Hereditary spherocytosis

01OverviewDefinition, clinical context and the essential points that orientate the chapter.

Membrane proteins such as ankyrin, spectrin, band 3 or protein 4.2 normally preserve the red cell's biconcave surface area and flexibility. Quantitative or functional defects cause progressive membrane loss, a spherical shape and reduced passage through splenic cords. Splenic macrophages remove the least deformable cells, creating extravascular haemolysis and compensatory marrow expansion. Inheritance is often autosomal dominant, but recessive and de novo disease occur, so a negative family history does not exclude the diagnosis.

Clinical severity is judged longitudinally. Mild disease may have normal haemoglobin with reticulocytosis and intermittent jaundice; moderate disease brings anaemia, splenomegaly and gallstones; severe disease may impair growth and require transfusion. Intercurrent infection can expose limited marrow reserve. A high reticulocyte count indicates compensation, whereas an unexpectedly low count during worsening anaemia should trigger urgent evaluation for parvovirus-related aplasia, nutrient deficiency or marrow disease.

Diagnosis integrates phenotype, film, haemolysis markers, antiglobulin testing and a validated membrane assay. Splenectomy is considered for clinically important anaemia, transfusion burden, impaired quality of life or symptomatic splenomegaly, not simply because spherocytes are present. Total splenectomy gives the largest haematological response; partial procedures may be discussed in selected children. Cholecystectomy decisions follow symptoms and gallbladder findings and should be coordinated with surgical and haematology teams.

Key points

Hereditary spherocytosis is an inherited red-cell membrane disorder causing poorly deformable spherocytes to be trapped and destroyed in the spleen.
Anaemia, jaundice, splenomegaly, reticulocytosis and pigment gallstones vary from an incidental compensated phenotype to transfusion-dependent disease in infancy.
A blood film may show dense spherocytes without central pallor, but autoimmune haemolysis also produces spherocytes and must be separated with a direct antiglobulin test.
Raised mean corpuscular haemoglobin concentration, unconjugated bilirubin and lactate dehydrogenase with low haptoglobin support haemolysis; indices can be subtle between crises.
Eosin-5-maleimide binding by flow cytometry is a useful confirmatory membrane test in most UK specialist laboratories; equivocal cases may need additional testing or genomic analysis.
Parvovirus B19 can abruptly suppress reticulocytes, producing a disproportionate haemoglobin fall and sometimes affecting several members of a household.
Folate is used when erythropoietic demand is substantial, while red-cell transfusion is reserved for symptomatic or severe anaemia rather than a habitual haemoglobin number alone.
Splenectomy improves haemolysis but does not correct the membrane defect; timing weighs disease burden against lifelong overwhelming infection and thrombotic risk.
Before elective splenectomy, address pneumococcal, meningococcal and influenza vaccination, antibiotic prophylaxis, fever action planning and a patient-held alert.
Persistent abdominal pain or cholestatic jaundice warrants gallstone and biliary assessment, particularly in adolescents and adults with longstanding haemolysis.

02AetiologyUnderlying causes, associations and risk factors, with why each one matters.

Membrane-protein variants

Pathogenic variants affecting ankyrin, spectrin, band 3 or protein 4.2 reduce membrane stability. Autosomal-dominant transmission is common, although recessive and newly arising variants explain some apparently sporadic cases.

Phenotypic modifiers

The specific protein defect, coinherited red-cell traits, splenic clearance and marrow compensation influence severity, so relatives carrying the same broad diagnosis can have markedly different transfusion and gallstone burdens.

03PathophysiologyThe causal sequence from the underlying abnormality to symptoms and harm.

1
Surface-area loss
Repeated membrane vesiculation lowers the surface-area-to-volume ratio, changing a flexible biconcave erythrocyte into a dense sphere that cannot deform normally through narrow splenic passages.
2
Splenic conditioning
Acidic, glucose-poor splenic cords stress abnormal cells further; macrophages remove damaged membrane or the whole erythrocyte, shortening red-cell survival and producing extravascular haemolysis.
3
Compensatory erythropoiesis
Erythropoietin-driven marrow expansion raises reticulocyte production and can maintain haemoglobin until infection, nutrient limitation or parvovirus temporarily overwhelms compensatory capacity.

04Clinical features and red flagsSymptoms, examination findings, patterns of presentation and time-critical warnings.

Compensated haemolysis

Mild scleral icterus, splenomegaly and reticulocytosis may coexist with a near-normal haemoglobin and few daily symptoms.

Characteristic film

Numerous small dense erythrocytes lack central pallor, accompanied by polychromasia; morphology supports but does not independently establish inheritance.

Gallstone presentation

Episodic right upper-quadrant pain, pancreatitis or cholestatic jaundice may be the presenting consequence of chronic bilirubin turnover.

Aplastic crisisRed flag

A sudden profound anaemia with an unexpectedly low reticulocyte count after fever or rash requires urgent haematology assessment.

Family pattern

A history of jaundice, gallstones, splenectomy or neonatal transfusion across generations supports dominant inheritance but can be absent.

05InvestigationsWhat to request, why it matters and how to interpret it.

Investigation order

Read from the initial assessment onwards. Tests may run in parallel in urgent care; first-line, preferred, confirmatory, definitive and gold-standard labels appear only when the chapter explicitly states them.

01
Full blood count and reticulocytesFirst step
Why
Quantify anaemia and marrow compensation.
Interpretation and limitations
Reticulocytosis usually accompanies haemolysis; reticulocytopenia during deterioration suggests aplasia, while microcytosis may indicate coincident iron deficiency or thalassaemia.
02
Blood film
Why
Identify spherocytes and competing morphological clues.
Interpretation and limitations
Dense spherocytes and polychromasia fit the diagnosis, but fragments, bite cells or marked elliptocytosis redirect the differential.
03
Bilirubin, LDH and haptoglobin
Why
Demonstrate active haemolysis and assess hepatic context.
Interpretation and limitations
Unconjugated bilirubin and LDH rise with reduced haptoglobin; results fluctuate and recent transfusion complicates interpretation.
04
Direct antiglobulin test
Why
Separate hereditary from immune spherocytosis.
Interpretation and limitations
A positive result supports antibody or complement coating and requires an immune haemolysis pathway; rare ambiguity needs specialist review.
05
Eosin-5-maleimide binding assay
Why
Test red-cell membrane fluorescence in suspected hereditary spherocytosis.
Interpretation and limitations
Reduced binding supports a membrane disorder in the appropriate phenotype; transfusion, newborn status and overlap disorders may require delayed or alternative analysis.
06
Abdominal ultrasonography
Why
Assess symptomatic gallstones, bile ducts and splenic size.
Interpretation and limitations
Stones without symptoms do not automatically mandate surgery; duct dilatation or pancreatitis changes urgency and imaging.

06Differential diagnosisRealistic alternatives and the features that help distinguish them.

Autoimmune haemolytic anaemia

Warm antibody haemolysis also creates spherocytes, jaundice and splenomegaly; a direct antiglobulin test, exposure history and clinical tempo help distinguish an acquired immune process.

Other congenital haemolysis

G6PD deficiency, pyruvate-kinase deficiency and haemoglobinopathies can cause reticulocytosis and jaundice, but their film, triggers, ancestry and specialist enzyme or haemoglobin studies differ.

Gilbert syndrome

Gilbert syndrome produces intermittent unconjugated hyperbilirubinaemia without anaemia, reticulocytosis, low haptoglobin or splenomegaly, although it can coexist and amplify jaundice in hereditary spherocytosis.

07ManagementImmediate care, first-line treatment, alternatives and escalation.

01Diagnostic routeConfirm inherited haemolysisFirst stepAnaemia, jaundice or splenomegaly occurs with spherocytes or a family history.

1Obtain blood count, reticulocytes, film, bilirubin, LDH and haptoglobin, documenting transfusion timing and the clinical family pedigree.
2Perform a direct antiglobulin test before attributing spherocytes to inheritance, then request eosin-5-maleimide testing through haematology when the phenotype remains compatible.
3Use broader membrane, enzyme or genomic testing for atypical, severe, transfused or equivocal cases and offer family counselling around the confirmed result.

02Acute deteriorationSeparate haemolytic from aplastic changeA person with stable disease develops abrupt pallor, breathlessness, fever or worsening jaundice.

1Assess haemodynamics and cardiac symptoms, repeat haemoglobin and reticulocytes urgently and send group-and-save or cross-match where compromise is possible.
2A high reticulocyte response with bilirubin rise suggests accelerated haemolysis, whereas a low response prompts parvovirus testing and infection precautions in vulnerable contacts.
3Transfuse for clinically important anaemia under haematology and transfusion guidance, reassessing symptoms and avoiding an automatic chronic threshold.

03Definitive planningBalance benefit from splenectomyDefinitiveAnaemia, transfusion, splenic symptoms or quality-of-life impairment remains substantial.

1Review measured disease burden, age, gallstones, previous crises and alternatives in a specialist multidisciplinary discussion rather than operating on morphology alone.
2Complete immunisation and antibiotic planning before elective surgery, document thrombosis assessment and coordinate any indicated cholecystectomy.
3After surgery continue lifelong fever education and infection precautions, while monitoring for thrombosis, gallstones if the gallbladder remains, and residual haemolysis.

Key medicines and prescribing safety2 treatments · regimens, roles and cautions

Prevents folate depletion during sustained marrow compensation rather than correcting the membrane defect.

Folic acid

Haematology commonly prescribes 5 mg orally once daily when haemolysis is moderate or severe, during pregnancy or when dietary folate may not meet erythropoietic demand.

Confirm the indication and consider vitamin B12 status before prolonged treatment; mild compensated disease may not require continuous supplementation.

Reduces invasive pneumococcal infection risk alongside vaccination and urgent treatment of fever.

Phenoxymethylpenicillin after splenectomy

A common adult regimen is 250 mg orally twice daily. Start after splenectomy, follow the current asplenia policy for duration and allergy alternatives, and continue lifelong when invasive pneumococcal risk remains high.

Check immediate penicillin allergy, adherence and local resistance advice. Prophylaxis and vaccination do not make fever safe to observe at home; provide an emergency antibiotic and assessment plan plus travel and animal-bite advice.

08ComplicationsImportant consequences, why they occur and why they matter clinically.

Aplastic crisis

Parvovirus B19 suppression of erythropoiesis causes a rapid haemoglobin fall with reticulocytopenia, creating cardiovascular compromise in a person whose red cells already have shortened survival.

Pigment gallstones

Chronic bilirubin turnover promotes black pigment stones, which may cause biliary colic, cholecystitis, pancreatitis or common-duct obstruction even when baseline jaundice is familiar.

Post-splenectomy sepsis

Loss of splenic clearance leaves lifelong vulnerability to rapidly progressive infection from encapsulated organisms; vaccination and prophylaxis reduce but never abolish this risk.

Iron loading

Repeated transfusion and, less commonly, increased absorption can accumulate iron, so ferritin trends and specialist imaging are considered when transfusion exposure becomes substantial.

09Monitoring and follow-upTreatment response, safety checks and longer-term review.

Follow haemoglobin, reticulocytes, bilirubin and symptoms at intervals matched to phenotype, growth, pregnancy and previous crisis frequency.
Ask about exertional limitation, school or work participation, abdominal pain and jaundice rather than relying on haemoglobin alone.
Review gallbladder symptoms and obtain imaging for biliary pain, pancreatitis or a cholestatic change instead of routine repeated scans in every stable adult.
After splenectomy check vaccine completion, antibiotic access, alert identification and understanding that fever needs immediate medical contact.
Record transfusion exposure and assess iron status when cumulative red-cell support, unexpected ferritin elevation or organ features justify it.

10Special situationsVariants, exceptions and circumstances that change the usual approach.

Spherocytes are not specific

They arise when macrophages remove antibody-coated membrane as well as in inherited membrane loss, making antiglobulin testing indispensable.

Reticulocytes reveal reserve

A falling haemoglobin with abundant reticulocytes differs mechanistically from parvovirus-associated reticulocytopenia and drives a different acute work-up.

Splenectomy changes anatomy

It prolongs survival of abnormal erythrocytes and improves anaemia but leaves the molecular membrane defect and future inheritance unchanged.

Jaundice can have two drivers

Coinherited Gilbert syndrome reduces bilirubin conjugation and may increase jaundice and gallstone risk beyond the degree of haemolysis.

11Common pitfallsFrequent interpretation and management errors.

01
Diagnosing inheritance from spherocytes without an antiglobulin test.
02
Calling a low-reticulocyte crisis ordinary haemolysis.
03
Offering splenectomy for a laboratory label without disease-burden review.
04
Assuming vaccination eliminates post-splenectomy sepsis.
05
Ignoring biliary obstruction because baseline bilirubin is raised.