Hemolytic Anaemia

 

• Background

  Anaemia due to lysis of red blood cells.

  Can be acquired or inherited:

  • Acquired: immune or non-immune mediated.
  • Inherited: RBC metabolism defects, RBC membrane defects, abnormal Hb production.

  Can be extra- or intra-vascular:

  • Extravascular haemolysis occurs via removal of defective or antibody-tagged RBCs from circulation, primarily in the spleen.
  • Intravascular haemolysis can result from microangiopathic haemolytic anaemia (MAHA), G6PD, paroxysmal nocturnal haemoglobinuria (PNH), or ABO incompatible transfusion.

• Acquired haemolytic anaemia

  Immune-mediated (DAT +ve)

  Warm autoimmune haemolytic anaemia:

  • Usually primary (idiopathic).
  • Can also be secondary to SLE, RA, CLL, or lymphoma.
  • 'Warm' refers to the temperature at which the antibodies (IgG) bind RBCs (37°C).

  Cold autoimmune haemolytic anaemia:

  • Aka cold agglutinin disease.
  • Less common than warm AIHA.
  • Primary (idiopathic) or secondary to lymphoproliferation (CLL, lymphoma, Waldenström's) or infection (Mycoplasma pneumoniae, infectious mononucleosis, or HIV).
  • Antibodies (usually IgM) bind RBCs at 28-31°C.
  • Triggers: cold weather, cold drinks, unwarmed IV fluids.

  Alloimmune haemolytic anaemia:

  • Post-transfusion.
  • Haemolytic disease of newborn.

  Drug-induced immune haemolytic anaemia:

  • β-lactams: cephalosporins, penicillin, piperacillin.
  • Methyldopa

  Non-immune (DAT -ve)

  • Drug-induced HA can also be non-immune, most commonly in the context of G6PD.
  • MAHA
  • PNH: triad of haemolytic anemia, pancytopenia, and large vein thrombosis (esp. hepatic, abdominal, cerebral, and dermal).
  • Infection: malaria, sepsis.
  • Liver or kidney disease.

• Hereditary haemolytic anaemia

  RBC metabolism defects

  Glucose-6-phosphate dehydrogenase deficiency (G6PD deficiency):

  • X-linked.
  • Affects 1/15 worldwide, mainly African, Asian, and Mediterranean.
  • Haemolysis triggered by infection, drugs (primaquine, chloroquine, sulfonamides), or fava beans ('favism').

  Pyruvate kinase deficiency:

  • Autosomal recessive.
  • Occurs worldwide, but may be commoner in ethnic Europeans, with 1/20,000 prevalence.

  RBC membrane defects

  • Spherocytosis: autosomal dominant, affects 1/5000 Europeans.
  • Elliptocytosis: usually autosomal dominant, occurring worldwide but commoner in Africans. Pyropoikilocytosis is a severe, autosomal recessive sub-type.

  Abnormal Hb production (haemoglobinopathies)

  • Thalassaemia
  • Sickle cell disease.

• Microangiopathic haemolytic anaemia (MAHA)

  Traumatic intravascular destruction of RBCs, often with associated endothelial injury, clotting activation, and platelet aggregation (leading to thrombocytopaenia).

  Causes

  • Primary thrombotic microangiopathy (TMA): thrombotic thrombocytopaenic purpura (TTP), haemolytic uraemic syndrome (HUS).
  • DIC
  • HELLP syndrome.
  • Autoimmune: vasculitis, SLE, scleroderma renal crisis.
  • Malignant hypertension.
  • Mechanical valves.

  Pathophysiology and presentation of TTP and HUS

  TTP

  Pathophysiology:

  • A deficiency of ADAMTS13 (defined as <10% activity), an enzyme which cleaves von Willebrand factor (VWF).
  • The resulting ultra large VWF multimers remain attached to the vascular endothelium, and become a site of platelet aggregation, reducing circulating platelet levels. In the microvasculature (e.g. CNS, kidneys), these microthrombi cause ischaemia and increase sheer stress, resulting in haemolysis.
  • 95% result from antibody formation to ADAMTS13, while the remainder are inherited in an autosomal recessive manner.
  • Most cases are idiopathic. Identified triggers for antibody formation include pregnancy, HIV, and drugs (quinine, co-trimoxazole, simvastatin). The latter are sometimes considered separate to TTP, as 'drug-induced thrombotic microangiopathy'.

  Presentation:

  • Classic pentad, FANTA: Fever, Anaemia, Neurological signs (confusion, headache, focal signs, seizures, stroke, coma), Thrombocytopaenia, AKI.
  • The full pentad is often absent. Renal impairment is usually mild or absent, and neurological signs only occur in 65%.
  • GI symptoms are common, and cardiac involvement may be seen
  • Onset may be acute or more insidious.

  HUS

  • Defined by triad of haemolytic anaemia, thrombocytopaenia, and acute kidney injury.
  • Commonest cause is Shiga-toxin (Stx) producing E. coli (usually serotype O157:H7), in which Stx binds to the glomerular endothelium triggering a range of inflammatory and thrombotic changes. This typically presents in children as HUS around 5-10 days following an episode of gastroenteritis with bloody diarrhoea.
  • Other causes of HUS include pneumococcal infection, and inherited complement or factor H mutations.

• Signs and symptoms

  • Pallor, fatigue, SOB.
  • Pre-hepatic jaundice.
  • Splenomegaly
  • RUQ pain if there are pigment gallstones.

• Investigations

  General bloods:

  • FBC: ↓Hb, MCV normal or ↑, ↑MCH in spherocytosis.
  • ↑Reticulocytes
  • ↑LDH: released from RBCs.
  • ↓Haptoglobin: normally binds free Hb, so low levels mean high free Hb. Commoner in intravascular haemolysis.
  • U&E and LFTs, as liver or kidney disease can be a cause, and LFTs may show ↑unconjugated BR.
  • Clotting studies can help delineate causes of MAHA: ↑PT/aPTT/D-dimer and ↓fibrinogen in DIC, while these are usually normal (or mildly deranged) in TTP and HUS.

  Blood film (aka peripheral smear):

  • Schistocytes: RBC fragments, including helmet cells and triangular cells, seen in MAHA.
  • Other findings: spherocytes, elliptocytes, sickle-shaped cells, target cells (thalassaemia).

  Specific diagnostic bloods:

  • Direct antiglobulin test (DAT, aka Coomb's): detects antibody or complement-coated RBCs, +ve = immune-mediated. IgG suggests warm AIHA, and C3d suggests cold AIHA.
  • Donath-Landsteiner test or cold agglutinin test (↑titres) to confirm cold AIHA.
  • Hb electrophoresis for suspected thalassaemia or sickle cell.
  • ADAMTS13 activity level if TTP suspected.

  Urinalysis:

  • ↑Urobilinogen.
  • Haemoglobinuria in MAHA: blood +ve on dipstick but no RBCs.

  Imaging:

  • CXR and ECG given SOB and risk of critical illness.
  • US for splenomegaly.

• Management

  General:

  • Remove precipitant and/or treat any underlying cause.
  • Transfuse if ↓↓Hb.
  • Folic acid if there is reticulocytosis, as it is needed for RBC production.

  Warm immune-mediated:

  • Steroids 1st line.
  • Further options: rituximab, cyclophosphamide, azathioprine, plasmapheresis.
  • Splenectomy if refractory.

  Cold immune-mediated:

  • Avoid cold. If IV fluids or transfusion needed, should be warmed before infusion.
  • Usually mild and doesn't require immunosuppression, but severe cases may benefit from rituximab. Steroids are usually ineffective.

  Non-immune:

  • Inherited RBC membrane disorders: splenectomy.
  • TTP: plasma exchange. 90% mortality if untreated.