Haemolytic anemias. Hemolysis

01Definition and overview

Haemolytic anaemia is anaemia caused by red cells being destroyed faster than they are made. When red cell survival shortens, the marrow expands erythropoiesis and releases reticulocytes early; while it keeps pace there is haemolysis without anaemia, and anaemia appears when destruction outruns production or the marrow is suppressed.

Haemolysis is classified by where cells die and by why. The cause lies inside the red cell, nearly always inherited, or outside it, nearly always acquired; PNH, an acquired defect of the cell itself, is the exception.

Haemolysis in babies and children is covered in haemolytic anaemias in childhood.

02Etiology and pathophysiology

Where red cells die

A red cell needs a flexible membrane, glycolysis for ATP, NADPH against oxidants and soluble haemoglobin; a defect in any, or an attack from outside, shortens its life.

Free haemoglobin binds haptoglobin until none is left, then passes into the urine, which tests positive for blood without red cells. It also scavenges nitric oxide, causing smooth muscle spasm, pulmonary hypertension and platelet activation. Haem becomes unconjugated bilirubin, so jaundice is mild and acholuric, and chronic haemolysis forms pigment gallstones.

Inherited causes

In hereditary spherocytosis, a defect in ankyrin (the commonest), spectrin, band 3 or protein 4.2 loosens the bilayer from the cytoskeleton; the cell sheds membrane, becomes a small rigid sphere and is destroyed in the spleen. About three quarters of families show dominant inheritance.

Glucose-6-phosphate dehydrogenase (G6PD) makes NADPH, which keeps glutathione reduced to neutralise peroxide. Without it, an oxidant (a drug, fava beans, an infection) turns haemoglobin into Heinz bodies, which the spleen bites out (bite and blister cells), and heavy stress lyses cells in the vessels. The gene is X-linked: men are affected, and heterozygous women can haemolyse too. Old cells have the least enzyme, so in the African A− variant haemolysis stops once they are gone, while the Mediterranean variant can haemolyse severely. WHO replaced the old classes I to V in 2022:

Pyruvate kinase deficiency, recessive, is the commonest glycolytic cause of chronic haemolysis: short of ATP, cells stiffen. 2,3-DPG builds up behind the block and eases oxygen delivery, so the anaemia is well tolerated.

Sickle haemoglobin (HbS) has valine in place of glutamic acid at position 6 of β-globin. Deoxygenated HbS polymerises and sickles the cell, so cells block small vessels (infarction and pain) and are haemolysed. Hypoxia, dehydration, acidosis, cold and infection promote sickling; fetal haemoglobin (HbF) inhibits it, which is why infants are spared at first and why raising HbF helps. Sickle cell disease means HbSS (sickle cell anaemia), HbSC and HbS with β-thalassaemia; the carrier state is usually silent and protects against severe malaria. In HbSS, infarcts leave the spleen functionless by mid-childhood.

In the thalassaemias, too little α- or β-globin leaves the partner chains unpaired; they precipitate, so many red cells die in the marrow (ineffective erythropoiesis) and the rest are haemolysed. The marrow expands, haemopoiesis spreads outside it, and iron accumulates from transfusion and increased absorption. Losing one or two of the four α genes is silent or causes mild microcytosis, three cause HbH disease, and four cause haemoglobin Bart's hydrops fetalis. β-thalassaemia carriers have microcytosis with HbA2 above about 3.5 per cent; patients are grouped as transfusion-dependent (TDT, once thalassaemia major, presenting at 3 to 6 months as HbF gives way to HbA) or non-transfusion-dependent (NTDT). Microcytosis with normal iron stores suggests thalassaemia trait (see iron deficiency anaemia).

Acquired causes

• Warm AIHA: IgG autoantibodies active at 37 °C; splenic macrophages nibble coated cells into spherocytes, then remove them. About half are primary; the rest come with chronic lymphocytic leukaemia or lymphoma, lupus, immunodeficiency or drugs. With immune thrombocytopenia it is Evans syndrome.
• Cold agglutinin disease: IgM, usually anti-I, binds red cells in the cool skin of the extremities and fixes complement; the liver removes the C3b-coated cells and some lyse in the vessels. Primary disease is a small clonal B-cell disorder of the marrow; secondary cold agglutinins follow Mycoplasma pneumoniae or Epstein–Barr virus, or come with lymphoma. Paroxysmal cold haemoglobinuria, mostly in children after a virus, is an IgG antibody that binds in the cold and lyses on warming.
• Drug-induced: antibodies that act only while the drug is present (ceftriaxone and piperacillin are among the commonest; ceftriaxone can cause sudden, severe haemolysis), or a true autoantibody (fludarabine, immune checkpoint inhibitors).
• Alloimmune: ABO-incompatible blood meets IgM anti-A or anti-B, which fix complement and lyse cells within minutes. A delayed reaction, 3 to 14 days after transfusion, is an IgG antibody from an earlier transfusion or pregnancy, too weak to detect, that returns. In haemolytic disease of the fetus and newborn, maternal IgG (anti-D, anti-c, anti-K) crosses the placenta (Rhesus blood groups).
• Paroxysmal nocturnal haemoglobinuria (PNH): a stem cell acquires a mutation in PIGA, an X-linked gene needed for the GPI anchor, so its progeny lack CD55 and CD59, which shield cells from complement, and red cells are lysed by the membrane attack complex. The clone probably expands because an immune attack on the marrow spares cells without the anchor, hence its tie to aplastic anaemia. PNH is strongly thrombotic.
• Microangiopathic: fibrin strands and microthrombi slice red cells into fragments (schistocytes): TTP (severe lack of the enzyme ADAMTS13), HUS (Shiga toxin-producing Escherichia coli, or uncontrolled complement in atypical HUS), DIC, HELLP, malignant hypertension, scleroderma renal crisis, cancer and some drugs (gemcitabine, calcineurin inhibitors, quinine).
• Mechanical and physical: leaking prosthetic valves, assist devices, march haemoglobinuria, burns.
• Infections and toxins: malaria parasites burst red cells, and massive intravascular haemolysis in falciparum malaria is blackwater fever; the toxin of Clostridium perfringens destroys red cell membranes within hours; babesiosis is worst without a spleen. Copper released from the liver in Wilson disease, lead and some snake venoms haemolyse too, and any large spleen traps cells.

03Clinical features

Patients have the signs of anaemia with mild jaundice and, in chronic extravascular haemolysis, a palpable spleen. Chronic haemolysis adds gallstones, leg ulcers and folate deficiency; intravascular haemolysis adds dark urine, loin pain and, when brisk, shock and kidney injury.

Sickle cell disease brings painful vaso-occlusive crises in bones, back and chest (dactylitis in infants); acute chest syndrome, a new lung infiltrate with fever or respiratory symptoms; stroke, mostly in children; splenic sequestration in young children (a rapidly enlarging spleen, falling haemoglobin and shock); aplastic crises; pneumococcal sepsis and Salmonella osteomyelitis; and priapism. Over the years come avascular necrosis of the hips, leg ulcers, retinopathy (worst in HbSC), kidney disease, pulmonary hypertension and chronic pain.

Thalassaemia trait causes no symptoms. Untreated TDT presents in infancy with pallor, failure to thrive, hepatosplenomegaly and bone changes; with transfusion, iron overload brings heart failure (once the main cause of death), endocrine failure and liver fibrosis. NTDT presents later, with extramedullary masses, thrombosis and iron overload.

04Diagnosis and management

Proving haemolysis and finding its cause

Blood and urine tests prove it, and the direct antiglobulin test (DAT, the Coombs test) shows whether antibody or complement coats the cells:

The blood film is the cheapest specialist in the hospital:

1. 1

   Prove haemolysis

   A falling haemoglobin with raised reticulocytes, unconjugated bilirubin and LDH and a low haptoglobin, after excluding bleeding and recovery from iron, B12 or folate deficiency.
2. 2

   Film and DAT

   The film looks for the shapes above; the DAT for IgG or complement (C3d) on the cells.
3. 3

   DAT positive

   IgG, with or without C3d: warm AIHA, a drug or a transfusion. C3d alone: cold agglutinins or paroxysmal cold haemoglobinuria. Then ask about transfusions, pregnancies and drugs, and look for lymphoma, CLL or autoimmune disease.
4. 4

   DAT negative

   Follow the clue: ADAMTS13 for fragments; G6PD or pyruvate kinase assays; eosin-5′-maleimide (EMA) binding for spherocytes; haemoglobin analysis by HPLC; flow cytometry for PNH; malaria films; gene panels if the cause stays hidden.

Chronic haemolysis is usually covered with folic acid, and patients learn the signs of an aplastic crisis.

the normal life of a red cell

120daysthe normal life of a red cell

to first analgesia in a sickle cell crisis

30minutesto first analgesia in a sickle cell crisis

haemoglobin before each transfusion in TDT

95–105g/Lhaemoglobin before each transfusion in TDT

from meningococcal vaccine to a complement inhibitor

2weeksfrom meningococcal vaccine to a complement inhibitor

Membrane and enzyme disorders

In hereditary spherocytosis, a family history, spherocytes, a raised MCHC and reticulocytes with a negative DAT make the diagnosis; in doubt, the EMA binding test or cryohaemolysis is used, not the osmotic fragility test, which misses too many cases. Severe disease is treated by splenectomy, total or partial, and moderate disease sometimes; it is delayed if possible until age 6, comes after vaccination against pneumococci, meningococci and Haemophilus influenzae type b, and is followed by an offer of antibiotic prophylaxis. Fever in a person without a spleen is treated as overwhelming sepsis, with antibiotics at once. In hereditary stomatocytosis, which can be mistaken for spherocytosis, splenectomy is contraindicated because of a high risk of thrombosis.

G6PD deficiency is diagnosed with a quantitative assay or a fluorescent spot test (the gene in women and unclear cases). Soon after an episode the assay can be falsely normal, so it is repeated about three months later. Testing comes before primaquine, tafenoquine, dapsone or rasburicase. An acute episode needs the trigger removed, hydration and transfusion if severe.

This grading follows a 2023 review of the evidence; older lists and some product information still warn against drugs in the low-risk row, and local guidance may be stricter. Methylene blue, the antidote for methaemoglobinaemia, can itself cause haemolysis and works poorly in G6PD deficiency.

Pyruvate kinase deficiency is confirmed by the enzyme assay and the PKLR gene, and treated with folic acid, transfusion, chelation and sometimes splenectomy, which helps less than in spherocytosis. Mitapivat, an oral activator of the enzyme, is licensed in the EU for adults with the deficiency and, since 2026, for the anaemia of α- and β-thalassaemia in adults; the liver is monitored, and it is not stopped abruptly, which can trigger haemolysis.

Sickle cell disease

Haemoglobin analysis by HPLC or electrophoresis makes the diagnosis (HbS without HbA in HbSS); a sickle solubility test cannot tell trait from disease and never stands alone.

• Painful crisis: analgesia within 30 minutes of arrival, a bolus of strong opioid for severe pain (never pethidine), regular paracetamol and an NSAID unless contraindicated; pain reassessed every 30 minutes until controlled; oxygen if the saturation is 95 per cent or below (oximeters can overestimate it in dark skin); no steroids. Every patient is watched for acute chest syndrome.
• Acute chest syndrome: oxygen, antibiotics covering atypical organisms, incentive spirometry, careful analgesia and early transfusion, simple or by exchange, with intensive care if the patient worsens.
• Stroke: urgent exchange transfusion to bring HbS below 30 per cent. Children with HbSS or HbSβ⁰ thalassaemia have yearly transcranial Doppler scans from age 2, and high velocities are treated with regular transfusion, which prevents most first strokes.
• Transfusion uses blood matched for Rh and Kell; a delayed reaction can destroy the patient's own cells too (hyperhaemolysis).

Hydroxycarbamide raises HbF and cuts crises, acute chest syndrome, transfusions and deaths. UK guidance offers it to every child with HbSS or HbSβ⁰ thalassaemia from 9 months, whatever the severity, with blood count monitoring and contraception. Children take penicillin V prophylaxis, and everyone is vaccinated against encapsulated bacteria. A matched sibling transplant cures, best in childhood. Exagamglogene autotemcel (exa-cel), the patient's own stem cells edited to switch HbF back on, has had conditional EU authorisation since February 2024, from 12 years, for recurrent crises when transplantation is suitable but no matched related donor exists.

Thalassaemias

Trait needs only a clear diagnosis, so that iron is not given needlessly, and partner testing in pregnancy. TDT is treated by transfusion every 2 to 5 weeks, keeping the haemoglobin before each one at 95 to 105 g/L with leucodepleted blood matched for Rh and Kell, and by iron chelation: desferrioxamine by slow subcutaneous infusion, oral deferasirox (kidney and liver monitoring) or oral deferiprone, which can cause agranulocytosis and needs weekly neutrophil counts in its first year. Ferritin is checked every 3 months, and MRI measures liver and heart iron (cardiac T2*) yearly from about age 8 to 10. Luspatercept, which helps late red cell maturation, cuts transfusions in transfusion-dependent β-thalassaemia and raises haemoglobin in the non-transfusion-dependent form, in adults (licensed in the EU since 2020, for the non-transfusion-dependent form since 2023), and mitapivat now treats adults with either form of α- or β-thalassaemia. A transplant from an HLA-identical sibling cures, best before 14; gene therapy (exa-cel, from 12 years) is an option for patients fit for a transplant who have no such donor. Splenectomy is now rare, because of infection and thrombosis.

Autoimmune haemolytic anaemia

In warm AIHA, prednisolone brings a response in about four in five patients and is tapered over months. Rituximab is the second line, or joins the steroid from the start in severe disease; splenectomy has moved further back. Folic acid, thromboprophylaxis in hospital (AIHA is strongly thrombotic) and treatment of any underlying disease complete the care. Transfusion is never withheld from life-threatening anaemia because fully compatible blood cannot be found; the least incompatible units are given slowly.

In cold agglutinin disease, blood and infusions go through a warmer. Rituximab treats the clone, and sutimlimab, an antibody against C1s that blocks the classical complement pathway, stops the haemolysis while it is given (EU authorisation since 2022). Infection-related cold haemolysis and paroxysmal cold haemoglobinuria settle with support; in drug-induced haemolysis the drug is stopped for good.

Transfusion reactions and disease of the newborn

1. 1

   Stop

   At the first suspicion, stop the transfusion and keep the line open with saline through a new giving set.
2. 2

   Check

   Check the patient's identity and wristband against the unit and the compatibility record: most ABO reactions follow a wrong sample or a wrong patient.
3. 3

   Treat

   Resuscitate, keep the urine flowing with fluids, and watch for kidney injury and DIC.
4. 4

   Investigate and report

   Return the unit with new samples (group, DAT, blood count, haemolysis markers, clotting, kidney function), test the urine for haemoglobin, and report to the haemovigilance system.

A delayed reaction shows days later as a falling haemoglobin, jaundice, a positive DAT and a new antibody; future blood must lack that antigen. Haemolytic disease of the newborn is prevented by antibody screening in pregnancy and anti-D immunoglobulin for RhD-negative women, routinely in the third trimester and after birth or any sensitising event; affected babies are treated as in neonatal jaundice.

PNH

High-sensitivity flow cytometry of red cells (CD59) and of neutrophils and monocytes (FLAER and other GPI-anchored markers) makes the diagnosis; the neutrophil clone is the reliable measure, because PNH red cells are lysed and transfused cells dilute them. Haemolytic PNH is treated with a complement inhibitor:

C5 blockers stop lysis in the vessels, but C3 still coats the cells, and some patients keep haemolysing in the liver and spleen; the proximal inhibitors (C3, factors B and D) block both. In the EU pegcetacoplan and iptacopan are licensed on their own for adults with haemolytic anaemia, and danicopan as an add-on for those who stay anaemic on a C5 blocker. Blocking complement exposes patients to meningococcal sepsis: they are vaccinated against meningococci (ACWY and B) at least 2 weeks before the first dose, or given antibiotics until 2 weeks after vaccination if treatment cannot wait, and any fever is treated as possible meningococcal infection. The C3 and factor B inhibitors also need pneumococcal and Haemophilus vaccines, and stopping one suddenly can cause severe haemolysis. Thrombosis is treated with anticoagulants; stem cell transplantation, the only cure, is kept for severe marrow failure.

Other acquired causes

With fragments and a low platelet count, a sample goes for ADAMTS13 and plasma exchange for presumed TTP starts the same day, unless another cause such as DIC or HELLP is clear; the PLASMIC score helps meanwhile. TTP and HUS are covered in thrombocytopenia, HELLP in hypertensive disorders of pregnancy. Malaria is sought with thick and thin films or an antigen test in anyone with fever after travel; after intravenous artesunate for severe malaria the haemoglobin is followed for a month, because a delayed haemolysis can come one to three weeks later. Clostridium perfringens haemolysis needs antibiotics and surgical source control within hours and is often fatal. Haemolysis with acute liver failure in a young person calls for urgent tests for Wilson disease and a liver unit.

05Epidemiology

• Sickle cell disease: about 7.7 million people lived with it in 2021, and about 515,000 babies were born with it that year, most in sub-Saharan Africa and India. It contributed to about 376,000 deaths, some eleven times the number certified as due to it. In Europe it is commonest in people of African, Caribbean, Middle Eastern and Indian ancestry, with old foci in Greece, Italy and Turkey.
• Thalassaemias: carriers are common around the Mediterranean (Cyprus, Greece, Sardinia, southern Italy), in the Middle East and in South and South-East Asia. Carrier screening and prenatal diagnosis have made new cases of β-thalassaemia major rare in Cyprus and Sardinia.
• G6PD deficiency: about 500 million people. Its map, like those of HbS and the thalassaemias, follows the old range of malaria, against which carriers are partly protected.
• Hereditary spherocytosis: about 1 in 2000 to 1 in 5000 people of northern European ancestry, the commonest inherited haemolytic anaemia there.
• AIHA: about 1 to 3 new cases per 100,000 adults a year, rising with age; about two thirds warm, most of the rest cold.
• PNH: roughly one to a few new cases per million people a year, most often in young adults.

06Prognosis

• Hereditary spherocytosis and G6PD deficiency: normal life expectancy for most; after splenectomy the risk of overwhelming infection is lifelong.
• Sickle cell disease: in Europe nearly all children now reach adulthood, thanks to screening, penicillin, vaccines, Doppler scans and hydroxycarbamide, but adult life is still shortened; in much of Africa child mortality remains high.
• Thalassaemias: with safe transfusion and MRI-guided chelation, survival into middle age and beyond is usual, and heart iron, once the main killer, is largely preventable.
• Warm AIHA: most patients respond to steroids, but relapse on tapering is common, and thrombosis and infection cause much of the mortality.
• PNH: before complement inhibitors, median survival was about 10 to 15 years, with thrombosis the main cause of death. In a UK cohort on eculizumab, survival matched that of age- and sex-matched controls, and thromboses fell from 5.6 to 0.8 per 100 patient-years.
• TTP: fatal in most patients untreated; with plasma exchange most survive, though it can relapse, so ADAMTS13 is followed in remission.