Haemolytic anaemia

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Haemolysis\: premature destruction of red blood cells (RBCs) before 120 days, leading to haemolytic anaemia when bone
marrow cannot compensate.
Pathophysiology\: RBCs normally destroyed in spleen after 120 days; erythropoietin from kidneys stimulates RBC
production; haemolytic anaemia results from premature RBC destruction, intravascular (within circulation) or extravascular
(in spleen).
Causes\:
Intravascular haemolysis\: complement activation (e.g., ABO mismatched transfusions), direct cellular destruction (toxins,
trauma, infections), microangiopathic haemolytic anaemia (e.g., DIC, TTP, HUS, HELLP), oxidative haemolysis (e.g., G6PD
de
Extravascular haemolysis\: antibody binding (e.g., AIHA), infection/toxins, intrinsic RBC defects (e.g., hereditary
spherocytosis), splenomegaly/hypersplenism.
Symptoms\: fatigue, dizziness, shortness of breath, reduced exercise tolerance, palpitations, back pain, dark urine
(haemoglobinuria).
Clinical signs\: pallor, tachycardia, high-output cardiac failure, pre-hepatic jaundice, splenomegaly, dark urine, gallstones.
Bedside investigations\: urinalysis (increased urobilinogen, haemoglobinuria).
Laboratory investigations\: FBC (anaemia, normal/increased MCV), reticulocyte count (reticulocytosis), bilirubin (increased
unconjugated), LDH (raised), plasma haptoglobin (decreased in intravascular haemolysis).
Special tests\: direct Coombs test (immune cause), peripheral blood smear\:
Hypochromic, microcytic picture\: can indicate thalassaemia.
Sickled RBC\: sickle cell anaemia.
Schistocytes\: microangiopathic haemolytic anaemias (TTP, HUS, HELLP, DIC).
Malignant cells\: haematological malignancy.
Spherocytes\: hereditary spherocytosis or in autoimmune haemolysis.
Heinz bodies and 'bite' cells\: G6PD de
Management\: consult haematologist, treat underlying cause (e.g., steroids for AIHA), supportive treatment (red cell
transfusions, correct haematinics), consider exchange transfusion in severe cases.
Complications\: decompensated anaemia, high-output cardiac failure, pruritus (due to jaundice), pigmented gallstones,
increased risk of venous thromboembolism (particularly in haemoglobinopathies and PNH).
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Introduction

Haemolysis is the premature destruction of red blood cells (RBCs) before their typical lifespan of 120 days.
1
Haemolytic anaemia results when the bone marrow cannot su
fall in red cell count and haemoglobin concentration.Aetiology
Pathophysiology
Normal RBCs have a lifespan of around 120 days, after which they are destroyed by macrophages in the reticuloendothelial
system (mainly the spleen). RBCs are continuously replenished through erythropoiesis, which in adults occurs in the bone
marrow under the in
2
Erythropoietin is released by the kidney in response to hypoxia. It binds to receptors on RBC precursors and stimulates
their di
Figure 1. The formation of RBCs (erythropoiesis) occurs in the bone marrow. A series of
successive di
form mature, di
the marrow into the circulation.
In haemolytic anaemia red cells are destroyed prematurely, either within the circulation (intravascular haemolysis) or
within the reticuloendothelial system (extravascular haemolysis).
The fall in the RBC count leads to a reduced oxygen-carrying capacity of the blood and relative hypoxia, which
stimulates EPO secretion, upregulating erythropoiesis.
2
This results in an increase in the reticulocyte count (reticulocytosis), a sign that the marrow is attempting to compensate
for a loss of red cells.
If the bone marrow is not able to su
Intravascular vs extravascular haemolysis
Haemolysis can occur in two locations. Extravascular haemolysis occurs primarily in the spleen. It is more common than
intravascular haemolysis.
Intravascular haemolysis is the breakdown of red blood cells within the circulation, leading to the release of free
haemoglobin into the blood. It is less common than extravascular haemolysis.
In clinical practice, the distinction between intravascular and extravascular haemolysis is not clear cut and there may be
signi
Causes of haemolytic anaemia
There are many conditions that can lead to haemolysis. Conditions leading to intravascular haemolysis include\:
1
Complement activation leading to intravascular lysis of RBCs. This can occur in ABO mismatched transfusions, severe
cases of autoimmune haemolytic anaemia (AIHA) and rarer diseases such as paroxysmal nocturnal haemoglobinuria
(PNH) and paroxysmal cold haemoglobinuria (PCH).
Direct cellular destruction by toxins, trauma or lysis. Insect or snake venom and certain infections such as malaria and
clostridial pathogens may cause direct cellular destruction. Freshwater drowning can lead to red cell lysis due to
osmotic forces. Traumatic causes include extracorporeal circuits (e.g. ECMO, haemodialysis), mechanical heart valves,
aortic stenosis and prolonged marching.Microangiopathic haemolytic anaemia (MAHA) occurs when abnormalities of the small blood vessels lead to shearing
forces and intravascular rupture of RBCs. Conditions in which MAHA occur include disseminated intravascular
coagulation (DIC), thrombotic thrombocytopenic purpura (TTP), haemolytic uraemic syndrome (HUS) and haemolysis,
elevated liver enzymes and low platelets (HELLP) syndrome – which are collectively referred to as the thrombotic
microangiopathies.
Oxidative haemolysis occurs where the protective mechanisms of RBCs are overwhelmed. For example, in G6PD and
pyruvate kinase de.
The primary mechanism of extravascular haemolysis is through phagocytosis of RBCs within the spleen. This can occur
due to\:
1
Antibody binding leading to opsonization and phagocytosis of tagged RBCs within the reticuloendothelial system.
Examples of conditions in which this occurs include haemolytic disease of the fetus and newborn (HDFN), delayed
haemolytic transfusion reactions and autoimmune haemolytic anaemia (although, as stated above in severe cases of
AIHA intravascular complement-mediated lysis can occur).
Infection and toxins which are detected by spleen-resident macrophages leading to RBC phagocytosis.
Intrinsic red cell defects such as haemoglobinopathies and membrane disorders (e.g. hereditary spherocytosis and
elliptocytosis). These cause the RBC to become trapped within the spleen where they are destroyed.
Splenomegaly/hypersplenism due to a variety of secondary causes. For instance, myeloproliferative disorders such as
chronic myeloid leukaemia (CML) or hypersplenism secondary to portal hypertension caused by cirrhosis.
A summary of the causes of haemolysis is shown in Figure 2.
3
Figure 2. There are many causes of haemolytic anaemia, which are commonly
classi
the underlying mechanism (immune vs. non-immune). Abbreviations\: Allo =
alloimmune; Auto = autoimmune; TMA = thrombotic microangiopathies.

Clinical features

History
Typical symptoms of anaemia may include\:
Fatigue
Dizziness, pre-syncope, or syncope
Shortness of breath on exertion
Reduced exercise tolerance
Palpitations
If intravascular haemolysis predominates, the patient may complain of back pain and dark urine due to haemoglobinuria.
Clinical examination
On examination, there may be non-speci
Pallor\: of the conjunctiva or palmar creases
Tachycardia &
demands of the body, causing symptoms and signs of biventricular failure.
4
More speci
Pre-hepatic jaundice\: due to an unconjugated hyperbilirubinaemia
Splenomegaly\: can be a sign of haemolysis, the underlying cause of haemolysis (especially if massive splenomegaly is
present) or can occur due to extramedullary haematopoiesis. This latter phenomenon occurs in chronic, severe
haemolytic anaemias such as the haemoglobinopathies when haematopoiesis moves from the bone marrow to the liver
and spleen, leading to an increase in their size.
Dark urine\: may be seen in severe haemolysis due to haemoglobinuria, which is most common with intravascular
haemolysis
Gallstones\: pigmented gallstones may occur leading to right upper quadrant pain and the other typical signs and
symptoms of gallstone disease.
Figure 3. In its early stages, jaundice may be most easily identi
haemolysis.

Investigations

To diagnose haemolytic anaemia and its underlying cause, a stepwise approach is taken.
Bedside investigations
Relevant bedside investigations include\:
Urinalysis\: in haemolysis there will be increased urinary urobilinogen, but conjugated bilirubin will be negative.
Dipstick testing is highly sensitive for haemolysis, but not very speci
urobilinogen including acute hepatitis and cirrhosis.
5
The presence of blood on a dipstick urine sample but the absence of red cells on microscopy suggests haemoglobinuria,
which is seen in intravascular haemolysis.
Laboratory investigations
Relevant laboratory investigations to con
1
Full blood count\: there will be anaemia with a normal or increased mean corpuscular volume (MCV). Increased MCV
occurs if there is signi
MCV measurement of mature erythrocytes.
Reticulocyte count\: the marrow may compensate for increased red cell turnover by increasing haematopoiesis and
releasing immature reticulocytes into the peripheral circulation. As such, there may be reticulocytosis.
Bilirubin\: there may be an increased unconjugated (indirect) bilirubin level, occurring due to haemoglobin breakdown.
Serum lactate dehydrogenase (LDH)\: LDH is a non-speci
haemolysis due to release from RBCs.
Other tests can be used to determine if the haemolysis is predominantly intravascular or extravascular.
Laboratory features of intravascular haemolysis include\:
1Decreased plasma haptoglobin\: haptoglobin is a protein that ‘mops up’ free circulating haemoglobin so that it can be
removed by the liver. It will therefore be reduced in intravascular haemolysis as a large amount of free haemoglobin is
present in the circulation.
Urinary dipstick & 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 on microscopy (Figure 4).
Haemosiderinuria
After several weeks of intravascular haemolysis, haemosiderinuria may occur. This happens when haptoglobin
capacity is depleted and free haemoglobin is
haemosiderin.
This is detected in the urine with Prussian blue staining at least one week after onset, as tubular cells slough o
the urine. Haemosiderinuria indicates the presence of chronic intravascular haemolysis (e.g. haemoglobinopathy).
Other investigations
Direct Coombs test
A direct Coombs test (direct antiglobulin test/DAT) is an important part of the haemolysis screen.
The DAT identi
haemolysis (Figure 5).
6
Figure 5. A direct Coombs test can be used to determine if a haemolytic anaemia has
an immune cause.
Peripheral blood smear
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\:
A hypochromic (pale), microcytic (low MCV) picture\: can indicate thalassaemia
Sickled red blood cells\: pathognomonic of sickle cell anaemia (Figure 6)
Schistocytes\: fragments of red blood cells that occur when abnormal intravascular shearing forces cause destruction of
red cells (Figure 7). These are seen in the microangiopathic haemolytic anaemias (TTP, HUS, HELLP, and DIC).
Malignant cells\: haematological malignancy (Figure 8)
Spherocytes\: may be seen in hereditary spherocytosis or in autoimmune haemolysis
Heinz bodies and ‘bite’ cells\: may be seen in G6PD deFigure 6. Abnormal sickle-shaped red blood cells are diagnostic of sickle cell anaemia.
Figure 7. This blood
haemolytic anaemias (MAHAs).Figure 8. A blood
important cause of autoimmune haemolytic anaemia.

Management

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 speci
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 speci
de

Complications

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 identi
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).References
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