L5 Sickle Cell Anaemia 5112BMBMOL

Sickle Cell Anaemia Overview

Introduction

• Sickle Cell Anaemia is a haematological disorder discussed in 5112BMBMOL Haematology & Transfusion Science at Liverpool John Moores University.

• Dr. Kate Phillips emphasizes the importance of understanding this condition in detail.

Learning Outcomes

• Understand the mutation causing sickle cell anaemia.

• Learn the pathophysiological features involved.

• Grasp the altered oxygen dissociation characteristics of sickle haemoglobin.

• Familiarize with laboratory methods for detecting sickle haemoglobin, both qualitative and quantitative.

Pathophysiology of Sickle Cell Anaemia

Overview of Disease Mechanism

• Abnormal red blood cells do not flow properly through capillaries and have reduced oxygen-carrying capacity.

• These cells are recognized and removed by the reticuloendothelial system, resulting in anaemia.

• Described as primarily haemolytic anaemia, specifically extravascular in nature.

Haemoglobinopathies________

Genetic Basis

• Haemoglobinopathies arise from genetic mutations in the globin gene.

• Such mutations result in either a different type or an altered amount of haemoglobin synthesized, leading to various forms of anaemia.

• Common examples include sickle cell anaemia and thalassaemia.

• Most haemoglobinopathies are inherited; cases of de novo mutations are rare.

• Sickle cell disease follows an autosomal recessive inheritance pattern.

Specifics of Sickle Cell Anaemia

Genetic Mutation

• The disorder stems from a mutation in the beta globin chain.

• Characterized by a single amino acid change in the DNA sequence, distinct from thalassaemia, which involves a shortage of globin proteins.

• Classified as a qualitative haemoglobinopathy — the globin protein is produced but is structurally altered.

Epidemiology of Sickle Cell Anaemia

• Approximately 275,000 births with this condition occur worldwide each year.

• It represents the most common haemoglobinopathy as well as the most prevalent single gene defect globally.

• In England, 350 babies are born with sickle cell anaemia annually, while about 9,500 babies are carriers.

Genotypes of Sickle Cell Anaemia

• Genotypes are based on the type and number of mutated genes.

  • HbSS: Homozygous condition (both genes mutated).

  • HbAS: Heterozygous condition (“carrier” status with one mutated gene).

HbS Point Mutation

• At position 6, the amino acid substitution alters the shape of the beta globin molecule leading to reduced oxygen carrying capacity.

• HbS exhibits a poor ability to carry oxygen compared to the normal HbA.

Oxygen Dissociation

Characteristics

• HbS releases oxygen more easily than HbA in tissues (right shift of dissociation curve).

• Affected by various conditions:

  • Higher CO2, lower pH, and higher temperature decrease Hb-O2 affinity (right shift).

  • Conversely, lower CO2, higher pH, and lower temperature increase affinity (left shift).

Red Blood Cell Sickling

• Sickling occurs under low oxygen tension, dehydration, or fever conditions.

• Initial sickling can reverse with oxygenation; persistent cycles lead to irreversible sickling.

Vaso-occlusion

• Sickled cells obstruct vessels leading to reduced perfusion downstream, causing local tissue hypoxia.

• Features reduced deformability and increased adhesion of sickled cells.

Red Cell Destruction

• Sickled cells are eliminated primarily by the reticuloendothelial system, notably by macrophages in the liver and spleen.

• This leads to chronic haemolytic anaemia characterized by extravascular haemolysis.

Clinical Manifestations of Sickle Crisis

• Starts from 9 months of age.

• Patients experience severe, debilitating pain due to vaso-occlusion initiating tissue hypoxia.

• Common sites include:

  • Bone pain: Hips, shoulders, vertebrae.

  • Lungs: Acute chest syndrome.

  • Spleen: Splenic sequestration.

  • Brain: Increased risk of stroke.

  • Hands/Feet: Dactylitis (swelling of fingers/toes).

Treatment Options

Management Strategies

• Transfusion: Introduces mature HbA red cells to relieve anaemia and improve oxygen transport.

• Prophylaxis: Includes immunization against pneumococcal infections and antibiotics; Penicillin recommended to prevent infections.

• Hydroxyurea: Stimulates production of HbF, providing some protection against complications.

• Bone marrow transplant: Considered as a last resort.

Laboratory Methods for Diagnosis

Full Blood Count Parameters

• RBC: Low, indicating short life span of red cells.

• Hb: Low levels indicating anaemia.

• MCV: Low, indicating microcytic anaemia.

• MCH: Normal levels showing normochromic microcytic anaemia.

• MCHC: Normal, related to MCH.

• HCT: Low indicates reduced RBC counts.

• RCD-W: Abnormal findings with sickle cells affecting normal patterns.

Solubility Testing

• The Sickledex test utilizes whole blood mixed with saponin and sodium dithionite to confirm the presence of HbS qualitatively.

Alkaline Electrophoresis

• Carried out at pH 8.4 – 8.7.

• Separation and migration of Hb towards the anode can identify the presence of HbS.

Quantitative Analysis of Hb

• High Performance Liquid Chromatography (HPLC): Hb separation based on charge and retention time which determines Hb concentrations spectrophotometrically.

Sickle Genotypes Summary

• HbSS: Classic sickle cell anaemia.

• HbAS: Sickle trait with mild features.

• HbSC and HbSD: Variable disease severities based on different mutations in the globin gene.

• Compound phenotypes reflect features of multiple haemoglobinopathies, including HbS beta thalassaemia.

Recommended Reading

• Moore, G., Knight, G., & Blann, A. (2016). Fundamentals of Biomedical Science: Haematology (2nd edition). Oxford University Press. Chapter 6.3 discusses haemoglobinopathies in detail.

Conclusion

• Mastering the knowledge of sickle cell anaemia's underlying mechanisms, treatment options, and diagnostic methods is crucial for effective management and understanding.