Haemolytic Diseases: A Comprehensive Guide for MRCP (UK) Part 1

Welcome to MEDIT & CME Academy's comprehensive guide on Haemolytic Diseases, specifically tailored for postgraduate medical doctors preparing for the MRCP (UK) Part 1 examination. This blog post will provide a detailed overview of this crucial topic in Clinical Haematology, covering its classification, pathophysiology, clinical features, and management strategies.

Introduction to Haemolytic Diseases

Haemolytic anaemia, at its core, involves the premature destruction of red blood cells (RBCs), leading to a shortened RBC lifespan and subsequent anaemia. Understanding the aetiology, diagnostic approaches, and management principles of haemolytic disorders is vital for success in the MRCP (UK) Part 1 examination. These diseases can be broadly categorised into intrinsic (intracorpuscular) and extrinsic (extracorpuscular) causes.

Learning Outcomes

By the end of this guide, you will be able to:

1. Define haemolytic anaemia and describe its classification into intrinsic (intracorpuscular) and extrinsic (extracorpuscular) causes.

2. Explain the pathophysiology of haemolysis, including increased red blood cell (RBC) destruction, compensatory erythropoiesis, and the effects on haemoglobin metabolism.

3. Classify haemolytic diseases into:

   a) Intrinsic causes (RBC membrane, enzyme, or haemoglobin defects):

   ➡️ Hereditary spherocytosis, elliptocytosis.

    ➡️ Glucose-6-phosphate dehydrogenase (G6PD) deficiency, pyruvate kinase deficiency.

     ➡️ Sickle cell anaemia, thalassaemia.

   b) Extrinsic causes (immune and non-immune mediated):

   ➡️ Autoimmune haemolytic anaemia (warm and cold antibody types).

   ➡️ Microangiopathic haemolytic anaemia (MAHA) – e.g., thrombotic thrombocytopenic purpura (TTP), haemolytic uremic syndrome (HUS), disseminated intravascular coagulation (DIC).

   ➡️ Mechanical trauma (prosthetic heart valves, march haemoglobinuria).

   ➡️ Infections (malaria, Clostridium perfringens).

   ➡️ Drug-induced haemolysis.

4. Recognize the clinical features of haemolytic diseases, including pallor, jaundice, splenomegaly, dark urine (haemoglobinuria), and symptoms of anaemia.

5. Interpret laboratory investigations for haemolysis, including:

    ➡️ Full blood count (FBC): Normocytic or macrocytic anaemia, reticulocytosis.

   ➡️ Peripheral blood smear: Spherocytes, schistocytes, Heinz bodies, bite cells.

    ➡️ Haemolysis markers: Elevated lactate dehydrogenase (LDH), low haptoglobin, increased indirect bilirubin.

   ➡️ Direct and indirect Coombs tests: Differentiate immune-mediated from non-immune haemolysis.

   ➡️ Special tests: Osmotic fragility test (hereditary spherocytosis), G6PD assay, haemoglobin electrophoresis (sickle cell, thalassaemia).

6. Differentiate between immune and non-immune causes of haemolysis based on Coombs test and clinical history.

7. Discuss the management of haemolytic diseases, including:

    ➡️ Supportive care: Folic acid supplementation, transfusions if severe.

    ➡️ Specific treatments:

    ➡️ Corticosteroids and rituximab for autoimmune haemolytic anaemia.

    ➡️ Splenectomy for hereditary spherocytosis.

    ➡️ Avoidance of oxidative triggers in G6PD deficiency.

   ➡️ Plasma exchange for TTP.

8. Describe the complications of haemolytic diseases, including bilirubin gallstones, iron overload, aplastic crisis (parvovirus B19 infection), and thrombotic events in MAHA.

9. Explain the role of genetic counseling and screening for inherited haemolytic disorders in high-risk populations.

10. Discuss emerging therapies for haemolytic diseases, including complement inhibitors (e.g., eculizumab for paroxysmal nocturnal haemoglobinuria) and gene therapy.

Pathophysiology of Haemolysis

Haemolysis occurs when RBCs are destroyed at a rate exceeding the bone marrow's capacity to produce new cells. This leads to:

• Increased RBC Destruction: Whether due to intrinsic defects or extrinsic factors, the premature breakdown of RBCs releases haemoglobin into the circulation.

• Compensatory Erythropoiesis: The bone marrow attempts to compensate by increasing RBC production, leading to reticulocytosis (increased reticulocyte count in the blood).

• Haemoglobin Metabolism Effects: The released haemoglobin is metabolized, leading to elevated levels of indirect bilirubin (causing jaundice), increased lactate dehydrogenase (LDH), and decreased haptoglobin (which binds free haemoglobin). In severe cases, haemoglobinuria (haemoglobin in urine) can occur.

Classification of Haemolytic Diseases

Intrinsic Causes of Haemolytic Diseases

These disorders result from defects within the RBC itself:

• RBC Membrane Defects: Hereditary spherocytosis and elliptocytosis are examples where abnormalities in membrane proteins lead to RBC shape changes and increased splenic destruction. The osmotic fragility test is useful in diagnosing hereditary spherocytosis.

• Enzyme Deficiencies: G6PD deficiency is the most common enzyme deficiency, rendering RBCs vulnerable to oxidative stress, leading to episodic haemolysis. Pyruvate kinase deficiency is another less common cause.

• Haemoglobinopathies: Sickle cell anaemia and thalassaemia involve abnormal haemoglobin production, resulting in chronic haemolysis and vaso-occlusive crises in sickle cell disease. Haemoglobin electrophoresis is crucial for diagnosis.

Extrinsic Causes of Haemolytic Diseases

These disorders involve factors external to the RBC that cause its destruction:

• Immune-mediated Haemolysis: Autoimmune haemolytic anaemia (AIHA) involves antibodies attacking RBCs. Warm AIHA is usually IgG-mediated, reacting at body temperature, while cold AIHA is typically IgM-mediated and reacts at lower temperatures. The direct Coombs test (DAT) is positive in AIHA.

• Microangiopathic Haemolytic Anaemia (MAHA): This occurs when RBCs are mechanically damaged as they pass through abnormal microvasculature, as seen in TTP, HUS, and DIC. Schistocytes (fragmented RBCs) are characteristic on peripheral blood smear.

• Mechanical Trauma: Prosthetic heart valves can cause mechanical destruction of RBCs, leading to haemolysis. March haemoglobinuria is another example, occurring after strenuous exercise.

• Infections: Malaria and Clostridium perfringens infections can directly damage RBCs, leading to haemolysis.

• Drug-induced Haemolysis: Certain drugs can induce haemolysis, either through immune mechanisms or by directly damaging RBCs (e.g., dapsone in G6PD deficient individuals).

Clinical Features

Patients with haemolytic diseases may present with:

• Pallor (due to anaemia)

• Jaundice (due to elevated bilirubin)

• Splenomegaly (due to increased splenic activity)

• Dark urine (haemoglobinuria)

• Fatigue, shortness of breath, and other symptoms of anaemia

Laboratory Investigations

Key investigations include:

• Full Blood Count (FBC): Typically shows anaemia with reticulocytosis. MCV may be normal (normocytic) or increased (macrocytic).

• Peripheral Blood Smear: May reveal spherocytes (hereditary spherocytosis), schistocytes (MAHA), Heinz bodies (G6PD deficiency), or sickle cells (sickle cell anaemia).

• Haemolysis Markers: Elevated LDH, low haptoglobin, and increased indirect bilirubin are indicative of haemolysis.

  

  Coombs Test

  Coombs Test (DAT): Positive in immune-mediated haemolysis, helping to differentiate between warm and cold AIHA.

• Special Tests: Osmotic fragility test (hereditary spherocytosis), G6PD assay (G6PD deficiency), haemoglobin electrophoresis (sickle cell, thalassaemia).

Management

Management strategies vary depending on the underlying cause:

• Supportive Care: Folic acid supplementation to support erythropoiesis, and blood transfusions in severe anaemia.

• Specific Treatments:

   ➡️ Autoimmune Haemolytic Anaemia: Corticosteroids are the first-line treatment, followed by rituximab if refractory.

   ➡️ Hereditary Spherocytosis: Splenectomy can reduce RBC destruction.

   ➡️ G6PD Deficiency: Avoidance of oxidative triggers (certain drugs and foods).

   ➡️ Thrombotic Thrombocytopenic Purpura (TTP): Plasma exchange is crucial to remove the ADAMTS13 inhibitor.

Complications

Potential complications include:

• Gallstones

• Iron overload (from repeated transfusions)

• Aplastic crisis (due to parvovirus B19 infection)

• Thrombotic events (especially in MAHA)

Genetic Counselling and Screening

Genetic counseling is essential for inherited haemolytic disorders, particularly in high-risk populations. Screening programs can help identify carriers and affected individuals.

Emerging Therapies

New therapies are emerging, including complement inhibitors like eculizumab (for paroxysmal nocturnal haemoglobinuria) and gene therapy for certain haemoglobinopathies.

Further Learning

Enhance your understanding of haematology with CME Academy! Explore our short course designed to help you ace the MRCP Part 1 exam: Clinical Haematology Part 1

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