Haemoglobinopathies Lecture Notes (PDF)

HONG KONG METROPOLITAN UNIVERSITY MLS 3009SEF Haematology & Transfusion Science H.LEE Haemoglobinopathies 10-2-2025 10/2/2025 Henry Lee Haemoglobinopathies 1 ...

HONG KONG METROPOLITAN UNIVERSITY MLS 3009SEF Haematology & Transfusion Science H.LEE Haemoglobinopathies 10-2-2025 10/2/2025 Henry Lee Haemoglobinopathies 1  Haemoglobinopathies Haemoglobinopathies ◦ Disorders where the production of normal adult hemoglobin is partly or completely suppressed or replaced by a variant hemoglobin. 10/2/2025 Henry Lee Haemoglobinopathies 2  Classification of Haemoglobin Disorders 1. Qualitative: ◦ Haemoglobins differ in sequence of amino acids composing globin chain ◦ Structural defect ◦ Disorders called haemoglobinopathies 2. Quantitative: ◦ Characterized by decreased rate of hemoglobin production ◦ Amino acid sequence NOT altered ◦ Called thalassemia 10/2/2025 Henry Lee Haemoglobinopathies 3  Thalassemia Inherited haemoglobin (Hb) disorders are classified into two disease groups: 1. haemoglobinopathy caused by the structural defects in Hb and 2. thalassemia caused by the impaired synthesis of globin, usually of normal structure; both are typically inherited in an autosomal recessive manner 10/2/2025 Henry Lee Haemoglobinopathies 4  Qualitative Disorders Qualitative abnormalities in globin structure, usually involving beta-chain. Heme portion is normal Arise from single amino acid substitution or deletion ◦ Rarely see multiple substitutions. May or may not cause abnormal laboratory test results. 10/2/2025 Henry Lee Haemoglobinopathies 5  Sickle Cell Anaemia Haemoglobin S (HbS) forms from point mutation for position 6 of beta-globulin chain with valine substituted for the normal glutamic acid Most common hemoglobinopathy Increased resistance to Malaria infection by - killing the parasite - causing infected RBCs to be sequestered in the spleen and destroyed. It is a world-wide disease but has high incidence rate in Africans ◦ Sickle cell disease occurs in 1 in 375 live African American births ◦ Sickle cell trait occurs in 20-40% 10/2/2025 Henry Lee Haemoglobinopathies 6  www.Frontier.com 10/2/2025 Henry Lee Haemoglobinopathies 7  Sickle Cell Anaemia Autosomal co-dominant Hemoglobin A and Hemoglobin S produced. AS is sickle cell trait. SS is sickle cell disease. Patient is homozygous for HbS (SS). Results in very severe anemia. Sickle Cell society 10/2/2025 Henry Lee Haemoglobinopathies 8  Pathophysiology of Sickle Cell Anemia HbS cells is normal and soluble when fully oxygenated Sickling occurs when O2 decreased, where HbS polymerizes into insoluble aggregates Other causes of sickling include decrease in pH and dehydration of patient. Cells become rigid and cause increased blood viscosity; impeding blood flow to tissues. The small microvasculature may blocked with the sickled cells leading to hypoxia, tissue demage, organ infarction, and “sickle cell crisis” 10/2/2025 Henry Lee Haemoglobinopathies 9  Cryo-Cell 10/2/2025 Henry Lee Haemoglobinopathies 10  Pathophysiology of Sickle Cell Anemia Sickling is reversible up to a point. Upon re-oxygenation, the RBC may return to its original shape. Repeated sickling may damage the permeability of the RBC membrane leading to premature death Repeated sickling may cause the RBCs become irreversibly and destroyed by spleen Have both extravascular hemolysis and intravascular hemolysis. 10/2/2025 Henry Lee Haemoglobinopathies 11  Clinical Findings of Sickle Cell Anemia Clinical signs appear at 6 months of age when HbF is replaced with HbS Have all physical symptoms of anemia Growth and sexual maturation slower Crisis – very painful. Anything that deoxygenates blood acts as trigger (exercise, illness and airplane flights). Sickle cells get stuck in capillaries. Strokes Chronic haemolytic anaemia due to extravascular haemolysis 10/2/2025 Henry Lee Haemoglobinopathies 12  Clinical Findings of Sickle Cell Anemia Organs Affected: ◦Liver: Enlarges, malfunctions, jaundice, hyperbilirubinemia ◦Heart: Cardiomegaly, iron deposits ◦ Spleen: Enlarges leading to infarction and fibrosis Eventually shrivels and becomes nonfunctional ◦Skin: Develop ulcers, jaundice ◦Kidney: Hematuria and eventual failure ◦Lungs: Infarction ◦Brain: Strokes ◦Blood: Hemolytic anemia ◦Bones: painful crisis 10/2/2025 Henry Lee Haemoglobinopathies 13 Clinical Findings of Sickle Cell Anemia 3 types of crises: - Aplastic crisis: associated with infections which causes temporary suppression of erythropoiesis. - Hemolytic crisis: Results in exaggerated anemia. - Vaso-occlusive crisis: Associated with severe pain. Hallmark symptom of sickle cell anemia. 10/2/2025 Henry Lee Haemoglobinopathies 14  Laboratory Findings of Sickle Cell Anemia Hb 6-10 g/dL Normocytic, normochromic anemia Marked anisocytosis and poikilocytosis Sickle cells and Target cells nRBCs with Polychromasia Increased Retics (10-20%) Basophilic Stippling Howell Jolly Bodies and Pappenheimer Bodies Leukocytosis with left shift Thrombocytosis 10/2/2025 Henry Lee Haemoglobinopathies 15  Laboratory Findings of Sickle Cell Anemia Hemoglobin Electrophoresis ◦ Use either alkaline/acid mediums to separate individual hemoglobins ◦ detects differences in the charge of proteins ◦ HbS/HbS most severe pattern Hemoglobin Solubility Test- Positive Osmotic Fragility – Decreased ESR – Decreased 10/2/2025 Henry Lee Haemoglobinopathies 16  Sickle Cell Anemia: Treatment No known effective long term therapy Blood transfusion Bone marrow transplant Gene therapy Prevention of infection Reduce organ damage ◦ Hydroxyurea (it is believed to induce production of Hgb F). Using chemotherapeutic agents ◦ Avoidance of situations that could cause a crisis Median life expectancy- 50 years 10/2/2025 Henry Lee Haemoglobinopathies 17  Sickle Cell Trait Heterozygous AS with more HbA than HbS, so condition is compensated for Patient often has normal life span Usually asymptomatic with occasional episodes of hematuria ◦ Sickling can occur with drastic reduction of oxygen tension such as severe respiratory infection, air travel in unpressurized aircraft, anesthesia or congestive heart failure ◦ Exercise that causes a buildup of lactic acid can cause sickling due to lowered pH 10/2/2025 Henry Lee Haemoglobinopathies 18  Laboratory Findings of Sickle Cell Trait Normal CBC – Few target cells Hemoglobin solubility test – positive Electrophoresis – Both A and S present 10/2/2025 Henry Lee Haemoglobinopathies 19  Hemoglobin C Disease 10/2/2025 Henry Lee Haemoglobinopathies 20  Haemoglobin C Amino acid substitution of lysine for glutamic acid at sixth position of Beta chain ◦ (α2β26Glu-Lys) Is homozygous CC Chronic hemolytic anemia with associated splenomegaly and abdominal discomfort 10/2/2025 Henry Lee Haemoglobinopathies 21  Laboratory Findings: Hb C Disease Mild to moderate anemia (8-12 g/dL) ◦ Normochromic/normocytic Retic count 4-8% (slightly increased) Electrophoresis ◦ Most hemoglobin is HbC ◦ no HbA present ◦ may or may not have increase in Hb F 10/2/2025 Henry Lee Haemoglobinopathies 22 Laboratory Findings of Hb C Disease Numerous target cells, few microspherocytes, schistocytes, and folded cells May see hexagonal or rod- shaped crystals ◦ "bar of gold” ◦ Usually intracellular. Are elongated with blunt ends and parallel sides. 10/2/2025 Henry Lee Haemoglobinopathies 23  Haemoglobin C Trait (AC) No symptoms – no anemia. Target cells frequent finding 10/2/2025 Henry Lee Haemoglobinopathies 24  Treatment for Hb C Splenectomy may be beneficial for symptomatic CC homozygous persons. AC heterozygous persons are usually asymptomatic, so no treatment required. 10/2/2025 Henry Lee Haemoglobinopathies 25  Hemoglobin E Disease 10/2/2025 Henry Lee Haemoglobinopathies 26  Hb E Disease β chain variant – lysine substituted for glutamic acid in 26th position in beta chain ◦ (α2β226Glu-Lys) Heterozygous and homozygous forms Homozygous individuals have mild microcytic anaemia with decreased RBC survival, target cells and increased osmotic fragility Heterozygous individuals have no symptom Frequently occurs with Beta thalassemia No clinical symptoms HbE has a decreased affinity for oxygen 10/2/2025 Henry Lee Haemoglobinopathies 27  Laboratory Findings of Hb E Disease Mild, microcytic, hypochromic hemolytic anemia Many target cells Electrophoresis shows E band. Normal Hb F, no Hb A May protect against malaria 10/2/2025 Henry Lee Haemoglobinopathies 28  Unstable Hemoglobin Variants 10/2/2025 Henry Lee Haemoglobinopathies 29  Unstable haemoglobin variants Unstable hemoglobins are hemoglobin variants in which amino acid substitutions or deletions have weakened the binding forces that maintain the structure of the molecule which leading to decrease stability Instability may cause Hb to denature and precipitate in the red cells as Heinz bodies which leads to increased cell rigidity, membrane damage and RBC haemolysis. Results in hemolytic anemia 10/2/2025 Henry Lee Haemoglobinopathies 30  Unstable haemoglobin disorder Most inherited as autosomal dominant disorders. When anemia is present, degree of hemolysis varies considerably: ◦ Most have mild compensated anemia with mild reticulocytosis ◦ Some have severe, chronic hemolysis with splenomegaly and jaundice. Hb electrophoresis usually not very helpful in diagnosis. 10/2/2025 Henry Lee Haemoglobinopathies 31  Methemoglobinemia (Hemoglobin M) 10/2/2025 Henry Lee Haemoglobinopathies 32  Methemoglobinemia (Hb M) HbM contains ferric iron (Fe3+); Can’t carry oxygen and results in cyanosis. 5 variants of Hb M which result from single amino acid substitution in the globin chain that stabilizes iron in the ferric form. Three causes of methemoglobinemia: ◦ Methemoglobin reductase system ⚫Overwhelmed ⚫Deficient ⚫Molecule is resistant to methemoglobin reductase 10/2/2025 Henry Lee Haemoglobinopathies 33 References A.V.HOFFBRAND & J.E.PETTIT: Essential Haematology. Blackwell Scientific Publications 3rd Edition. 10/2/2025 Henry Lee Haemoglobinopathies 34