Anaemia 2: Haemolytic and Haemoglobinopathies

Haemolytic Anaemia

This is anaemia due to destruction (lysis) of red blood cells before they reach their natural life of 120 days. Intravascular lysis means that the haemoglobin is destroyed in the circulation. Extravascular means that cells are lysed by macrophages in the liver and spleen (where they are normally broken down).

The presentation is that of anaemia. Hyperbilirubinaemia may develop resulting in jaundice and gallstones. Splenomegaly and skeletal abnormalities may develop with specific forms of this anaemia.

Investigation:

1. Anaemia: normocytic or mildly macrocytic
2. Reticulocytosis (stimulation of RBC regeneration)
3. Blood film: reticulocytosis (young red blood cells in the circulation), spherocytes (no central pallor, sphere shaped, present in spherocytosis and autoimmune haemolytic anaemia).
4. Bone marrow: normoblastic hyperplasia
5. Bile: Unconjugated hyperbilirubinaemia (hence it does not enter the urine)
6. Free haemoglobin: haemogobinaemia, haemoglobinuria, haemosiderinuria (renal tubular cells damaged and excreted), absent haptoglobins (which normally mop up excess haemoglobin)

Haemolytic anaemia can be divided as follows:

Congenital

Membrane defect {hereditary spherocytosis}, enzyme defect {eg. G6PD deficiency}, Hbg defect {sickle cell anaemia, thalassaemia}

Acquired

Immune {incompatible blood transfusion, autoimmune haemolytic anaemia}. infection {eg malaria}. drugs/chemicals {eg dapsone/amyl nitrate}, mechanical {prosthetic heart valve, microangiopathic haemolytic anaemia}

Glucose 6 Phosphatase Deficiency

This condition is x-linked, hence only men can suffer from it. It is the commonest RBC enzyme deficiency causing haemolysis. G6PD helps protect against oxidative stress. It is normally asymptomatic, but crises are provoked by:

• Acidosis eg DKA
• Infections
• Oxidant drugs (antimalarials, sulfonamides, synthetic vitamin K nitrofurans)
• Fava beans: a classic for exams!

On investigation Heinz Bodies are seen on the blood film. These are precipitates of oxidised, denatured Hbg cells that have had Heinz removed by the spleen.

Automimmune Haemolytic Anaemia

In this disease RBCs are destroyed by an autoantibody which binds to RBC membrane antigens. There condition is divided in to antibodies which are most active in the cold or warm. A way of memorising the specific antibody is to think of IgG representing "Great" heat, whilst IgM represents "Mild" heat.

Warm (IgG)

This is the most common type, and results in severe anaemia. The antibodies are optimally active at 37 degrees centigrade. Extravascular haemolysis. Idiopathic or associated with lymphoma/SLE/chronic lymphocytic leukaemia or drugs (methyldopa). On the blood film, spherocytes, Reticulocytes are seen. Treatment is with steroids and sometimes splenectomy.

Cold ("cold agglutin disease") (IgM)

These antibodies are optimally active at 4 degrees centigrade and they cause RBC agglutination (RBCs sticking together mediated by complement) and intravascular haemolysis in cold exposed parts of the body. The condition may be idiopathic or associated with eg lymphoma. On the blood film RBC agglutination is seen. Patients are advised to keep warm, and chlorambucil is given, which deregulates lymphoid cells which produce Igm.

The direct antiglobulin (Coombs) test can be used to diagnose autoimmune haemolytic anaemia. Antiglobulin containing anti-IgG and anti-complement is added to a washed suspension of patient's RBCs suspended in normal saline. IgG or complement on the surface of the membrane cause RBCs to agglutinate.

Haemoglobinopathies

These are problems with the synthesis of haemoglobin. The two commonest types are:

• Thalassaemia: disorders of the quantity of haemoglobin
• Sickle cell anaemia: disorders of the structure of haemoglobin

Sickle Cell Anaemia

This comes up extremely frequently in written exam questions for some reason. The disease is recessive.

Sickle cell anaemia remains common because in the carrier state it protects against malaria. The carrier state is termed Sickle cell trait , and denoted HbS (as opposed to the homozygous state of HbSS). Less than 50% of RBCs are sickle cells. It is of not much significance and has a normal life expectancy although renal papillary necrosis (inability to concentrate urine) is a complication.

The homozygous state is more severe with a life expectancy of about 40y. It has a variety of clinical manifestations. These can be remembered using the mnemonic SICKLE :

S

Swellings {Painful transient. Hand and foot syndrome, dactylitis}, Splenic sequestration {occlusion of splenic vessels and splenomegaly. Big spleen can take all blood supply. Treatment: splenectomy}

I

Infections {including osteomyelitis}, Infarctions {aseptic necrosis of femoral head}

C

Chronic haemolysis {due to rigidity of RBCs}, Crises {vaso-occlusive (acute episodes bone pain, worsening anaemia, pulmonary and neurological compl's, precipitated by cold/dehydration/infections, varying frequency weeks to months), Aplastic (parvovirus turns off erythroid stem cells, cos half life anaemia}, Cholelithiasis (Gallstones)

K

Kidney

L

Lungs (Chronic chest syndrome)

E

Erection (priapism), Eye (retinopathy)

On investigation:

1. Anaemia: 6-10 g/dl
2. Blood film: reticulocytes, sickle cells, target cells
3. Sickle solubility test: Sickle S is insoluble in phosphate buffer.
4. Haemoglobin electrophoresis

Treatment is with penicillin and folic acid prophylaxis (folic acid is required due to increased turnover of cells). Hydroxyurea is given, which upregulates fetal haemoglobin. Acute episodes are managed with IV fluids, oxygen, analgesia, antibiotics and blood transfusion. Bone marrow transplantation can be curative.

Thalassaemia

This is decreased synthesis of either alpha or beta haemoglobin chains. It also protects against Malaria.

Beta thalasaemia may be heterozygous (trait) or homozygous. The less severe beta thalasseamia trait gives rise to mild anaemia although it is usually asymptomatic. It is useful to diagnose to ensure that innappropriate oral iron is not given, and to identify family members with the condition.

The homozygous form - beta thalassaemia major - gives rise to severe anaemia. Infants present in the first few months after birth (when fetal haemoglobin does not contain beta chains). 80% of affected infants would die without treatment. Treatment is with lifelong blood transfusions. Desferrioxamine is given to reduce the iron excess that results from transfusions. Folic acid supplementation is necessary. Splenectomy is sometimes performed if the spleen becomes too large. Bone marrow transplantation in early life may be curative.

The severity of alpha thalassaemia depends on how many of the alleles is affected. Each of us has 4 alpha haemoglobin alleles.

1 or 2 chains affected

Asymptomatic or mild anaemia

3 chains affected: "HbH disease"

Increased beta chain synthesis gives rise to beta4 tetramers. Presentation is with jaundice, hepatosplenomegaly, leg ulcers and gallstones. A hypochromic microcytic anaemia is seen, with "golf ball" dots on RBCs. Treatment is with folic acid, transfusions and splenectomy

4 chains affected: "Hb Barts Hydrops"

This causes intrauterine death