Tales from the haematology clinic session 1

What is α-thalassaemia?

An inherited disorder caused by reduced synthesis of α-globin chains, resulting in reduced haemoglobin production and microcytic red cells.

What is β-thalassaemia?

An inherited disorder caused by reduced or absent synthesis of β-globin chains, resulting in reduced haemoglobin production and microcytic red cells.

Why are thalassaemias classified as haemoglobinopathies?

They are inherited disorders affecting haemoglobin production through abnormal globin-chain synthesis.

How many α-globin genes does a normal individual possess?

Four α-globin genes, with two copies on each chromosome 16.

How many β-globin genes does a normal individual possess?

Two β-globin genes, one on each chromosome 11.

What is the usual genetic defect in α-thalassaemia?

Deletion of one or more α-globin genes.

What is the usual genetic defect in β-thalassaemia?

Point mutations causing reduced (β+) or absent (β0) β-globin production.

What is α-thalassaemia silent carrier state?

Loss of one α-globin gene causing little or no haematological abnormality.

What is α-thalassaemia trait?

Loss of two α-globin genes causing mild microcytosis with minimal or no anaemia.

What is HbH disease?

A severe form of α-thalassaemia caused by deletion of three α-globin genes.

What abnormal haemoglobin forms in HbH disease?

β-globin tetramers called HbH.

Why is HbH abnormal?

It binds oxygen very tightly and releases little oxygen to tissues.

What is hydrops fetalis due to α-thalassaemia?

A severe condition caused by deletion of all four α-globin genes, usually fatal before or shortly after birth.

What abnormal haemoglobin forms in hydrops fetalis?

Hb Bart's, which consists of γ-globin tetramers.

Why is Hb Bart's incompatible with life?

It has an extremely high oxygen affinity and cannot deliver oxygen effectively to tissues.

What is β-thalassaemia trait (minor)?

Heterozygous β-globin deficiency causing mild anaemia or isolated microcytosis.

What is β-thalassaemia major?

Severe β-globin deficiency causing profound anaemia and transfusion dependence.

What is β-thalassaemia intermedia?

A condition with clinical severity between β-thalassaemia trait and β-thalassaemia major.

Why does β-thalassaemia major cause severe anaemia?

Excess α-globin chains precipitate within erythroid precursors, causing ineffective erythropoiesis and haemolysis.

What is ineffective erythropoiesis?

Destruction of erythroid precursors within the bone marrow before they mature into circulating red cells.

Why is ineffective erythropoiesis a major feature of β-thalassaemia major?

Excess unpaired α-globin chains damage developing erythroblasts and lead to apoptosis.

Why do patients with β-thalassaemia major develop marrow expansion?

Severe anaemia stimulates massive erythropoietin production and marrow activity.

Why can β-thalassaemia major cause skeletal deformities?

Extreme bone-marrow expansion alters normal bone architecture.

What blood film findings are common in thalassaemia?

Microcytosis, hypochromia, target cells and marked anisopoikilocytosis.

What is HbA₂?

A normal haemoglobin consisting of two α chains and two δ chains (α₂δ₂).

What is the normal proportion of HbA₂ in adults?

Approximately 2-3.5% of total haemoglobin.

Why is HbA₂ elevated in β-thalassaemia trait?

Reduced β-globin production causes a relative increase in δ-chain incorporation into haemoglobin.

What HbA₂ level strongly suggests β-thalassaemia trait?

Usually greater than 3.5%.

Why is haemoglobin electrophoresis useful in β-thalassaemia trait?

It often demonstrates an elevated HbA₂ fraction.

Why is haemoglobin electrophoresis often normal in α-thalassaemia trait?

There is no significant abnormal haemoglobin fraction, despite reduced α-chain production.

Case: A Cypriot man has Hb 132 g/L, MCV 67 fL, MCH 22 pg, ferritin normal and RBC count increased. What is the most likely diagnosis?

β-thalassaemia trait.

Case: Which laboratory feature most strongly distinguishes thalassaemia trait from iron deficiency?

An elevated RBC count despite marked microcytosis.

Case: Why is RBC count often increased in thalassaemia trait?

The marrow compensates by producing large numbers of small red cells.

Case: Why is RBC count usually low or normal in iron deficiency anaemia?

Iron deficiency limits red-cell production.

Case: Why is ferritin normal in thalassaemia trait?

The disorder affects globin synthesis rather than iron availability.

Case: Why is ferritin low in iron deficiency anaemia?

Body iron stores have been depleted.

Case: A patient has microcytosis, target cells and raised HbA₂. What is the most likely diagnosis?

β-thalassaemia trait.

Case: A patient has microcytosis, normal ferritin and normal Hb electrophoresis. What inherited condition should still be considered?

α-thalassaemia trait.

How does MCH differ between iron deficiency and thalassaemia trait?

MCH is reduced in both conditions.

How does MCHC differ between iron deficiency and thalassaemia trait?

MCHC is usually reduced in iron deficiency but relatively preserved in thalassaemia trait.

Why should iron therapy not automatically be given to every patient with microcytosis?

The patient may have thalassaemia trait rather than iron deficiency.

What is normocytic anaemia?

Anaemia in which red cells are of normal average size (normal MCV).

What MCV range generally defines normocytic anaemia?

Approximately 82-98 fL.

What are common causes of normocytic anaemia?

Recent blood loss, marrow failure, haemolysis and anaemia of chronic disease.

Why can recent blood loss initially produce normocytic anaemia?

The cells lost are normal-sized and remaining cells are initially unaffected.

How can chemotherapy cause normocytic anaemia?

It suppresses bone marrow activity and reduces erythropoiesis.

How can leukaemia cause normocytic anaemia?

Leukaemic cells infiltrate bone marrow and impair normal red-cell production.

What is hypersplenism?

Excessive sequestration and destruction of blood cells by the spleen.

How can liver cirrhosis cause normocytic anaemia?

It may lead to hypersplenism and increased splenic sequestration of red cells.

What is polycythaemia?

An increase in the number of circulating red blood cells resulting in elevated Hb, Hct and RBC count.

What is pseudo-polycythaemia?

Apparent polycythaemia caused by reduced plasma volume rather than increased red-cell mass.

What is true polycythaemia?

A genuine increase in total red-cell mass.

What is polycythaemia vera?

A myeloproliferative disorder causing excessive red-cell production independent of normal erythropoietin regulation.

Case: A breathless cyanosed patient develops polycythaemia. What is the mechanism?

Hypoxia stimulates increased erythropoietin production and red-cell synthesis.

Case: A patient with a kidney carcinoma develops polycythaemia. What is the mechanism?

Inappropriate erythropoietin production by the tumour.

Case: A patient with splenomegaly and markedly elevated haemoglobin has abnormal marrow function. What diagnosis should be considered?

Polycythaemia vera.

Case: A young healthy athlete has an unexpectedly high haemoglobin concentration. What possibility should be considered?

Blood doping or erythropoietin misuse.

Why can polycythaemia due to hypoxia be beneficial?

It increases oxygen-carrying capacity.

Why can polycythaemia due to hypoxia be harmful?

It increases blood viscosity and predisposes to thrombosis.

What is hyperviscosity?

Abnormally thick blood due to excessive cellular content.

Why does hyperviscosity increase thrombosis risk?

Sluggish blood flow promotes clot formation.

How can true polycythaemia be distinguished from dehydration-induced pseudo-polycythaemia?

True polycythaemia involves increased red-cell mass, whereas pseudo-polycythaemia results from reduced plasma volume.

What is the key principle when interpreting any blood count?

Always interpret laboratory findings in the context of the patient's history, examination findings and underlying physiology.

What are the three major dietary sources of iron?

Red meat, green leafy vegetables and pulses.

What are three important dietary sources of vitamin B12?

Meat, fish and dairy products such as milk and cheese.

What are three important dietary sources of folate?

Green leafy vegetables, whole-grain cereals and fruit.

What is ferritin?

Ferritin is the major iron storage protein in the body and reflects total body iron stores.

What is transferrin?

Transferrin is the plasma protein responsible for transporting iron in the circulation.

What is ferroportin?

Ferroportin is the major iron export protein that transports iron out of enterocytes and macrophages into the bloodstream.

How does hepcidin regulate iron absorption?

Hepcidin binds to ferroportin and causes its internalisation and degradation, preventing iron export into the bloodstream.

What happens to iron trapped inside an enterocyte after hepcidin acts?

The iron remains inside the enterocyte and is lost when the enterocyte is shed into the intestinal lumen.

How do low iron stores affect hepcidin production?

Low ferritin and low iron stores reduce hepcidin production, increasing iron absorption and release of stored iron.

How does increased erythropoiesis affect hepcidin production?

Increased erythropoietic demand suppresses hepcidin production to increase iron availability for haemoglobin synthesis.

What effect does inflammation have on hepcidin?

Inflammation increases hepcidin production, reducing iron absorption and trapping iron within storage sites.

Why does low hepcidin increase iron absorption?

More ferroportin remains active on enterocytes and macrophages, allowing greater iron release into plasma.

What are the three major mechanisms that can cause anaemia?

Reduced red cell production, blood loss and haemolysis.

Give examples of reduced red cell production causing anaemia.

Iron deficiency, vitamin B12 deficiency, folate deficiency and leukaemia.

Give examples of blood loss causing anaemia.

Gastrointestinal bleeding, trauma and heavy menstrual bleeding.

Give examples of haemolysis causing anaemia.

Sickle cell disease, G6PD deficiency and hereditary spherocytosis.

Why is it important to distinguish the mechanism of anaemia from the cause?

The same mechanism may result from many different diseases and identifying the cause determines treatment.

What is the mechanism of iron deficiency anaemia?

Failure of red cell production due to inadequate haem synthesis.

What is the mechanism of thalassaemia?

Failure of red cell production due to defective globin synthesis.

Why does reduced haemoglobin synthesis cause microcytosis?

Erythroblasts undergo extra divisions before reaching the target intracellular haemoglobin concentration, producing smaller red cells.

Why are microcytic cells commonly hypochromic?

Reduced haemoglobin synthesis decreases both haemoglobin content and concentration within red cells.

What is hypochromia?

A reduction in red cell haemoglobin concentration producing increased central pallor on a blood film.

Which two conditions are the most common causes of microcytosis?

Iron deficiency and thalassaemia trait.

What laboratory finding is most characteristic of iron deficiency anaemia?

Low ferritin.

Why is ferritin low in iron deficiency anaemia?

Body iron stores have become depleted.

Why is ferritin usually normal or raised in anaemia of chronic disease?

Iron is present but trapped within storage sites by the effects of hepcidin and inflammation.

Case: A 73-year-old woman has fatigue, dizziness, microcytosis and a low ferritin. What is the most likely diagnosis?

Iron deficiency anaemia.

Case: Why does a low ferritin strongly support iron deficiency anaemia?

Because ferritin reflects iron stores and low ferritin indicates iron depletion.

Case: Why does a previously normal blood count argue against thalassaemia trait?

Thalassaemia trait is inherited and typically causes lifelong microcytosis rather than newly developed microcytosis.

Case: Why should occult gastrointestinal bleeding be suspected in an elderly patient with iron deficiency anaemia?

Gastrointestinal blood loss is a common cause of iron deficiency in older adults and may occur without obvious symptoms.

Case: What further history should be taken from an elderly patient with newly diagnosed iron deficiency anaemia?

Dietary history, travel history, gastrointestinal symptoms and any vaginal bleeding.

Case: Why is postmenopausal vaginal bleeding important in iron deficiency anaemia?

It may indicate pathology of the female genital tract and requires investigation.

Case: What investigations may identify occult gastrointestinal blood loss?

FIT testing, colonoscopy and upper gastrointestinal endoscopy.

Case: How would iron deficiency anaemia be treated initially?

Iron replacement therapy such as oral ferrous sulphate.

Case: Why is treating iron deficiency alone not enough?

The underlying cause of the iron deficiency must also be identified and treated.

What are common causes of iron deficiency anaemia?

Blood loss, poor dietary intake, malabsorption and increased physiological requirements.

What is the most common cause of iron deficiency anaemia in adults?

Blood loss.