Haemolytic Anaemia

Red cells normally circulate for about 120 days before senescent cells are removed. Haemolysis is premature destruction and hence a shortened RBC lifespan.

Anaemia results when bone marrow production can no longer compensate for the shortened survival (uncompensated haemolytic anaemia); if the marrow can compensate, it is compensated haemolytic anaemia.

Haemolysis may be acute, chronic or episodic, and extravascular, intravascular or both.

Causes

Haemolysis is classified by whether it is extrinsic (from a source outside the red cell — usually acquired) or intrinsic (a defect within the red cell — usually inherited).

Extrinsic (acquired) disorders:

Mechanism	Disorder/agent
Immunologic	Autoimmune haemolytic anaemias — cold antibody, warm antibody, drug-induced, EBV, mycoplasma, paroxysmal cold haemoglobinuria; acquired TTP; transfusion (alloantibody) reactions
Infectious organisms (direct invasion)	Babesia, Bartonella bacilliformis, Plasmodium falciparum/malariae/vivax
Mechanical trauma	Microangiopathic haemolysis — DIC, thrombotic microangiopathies (TTP, atypical/complement-mediated HUS, Shiga-toxin HUS); march haemoglobinuria; valvular heart disease and mechanical valves; ECMO/ventricular assist devices
Reticuloendothelial hyperactivity	Hypersplenism
Toxin-producing organisms	Clostridium perfringens, Shiga toxin
Toxins	Oxidant compounds (dapsone, phenazopyridine, naphthalene), copper (Wilson disease), lead, insect/snake venom
Thermal injury	Burns

Intrinsic (congenital) RBC abnormalities:

Mechanism	Disorder/agent
Acquired membrane disorders	Severe hypophosphataemia (ATP depletion), paroxysmal nocturnal haemoglobinuria, stomatocytosis, spur cell anaemia
Congenital membrane disorders	Hereditary elliptocytosis, spherocytosis, stomatocytosis
Haemoglobin synthesis disorders	Hb C/E disease, sickle cell disease, thalassaemias, unstable haemoglobins
RBC metabolism disorders	Glycolytic pathway defects (e.g. pyruvate kinase deficiency); hexose monophosphate shunt defects (e.g. G6PD deficiency)

Infectious organisms cause haemolysis through several mechanisms: direct toxin action (Clostridium perfringens), invasion and destruction of the RBC (Plasmodium, Bartonella, Babesia), antibody production (EBV, mycoplasma), and haemolytic-uraemic syndrome from Shiga-toxin–producing E. coli.

Pathophysiology

Senescent RBCs lose membrane and are cleared by the phagocytic cells of the reticuloendothelial system in the spleen, liver and bone marrow.

Haemoglobin is broken down mainly by haem oxygenase: iron is conserved and reused, and haem is degraded to bilirubin, which is conjugated in the liver to bilirubin glucuronide and excreted in bile.

• Extravascular haemolysis: most pathological haemolysis is extravascular, when damaged or abnormal RBCs are cleared by the spleen and liver. The spleen destroys mildly abnormal cells and cells coated with warm antibodies; severely abnormal cells, or cells coated with IgG or complement (C3), are destroyed in the spleen and liver. The smear may show spherocytes, or — with cold agglutinins — erythrocyte agglutination if the blood is not warmed on collection.
• Intravascular haemolysis: premature destruction when the cell membrane is severely damaged by immune phenomena, direct trauma (march haemoglobinuria), shear stress (defective mechanical valves, thrombotic microangiopathy), DIC, or toxins (clostridial toxins, venomous snake bite). Free plasma haemoglobin exceeds the binding capacity of haptoglobin, so unbound plasma haptoglobin falls; haemoglobin dimers are filtered and partly reabsorbed by renal tubular cells, and haemoglobinuria follows once reabsorptive capacity is exceeded, with iron laid down as tubular haemosiderin.
• Consequences: unconjugated (indirect) hyperbilirubinaemia and jaundice when haemoglobin-to-bilirubin conversion exceeds the liver’s conjugating and excretory capacity; increased stercobilin (stool) and urobilinogen (urine), sometimes cholelithiasis.
• Increased renal erythropoietin drives the marrow to accelerate RBC production, causing reticulocytosis.
• Thrombosis risk is increased with many forms of haemolytic anaemia.

Clinical features

• Systemic features resemble those of other anaemias — pallor, fatigue, dizziness, weakness — with possible hypotension.
• Scleral icterus or jaundice may occur and the spleen may enlarge.
• Haemolytic crisis (acute, severe haemolysis) is uncommon and may present with chills, fever, back and abdominal pain, prostration and shock.
• Haemoglobinuria causes red or reddish-brown urine.

Diagnosis

Haemolysis is suspected in a patient with anaemia and reticulocytosis.

The peripheral smear and reticulocyte count are the most important tests; serum bilirubin, LDH and haptoglobin are then measured, plus urinalysis.

• Peripheral smear and reticulocyte count — an elevated reticulocyte count (>2.5%) indicates an appropriate marrow response. RBC morphology suggests the cause: spherocytes point to an extravascular cause (autoimmune haemolytic anaemia or hereditary spherocytosis); schistocytes or other fragmented cells point to an intravascular cause such as microangiopathic haemolytic anaemia (TTP, HUS, complement-mediated TMA, valvular haemolysis).
• Serum bilirubin (indirect), LDH, haptoglobin, ALT — raised LDH and indirect bilirubin with a normal ALT, decreased haptoglobin, and urinary urobilinogen support haemolysis. A haptoglobin below 25 mg/dL has about an 87% probability of predicting haemolytic disease, though haptoglobin also falls with hepatocellular dysfunction and rises with systemic inflammation. LDH is markedly raised in intravascular haemolysis and only mildly in extravascular. Intravascular haemolysis is also suggested by urinary haemosiderin and by schistocytes with a low haptoglobin.
• Direct antiglobulin (Coombs) test and/or haemoglobinopathy screen — the direct Coombs test detects RBC-bound antibody (IgG) or complement (C3) on the membrane; a positive result suggests autoantibodies to the patient’s RBCs (or, within 3 months of transfusion, alloantibodies). Severity of haemolysis broadly correlates with DAT strength. In warm AIHA the DAT is positive for IgG and/or C3d; cold agglutinin disease is typically C3d-positive with IgG negative or weak.
• Further tests to identify the cause — haemoglobin electrophoresis and HPLC, RBC enzyme assays, flow cytometry for a PNH clone, cold agglutinins, osmotic fragility, genetic testing for membranopathies and enzymopathies, and — if thrombotic microangiopathy is considered — ADAMTS13 activity and Shiga toxin testing.

Occasionally the reticulocyte count fails to rise despite haemolysis (renal insufficiency, infection, marrow failure, parvovirus B19, marrow infiltration). This reticulocytopenia is a haematological emergency and needs prompt transfusion.

Management

Treatment depends entirely on the cause, since a treatment appropriate for one category can be harmful in another.

• Transfusion is the mainstay for severe or symptomatic anaemia; long-term transfusion can cause iron overload requiring chelation.
• Warm antibody autoimmune haemolysis — corticosteroids first-line; rituximab, other immunosuppressants or splenectomy for refractory or relapsing disease.
• Cold agglutinin disease — avoid cold exposure; warm blood before transfusion.
• Splenectomy can help when splenic sequestration is the major site of destruction.
• G6PD deficiency — avoidance of oxidant drugs and foods is the primary management; the disease is rarely fatal.
• Folate replacement for patients with ongoing long-term haemolysis.