Haemolytic Anaemia

General Definition and Diagnostic Thresholds

• Anaemia is defined as a haemoglobin concentration below established reference values, typically <13 g/dL in men and <12 g/dL in women, according to World Health Organisation criteria. These thresholds may require adjustment based on age, sex, ethnicity, comorbid illness, and environmental factors such as high altitude or smoking status.
• In the context of haemolytic anaemia, the defining feature is not only the low haemoglobin but also evidence of enhanced erythrocyte destruction. Causes are diverse and may include immune processes, red cell membrane or enzyme defects, mechanical shear stress, infections, or exposure to haemolytic agents.

Hereditary (Intrinsic) Causes

Membrane Defects (Membranopathies)

• Hereditary spherocytosis: Autosomal dominant; characterised by spectrin or ankyrin defects, resulting in loss of membrane surface area and spherical RBCs.
• Hereditary elliptocytosis and pyropoikilocytosis: Affect cytoskeletal proteins like protein 4.1 or spectrin, leading to decreased deformability and fragmentation under shear stress.

Enzyme Deficiencies (Enzymopathies)

• Glucose-6-phosphate dehydrogenase (G6PD) deficiency: X-linked; reduced protection against oxidative stress leads to episodic haemolysis. Triggers include infections, certain drugs (e.g. dapsone, sulfa drugs, antimalarials), and foods like fava beans.
• Pyruvate kinase deficiency: Autosomal recessive; impairs ATP production leading to rigid RBCs and chronic haemolysis.

Haemoglobinopathies

• Sickle cell disease: Mutation in β-globin gene causes polymerisation of haemoglobin under hypoxic conditions, resulting in sickling, vaso-occlusion, and haemolysis.
• Thalassaemias: Caused by partial or complete failure in α- or β-globin chain synthesis, leading to ineffective erythropoiesis and RBC destruction in bone marrow and spleen.

Acquired (Extrinsic) Causes

Immune-Mediated Haemolysis

• Warm AIHA: IgG autoantibodies bind optimally at body temperature; destruction is mostly extravascular in the spleen.
• Cold AIHA: IgM antibodies bind at cooler temperatures; complement-mediated intravascular lysis occurs, often in the liver.
• Mixed-type AIHA: Coexistence of both warm and cold-reactive antibodies.
• Secondary causes: Systemic lupus erythematosus (SLE), autoimmune hepatitis, lymphoproliferative disorders (e.g., chronic lymphocytic leukaemia), infections (e.g., H1N1 influenza), and post-allogeneic stem cell transplantation.
• Haemolytic disease of the newborn: Maternal alloantibodies against fetal RBC antigens.
• Transfusion reactions: Due to mismatched RBC antigens between donor and recipient.
• Hapten mechanism: Drugs (e.g., penicillin) bind to RBCs and trigger antibody formation.
• Autoantibody induction: e.g., methyldopa
• Immune complex formation: e.g., quinidine-type reactions

Non-Immune-Mediated Acquired Causes

Mechanical RBC Destruction

• Prosthetic heart valves: Shearing forces damage RBC membranes.
• March haemoglobinuria: Physical exertion (e.g., running) causes footstrike haemolysis.

Microangiopathic Haemolytic Anaemias (MAHA)

• Thrombotic thrombocytopenic purpura (TTP)
• Haemolytic uraemic syndrome (HUS)
• Disseminated intravascular coagulation (DIC)
• HELLP syndrome (Haemolysis, Elevated Liver enzymes, Low Platelets)
• Malignant hypertension
• All share the common feature of schistocyte formation due to mechanical fragmentation.

Infections

• Malaria, babesiosis, bartonellosis: Intracellular pathogens destroy RBCs directly.
• Clostridium perfringens: Produces alpha toxin (phospholipase C), causing massive haemolysis.
• Other organisms: H1N1 influenza, Mycoplasma pneumoniae, and Epstein-Barr virus have been linked to AIHA.

Drugs and Toxins

• Non-immune oxidative damage: Antimalarials, sulfonamides, nitrites, phenazopyridine, and certain antivirals (e.g., ribavirin).
• Iomeprol (radiographic contrast medium): Rarely associated with haemolysis.

Other Conditions

• Paroxysmal nocturnal haemoglobinuria (PNH): Acquired clonal disorder involving complement-mediated intravascular haemolysis due to deficiency of GPI-anchored surface proteins (CD55/CD59).
• Liver disease: Structural RBC changes and hypersplenism contribute to haemolysis.
• Hypersplenism: Accelerated clearance of normal or near-normal RBCs.

Sites and Mechanisms of RBC Destruction

Extravascular Haemolysis

• Occurs predominantly in the spleen, liver, and other reticuloendothelial tissues.
• RBCs are phagocytosed by macrophages after being marked by immunoglobulins or due to structural abnormalities.
• Common in:
  • Warm autoimmune haemolytic anaemia: IgG-coated RBCs are cleared via Fc receptor-mediated phagocytosis.
  • Hereditary spherocytosis: Abnormal membrane proteins lead to reduced deformability, resulting in splenic sequestration.
  • Haemoglobinopathies: Misshaped cells like sickled or unstable haemoglobin-containing RBCs are cleared by the spleen.

Intravascular Haemolysis

• RBCs are lysed directly within the circulation.
• Mechanisms include:
  • Complement-mediated lysis: Seen in cold AIHA and paroxysmal nocturnal haemoglobinuria (PNH).
  • Mechanical trauma: Occurs with prosthetic heart valves or microangiopathic haemolytic anaemias (e.g., TTP, HUS, DIC).
  • Oxidative injury: G6PD deficiency predisposes to oxidative damage following exposure to triggers.
  • Severe infections: Certain pathogens and inflammatory states (e.g., COVID-19) can cause haemolysis.
• Consequences:
  • Release of free haemoglobin into plasma → haemoglobinaemia and haemoglobinuria.
  • Binding of haemoglobin to haptoglobin → decreased serum haptoglobin.
  • Conversion of haemoglobin to bilirubin → elevated unconjugated bilirubin and urobilinogen.

Intramedullary Haemolysis

• Destruction of immature erythroid precursors in the bone marrow before entering circulation.
• Seen in:
  • Thalassaemia major
  • Megaloblastic anaemia (e.g., pernicious anaemia)
• Leads to ineffective erythropoiesis, skeletal deformities (e.g., skull expansion in thalassaemia), and chronic anaemia.

Key Haematological and Biochemical Indicators

• Elevated lactate dehydrogenase (LDH): Released from lysed RBCs.
• Increased unconjugated (indirect) bilirubin: From breakdown of haem.
• Reduced haptoglobin: Consumed by binding free haemoglobin.
• Peripheral blood smear findings:
  • Spherocytes: Seen in autoimmune haemolysis and hereditary spherocytosis.
  • Schistocytes: Fragmented RBCs in microangiopathic haemolysis.
• Haemoglobinuria: Marker of intravascular destruction.

Compensatory Bone Marrow Response

• Reticulocytosis: Elevated reticulocyte count indicates marrow compensation.
• If bone marrow function is impaired (e.g., by parvovirus B19), even low-grade haemolysis can precipitate severe anaemia—a scenario termed an aplastic crisis.

Hereditary Pathophysiological Mechanisms

• Membranopathies (e.g., hereditary spherocytosis, elliptocytosis): Structural defects lead to increased rigidity and premature splenic clearance.
• Enzymopathies (e.g., G6PD and pyruvate kinase deficiency):
  • G6PD protects against oxidative stress; deficiency leads to haemolysis after exposure to certain drugs or infections.
  • Pyruvate kinase deficiency reduces ATP generation, impairing RBC deformability.
  • Haemoglobinopathies (e.g., sickle cell disease, thalassaemia): Result in ineffective erythropoiesis and increased haemolysis both intravascularly and extravascularly.

General Prevalence

• Haemolytic anaemia accounts for approximately 5% of all anaemias.
• Autoimmune haemolytic anaemia (AIHA) is rare, with an estimated incidence of 1 to 3 cases per 100,000 people per year.
• Non-immune haemolytic anaemia is less frequently recognised in routine practice but is particularly noted in patients with alcoholic liver disease, where it carries a worse prognosis:
  • Prevalence: ~0.17% in hospitalised patients with alcoholic liver disease.
  • Associated outcomes: Increased mortality (9.0% vs 5.6%), longer hospital stays, and higher healthcare costs.

Age and Sex Distribution

• Hereditary haemolytic disorders (e.g., thalassaemia, G6PD deficiency, hereditary spherocytosis) usually manifest in childhood or early adulthood.
• Acquired haemolytic anaemias, particularly AIHA, are more commonly diagnosed in middle-aged and older adults.
• Warm AIHA demonstrates a female predominance, whereas G6PD deficiency, being X-linked, predominantly affects males with females more often being carriers.

Ethnic and Regional Variations

G6PD deficiency

• Affects 360 to 400 million people globally.
• Highest prevalence in:
  • Sub-Saharan Africa: very common
  • Kurdish Jews: up to 50%
  • Black males in the U.S.: ~11%
• Less frequent in:
  • Northern Europeans: <1 in 1000
  • East Asians: rare in Japan, present in Chinese and Southeast Asian populations
  • Mediterranean basin: moderate prevalence
• Multiple variants exist:
  • A(-) variant in West Africans and African Americans
  • Mediterranean variant in people of Southern European and some Asian ancestry

Sickle cell disease

• Predominantly found in:
  • Africans and African Americans
  • Some Middle Eastern and Indian (especially southern India) populations

Hereditary elliptocytosis (HE)

• Found worldwide but particularly common in malaria-endemic regions such as West Africa.
• Believed to offer some protective advantage against malaria.

Population-Level Haematological Norms

• Databases like NHANES-III and the Scripps-Kaiser dataset help define population norms by excluding individuals with chronic disease or other abnormalities.
• These studies show consistent haemoglobin ranges across adult men (ages 20–59) and women (ages 20–49), aiding in interpretation of laboratory results.
• African American populations often exhibit:
  • Lower baseline haemoglobin concentrations
  • Lower serum transferrin saturation
  • Higher serum ferritin levels
  • Lower bilirubin and leukocyte counts
  • Likely influenced by the higher prevalence of alpha-thalassaemia and G6PD deficiency

Symptom-Based Historical Clues

General Anaemic Symptoms

• Fatigue, dyspnoea, dizziness, and weakness are common and non-specific indicators of reduced oxygen-carrying capacity.
• Tachycardia, angina, and exertional shortness of breath may indicate severe or rapid-onset anaemia, particularly in patients with underlying cardiac disease.

Haemolysis-Specific Features

• Dark urine:
  • Suggests intravascular haemolysis and haemoglobinuria.
  • Chronic intravascular haemolysis may result in iron deficiency.
• Abdominal pain:
  • May indicate bilirubin gallstones, secondary to prolonged haemolysis.
• Bronze skin and diabetes:
  • Suggest haemosiderosis due to iron overload, particularly in those with repeated transfusions or inappropriate iron therapy.

Thrombotic and Vascular Complications

• Venous thromboembolism:
  • Occurs in 15–33% of adults with warm autoimmune haemolytic anaemia (AIHA), particularly early in the disease course.
• Leg ulcers:
  • Often seen in sickle cell anaemia and thalassaemia major, due to endothelial damage and chronic hypoxia.

Specific Diagnostic Clues from History

Drug History

• Recent or chronic use of haemolysis-associated medications:
  • Immune-mediated: penicillin, cephalosporins, quinine, quinidine, levodopa, dimethyl fumarate.
  • Oxidative haemolysis in G6PD deficiency: sulfa drugs, dapsone, ribavirin, nitrites, phenazopyridine, and naphthalene (found in mothballs).

Dietary Triggers

• Fava bean ingestion in susceptible individuals with G6PD deficiency, particularly those of Mediterranean descent.

Cold Exposure

• Suggests cold agglutinin disease (presence of Donath-Landsteiner antibodies), where haemolysis may be precipitated or worsened by cold temperatures.

Risk Factors to Elicit from History

Autoimmune Disorders

• Personal history of systemic lupus erythematosus (SLE), rheumatoid arthritis, scleroderma, or inflammatory bowel disease, which are associated with autoantibody formation and warm AIHA.

Lymphoproliferative Disorders

• History of chronic lymphocytic leukaemia (CLL), non-Hodgkin’s lymphoma (NHL), or plasma cell dyscrasias, which are well-established causes of secondary AIHA.
• AIHA is present in up to 10% of patients with CLL and around 3% of those with NHL.

Inherited or Familial Clues

• Family history of:
  • Haemoglobinopathies (e.g., sickle cell anaemia, thalassaemia)
  • Red cell membrane disorders (e.g., hereditary spherocytosis, elliptocytosis)
  • G6PD deficiency
• Ethnic and geographic origin:
  • G6PD deficiency and haemoglobinopathies are more prevalent in individuals from:
    • Mediterranean region
    • Middle East
    • Sub-Saharan Africa
    • Southeast Asia

Prosthetic Heart Valves

• Mechanical valves, especially older or poorly aligned ones, can cause mechanical haemolysis. Even with modern valves, subclinical haemolysis is not uncommon.

Infection-Related Historical Indicators

• Recent or chronic infection with organisms known to induce haemolysis:
  • Parasitic infections: malaria, babesiosis, bartonellosis, leishmaniasis
  • Bacterial infections:
    • Clostridium perfringens (via α-toxin)
    • Haemophilus influenzae type B (via antibody formation against RBC–polysaccharide complex)
    • E. coli, pneumococci, and staphylococci
• Systemic symptoms: such as fever and malaise, may indicate a systemic infection or thrombotic microangiopathy (e.g., TTP).

Environmental and Chemical Exposures

• Thermal injury: such as burns can result in red cell fragmentation.
• Oxidative chemicals: paraquat ingestion or industrial exposure to oxidants.
• Extreme physical exertion: prolonged or repetitive activities may cause march haemoglobinuria (footstrike haemolysis).

General Features of Anaemia

 Pallor

• Commonly seen in mucous membranes (e.g. conjunctivae), nail beds, and skin.
• Non-specific and present in many types of anaemia.

Tachycardia, tachypnoea, hypotension

• Often reflect significant anaemia or hypovolaemia.
• Not specific to haemolytic processes, but suggest haemodynamic compromise in acute haemolysis.

Haemolysis-Specific Findings

 Jaundice

• Subtle scleral icterus may be noted with mild hyperbilirubinaemia.
• Due to increased indirect (unconjugated) bilirubin from haem degradation.
• Jaundice in haemolysis rarely exceeds total bilirubin levels of 3 mg/dL unless complicated by liver disease or biliary obstruction.

Splenomegaly

• May occur in:
  • Hereditary spherocytosis
  • Autoimmune haemolytic anaemia
  • Thalassaemia major
• Typically absent in G6PD deficiency.
• May also indicate coexisting conditions such as CLL, lymphoma, or SLE.
• Splenomegaly may not always be palpable; imaging may be required to assess spleen size.

Right upper quadrant tenderness

• May suggest cholelithiasis (bilirubin gallstones), particularly in chronic haemolytic states.

Leg ulcers

• Seen in chronic haemolytic conditions like:
  • Sickle cell disease
  • Thalassaemia major
• Result from impaired microvascular perfusion, chronic hypoxia, and reduced RBC deformability.

Signs of folate deficiency

• Seen in chronic haemolysis due to increased erythropoiesis.
• May include:
  • Patchy hyperpigmentation
  • Glossitis or sore tongue
  • Gastrointestinal disturbances

System-Specific Examination Clues to Underlying Aetiology

 Lymphadenopathy

• Suggests a possible lymphoproliferative disorder such as CLL or NHL.

Butterfly malar rash and arthritis

• Suggestive of systemic lupus erythematosus.

Hepatosplenomegaly in infants or children

• May point to severe congenital haemolytic disorders or infections such as CMV or parvovirus.

Associated Systemic Findings

 Heart failure signs (in severe or abrupt haemolysis in predisposed individuals)

• Raised jugular venous pressure, peripheral oedema, basal crackles.

Neurological abnormalities

• May occur in thrombotic microangiopathies (e.g., TTP) coexisting with haemolysis.
• Look for altered mental status, focal deficits, or seizures.

Initial Laboratory Investigations

Complete Blood Count (CBC)

• Haemoglobin (Hb): Typically decreased.
• Mean Corpuscular Haemoglobin Concentration (MCHC):
  • May be elevated in hereditary spherocytosis or due reticulocytosis.
• Red Blood Cell Indices:
  • Low MCV/MCH: Suggest microcytosis from iron deficiency due to chronic haemoglobin loss.
  • High MCV: Seen in reticulocytosis (as reticulocytes are larger) or folate deficiency from increased erythropoietic turnover.
• Red Cell Distribution Width (RDW):
  • Increased in haemolytic anaemia due to anisocytosis.

Reticulocyte Count

• Elevated as a compensatory marrow response.
• May be suppressed during aplastic crisis (e.g., parvovirus B19 infection).
• A raised reticulocyte index is a hallmark of active haemolysis but is not specific.

Peripheral Blood Smear

• Helps identify morphological clues to underlying causes:
  • Schistocytes: Microangiopathic haemolysis (TTP, HUS, DIC, prosthetic valves).
  • Spherocytes: Autoimmune haemolysis or hereditary spherocytosis.
  • Elliptocytes: Hereditary elliptocytosis.
  • Bite/Blister cells: Oxidative damage (e.g., G6PD deficiency).
  • Spur cells: Seen in advanced liver disease.
  • Tear drop cells: Can suggest marrow infiltration or myelofibrosis.
  • RBC inclusions: Infections such as malaria, babesiosis, and bartonellosis

Serum Lactate Dehydrogenase (LDH)

• Elevated due to red cell lysis.
• Highly sensitive but non-specific (may rise with malignancy, tissue injury).
• LDH-1 and LDH-2 are more specific to RBC destruction.

Haptoglobin

• Binds free haemoglobin; levels fall during intravascular haemolysis.
• May remain normal in extravascular haemolysis or be elevated in inflammatory states (as an acute-phase reactant).
• Low haptoglobin in combination with high LDH is ~90% specific for haemolysis.

Unconjugated (Indirect) Bilirubin

• Raised due to haem breakdown.
• Typically <85 µmol/L (<5 mg/dL); higher levels suggest concurrent liver dysfunction or gallstone disease.

Urinalysis

• Haemoglobinuria: Suggests intravascular haemolysis.
• Urine dipstick: Positive for blood without red cells on microscopy.
• Urine hemosiderin: Indicates prolonged or severe intravascular haemolysis.

Immunohaematological Testing

Direct Antiglobulin Test (DAT / Coombs’ Test)

• Detects antibody (IgG) and/or complement (C3d) on RBC surface.
• Positive in most AIHA; distinguishes between:
  • Warm AIHA (IgG)
  • Cold AIHA (C3d)
• DAT-negative AIHA: ~5–10% of cases; may require polybrene testing or immunoradiometric assay (IRMA) for confirmation.

Donath-Landsteiner Antibody

• Used in suspected paroxysmal cold haemoglobinuria.
• Detects biphasic IgG antibodies that bind RBCs at low temperature and activate complement upon warming.

Additional Targeted Tests Based on Clinical Suspicion

Red Cell Enzyme and Haemoglobin Studies

• G6PD Assay:
  • Spot test and spectrophotometry are initial screens.
  • Results can be falsely normal in the setting of reticulocytosis.
  • Heinz body preparation supports the diagnosis.
• Hb Electrophoresis:
  • Confirms sickle cell disease, thalassaemia, or other haemoglobinopathies.
  • HbS, HbC, HbF and HbA2 levels distinguish specific disorders.

Paroxysmal Nocturnal Haemoglobinuria (PNH)

• Flow cytometry for CD55 and CD59 on RBCs and granulocytes.
• Demonstrates PNH clone in haemolysis with unexplained cytopenias or thrombosis.

Systemic and Ancillary Tests

Liver Function Tests (LFTs)

• Elevated in liver disease-associated haemolysis (e.g., alcoholic cirrhosis).

Renal Function (Creatinine, Urea)

• Elevated in TTP, HUS, or in cases with haemoglobinuric acute kidney injury.

Cold Agglutinin Titre

• Increased in cold agglutinin disease.
• Specific antibodies may suggest underlying infections:
  • Anti-I: Mycoplasma pneumoniae
  • Anti-i: Infectious mononucleosis
  • Anti-P: Parvovirus B19 (in paroxysmal cold haemoglobinuria)

Antinuclear Antibody (ANA)

• Positive in autoimmune conditions like SLE, which may underlie secondary AIHA.

Rare or Research-Based Tests

• Red Blood Cell Survival Test:
  • 51Cr-labelled RBC studies; rarely performed, reserved for equivocal cases.
• MicroRNA Profiling:
  • May support diagnosis in CLL-related AIHA.
• Novel IgG Binding Assays:
  • May replace or supplement DAT in low-titre antibody states.

Anaemia Due to Blood Loss

• Key Features:
  • Often acute or chronic bleeding history.
  • Symptoms: pallor, fatigue, dizziness; melena or menorrhagia may be present.
  • Reticulocyte count may rise similarly to haemolysis due to marrow compensation.
• Investigations:
  • MCV: Typically microcytic if iron deficiency develops.
  • Haptoglobin: Normal.
  • LDH and bilirubin: Normal.
  • Stool occult blood: May be positive in chronic gastrointestinal blood loss.

Underproduction Anaemias

• Causes:
  • Bone marrow failure: Myelofibrosis, myelodysplasia, aplastic anaemia.
  • Deficiencies: Iron, vitamin B12, folate.
  • Anaemia of chronic disease.
• Distinguishing Features:
  • Low or inappropriately normal reticulocyte count despite anaemia.
  • Absence of haemolytic markers (e.g., LDH, indirect bilirubin).
  • Often normocytic or macrocytic depending on aetiology.
  • May present with pancytopenia if marrow is suppressed.

Transfusion Reactions

• Types:
  • Acute haemolytic reaction:
    • Occurs minutes to hours post-transfusion.
    • Symptoms: chills, fever, flank pain, hypotension, haemoglobinuria.
  • Delayed haemolytic transfusion reaction:
    • Occurs days to weeks later.
    • Symptoms: jaundice, falling haemoglobin, positive direct antiglobulin test (DAT).
• Investigations:
  • DAT (Coombs' test): Usually positive.
  • Serum haptoglobin: Decreased.
  • LDH and bilirubin: Elevated.
  • Post-transfusion blood sample: Pink/red plasma due to free haemoglobin.
  • Serologic testing: May reveal alloantibodies to red cell antigens.
  • In anaphylactic reactions: Serum IgA may be low; anti-IgA antibodies may be present.

Disseminated Intravascular Coagulation (DIC)

• Features:
  • Systemic activation of clotting leading to consumption of clotting factors and platelets.
  • Associated with sepsis, malignancy, trauma, or obstetric complications.
• Overlap with Haemolysis:
  • Microangiopathic haemolytic anaemia (MAHA) features may mimic haemolysis.
  • Schistocytes present on peripheral smear.
• Distinguishing Investigations:
  • Prolonged PT and aPTT.
  • Elevated D-dimer.
  • Low fibrinogen.
  • Thrombocytopenia and evidence of bleeding.

Thrombotic Microangiopathies (TTP, HUS, HELLP)

• Shared Characteristics:
  • Presence of schistocytes on blood smear.
  • Microangiopathic haemolytic anaemia.
  • Thrombocytopenia.
• Specific Features:
  • TTP: Neurological symptoms, renal dysfunction, fever, MAHA, thrombocytopenia (classic pentad).
  • HUS: Predominantly renal failure; associated with E. coli O157:H7 in children.
  • HELLP syndrome: Occurs in pregnancy—Haemolysis, Elevated Liver enzymes, Low Platelets.

Paroxysmal Nocturnal Haemoglobinuria (PNH)

• Mechanism:
  • Complement-mediated intravascular haemolysis due to absence of CD55/CD59 on RBCs.
• Distinguishing Features:
  • Haemoglobinuria, especially in the morning.
  • Thrombosis at unusual sites (e.g., hepatic vein).
  • May occur in conjunction with aplastic anaemia or myelodysplasia.
• Investigations:
  • Flow cytometry for CD55/CD59-deficient cells.
  • Negative DAT despite haemolysis.

Mechanical Haemolysis from Cardiac Valves

• Features:
  • Haemolysis due to shear stress from prosthetic heart valves or mechanical circulatory support.
  • Schistocytes may be present.
• Distinguishing Factors:
  • Typically DAT-negative.
  • Less kidney injury compared to PNH unless underlying disease exists.
  • History of valve replacement or known device.

Universal Management Principles

• Folic acid supplementation is routinely advised due to increased erythropoietic demand.
• Transfusions may be life-saving in severe anaemia but should not delay treatment of the underlying cause.
• Plasmapheresis may be considered in refractory or life-threatening autoimmune haemolysis.
• Close monitoring for haemodynamic instability, relapse, or treatment side effects is crucial.

Immune-Mediated Haemolytic Anaemia (DAT-Positive)

Warm Autoimmune Haemolytic Anaemia (AIHA)

• First-line therapy:
  • Corticosteroids (e.g. prednisolone) – typically effective within 1–3 weeks.
  • Taper steroids once haemolysis resolves; lack of response by day 21 suggests steroid failure.
• Second-line options:
  • Rituximab – especially for steroid-refractory cases or relapses.
  • Splenectomy – for persistent or steroid-resistant disease; not effective in cold AIHA.
• Third-line and steroid-sparing agents:
  • Azathioprine, ciclosporin, mycophenolate, danazol.

Cold Autoimmune Haemolytic Anaemia

• Cold avoidance and passive warming during transfusion or fever management.
• Pharmacological agents:
  • Sutimlimab: anti-C1s monoclonal antibody; reduces haemolysis in cold agglutinin disease.
    • Requires vaccination against encapsulated organisms.
• Rituximab is useful but less effective than in warm AIHA.
• Splenectomy is typically ineffective (liver is the primary site of haemolysis in cold AIHA).

Secondary AIHA

Haematological Malignancies (CLL, NHL)

• Treat the underlying malignancy (e.g., chemoimmunotherapy, targeted agents).
• AIHA management as per warm or cold classification.

Infectious Triggers

• Address the infection (e.g., Mycoplasma, EBV, Leishmania).
• Corticosteroids may be used in severe persistent cold agglutinin disease secondary to infection.

Drug-Induced AIHA

• Immediate cessation of the causative drug (e.g., cephalosporins, rifampicin, fludarabine).
• Corticosteroids may be considered based on severity, though efficacy is unclear.

Non-Immune Haemolytic Anaemia (DAT-Negative)

Drug-Induced (Oxidative)

• Discontinue drugs (e.g., dapsone, nitrofurantoin, sulfa drugs).
• Corticosteroids and splenectomy are not helpful.

Mechanical or Physical Injury

• Footstrike haemolysis: resolves with cessation of activity.
• Prosthetic heart valves:
  • Subclinical haemolysis is common.
  • Severe cases may require surgical intervention if dysfunction is identified.

Liver Disease

• Splenectomy may be considered in cases with significant hypersplenism.
• Portal hypertension is not an absolute contraindication but requires careful surgical planning.

Thrombotic Thrombocytopenic Purpura (TTP)

• Plasma exchange + corticosteroids are first-line therapy.

Paroxysmal Nocturnal Haemoglobinuria (PNH)

• Eculizumab, ravulizumab: monoclonal antibodies against complement C5.
• Iptacopan, pegcetacoplan: complement inhibitors (C3 and factor B) offer newer alternatives.

Inherited Haemolytic Disorders

Red Cell Membrane Disorders

• Hereditary spherocytosis / elliptocytosis / pyropoikilocytosis:
  • Splenectomy often results in durable remission.
  • Reserved for severe or transfusion-dependent cases.

Red Cell Enzyme Deficiencies

• G6PD Deficiency:
  • Avoid triggers: fava beans, sulfa drugs, nitrofurantoin, naphthalene, dapsone.
  • Management is supportive; transfusions for severe haemolysis.
• Pyruvate Kinase Deficiency:
  • Supportive care and splenectomy in severe cases.
  • Mitapivat (oral PK activator): reduces transfusion needs; approved in adults.

Haemoglobinopathies

• Sickle Cell Disease / Thalassaemia:
  • Supportive care: hydration, analgesia, oxygen, infection control.
  • Preventive strategies: folic acid, vaccinations, hydroxyurea (in SCD).
  • Transfusions for acute crises or preparation for surgery.

General Prognostic Factors

• Overall mortality from haemolytic anaemias is low, but prognosis worsens in:
  • Older individuals
  • Patients with cardiovascular comorbidities
  • Those with delayed diagnosis or ineffective treatment
• Anaemia, regardless of cause, contributes to poorer outcomes in other chronic illnesses such as:
  • Chronic kidney disease
  • Congestive heart failure
  • Malignancy
• This is supported by findings from landmark trials such as TRICC, TRISS, and TRACS.

Autoimmune Haemolytic Anaemia (AIHA)

 Children

• Often experience transient disease courses.
• Fewer relapses and better long-term outcomes.

Adults

• More likely to have a relapsing-remitting pattern.
• Risk of refractoriness to first-line treatment (e.g. corticosteroids) increases in those with marked anaemia at onset.
• AIHA linked to lymphoproliferative disorders tends to follow the course of the underlying malignancy.

Drug- or infection-induced AIHA

• Typically resolves with removal of the trigger.
• Relapse is rare if the inciting agent is avoided.

Haemoglobinopathies

 Sickle Cell Disease (SCD)

• Chronic haemolysis leads to organ damage, vaso-occlusive crises, and stroke.
• Patients with Hb <8 g/dL have:
  • Increased risk of hospital complications
  • Higher mortality
• Despite advances in therapy, long-term complications (pulmonary hypertension, nephropathy, cerebrovascular disease) contribute to poorer prognosis.

Thalassaemia

• Repeated transfusions may lead to iron overload, which contributes to cardiac and hepatic complications.
• Outcomes have improved with iron chelation and better transfusion protocols.

Red Cell Enzyme and Membrane Disorders

 G6PD Deficiency

• Prognosis is excellent with avoidance of oxidative stressors.
• Haemolysis episodes are typically self-limited.
• Risk for severe infections and sepsis is increased, especially in neonates and during haemolytic crises.

Pyruvate Kinase Deficiency

• Variable severity; some require chronic transfusions.
• Splenectomy and mitapivat (in adults) improve quality of life.
• Long-term outlook depends on transfusion burden and iron management.

Hereditary Spherocytosis

• Most patients achieve symptom control with splenectomy, reducing haemolytic burden.
• Disease is non-progressive if well managed.

Thromboembolic Events

• Haemolysis contributes to a hypercoagulable state via release of free haemoglobin and iron, endothelial activation, and altered phospholipid membrane asymmetry.
• Sickle cell disease (SCD) and thalassaemia are associated with increased thrombotic risk due to chronic haemolysis and vascular dysfunction.
• Paroxysmal nocturnal haemoglobinuria (PNH):
  • Thromboembolism is the leading cause of death, affecting 15%–44% of patients.
  • Risk is elevated even in the absence of traditional thrombophilia.
• Management:
  • Consider prophylactic anticoagulation in high-risk individuals (e.g. prior thromboembolism, pregnancy).

Renal Impairment

• Intravascular haemolysis leads to:
  • Release of free haemoglobin → filtered by glomeruli.
  • Accumulation of iron and hemosiderin in renal tubular cells.
  • Associated with acute kidney injury and long-term nephropathy.
• PNH and other forms of sustained intravascular haemolysis are particularly implicated.

Hepatobiliary Complications

• Cholelithiasis:
  • Common in hereditary haemolytic anaemias (e.g. hereditary spherocytosis, thalassaemia, sickle cell disease).
  • Caused by chronic hyperbilirubinaemia leading to pigment gallstones.
  • Less frequently seen in acquired haemolytic disorders.
• Wilson disease:
  • Haemolysis can be an initial presentation.
  • Delayed diagnosis may result in hepatic and neurological sequelae.

Transfusion-Related Issues

Alloimmunisation

• Recurrent transfusions increase the risk of forming red cell antibodies, making future cross-matching difficult.
• Cross-match incompatibility complicates emergency transfusion and delays treatment.

Iron Overload

• Occurs in chronically transfused patients (e.g. thalassaemia major, pyruvate kinase deficiency).
• Monitoring:
  • Annual serum ferritin, liver iron concentration (MRI or biopsy), and echocardiography.
• Chelation therapy:
  • Desferrioxamine
  • Deferiprone
  • Deferasirox

Complications in Sickle Cell Disease (SCD)

• Chronic haemolysis contributes to:
  • Tissue hypoxia → fatigue, muscle pain.
  • Higher rates of stroke, organ dysfunction, and hospitalisation in patients with Hb <8 g/dL.
• Haemolytic burden correlates with adverse outcomes.

Complications in Hereditary Spherocytosis (HS)

• Patients may remain undiagnosed until adulthood, when complications present.
• Recurrent cholelithiasis is common.
• Severe recessive forms may require regular transfusions, increasing risk for iron overload and alloimmunisation.

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