Asia due to malaria selection pressure.
Management: same as HS (supportive, folate supplementation, splenectomy for severe cases).
Disorders of red cell membrane causing inherited anaemia: Hereditary spherocytosis, hereditary elliptocytosis and hereditary pyropoikilocytosis, Southeast Asian ovalocytosis, hereditary acanthocytosis, hereditary stomatocytosis ^[2].

High Yield Summary

Elliptocytes on film ≠ HE. The DDx includes IDA (pencil cells), megaloblastic anaemia (macro-ovalocytes), thalassaemia, MDS, myelofibrosis, and normal variant ( < 15%).
For inherited haemolytic anaemia, think: Membrane (HS, HE, SAO, acanthocytosis, stomatocytosis), Metabolism (G6PD, PK), Haemoglobin (thalassaemia, sickle cell, unstable Hb) ^[2]^[10].
DAT is the key test to separate inherited from immune-mediated haemolysis — negative in HS/HE/G6PD, positive in AIHA ^[5]^[13].
Most common cause of spherocytes on film is warm AIHA, not HS ^[12].
LDH is the most important parameter — if normal, it is not haemolysis ^[12].
In HK, the most relevant DDx conditions for inherited anaemia are G6PD deficiency, α-thal trait, and β-thal trait, all of which are far more common than HE.
IDA pencil cells: microcytic, hypochromic, variable size (high RDW) — distinct from HE elliptocytes which are normochromic, normocytic, uniform ^[8]^[9].
EMA binding and osmotic fragility distinguish HS from HE (both abnormal in HS, usually normal in HE) ^[5]^[11].
Hb electrophoresis/HPLC is essential to exclude thalassaemia and haemoglobinopathies in the HK setting.

High Yield Summary

HE is a clinical-morphological diagnosis — no formal scoring criteria. Diagnosis = characteristic blood film (elliptocytes > 15%) + exclusion of acquired causes + negative DAT ± positive family history.
Blood film is the single most important investigation — look for elliptocytes (common HE), poikilocytes/fragments (HPP), stomatocytes (SAO), or mixed spherocytes + elliptocytes (HSE).
Haemolysis markers (LDH, unconjugated bilirubin, haptoglobin, reticulocyte count) confirm functional significance. If LDH is normal, it is not haemolysis ^[12].
DAT must be negative — a positive DAT points to immune haemolysis (AIHA), not HE.
Osmotic fragility test and EMA binding are normal in HE but abnormal in HS — key differentiating point. Both tests detect membrane loss (vertical defect), which is not the mechanism in HE (horizontal defect).
MCHC is elevated in HS (≥ 36 g/dL) but usually normal in HE — another useful distinguishing parameter.
Specialised tests (thermal sensitivity, SDS-PAGE, genetic testing) are reserved for atypical/severe cases (HPP, diagnostic uncertainty, genetic counselling).
Screen for complications: USS abdomen (gallstones), folate levels, ferritin (if transfused), Parvovirus B19 serology (if aplastic crisis suspected).
Key protein–disease associations for exam: α-spectrin → HS + HE; β-spectrin → HPP + HS + HE; Protein 4.1 → HE; Ankyrin → HS; Band 3 → HS + SAO ^[10].

High Yield Summary

No specific treatment can target the underlying membrane defect — management is entirely supportive ^[1]^[5].
Management of HE is the same as HS ^[1].
Folic acid supplementation: 1–2 mg/day (5 mg/day if pregnant) — prevents megaloblastic crisis from increased folate consumption ^[1]^[5].
Splenectomy indications: transfusion-dependence or severely symptomatic anaemia beyond 1 year of age. Usually deferred till > 6–7 years to decrease risk of sepsis ^[1]^[5].
Pre-splenectomy vaccines against encapsulated organisms: Pneumococcus, Meningococcus, Haemophilus influenzae type b.
Post-splenectomy: lifelong penicillin prophylaxis, MedicAlert bracelet, annual influenza vaccine, booster vaccines.
Allogeneic HSCT is NOT used — unfavourable risk-benefit ratio ^[1]^[5].
EPO may be useful in infants < 9 months to reduce transfusion requirement ^[1]^[5].
Cholecystectomy for symptomatic gallstones ^[11].
Iron chelation (DFO, DFP, Deferasirox) for chronically transfused patients to prevent iron overload ^[8].
Most HE patients (common HE) need no treatment — observation, folate, and reassurance only.

High Yield Summary

Complications of haemolysis: NNJ, splenomegaly, and pigmented gallstones (~50% of adults) ^[1]^[5].
Three acute crises: Aplastic (Parvovirus B19 — reticulocytes ↓↓), Haemolytic (infections — reticulocytes ↑), Megaloblastic (folate deficiency — ↑MCV).
Aplastic crisis is the most dangerous — marrow stops producing RBCs while haemolysis continues unabated → precipitous Hb drop. The key diagnostic clue is a near-zero reticulocyte count.
OPSI is the most feared post-splenectomy complication — fulminant sepsis from encapsulated bacteria (S. pneumoniae, N. meningitidis, H. influenzae). Prevented by vaccination + lifelong penicillin.
Iron overload from chronic transfusion is the leading cause of mortality in transfusion-dependent patients — cardiac iron deposition causing cardiomyopathy. Managed with chelation therapy.
Most complications are shared across all chronic haemolytic anaemias — the same framework applies to HS, HE, thalassaemia intermedia/major, PK deficiency, and sickle cell disease.
Most common HE patients (common HE) develop no significant complications because haemolysis is compensated.

Hereditary Elliptocytosis

1. Definition

2. Epidemiology

3. Anatomy and Function of the RBC Membrane Skeleton

3.1 Normal RBC Structure

3.2 Membrane Skeleton Components

A. Lipid Bilayer

B. Cytoskeletal Meshwork (Underneath the lipid bilayer)

3.3 Horizontal vs. Vertical Interactions — The Key Concept

3.4 How the Normal RBC Maintains Shape

4. Aetiology

4.1 Genetic Basis

4.2 Inheritance Pattern

4.3 Hong Kong Context

5. Pathophysiology

5.1 Molecular Defect → Cellular Consequence

5.2 Why Elliptocytes and Not Spherocytes?

5.3 Site and Mechanism of Haemolysis

5.4 Why Most HE Patients Are Asymptomatic

6. Classification / Subtypes

7. Clinical Features

7.1 General Principles

7.2 Symptoms (with pathophysiological basis)

7.3 Signs (with pathophysiological basis)

7.4 Haemolytic Crises

7.5 Special Considerations by Subtype

Common HE

HPP

SAO

8. Summary of Key Comparisons: HE vs HS

Active Recall - Hereditary Elliptocytosis

References

1. Clinical Context — Why Differential Diagnosis Matters

2. Differential Diagnosis of Elliptocytes on Blood Film

3. Differential Diagnosis of Inherited Haemolytic Anaemia

3.1 Other RBC Membrane Disorders

3.2 RBC Enzyme Defects

3.3 Haemoglobinopathies and Thalassaemias

4. Differential Diagnosis of Acquired Haemolytic Anaemias

5. Approach to Differential Diagnosis — Decision Algorithm

6. Key Distinguishing Investigations at a Glance

7. Summary Table — "The Big Picture" DDx of HE

Active Recall - Differential Diagnosis of Hereditary Elliptocytosis

1. Diagnostic Criteria

2. Diagnostic Algorithm

3. Investigation Modalities — Detailed Interpretation

3.1 First-Line Investigations

3.1.1 Complete Blood Count (CBC / CBP)

3.1.2 Peripheral Blood Film (Manual Smear)

3.1.3 Haemolysis Markers

3.1.4 Direct Antiglobulin Test (DAT / Direct Coombs' Test)

3.2 Second-Line Investigations (Exclusion of Other Inherited Causes)

3.2.1 Haemoglobin Electrophoresis / HPLC

3.2.2 G6PD Assay

3.2.3 Iron Studies

3.3 Confirmatory / Specialised Investigations

3.3.1 Osmotic Fragility Test (OFT)

3.3.2 Eosin-5-Maleimide (EMA) Binding Test (Flow Cytometry)

3.3.3 Thermal Sensitivity / Heat Fragmentation Test

3.3.4 SDS-PAGE (Sodium Dodecyl Sulfate – Polyacrylamide Gel Electrophoresis) of Membrane Proteins

3.3.5 Molecular / Genetic Testing

3.3.6 Bone Marrow Examination

3.3.7 Labelled RBC Study (51-Chromium)

3.4 Investigations for Complications

4. Summary: Investigations at a Glance

Active Recall - Diagnosis and Investigation of Hereditary Elliptocytosis

1. Overarching Principles

2. Management Algorithm

3. Treatment Modalities — Detailed

3.1 General Measures (All Patients)

3.1.1 Folic Acid Supplementation

3.1.2 Patient and Family Education

3.1.3 Regular Follow-up and Monitoring

3.2 Transfusion Therapy

3.2.1 Indications

3.2.2 Considerations in Chronic Transfusion

3.2.3 EPO (Erythropoietin)

3.3 Splenectomy — The Definitive Intervention

3.3.1 Rationale

3.3.2 Indications