Anaemia — MRCS Part B Surgical pathology

A young man with a microcytic anaemia found before an elective arthroscopy. The station uses him and a second patient with a metallic valve to cover the classification of anaemia, sickle cell disease, haemolysis and thalassaemia.

A low haemoglobin with a low MCV

Microcytosis means the cells have too little haemoglobin in them, so the causes are the causes of failed haemoglobin synthesis: iron deficiency (blood loss from the gut in a man of 35 until proved otherwise, then poor intake, malabsorption in coeliac disease), thalassaemia trait, anaemia of chronic disease in its later stages, sideroblastic anaemia and lead poisoning. Iron studies separate them: ferritin low in iron deficiency, normal or high in thalassaemia and chronic disease; transferrin saturation low in iron deficiency; and a haemoglobin electrophoresis if the iron is normal, showing a raised HbA2 in beta thalassaemia trait. A blood film, reticulocyte count, B12, folate and haematinics, coeliac serology, and in this man the question of whether he needs an endoscopy before or after his knee.

Classifying anaemia

By mechanism: blood loss, reduced production (deficiency of iron, B12 or folate; marrow failure or infiltration; chronic disease and renal failure) or increased destruction (haemolysis). By cell size: microcytic, normocytic (acute blood loss, chronic disease, renal failure, marrow failure, most haemolysis, mixed deficiencies) and macrocytic (B12 and folate deficiency, alcohol, liver disease, hypothyroidism, myelodysplasia, drugs such as methotrexate and azathioprine, and reticulocytosis). The reference ranges differ by sex: below about 130 g/L in a man and 120 g/L in a woman.

Sickle cell disease

A single amino acid substitution, glutamate to valine at position 6 of the beta globin chain, inherited as an autosomal recessive trait, gives haemoglobin S, which polymerises when deoxygenated and deforms the red cell into a rigid sickle. Homozygotes have the disease: chronic haemolytic anaemia, with a haemoglobin of 60–90 g/L, jaundice and gallstones, and recurrent crises. Heterozygotes with the trait are well, with a normal blood count, sickling only under severe hypoxia; they have some protection from malaria, which is why the gene persists. Complications: vaso-occlusive crises, acute chest syndrome, stroke, splenic sequestration in children and hyposplenism with infection in adults, aplastic crisis with parvovirus, priapism, avascular necrosis of the femoral head, leg ulcers, retinopathy, renal failure and pulmonary hypertension.

A vaso-occlusive crisis is sickled cells blocking the small vessels of bone, marrow or an organ, causing infarction and severe pain. Anything that lowers oxygen tension, dehydrates or cools the patient provokes it: infection, dehydration, cold, hypoxia, acidosis, exertion, stress, and surgery and anaesthesia, which is why these patients need pre-operative haematology advice, warming, hydration, oxygen and sometimes transfusion.

The patient with a metallic valve

Normocytic anaemia has many causes: acute blood loss, chronic disease and inflammation, renal failure, early iron deficiency, marrow failure or infiltration, and haemolysis. A film in this man showing fragmented red cells, schistocytes and helmet cells, with a raised reticulocyte count, unconjugated bilirubin and lactate dehydrogenase and a low haptoglobin, is mechanical haemolysis: red cells being sheared by the turbulent flow across a leaking or malfunctioning prosthetic valve, and it needs an echocardiogram.

Causes of haemolysis

Inherited: membrane defects (hereditary spherocytosis), enzyme defects (G6PD deficiency, pyruvate kinase deficiency) and haemoglobinopathies (sickle cell disease, thalassaemia). Acquired: immune, whether autoimmune (warm or cold antibody), alloimmune (transfusion reaction, haemolytic disease of the newborn) or drug-induced; and non-immune, whether mechanical (prosthetic valves, microangiopathic haemolysis in DIC, thrombotic thrombocytopenic purpura and haemolytic uraemic syndrome, march haemoglobinuria), infective (malaria, clostridial sepsis), chemical (drugs, snake venom, burns) or paroxysmal nocturnal haemoglobinuria.

Thalassaemia

Inherited reduction or absence of the synthesis of one of the globin chains, alpha or beta, common around the Mediterranean, in the Middle East and across Asia. The chains that are made in excess precipitate and damage the red cells, so the anaemia is both from poor production and from haemolysis. Beta thalassaemia major, with no beta chains, presents in infancy with severe anaemia, failure to thrive, hepatosplenomegaly and the bossed skull of marrow expansion, and depends on transfusion, with iron chelation to prevent the overload that would otherwise kill; the trait gives a mild microcytosis with a raised HbA2 that is mistaken for iron deficiency. Alpha thalassaemia ranges from a silent carrier state to haemoglobin H disease with three genes lost and hydrops fetalis with all four.