Q4 LONG ANSWER 10M ★ High-yield

Classify haemolytic anaemias. Describe the laboratory findings and differentiate intravascular from extravascular haemolysis.

Pathology · 2nd Professional — Para-Clinical

Definition

Haemolytic anaemia results when the rate of red cell destruction exceeds the capacity of the marrow to replace them. The normal red cell lifespan of 120 days is shortened.

The marrow can increase output six to eight fold, so mild haemolysis may be fully compensated and cause no anaemia — "compensated haemolytic disease"

Classification

Basis	Categories
Site	Extravascular (in the spleen and liver — commoner) or intravascular (within the circulation)
Cause	Intracorpuscular (defect within the cell — almost all hereditary) or extracorpuscular (defect outside the cell — almost all acquired)

Category	Disorders
Membrane defects	Hereditary spherocytosis, elliptocytosis; paroxysmal nocturnal haemoglobinuria (acquired)
Enzyme defects	G6PD deficiency (commonest enzymopathy), pyruvate kinase deficiency
Haemoglobin defects	Sickle cell disease, thalassaemia, other haemoglobinopathies
Immune	Autoimmune (warm and cold), alloimmune (haemolytic disease of the newborn, transfusion reaction), drug-induced
Mechanical	Microangiopathic — DIC, thrombotic thrombocytopenic purpura, haemolytic uraemic syndrome, malignant hypertension; prosthetic heart valves; march haemoglobinuria
Infection	Malaria (much the most important in India), clostridial sepsis, babesiosis
Chemical and physical	Snake and spider venom, lead, copper (Wilson), burns
Hypersplenism	Any cause of splenomegaly

Laboratory Findings

Category	Test	Result
Increased red cell breakdown	Unconjugated (indirect) bilirubin	Raised — acholuric jaundice, since unconjugated bilirubin does not enter the urine
—	Serum LDH	Raised
—	Serum haptoglobin	Low or absent — it binds free haemoglobin and is cleared
—	Urinary urobilinogen	Raised
Increased red cell production	Reticulocyte count	Raised — the hallmark; with polychromasia on the smear
—	Bone marrow	Erythroid hyperplasia; myeloid:erythroid ratio reversed
Intravascular haemolysis only	Haemoglobinaemia and haemoglobinuria	Present — pink plasma, red-brown urine
—	Haemosiderinuria	Present after some days — iron in shed tubular cells; a useful marker of chronic intravascular haemolysis
—	Methaemalbuminaemia	Present

CLINICAL PEARL

Haptoglobin is the most sensitive marker of intravascular haemolysis. It binds free haemoglobin in a 1:1 complex which is removed by the liver, so even a small amount of intravascular breakdown exhausts it. A normal haptoglobin makes significant intravascular haemolysis unlikely — though it is an acute phase protein and may be falsely normal in inflammation.

Extravascular Compared with Intravascular

Feature	Extravascular	Intravascular
Site	Macrophages of spleen and liver	Within blood vessels
Mechanism	Cells are abnormal in shape or coated with antibody, and are removed as they pass through the splenic cords	Direct lysis of the membrane
Splenomegaly	Usual	Not a feature
Haemoglobinaemia and haemoglobinuria	Absent	Present
Haptoglobin	Mildly reduced	Markedly reduced
Examples	Hereditary spherocytosis, warm autoimmune haemolytic anaemia, haemoglobinopathies	ABO incompatible transfusion, G6PD crisis, PNH, microangiopathy, blackwater fever

Clinical Features

The triad of anaemia, jaundice and splenomegaly suggests haemolysis
Pigment (bilirubin) gallstones from chronic haemolysis, even in children
Aplastic crisis — parvovirus B19 infects erythroid precursors and stops production for about a week; harmless in a normal person but causes a precipitous fall in anyone with a shortened red cell lifespan
Skeletal changes from marrow expansion in severe chronic haemolysis — "hair-on-end" skull, frontal bossing
Leg ulcers, and folate deficiency from increased turnover
Iron overload in the transfusion-dependent

Applied Aspects

The direct COOMBS (antiglobulin) test is the single most important investigation — it separates immune from non-immune haemolysis and directs everything that follows
In India, malaria must be excluded in any acute haemolysis; blackwater fever is severe intravascular haemolysis with haemoglobinuria in falciparum malaria
Splenectomy helps in extravascular haemolysis — particularly hereditary spherocytosis — but not in intravascular haemolysis; vaccination against encapsulated organisms is mandatory beforehand
Folic acid supplementation is given in all chronic haemolytic states, because demand is greatly increased
Transfusion may be hazardous in autoimmune haemolysis, since cross-matching is difficult and the transfused cells are destroyed too
Newborn screening and premarital counselling for haemoglobinopathies is increasingly important in India, where thalassaemia and sickle cell disease are common
Paroxysmal nocturnal haemoglobinuria — an acquired clonal defect of the GPI anchor, losing CD55 and CD59, so complement lyses the cells; diagnosed by flow cytometry and associated with thrombosis and marrow failure
Haemolysis with a normal reticulocyte count should raise suspicion of a coexisting marrow problem, such as parvovirus infection or a nutritional deficiency
Chronic haemolysis raises the risk of pigment gallstones, and abdominal ultrasound is worthwhile in any long-standing case
Haemolytic disease of the newborn — maternal IgG crossing the placenta; prevented by anti-D and detected by a positive direct Coombs test on cord blood
March haemoglobinuria and prosthetic valve haemolysis are mechanical, and the smear shows schistocytes without any immune cause
Reticulocytosis raises the MCV, so brisk haemolysis may give a macrocytic picture without any deficiency — a common source of confusion

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