Haemolysis refers to the untimely destruction of red blood cells (RBCs), which normally have a lifespan of 120 days.1
Haemolytic anaemia develops when the bone marrow is not able to properly replace the lost RBCs, ultimately leading to a decrease in red cell count and haemoglobin concentration.
Under normal circumstances, RBCs live for around 120 days before they are broken down by macrophages in the reticuloendothelial system, predominantly the spleen. New RBCs are formed through erythropoiesis, which is accomplished in adults within the bone marrow by the cytokine erythropoietin.2
Erythropoietin is secreted by the kidney in reaction to hypoxia and binds to receptors on RBC precursors, prompting their development into mature erythrocytes which are released into the bloodstream.
In haemolytic anaemia, RBCs are destroyed prematurely, either within the circulation (intravascular haemolysis) or within the reticuloendothelial system (extravascular haemolysis).
The decrease in RBC count leads to a reduction in the oxygen-carrying capacity of the blood and causes relative hypoxia, thus stimulating EPO secretion and activating erythropoiesis.2
This is indicated by an increase in the reticulocyte count (reticulocytosis), signifying that the bone marrow is attempting to make up for the loss of red cells.
When the replacement of RBCs is not adequate, levels of haemoglobin decrease and anaemia appears.
Haemolysis can take place in two different locations. Extravascular haemolysis primarily occurs in the spleen and is more common than intravascular haemolysis.
Intravascular haemolysis is the breakdown of red blood cells within the circulation, releasing free haemoglobin into the blood. It is less common than extravascular haemolysis.
In clinical practice there may be significant overlap between the two types of haemolysis.
There are many conditions that can lead to haemolysis. These include:
The primary mechanism of extravascular haemolysis is through phagocytosis of red blood cells within the spleen, due to:
Haemolytic anaemia is commonly classified according to the location of haemolysis (intravascular vs. extravascular) and the underlying mechanism (immune vs. non-immune). Abbreviations: Allo = alloimmune; Auto = autoimmune; TMA = thrombotic microangiopathies.
Typical symptoms of anaemia may include fatigue, dizziness, pre-syncope, or syncope, shortness of breath on exertion, reduced exercise tolerance, and palpitations. If intravascular haemolysis predominates, the patient may complain of back pain and dark urine due to haemoglobinuria.
On examination, there may be non-specific signs of anaemia including pallor, tachycardia and flow murmurs due to a hyperdynamic circulation, and high-output cardiac failure which occurs rarely in severe anaemia. Cardiac output is high but is insufficient to meet metabolic demands of the body, causing symptoms and signs of biventricular failure.
More specific signs of haemolysis include pre-hepatic jaundice, splenomegaly (can be a sign of haemolysis, the underlying cause of haemolysis, or extramedullary haematopoiesis), dark urine, and gallstones.
To diagnose haemolytic anaemia and its underlying cause, a stepwise approach is taken.
Relevant bedside investigations include:
Relevant laboratory investigations to confirm red cell breakdown include:
Other tests can be used to determine if the haemolysis is predominantly intravascular or extravascular.
Laboratory features of intravascular haemolysis include:
Urinary dipstick and microscopy may show haemoglobinuria, which is the red-brown discolouration of urine and a positive dipstick test for blood in the absence of red blood cells.
After several weeks of intravascular haemolysis, haemosiderinuria may occur. This happens when haptoglobin capacity is depleted and free haemoglobin is filtered by the kidneys, accumulating in the renal tubules as haemosiderin. This can be detected in the urine with Prussian blue staining at least one week after onset, as tubular cells slough off into the urine. Haemosiderinuria indicates the presence of chronic intravascular haemolysis (e.g. haemoglobinopathy).
A direct Coombs test (direct antiglobulin test/DAT) is an important part of the haemolysis screen. The DAT identifies red cells coated with antibody or complement components, which suggests an immune cause for the haemolysis.
The peripheral blood smear is another important part of the haemolysis screen. It can give important clues as to the underlying diagnosis.
Some features of note include:
Haemolytic anaemia involves a fall in haemoglobin concentration caused by a shortened lifespan of circulating erythrocytes. Haemolysis can occur in the vasculature (intravascular) or within the spleen (extravascular), although the latter is more common. Causes can be divided into immune and non-immune conditions.
Immune conditions include autoimmune haemolysis and alloimmunisation due to transfusion mismatch or haemolytic disease of the newborn. Non-immune conditions leading to haemolysis are varied but include haemoglobinopathies, red cell membrane disorders, microangiopathic haemolytic anaemias and red cell enzyme deficiencies.
Symptoms and signs are those of any anaemia. Dark urine may occur in some patients, particularly if there is intravascular haemolysis.
Investigations first aim to detect if there is increased red cell turnover (low haemoglobin, raised LDH, reticulocytosis, unconjugated hyperbilirubinaemia). Laboratory tests can also determine if haemolysis is predominantly intravascular (low haptoglobins, haemoglobinuria and haemosiderinuria) or extravascular.
The advice of a haematologist should be sought for the management of a patient with haemolytic anaemia. Treatment of the underlying cause should be instigated, which varies depending on the specific diagnosis. For example, in autoimmune haemolysis steroids with or without intravenous immunoglobulin are the primary treatment. In sickle cell disease, the chemotherapeutic agent hydroxycarbamide reduces haemolysis and crises.
Supportive treatment should also be given including red cell transfusions if the patient has symptomatic anaemia, is actively bleeding or if the haemoglobin concentration is under 70g/L. Haematinics (B12, iron and folate) should be checked and corrected if low. Folate is also given as standard in chronic haemolysis even if levels are normal to avoid depletion of folate levels due to increased erythropoiesis.
Exchange transfusion can be considered in specific situations. For instance, with life-threatening haemolysis in G6PD deficiency, or in severe sickle cell crises. Advice from a consultant haematologist should be sought in these cases.
Severe haemolysis can lead to decompensated anaemia with shortness of breath and fatigue. Red cell transfusions are required in these cases. High-output cardiac failure rarely occurs in particularly severe cases, giving the typical signs and symptoms of congestive cardiac failure. Unlike in other forms of heart failure, cardiac output is preserved. Management involves correcting the anaemia to restore oxygen delivery to the tissues thus reducing myocardial workload.
Pruritus may occur due to jaundice secondary to persistent haemolysis. The cause of haemolysis should be identified and treated if possible. Symptomatic management includes the use of ursodeoxycholic acid and/or cholestyramine.
Pigmented gallstones can occur with chronic haemolysis. Treatment for symptomatic gallstones is with laparoscopic cholecystectomy.
Haemolysis increases the risk of venous thromboembolism. The risk is particularly high in the haemoglobinopathies and in a rare disorder known as paroxysmal nocturnal haemoglobinuria (PNH).
A peripheral blood film and direct antiglobulin test (DAT) are helpful in diagnosing the cause of haemolysis and should be done in patients with suspected haemolysis.
Treatment depends on the underlying cause. Severe symptomatic anaemia can require blood product support and should involve following local protocols and consulting with a haematologist.
Potential complications include symptomatic anaemia, high-output cardiac failure, symptomatic jaundice, pigmented gallstones and venous thromboembolism.
