Red cells and marrow
Haemolysis
Approach
Confirm anaemia with reticulocytosis and biochemical evidence: raised bilirubin/LDH, low haptoglobin and blood-film changes. Determine intravascular versus extravascular and inherited versus acquired causes.
- Haemolysis = premature red cell destruction (lifespan under 120 days). It is compensated if the marrow keeps up, uncompensated if anaemia develops1.
- Extrinsic (usually acquired): immune (autoimmune, drug-induced, transfusion reaction), infection (malaria, Babesia, Clostridium toxin), mechanical (microangiopathic, prosthetic valve, march haemoglobinuria), hypersplenism, toxins, burns. Intrinsic (usually inherited): membrane (hereditary spherocytosis), enzyme (G6PD deficiency), haemoglobin (sickle cell, thalassaemia); PNH is the acquired membrane defect1.
- Shared features of all haemolysis: a shorter red cell lifespan, EPO-driven marrow expansion with reticulocytosis, and a rise in unconjugated bilirubin. Jaundice is rarely deep if the liver is normal; chronic haemolysis causes pigment gallstones5.
Where the red cells are destroyed5.
| Feature | Extravascular (most cases) | Intravascular |
|---|---|---|
| Mechanism | Stiff or antibody-coated cells caught by macrophages in spleen and liver | Cells burst in the circulation |
| Typical causes | Hereditary spherocytosis, warm AIHA, sickle cell, thalassaemia | Mechanical valves, microangiopathy, complement (ABO reaction, PNH), falciparum malaria, clostridial toxin |
| Spleen | Often enlarged | Not enlarged |
| Blood and urine | Haptoglobin mildly low | Haptoglobin very low, haemoglobinaemia, haemoglobinuria, later haemosiderinuria |
- Why splenectomy helps in extravascular haemolysis: the spleen is where rigid cells are trapped, so removing it corrects the anaemia even though the abnormal cells persist5.
Assessment
Jaundice, dark urine, pain, infection, drugs, transfusion, prosthetic valve, family/ethnic history and autoimmune disease. Examine for splenomegaly and thrombosis.
- Drugs reported to cause immune haemolysis include quinine/quinidine, beta-lactams, methyldopa, co-trimoxazole and fludarabine; oxidant haemolysis with dapsone1.
- Intravascular haemolysis can cause haemoglobinuria (red-brown urine), back/abdominal pain and shock1.
- Hereditary spherocytosis: usually autosomal dominant, commonest in northern Europeans. Defects in membrane skeleton proteins (spectrin, ankyrin, band 3, band 4.2) make cells shed membrane and become small rigid spheres that are trapped in the spleen. Features are anaemia, splenomegaly and jaundice; gallstones occur in 40-50% of adults; parvovirus can cause a sudden aplastic crisis. Splenectomy corrects the anaemia but adds lifelong sepsis risk5.
- G6PD deficiency: X-linked, so mostly males. Red cells cannot regenerate NADPH and reduced glutathione, leaving them exposed to oxidants. Triggers are infection (most common), oxidant drugs (e.g. primaquine, sulfonamides, nitrofurantoin) and fava beans; haemolysis starts 2-3 days after exposure, with Heinz bodies and bite cells on the film. Only older cells run short of enzyme, so episodes stop on their own and an enzyme level taken soon after can look normal5.
- Warm AIHA: IgG coats red cells, and macrophages nibble off membrane, turning cells into spherocytes; so spherocytes are not specific for hereditary spherocytosis. About half are idiopathic; the rest follow SLE, lymphoid cancers or drugs5.
- Drug-induced immune haemolysis: either the drug sticks to red cells and becomes the antibody target (e.g. high-dose IV penicillins or cephalosporins, usually after 1-2 weeks), or the drug breaks tolerance to red cell antigens (methyldopa: about 10% develop a positive DAT, about 1% haemolyse)5.
- Cold agglutinins: IgM binds red cells in cool fingers, toes and ears, causing acrocyanosis and Raynaud phenomenon; complement coating then leads to removal by macrophages. Transient after Mycoplasma or EBV; chronic with B-cell neoplasms. Paroxysmal cold haemoglobinuria is a rare post-viral IgG cold antibody in children that causes intravascular haemolysis on rewarming, and usually settles within a month5.
- PNH: look for venous clots in unusual sites (hepatic, portal, cerebral veins) alongside haemolysis; 5-10% progress to AML or MDS. Complement C5 inhibitors reduce haemolysis and clots but raise meningococcal infection risk5.
- Mechanical causes: mechanical heart valves (more than tissue valves) and microangiopathy, most often DIC, also TTP, HUS, malignant hypertension, SLE and disseminated cancer. Fibrin and platelet deposits narrow small vessels and shear passing red cells5.
Emergencies
Transfusion reaction, severe symptomatic anaemia, haemoglobinuria with AKI, sickle crisis, TTP/HUS or rapidly falling haemoglobin requires urgent senior/haematology review.
- Fragments on the film with low platelets suggest microangiopathy (TTP, HUS, DIC): TTP is fatal if untreated but survival is over 95% with prompt plasma exchange plus steroids and rituximab2. Do not transfuse platelets in TTP unless life-threatening bleeding3.
- Warm autoimmune haemolysis with reticulocytopenia can be fatal4.
Investigations
FBC/film, reticulocytes, bilirubin, LDH, haptoglobin, DAT, UEC and urinalysis; then targeted G6PD, haemoglobin studies or other tests.
- Peripheral smear and reticulocyte count are the most important tests. Then indirect bilirubin, LDH and haptoglobin; a direct antiglobulin (Coombs) test or haemoglobinopathy screen (e.g. HPLC) to find the cause1.
- DAT positive = immune: warm antibody (IgG, usually extravascular) vs cold agglutinin disease (reacts below 37 degrees C)4.
- Coombs tests: the direct test looks for antibody or complement already on the patient's red cells; the indirect test looks for free antibody in the patient's serum using reagent red cells5.
- Hereditary spherocytosis: spherocytes (small, dense, no central pallor), a raised MCHC, and increased osmotic fragility in about two-thirds5.
- PNH: flow cytometry shows red cells missing GPI-anchored proteins such as CD55 and CD595.
- G6PD levels can be falsely normal during or just after a haemolytic episode.
Management
Treat cause, stop culprit drugs, support with transfusion when indicated and use folate in chronic haemolysis. Immune haemolysis and microangiopathy require specialist-directed therapy.
- Warm AIHA (idiopathic): glucocorticoids first-line, often with rituximab; refractory cases may need IVIG, azathioprine/mycophenolate/cyclophosphamide or splenectomy4.
- Cold agglutinin disease: avoid cold, warm blood before transfusion, treat the underlying disorder; sometimes rituximab or complement inhibitors4.
- Drug-induced: withdraw the drug4. Give folate for ongoing long-term haemolysis4.
- TTP: plasma exchange with glucocorticoids and rituximab; caplacizumab can speed platelet recovery2.
References
- Merck Manual Professional: Overview of hemolytic anemia
- Merck Manual Professional: Thrombotic thrombocytopenic purpura
- National Blood Authority: PBM Guidelines Module 3 (Medical), Quick Reference Guide
- Merck Manual Professional: Autoimmune hemolytic anemia
- Kumar V, Abbas AK, Aster JC, editors. Robbins and Cotran Pathologic Basis of Disease. 9th ed. Philadelphia: Elsevier Saunders; 2015. Chapter 14, Red blood cell and bleeding disorders.
Last updated from Sen’s notes on 22 October 2026.