Haemolytic Anaemia

Introduction

Haemolytic anaemia is anaemia resulting from accelerated destruction of red blood cells, occurring at a rate that outstrips the bone marrow's considerable ability to compensate by increasing production up to sixfold. Normal red cell lifespan is around 120 days; in significant haemolysis this can fall to days.¹

The topic is approached in two steps: first, confirm that haemolysis is actually happening, using a consistent set of laboratory markers; second, work out the mechanism and cause, which determines both prognosis and treatment.

Classification and aetiology

Haemolysis is classified along two axes: where it happens (intravascular vs extravascular) and why it happens (inherited vs acquired).

Intravascular vs extravascular

Inherited causes

• Membrane defects: hereditary spherocytosis, hereditary elliptocytosis
• Enzyme deficiencies: glucose-6-phosphate dehydrogenase (G6PD) deficiency, pyruvate kinase deficiency
• Haemoglobinopathies: sickle cell disease, thalassaemia

Acquired causes

• Autoimmune haemolytic anaemia (AIHA) - warm (IgG-mediated, usually extravascular) or cold (IgM-mediated, complement-fixing, often triggered by Mycoplasma or EBV, exacerbated by cold)
• Alloimmune - haemolytic transfusion reactions, haemolytic disease of the newborn
• Mechanical (microangiopathic haemolytic anaemia, MAHA) - prosthetic heart valves, disseminated intravascular coagulation, thrombotic thrombocytopenic purpura, hae­molytic uraemic syndrome, severe pre-eclampsia/HELLP syndrome - red cells are physically sheared, producing schistocytes
• Infective - malaria, Clostridium perfringens sepsis
• Drug-induced - e.g. penicillin (immune-mediated), or oxidative haemolysis precipitated by certain drugs in G6PD deficiency
• Paroxysmal nocturnal haemoglobinuria (PNH) - acquired clonal defect causing complement-mediated intravascular haemolysis, with a characteristic association with venous thrombosis at unusual sites
• Hypersplenism - any cause of splenomegaly can increase red cell destruction

Clinical features

Features reflect both the anaemia itself and the breakdown of hae­moglobin:

• Generic anaemic symptoms - fatigue, dyspnoea, pallor
• Jaundice - from unconjugated hyperbilirubinaemia. Because this is a pre-hepatic process, urine and stool colour are normal (unconjugated bilirubin is not water-soluble and is not excreted in urine) - a key point that distinguishes it from obstructive (cholestatic) jaundice
• Splenomegaly - from increased reticuloendothelial workload, particularly in extravascular and chronic haemolysis
• Dark urine specifically in intravascular haemolysis, from haemoglobinuria - distinct from the bilirubinuria of obstructive jaundice
• History of gallstones (pigment stones from chronic excess bilirubin turnover) or leg ulcers in chronic haemolytic states
• Family history in inherited causes

Investigations

Step one: confirm haemolysis is occurring

• Reticulocyte count raised - the marrow's compensatory response; a low reticulocyte count in an anaemic, jaundiced patient should prompt reconsideration (e.g. an aplastic crisis, or a non-haemolytic cause of jaundice)
• LDH raised - released from destroyed red cells
• Unconjugated bilirubin raised
• Haptoglobin low - haptoglobin binds free haemoglobin and is cleared with it, so it falls, especially in intravascular haemolysis
• Blood film - polychromasia (reflecting reticulocytosis) is seen in haemolysis of any cause; specific red cell morphology often points to the mechanism (see below)

Step two: find the mechanism and cause

• Direct antiglobulin test (Coombs test) - the pivotal test. Positive indicates an immune-mediated cause (autoimmune or alloimmune); negative points to an inherited or mechanical cause
• Blood film morphology - spherocytes (hereditary spherocytosis or warm AIHA), schistocytes/red cell fragments (MAHA - DIC, TTP, HUS, mechanical valve), bite and blister cells with Heinz bodies (G6PD deficiency, oxidative haemolysis), sickle cells (sickle cell disease)
• Haemoglobinuria/urinary haemosiderin - supports intravascular haemolysis
• For suspected inherited causes: osmotic fragility test or eosin-5-maleimide (EMA) binding test (hereditary spherocytosis), G6PD assay (ideally after the acute crisis, as levels can transiently normalise), haemoglobin electrophoresis (haemoglobinopathies)
• Flow cytometry (FLAER) for suspected PNH
• Coagulation screen, platelet count and renal function if MAHA is suspected, since this group includes medical emergencies (TTP, HUS, DIC)

Differential diagnosis

The main alternative to consider when a patient is anaemic and jaundiced is hepatobiliary disease causing conjugated hyperbilirubinaemia, which is distinguished by dark urine, pale stools, deranged liver enzymes and a normal reticulocyte count. Also consider ineffective erythropoiesis (e.g. severe B12/folate deficiency, myelodysplasia), which can mimic haemolysis biochemically (raised LDH and bilirubin from intramedullary cell death) but with a low, not raised, reticulocyte count.

Management

• Treat the underlying cause - stop an implicated drug, treat the triggering infection, manage the underlying autoimmune or malignant condition
• Folic acid supplementation, given the greatly increased erythropoietic demand depletes folate stores
• Warm AIHA: first-line oral corticosteroids; second line includes rituximab or splenectomy for refractory cases²
• Cold AIHA: avoid cold exposure; corticosteroids are typically less effective (the pathology is complement-mediated), so rituximab is often used instead
• Transfusion for severe or symptomatic anaemia - use with caution and cross-match carefully, since autoantibodies can make compatibility testing difficult
• Splenectomy for selected cases of hereditary spherocytosis (with pre-operative vaccination and lifelong penicillin prophylaxis given the hyposplenism risk) and for refractory autoimmune haemolysis
• MAHA emergencies (TTP, HUS) require urgent specialist management (e.g. plasma exchange in TTP) rather than routine haemolysis work-up

Complications

• Pigment gallstones, from chronically increased bilirubin turnover
• Aplastic crisis - a sudden, transient cessation of erythropoiesis, classically triggered by parvovirus B19 infection, causing a dangerous fall in haemoglobin in patients who depend on continuous high marrow output (e.g. hereditary spherocytosis, sickle cell disease)
• Folate deficiency, from ongoing depletion
• Iron overload in patients requiring recurrent transfusion
• Chronic leg ulcers in some inherited haemolytic anaemias
• Thromboembolism, notably in PNH and cold AIHA

Red flags

Prognosis

Prognosis depends entirely on the underlying cause. Drug-induced and infection-triggered haemolysis typically resolve once the precipitant is removed or treated. Warm AIHA responds to corticosteroids in the majority of patients, though relapse is common and some require second-line therapy.² Inherited causes (hereditary spherocytosis, G6PD deficiency, haemoglobinopathies) are lifelong, with severity ranging from mild and well-compensated to transfusion-dependent, and management focuses on avoiding triggers and managing complications rather than cure - splenectomy aside.