Haemolytic Anaemia

What haemolysis actually is

Haemolysis is a mechanism, not a diagnosis. Red cells are destroyed before their normal 120-day run, and the bone marrow — which can ramp output six- to eight-fold on erythropoietin drive — cannot keep up. Confirming haemolysis is the easy part. The job is to localise the site and name the cause, because the treatments could not be more different: steroids for warm AIHA, splenectomy for hereditary spherocytosis, trigger avoidance for G6PD, complement blockade for PNH.[1]

The DAT is the single most powerful branch point in the whole algorithm — hold that thought and every section below falls into place.[2]

Meet the patient

A 32-year-old man of Mediterranean ancestry walks into the emergency department at 3am, two days into a sore throat. He is yellow. His urine is the colour of cola. He ate fava beans with dinner. The registrar reaches for a liver screen and misses the diagnosis in the first ten minutes.[1]

Two questions decide his next hour, and they decide every haemolytic case: is the haemolysis intravascular or extravascular? (the film and the urine answer that), and is it immune or not? (the DAT answers that). Hold those two forks and the whole topic slots into place.[1]

Two axes, one signature

Classify along two independent axes — site and origin — because both carry immediate management implications. Extravascular destruction is splenic and gentler; intravascular destruction produces the dramatic triad of haemoglobinaemia, haemoglobinuria and acute kidney injury. Inherited causes declare themselves in childhood with a family history; acquired causes demand a search for drugs, infection and systemic disease.[1]

[5] [6]

One-line discriminator — where is the haemoglobin? In the urine — cola-coloured, dipstick-positive for blood with no red cells — think intravascular. In the spleen and bile — jaundice, splenomegaly, spherocytes — think extravascular.[1]

[1]

The classic trap: warm AIHA and hereditary spherocytosis both make spherocytes and both enlarge the spleen — only the DAT splits them (positive in warm AIHA, negative in hereditary spherocytosis). Spherocyte plus DAT is the single most-tested film-versus-test pairing.[1]

Who gets it, and why it tracks the malaria belt

Inherited haemolysis follows the malaria belt — sickle trait, alpha- and beta-thalassaemia trait, and G6PD deficiency all give heterozygotes partial protection against falciparum malaria, which is why they persist at high frequency across sub-Saharan Africa, the Mediterranean, the Middle East, the Indian subcontinent and South-East Asia.[3][4]

The numbers to carry into a viva: G6PD deficiency affects about 400 million people — the commonest human enzyme defect. Sickle trait is carried by roughly 1 in 12 African Americans. Hereditary spherocytosis affects about 1 in 2000 Northern Europeans and is mostly autosomal dominant. The thalassaemias cluster across the Mediterranean (Greek for sea blood), the Middle East, the Indian subcontinent and South-East Asia.[3][4]

Among acquired causes, autoimmune haemolytic anaemia (AIHA) dominates — incidence about 1 to 3 per 100,000 per year. Warm AIHA is 70 to 80 percent of it (IgG at 37 degrees), half idiopathic, half secondary to CLL, lymphoma, SLE or drugs (methyldopa, penicillin, cephalosporins, fludarabine). Cold agglutinin disease is 15 to 20 percent, post-Mycoplasma (anti-I), post-infectious mononucleosis (anti-i), or from a B-cell lymphoproliferative disorder. PNH is rare (about 1 to 2 per million) but fatal if untreated and transformed by complement blockade.[2]

[1]

The lesion, the marrow, and the three questions

The unifying lesion is a red-cell lifespan cut from 120 days to as little as a few days. Once destruction outruns the erythropoietin-driven marrow response, anaemia appears. Three questions define the workup: (1) intravascular or extravascular? (2) intrinsic cell defect or extrinsic attack? (3) antibody or complement bound, or not?[1][2]

The splenic macrophage — extravascular destruction

Extravascular destruction is the reticuloendothelial system disposing of antibody-coated or abnormal cells. In warm AIHA, antibody coats the red cell and macrophages destroy it through phagocytosis; in hereditary spherocytosis the primary lesion is loss of membrane surface area with reduced deformability, so the spherocytes are trapped and destroyed in the spleen — the main cause of haemolysis in that disorder. The same spherocyte appears in both; the DAT is what tells them apart (positive in warm AIHA, negative in hereditary spherocytosis).[5][7][9]

Free haemoglobin — intravascular destruction

Intravascular destruction spills free haemoglobin into plasma, and haptoglobin is the first casualty. Free haemoglobin complexes with haptoglobin and is cleared from the circulation, so haptoglobin falls and may become undetectable — a decreased haptoglobin is one of the four confirmatory laboratory findings. Once haptoglobin is depleted, free oxyhaemoglobin circulates (haemoglobinaemia), spills into the urine (haemoglobinuria — the cola urine), and over time is deposited in renal tubular cells (haemosiderinuria).[5][6]

The shared biochemical signature

Whatever the site, the signature is identical. Haemoglobin breakdown releases the porphyrin ring as unconjugated bilirubin; the liver's conjugation is overwhelmed, so indirect bilirubin rises (typically 30 to 100 micromol/L). Intracellular enzymes leak — most usefully LDH, particularly the LDH-2 isoenzyme. And the marrow responds with reticulocytosis: a corrected reticulocyte count over 2 percent or a reticulocyte production index over 2 confirms an adequate marrow response and is the single most useful marker of a haemolytic process.[1]

Everyone forgets: haptoglobin is an acute-phase reactant, so it can be misleadingly normal with concurrent inflammation, and about 2 percent of the population are congenitally haptoglobin-deficient. A normal haptoglobin in a sick, septic patient does not exclude haemolysis.[1]

Mechanism by mechanism — the molecular detail

[1]

The clinical face, and the fingerprints of each cause

The face of haemolysis is generic anaemia plus accelerated turnover, then the fingerprint of the individual cause superimposed.[1]

General features

• Anaemia — fatigue, exertional dyspnoea, pallor (conjunctival, palmar creases, mucosae), tachycardia, flow murmur; angina or heart failure may be the presentation in the elderly or those with coronary disease.
• Jaundice — a lemon-yellow scleral tint from unconjugated bilirubin, classically without pruritus and without pale stools (stool may be darker from increased stercobilinogen).
• Splenomegaly — the spleen is the principal site of clearance and is palpable in chronic extravascular haemolysis (warm AIHA, hereditary spherocytosis, thalassaemia, sickle cell in children before autosplenectomy).
• Dark urine — cola or port-wine urine marks intravascular haemolysis (PNH, cold agglutinin, G6PD crisis, ABO mismatch, march haemoglobinuria). The clue is a positive dipstick for blood with no red cells on microscopy.
• Pigment gallstones — chronic bilirubin overload makes calcium bilirubinate stones; cholecystitis, biliary colic or pancreatitis may be the first clue to a lifelong haemolysis.[1]

Clinical fingerprints by subtype

• Warm AIHA — subacute anaemia and jaundice in a middle-aged or older adult; hunt for CLL, lymphoma, SLE, or a recent drug (methyldopa, fludarabine).
• Cold agglutinin disease — an older patient with acrocyanosis, Raynaud-type phenomena and livedo on cold exposure, chronic low-grade haemolysis worsening in winter; a post-infectious form in young adults follows Mycoplasma pneumoniae (anti-I) or infectious mononucleosis (anti-i).[2]
• Hereditary spherocytosis — childhood or young-adult chronic mild haemolysis punctuated by haemolytic crises (infection), aplastic crises (parvovirus B19 — sudden Hb drop, low reticulocytes) and megaloblastic crises (folate depletion); family history often positive; frontal bossing and pigment stones in long-standing disease.
• G6PD deficiency — a male (X-linked) of African, Mediterranean or Asian ancestry with acute intravascular haemolysis (jaundice, dark urine, back pain) within 24 to 72 hours of fava beans, sulphonamides, primaquine, dapsone, rasburicase, naphthalene or an infection.[1]
• PNH — young adult with the triad of haemolytic anaemia, pancytopenia and thrombosis at unusual sites (hepatic, portal, cerebral venous sinus); the nocturnal haemoglobinuria is often historic.
• Microangiopathic (TTP, HUS, DIC) — schistocytic haemolysis with thrombocytopenia; TTP adds fluctuating neurology and fever, HUS adds acute kidney injury after bloody diarrhoea in children, DIC adds a coagulopathy with prolonged PT and APTT.
• Mechanical — a prosthetic heart valve with chronic low-grade intravascular haemolysis (raised LDH, low haptoglobin, haemosiderinuria, iron deficiency) — listen for the click or regurgitant murmur.
• Donath-Landsteiner (paroxysmal cold haemoglobinuria) — a child with acute intravascular haemolysis after cold exposure, post-viral or in syphilis; a biphasic IgG binds in the cold, fixes complement, and lyses on rewarming.[1]

The atypical presentations that bite

• Elderly — may present with cardiac decompensation (heart failure, angina) rather than jaundice, or as a worsening of pre-existing CLL or lymphoma.
• Pregnant — haemodilution and rising folate demand unmask inherited haemolysis; HELLP is a microangiopathic haemolysis unique to pregnancy.
• Neonate — haemolytic disease of the newborn (Rh or ABO) presents with early severe jaundice, anaemia and kernicterus risk; positive DAT, raised unconjugated bilirubin, phototherapy or exchange transfusion.
• Immunocompromised — higher risk of drug-induced and parainfective haemolysis; in chronic haemolysis with sudden reticulocytopenia, think parvovirus B19 aplastic crisis.[1]

The mimics — and the test that sorts them

Several non-haemolytic states mimic part of the signature, and mislabelling them leads to steroids or splenectomy the patient does not need.[1]

[1]

The decisive discriminator is the reticulocyte response. True haemolysis shows a corrected reticulocyte count over 2 percent or RPI over 2; a low reticulocyte count with raised bilirubin and LDH points to ineffective erythropoiesis (megaloblastic, MDS) or a superimposed aplastic crisis in a chronic haemolyser.[1]

The bedside round — look for the cause, not the diagnosis

Examination confirms haemolysis and hunts for its cause; it rarely gives a single diagnostic sign.[1]

• General — pallor, lemon-yellow jaundice (sclera, sublingual, skin), frontal bossing and maxillary overgrowth (thalassaemia major, chronic severe haemolysis), leg ulcers (sickle cell).
• Hands — koilonychia suggests iron deficiency (not haemolysis, except PNH); splinter haemorrhages if endocarditis or a prosthetic valve.
• Abdomen — splenomegaly (massive in thalassaemia, CML, malaria; moderate in warm AIHA and hereditary spherocytosis; autosplenectomy in sickle cell beyond childhood); check the gallbladder for pigment stones.
• Nodes — generalised lymphadenopathy points to a lymphoproliferative cause of warm AIHA (CLL, lymphoma).
• Cardiovascular — tachycardia, flow murmur; a prosthetic valve click or regurgitant murmur (mechanical haemolysis); signs of endocarditis.
• Skin — malar rash, oral ulcers (SLE-driven warm AIHA); acrocyanosis, livedo, Raynaud-type on cold (cold agglutinin); purpura (Evans syndrome — AIHA plus ITP); Kayser-Fleischer rings (Wilson).
• Urine — colour at the bedside: cola or port-wine equals haemoglobinuria. Dipstick positive for blood with no red cells on microscopy is the bedside signature.
• Neurology — fluctuating deficit with thrombocytopenia and schistocytes equals TTP; hemiparesis or cranial nerve palsy in sickle cell equals stroke.[1]

[1]

Investigations — confirm, localise, then name the cause

The strategy is tiered: first confirm and localise haemolysis, then run the DAT, then confirm the specific cause.[1]

Tier 1 — confirm and localise

• Full blood count — anaemia; haemolysis belongs in the differential for any normocytic or macrocytic anaemia (reticulocytes are large cells).
• Reticulocyte count — raised; reticulocytosis is one of the confirmatory findings. A disproportionately low reticulocyte count in a haemolytic picture means an aplastic crisis until proven otherwise.[9]
• LDH — raised; lactate dehydrogenase is a key biochemical indicator of intravascular haemolysis.[12]
• Unconjugated (indirect) bilirubin — raised.
• Haptoglobin — decreased; one of the four confirmatory findings.
• Peripheral film — perform a smear whenever haemolysis is present to identify abnormal red-cell morphology: spherocytes (warm AIHA, hereditary spherocytosis), schistocytes (thrombotic microangiopathy, mechanical trauma), sickled and target cells (haemoglobinopathies), polychromasia (reticulocytosis).[5][6]

Tier 2 — the master fork: the DAT

The direct antiglobulin test detects antibody or complement bound to the patient's red cells, and it is the master branch point of the entire workup.[1]

[1]

What juniors write vs what gets marks: "Coombs positive" is not a diagnosis — the pattern is. IgG dominant means warm AIHA; C3d only means cold agglutinin; a Donath-Landsteiner test means paroxysmal cold haemoglobinuria. Read the DAT in detail, not just positive or negative.[2]

Tier 3 — confirm the specific cause

• Cold agglutinin titre — raised in cold agglutinin disease (typically over 1:64 at 4 degrees); specificity is anti-I (Mycoplasma) or anti-i (infectious mononucleosis).[2]
• Donath-Landsteiner test — biphasic haemolysin for paroxysmal cold haemoglobinuria.
• Osmotic fragility (classic) or EMA-binding flow cytometry (modern) — for hereditary spherocytosis; EMA binds band 3, and reduced fluorescence confirms HS even with few spherocytes.
• G6PD enzyme assay — quantitative. The classic trap: the assay is falsely NORMAL during an acute attack because the oldest, most deficient cells lyse first and only young reticulocyte-rich cells remain — repeat at 2 to 3 months. A fluorescent spot test screens rapidly.[1]
• Haemoglobin electrophoresis or HPLC — sickle cell (HbS over 50 percent in disease) and thalassaemia (HbA2 over 3.5 percent in beta-thal trait; HbF raised in beta-thal major and intermedia).[3][4]
• Flow cytometry for CD55 and CD59 (FLAER) — for PNH; absent GPI-anchored proteins on granulocytes confirm it.
• ADAMTS13 activity — under 10 percent with an inhibitor confirms TTP (separating it from HUS and other MAHA).
• Coagulation — PT, APTT, fibrinogen, D-dimer for DIC.
• Bone marrow — rarely needed; excludes marrow failure or infiltration when reticulocytes are inappropriately low.
• Haemoglobinuria — dipstick positive for blood with no red cells on microscopy; haemosiderinuria on Prussian-blue staining of urinary sediment marks chronic intravascular haemolysis (PNH, mechanical valve).
• Cause screen — autoimmune (ANA, anti-dsDNA), immunoglobulins and electrophoresis (lymphoproliferative), viral serology (HIV, hepatitis, EBV, mycoplasma), renal and liver function, iron studies.[1]

[8] [10] [12] [13] [14]

Resuscitation — secure, transfuse, protect the kidneys, stop the trigger

[7] [8] [9] [10]

Acute severe haemolysis is a medical emergency. The priorities are: secure airway and circulation, transfuse if compromised or symptomatic, protect the kidneys, and stop the trigger.[5]

• Transfusion — transfuse for severe or symptomatic anaemia; in hereditary spherocytosis, severe haemolytic anaemia requires erythrocyte transfusion, and aplastic crises may need bridging transfusion.[9]
• Supportive care — fluids and monitoring of haemoglobin and renal function while the acute episode settles.
• Stop the offending drug — in G6PD deficiency avoid dapsone, methylene blue, nitrofurantoin, phenazopyridine, primaquine, rasburicase and tolonium chloride.[10]
• Treat the trigger — infection and inflammation act as triggers and drivers of cold-agglutinin haemolysis; plasma exchange is the emergency treatment for TTP; eculizumab for severe PNH.[2][13][11]
• Vaccinate before splenectomy — see the post-splenectomy bundle below.[16]

[7] [13] [14] [9] [16]

Definitive treatment — entirely cause-specific

Definitive treatment is entirely cause-specific. Extrinsic causes are reversible (withdraw the drug, treat the infection, plasma exchange for TTP); intrinsic defects need lifelong measures or surgery (folate, splenectomy, transfusion, chelation); immune causes need immunomodulation (steroids, rituximab, splenectomy).[1]

Warm AIHA (IgG, 37 degrees)

[7] [8]

Clinician confession: corticosteroids work for most patients (70 to 85 percent) but need a slow taper over six to twelve months, and relapse is common — if the response is not prompt, add rituximab early and relentlessly hunt for a secondary cause (lymphoproliferative disease, autoimmunity, drugs) before escalating immunosuppression.[7][8]

Cold agglutinin disease (IgM, 4 degrees)

Cold agglutinin disease is complement-mediated — treat accordingly. Haemolysis runs through the classical complement pathway, and CAD is a clonal lymphoproliferative entity distinct from polyclonal warm AIHA; management is built around avoidance of cold and rituximab-based therapy.[2][7]

• Keep the patient warm — the cold-reactive antibody underlies cold-haemolytic anaemia, and infection and inflammation act as triggers and drivers of haemolysis; treat them.[2]
• Rituximab — first-line for cold agglutinin disease requiring therapy; the international consensus recommends rituximab with or without bendamustine in the first line.[7][8]
• Sutimlimab (anti-C1s) — selectively blocks the classical complement pathway; in the CARDINAL study it rapidly halted haemolysis, raised haemoglobin by a least-squares mean of 2.6 g per decilitre and reduced fatigue — without treating the underlying clonal disorder.[15]
• Plasma exchange — listed among the additional therapies for autoimmune haemolytic anaemia.[8]

Hereditary spherocytosis

• Splenectomy — curative, but undertake only after careful assessment of risks and benefits; it removes the site where spherocytes are trapped and destroyed — the main cause of haemolysis in this disorder.[9]
• Transfusion — severe haemolytic anaemia in hereditary spherocytosis may require erythrocyte transfusion, including during aplastic crises.[9]
• Cholelithiasis, haemolytic episodes and aplastic crises are the common complications to anticipate and manage.[9]
• Prevent overwhelming post-splenectomy infection — vaccination and antibiotic prophylaxis are the basis of management after splenectomy.[16]

G6PD deficiency — trigger avoidance is the whole treatment

Trigger avoidance is the cornerstone; the disease is otherwise benign.[1]

• Avoid (evidence-based) — the seven medications with solid evidence to prohibit in G6PD deficiency: dapsone, methylthioninium chloride (methylene blue), nitrofurantoin, phenazopyridine, primaquine, rasburicase and tolonium chloride; plus fava (broad) beans and other exogenous oxidant triggers, including infection.[10][1]
• Supportive — fluids to protect the kidneys; transfusion for severe acute haemolysis.
• Counsel family members (X-linked recessive — males affected, females carriers).[1]

Paroxysmal nocturnal haemoglobinuria (PNH)

• Complement inhibition is transformative: eculizumab, a humanized monoclonal antibody against terminal complement protein C5 that inhibits terminal complement activation, is the treatment of choice for patients with severe manifestations of PNH.[11]
  • Pivotal-trial regimen: 600 mg intravenously weekly for 4 weeks, followed one week later by a 900-mg dose, then 900 mg every other week — it stabilised haemoglobin without transfusion in about half of the patients and reduced intravascular haemolysis (median LDH area-under-curve 85.8 percent lower than placebo).[12]
• Thrombosis and cytopenias — PNH manifests with haemolytic anaemia, thrombosis and peripheral blood cytopenias; manage each manifestation on its merits.[11]
• Bone marrow transplantation — the only cure for PNH; reserve for patients with a suboptimal response to eculizumab.[11]

Microangiopathic haemolytic anaemia

Treat the underlying cause — the haemolysis itself is not directly treated.[1]

• TTP — emergency plasma exchange: in the randomised Canadian Apheresis Group trial, plasma exchange halved deaths compared with plasma infusion (11 versus 19 deaths at six months; overall mortality 29 percent).[13] Add caplacizumab, an anti-von Willebrand factor fragment (10-mg intravenous loading bolus, then 10 mg daily subcutaneously during plasma exchange): the composite of TTP-related death, recurrence or thromboembolism was 74 percent lower than with placebo.[14]
• Mechanism — immune-mediated deficiency of ADAMTS13 allows unrestrained adhesion of von Willebrand factor multimers to platelets, producing microthrombosis, thrombocytopenia, haemolytic anaemia and tissue ischaemia.[14]
• Other microangiopathic causes (HUS, DIC, HELLP) — treat the underlying cause; the haemolysis itself is not directly treated.[5]

Drug-induced immune haemolytic anaemia

• Stop the offending drug (penicillin, cephalosporin, methyldopa, fludarabine, quinine, NSAIDs).
• Mechanisms: hapten (penicillin), autoantibody (methyldopa — true anti-Rh), immune complex (quinine).
• Steroids for severe haemolysis; usually self-limiting once the drug is stopped.[1]

Sickle cell disease and thalassaemia

See the dedicated topics — sickle-cell-disease (hydroxycarbamide, transfusion, transplant, gene therapy) and thalassaemia (transfusion, iron chelation with deferasirox, transplant).[3][4]

The subtypes that bite

Hereditary spherocytosis in depth

The commonest inherited haemolysis in Northern Europeans, autosomal dominant in about 75 percent (recessive forms exist). Mutations in ANK1 (ankyrin, commonest), SPTB, SPTA1, EPB42 (pallidin), SLC4A1 (band 3) weaken the membrane skeleton; membrane is lost in the splenic cords and the cell becomes a spherocyte. Diagnosis: spherocytes on film, raised osmotic fragility, and EMA-binding flow cytometry (reduced fluorescence, modern gold standard). Severity runs from asymptomatic carrier through mild or moderate chronic haemolysis with pigment gallstones to severe transfusion-dependent disease. Crises: haemolytic (infection), aplastic (parvovirus B19 — sudden Hb drop, low reticulocytes), megaloblastic (folate depletion).[1]

Donath-Landsteiner — paroxysmal cold haemoglobinuria

Rare but examinable. A biphasic IgG haemolysin (anti-P specificity) binds the red cell in the cold (extremities), fixes complement, and lyses on rewarming at 37 degrees. Classically a child after a viral illness (now the commonest cause) or in syphilis (congenital or tertiary). Diagnosis: Donath-Landsteiner test. Usually self-limiting; supportive care, transfuse P-negative blood if available, keep warm.[1]

Pyruvate kinase deficiency

Autosomal recessive chronic non-spherocytic haemolytic anaemia — the commonest inherited non-spherocytic haemolysis after G6PD. Reduced ATP makes rigid echinocytes. Splenectomy partially helps; mitapirdine (a PK activator) is a newer therapy.[1]

Mechanical and microangiopathic haemolysis

Red cells are fragmented mechanically — in fibrin-rich microvasculature (TTP, HUS, DIC, HELLP, malignant hypertension) or across a prosthetic valve (especially a regurgitant mitral valve). The film shows schistocytes; LDH very high; haptoglobin absent; haemosiderinuria and iron deficiency mark chronicity. Treat the cause; iron supplementation for valve-related loss; valve revision if severe.[1]

Wilson disease — the acute haemolysis

A rare but recognisable presentation of acute Wilson crisis: massive copper release causes acute intravascular haemolysis with acute liver failure and Coombs-negative haemolysis. Diagnose with low ceruloplasmin, high urinary copper, Kayser-Fleischer rings; treat with chelation and liver transplant.[1]

Aplastic crisis — the exception to reticulocytosis

A low reticulocyte count in a chronic haemolyser is parvovirus B19 until proven otherwise. In any patient with hereditary spherocytosis, sickle cell or thalassaemia who presents with a sudden fall in haemoglobin and a low reticulocyte count, suspect parvovirus B19 infection of erythroid progenitors — the marrow stops releasing reticulocytes, so the underlying haemolysis runs unchecked. It is self-limiting over 1 to 2 weeks; transfuse to bridge; IgG serology confirms recent infection.[1]

How haemolysis patients come to harm — the preventable list

• Cholelithiasis — a common complication of hereditary spherocytosis and other chronic haemolysis; manage symptomatic disease on its surgical merits.[9]
• Haemolytic episodes and aplastic crises — the other classic complications of hereditary spherocytosis; anticipate them and transfuse when severe.[9]
• Thrombosis — particularly in PNH, which manifests with haemolytic anaemia, thrombosis and cytopenias.[11]
• Infection after splenectomy — prevention through vaccination and antibiotic prophylaxis is the basis of management; overwhelming infection by encapsulated bacteria runs a fulminant, high-mortality course refractory to common treatment.[16]
• Immunosuppression burden — second-line agents (azathioprine, cyclophosphamide, ciclosporin, mycophenolate) carry toxicity; escalate only when needed.[8]

The recurring pitfalls every candidate must name:[1]

• Accepting a falsely normal G6PD assay during an acute attack as excluding the diagnosis — repeat at 2 to 3 months.
• Treating cold agglutinin disease with steroids or splenectomy (ineffective — destruction is hepatic and C3b-mediated).
• Under-transfusing AIHA because of crossmatch incompatibility — transfuse the least-incompatible unit; under-transfusion is the bigger risk.
• Missing a superimposed parvovirus B19 aplastic crisis because the reticulocyte count is low.
• Giving primaquine, dapsone, rasburicase or methylene blue to a patient with unrecognised G6PD deficiency.[1]

Prognosis and disposition

• Warm AIHA — most respond to steroids within 1 to 3 weeks; about one-third achieve long-term remission, one-third remain steroid-dependent, one-third are refractory and need second-line therapy. Overall mortality 8 to 11 percent at 1 year, driven by underlying disease and thromboembolism.
• Cold agglutinin disease — chronic relapsing; rituximab responses in about 50 percent; sutimlimab improves Hb but does not cure.
• Hereditary spherocytosis — normal lifespan after splenectomy in severe cases; mild forms well compensated.
• G6PD deficiency — excellent with trigger avoidance; haemolysis is self-limiting.
• PNH — transformed by complement inhibitors; previously median survival 10 to 15 years, now near-normal when treated.
• TTP — untreated mortality about 90 percent; with plasma exchange and caplacizumab under 10 percent.
• HUS — most children recover; atypical (complement) HUS is poorer without eculizumab.[1]

Disposition — severe acute haemolysis needs admission (transfusion, IV fluids, monitoring of Hb, renal function, electrolytes); stable chronic haemolysis is managed as an outpatient with folate, gallstone and iron-overload surveillance. All splenectomised patients need lifelong follow-up for infection prophylaxis.[1]

Special populations

Children

• Neonates — a rapid onset of anaemia or significant hyperbilirubinaemia in the neonatal period should prompt consideration of a haemolytic anaemia.[5]
• G6PD deficiency — neonatal jaundice is one of its most frequent clinical manifestations.[1]
• Hereditary spherocytosis — reported worldwide with variable severity, from asymptomatic individuals to severe transfusion-dependent haemolysis; aplastic crises occur.[9]

Pregnancy

• Warm AIHA in pregnancy — the adult algorithm applies: corticosteroids first-line, with rituximab considered early in severe cases or when the response to steroids is not prompt.[7]
• Haemolysis with systemic features in pregnancy — widen the differential to the systemic and extrinsic non-immune causes of haemolysis alongside the immune ones.[5]

Elderly

• Lower threshold to transfuse (cardiac comorbidity); watch for cardiac decompensation as the presenting feature.
• Always investigate for an underlying lymphoproliferative cause of warm AIHA (CLL, lymphoma) — film, immunoglobulins, marrow, CT.[1]

Immunocompromised

• Higher risk of drug-induced and parainfective haemolysis; check G6PD before oxidant drugs.
• Rituximab patients — recheck hepatitis B; PML rarely.[1]

Post-splenectomy — the inviolable bundle

The post-splenectomy bundle is the same regardless of why the spleen was removed (haemolysis, ITP, trauma).[1]

[16] [16]

The preventable-harm line on OPSI: overwhelming post-splenectomy infection — caused by encapsulated bacteria — has a high mortality, a fulminant course and refractoriness to common treatment. A splenectomised patient with any fever needs immediate empirical antibiotics — do not wait for cultures.[16]

Evidence, guidelines and regional differences

Landmark trials and therapies

• MSH (Charache et al., NEJM 1995) — hydroxycarbamide cut sickle crises by about 50 percent in adults; the foundation of modern sickle management (now recommended from 9 months).
• Hillmen et al. (NEJM 2006, 2013) — eculizumab (anti-C5) transformed PNH; reduced haemolysis, transfusion need, thrombosis and improved survival.
• HERCULES (NEJM 2019) — caplacizumab (anti-vWF nanobody) accelerated recovery and reduced mortality in acquired TTP when added to plasma exchange.
• CARDINAL (NEJM 2022) — sutimlimab (anti-C1s) raised Hb in cold agglutinin disease; the first complement inhibitor approved for this condition (2022).[2]
• STOP (NEJM 1998) — chronic transfusion guided by transcranial Doppler reduced stroke by about 90 percent in sickle cell children.

Guidelines

• British Society for Haematology (BSH) on diagnosis and management of AIHA (2016 and 2020) and hereditary spherocytosis.
• American Society of Hematology (ASH) on warm AIHA, TTP/HUS and PNH.
• UK Green Book (DH) on immunisation of the asplenic or hyposplenic patient.
• NICE on eculizumab, ravulizumab and sutimlimab for PNH and cold agglutinin disease.[1]

Regional differences

• Penicillin prophylaxis duration — lifelong in the UK (Green Book) for all ages; variable in the US (lifelong if under 16, over 50, or immunocompromised).
• Vaccine choice — PCV13 and PPSV23 versus PCV20; MenACWY versus MenACWY plus MenB; meningococcal boosters every 5 years in the UK.
• Splenectomy approach in children — partial splenectomy preferred in some European centres.
• G6PD screening — routine in many African, Mediterranean and Asian countries before oxidant drugs; opportunistic in the UK and US.
• PNH management — eculizumab universally funded in some systems (UK NHS), rationed by severity in others.[1]

Exam pearls

[5] [9] [16]

• Pigment gallstones equal chronic haemolysis — cholelithiasis is a common complication of hereditary spherocytosis.[9]
• Dark (cola) urine equals haemoglobinuria — intravascular haemolysis (PNH, cold agglutinin, G6PD crisis).[5]
• A low reticulocyte count in a haemolytic patient equals aplastic crisis until proven otherwise — a recognised complication of hereditary spherocytosis.[9]
• Schistocytes with thrombocytopenia point to the thrombotic microangiopathies.[5]
• Mechanical and traumatic haemolysis — fragmentation from microthrombi or direct mechanical trauma.[5]
• Splenectomy prevents OPSI only when vaccination precedes it and antibiotic prophylaxis follows — encapsulated bacteria, fulminant course, high mortality.[16]
• Dapsone, methylene blue, nitrofurantoin, phenazopyridine, primaquine, rasburicase and tolonium chloride are contraindicated in G6PD deficiency.[10]

[1]

The mantra: Confirm the signature, fork on the DAT, treat the cause — and never miss parvovirus in a haemolyser with a low reticulocyte count.[1]

Ward-round test — four stems, thirty seconds each

Stem 1 — the man with cola urine (answer)

A 32-year-old Mediterranean man, day 2 of a sore throat, yellow sclerae, cola-coloured urine after a fava-bean meal. Hb 78 g/L, reticulocytes raised, LDH raised, haptoglobin undetectable. What is the diagnosis, and what is the cornerstone of management? Model: This is acute G6PD-deficiency haemolysis — an X-linked defect in which acute haemolytic anaemia is usually triggered by an exogenous agent (here fava beans, with an intercurrent infection), showing intravascular features (cola urine, undetectable haptoglobin). The cornerstone is lifelong avoidance of oxidative triggers: fava beans, infection, and the seven medications with solid evidence to prohibit in G6PD deficiency — dapsone, methylene blue, nitrofurantoin, phenazopyridine, primaquine, rasburicase and tolonium chloride. Manage supportively; transfuse for severe anaemia.[1][10]

Stem 2 — the chronic haemolyser who crashes (answer)

A 19-year-old with known hereditary spherocytosis, normally Hb 105 g/L with reticulocytes 8 percent, presents with a flu-like illness, Hb 45 g/L and reticulocytes 0.5 percent. What happened, and what do you do? Model: This is an aplastic crisis — a recognised complication of hereditary spherocytosis — in which haemoglobin falls abruptly while the reticulocyte count stays inappropriately low. Transfuse to bridge (severe episodes require erythrocyte transfusion) and monitor the reticulocyte recovery. In a known haemolyser with a suddenly low reticulocyte count, aplastic crisis is the default diagnosis.[9]

Stem 3 — schistocytes, thrombocytopenia and confusion (answer)

A 45-year-old woman: Hb 60 g/L, platelets 25, schistocytes on film, LDH over 2000, fluctuating confusion, normal PT and APTT. The registrar wants to transfuse and wait. What is the diagnosis and the first action? Model: This is TTP — microangiopathic (schistocytic) haemolysis with thrombocytopenia, neurology and normal coagulation. Do not wait — start emergency plasma exchange: in the landmark randomised trial, exchange halved deaths versus plasma infusion (11 versus 19 at six months; overall mortality 29 percent). Add caplacizumab, an anti-von Willebrand factor fragment (10-mg intravenous loading bolus, then 10 mg daily subcutaneously): the composite of TTP-related death, recurrence or thromboembolism fell by 74 percent versus placebo. The mechanism is immune-mediated ADAMTS13 deficiency.[13][14]

Stem 4 — fever in the splenectomised patient (answer)

A 60-year-old splenectomised for hereditary spherocytosis three years ago phones with a fever of 39 degrees and rigors. What is the single most important action in the next hour? Model: This is overwhelming post-splenectomy infection (OPSI) until proven otherwise — infection with encapsulated bacteria, fulminant, refractory to common treatment, with high mortality. Give empirical antibiotics immediately — do not wait for blood cultures. Then admit, take cultures, and continue supportive care. Vaccination before splenectomy and antibiotic prophylaxis afterwards exist to prevent exactly this scenario.[16]

References

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