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Questions and Answers
What occurs when the rate of red cell destruction exceeds the increased production rate in haemolytic anaemia?
What occurs when the rate of red cell destruction exceeds the increased production rate in haemolytic anaemia?
Which of the following describes a mechanism involved in extravascular haemolysis?
Which of the following describes a mechanism involved in extravascular haemolysis?
What is the primary consequence of glucose-6-phosphate dehydrogenase deficiency?
What is the primary consequence of glucose-6-phosphate dehydrogenase deficiency?
Which condition results in increased red cell destruction due to autoantibodies?
Which condition results in increased red cell destruction due to autoantibodies?
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What physiological adaptation may occur in bone marrow in response to increased red cell destruction?
What physiological adaptation may occur in bone marrow in response to increased red cell destruction?
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What is a possible result of intravascular haemolysis?
What is a possible result of intravascular haemolysis?
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Which of the following statements about hereditary elliptocytosis is true?
Which of the following statements about hereditary elliptocytosis is true?
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Why might heterozygotes for glucose-6-phosphate dehydrogenase deficiency have an advantage in malarial regions?
Why might heterozygotes for glucose-6-phosphate dehydrogenase deficiency have an advantage in malarial regions?
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What is the main treatment approach for idiopathic cold agglutinin disease?
What is the main treatment approach for idiopathic cold agglutinin disease?
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Which monoclonal antibody has shown effectiveness in treating paroxysmal nocturnal haemoglobinuria?
Which monoclonal antibody has shown effectiveness in treating paroxysmal nocturnal haemoglobinuria?
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In which type of haemoglobinopathy do mutations predominantly affect the globin chain genes?
In which type of haemoglobinopathy do mutations predominantly affect the globin chain genes?
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What is a major risk associated with long-term immunosuppressive therapy using azathioprine or cyclophosphamide in young patients?
What is a major risk associated with long-term immunosuppressive therapy using azathioprine or cyclophosphamide in young patients?
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What is a significant complication associated with sickle cell disease affecting men?
What is a significant complication associated with sickle cell disease affecting men?
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What feature distinguishes paroxysmal nocturnal haemoglobinuria from other blood disorders?
What feature distinguishes paroxysmal nocturnal haemoglobinuria from other blood disorders?
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How is sickle cell disease typically diagnosed definitively?
How is sickle cell disease typically diagnosed definitively?
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How can haemoglobinopathies be categorized?
How can haemoglobinopathies be categorized?
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What management strategy should be employed for patients with sickle cell disease to prevent infections?
What management strategy should be employed for patients with sickle cell disease to prevent infections?
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What is the genetic cause of sickle-cell anaemia?
What is the genetic cause of sickle-cell anaemia?
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Which treatment option is used to increase HbF levels in sickle cell disease patients?
Which treatment option is used to increase HbF levels in sickle cell disease patients?
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What do all patients with cold agglutinin disease require as part of their treatment?
What do all patients with cold agglutinin disease require as part of their treatment?
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What is the genetic mode of inheritance for thalassemia disorders?
What is the genetic mode of inheritance for thalassemia disorders?
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What type of thalassemia is characterized by a reduction or absence of the beta chain of hemoglobin?
What type of thalassemia is characterized by a reduction or absence of the beta chain of hemoglobin?
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What clinical benefit does a high level of HbF provide to sickle cell disease patients?
What clinical benefit does a high level of HbF provide to sickle cell disease patients?
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Which of the following is NOT part of the management for vaso-occlusive crises in sickle cell disease?
Which of the following is NOT part of the management for vaso-occlusive crises in sickle cell disease?
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What is the primary purpose of a reticulocyte count in diagnosing anemia?
What is the primary purpose of a reticulocyte count in diagnosing anemia?
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Which method is NOT typically used to diagnose thalassemia?
Which method is NOT typically used to diagnose thalassemia?
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What is the recommended maintenance hemoglobin level according to WHO for patients with thalassemia?
What is the recommended maintenance hemoglobin level according to WHO for patients with thalassemia?
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Which of the following treatments is indicated for patients >10 years old with splenomegaly?
Which of the following treatments is indicated for patients >10 years old with splenomegaly?
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Which of the following is NOT part of the prevention strategies for thalassemia?
Which of the following is NOT part of the prevention strategies for thalassemia?
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What determines the severity of thalassemia?
What determines the severity of thalassemia?
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What condition is indicated by having two defective or missing alpha genes?
What condition is indicated by having two defective or missing alpha genes?
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How many alpha gene alleles does each individual carry?
How many alpha gene alleles does each individual carry?
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What is the potential outcome when all four alpha genes are defective or missing?
What is the potential outcome when all four alpha genes are defective or missing?
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Which form of thalassemia generally does not require transfusion therapy?
Which form of thalassemia generally does not require transfusion therapy?
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What is another term for thalassemia major?
What is another term for thalassemia major?
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What genetic makeup causes alpha thalassemia minima?
What genetic makeup causes alpha thalassemia minima?
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What is a common symptom of Hemoglobin H disease?
What is a common symptom of Hemoglobin H disease?
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What type of antibodies primarily account for warm autoimmune hemolysis?
What type of antibodies primarily account for warm autoimmune hemolysis?
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What is the typical incidence of warm autoimmune hemolysis in the population per year?
What is the typical incidence of warm autoimmune hemolysis in the population per year?
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Which laboratory test is pivotal in confirming the diagnosis of warm autoimmune hemolysis?
Which laboratory test is pivotal in confirming the diagnosis of warm autoimmune hemolysis?
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What is the first-line management for patients with warm autoimmune hemolysis?
What is the first-line management for patients with warm autoimmune hemolysis?
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What percentage of warm autoimmune hemolytic anemia cases may test negative on the Coombs test?
What percentage of warm autoimmune hemolytic anemia cases may test negative on the Coombs test?
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What temperature range do cold antibodies primarily bind at?
What temperature range do cold antibodies primarily bind at?
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What is the primary action of corticosteroids in treating autoimmune hemolysis?
What is the primary action of corticosteroids in treating autoimmune hemolysis?
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What occurs as a result of spherocyte formation in the blood?
What occurs as a result of spherocyte formation in the blood?
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Study Notes
Hemolytic Anemia
- Hemolysis is the shortening of the normal lifespan of red blood cells.
- Bone marrow compensates by increasing its red blood cell production, sometimes 6-8 times the normal rate.
- This increased production includes growing the active bone marrow and prematurely releasing reticulocytes.
- Anemia only develops if the rate of red blood cell destruction is higher than the bone marrow's increased production rate.
Red Cell Destruction
- Hemoglobin breakdown in the liver results in a moderate rise in unconjugated bilirubin in the blood and mild jaundice.
- Increased reabsorption of urobilinogen from the gut leads to increased urinary urobilinogen.
- LDH is released into the serum when red blood cells are destroyed.
Extravascular Hemolysis
- Physiological destruction of red blood cells occurs within reticuloendothelial cells in the liver or spleen, preventing free hemoglobin in the plasma.
- Extravascular hemolysis is the prevalent type in most hemolytic states.
Intravascular Hemolysis
- Red cell lysis occurs inside the bloodstream, less commonly.
- Causes include:
- Membrane damage by the complement system (e.g., in ABO transfusion reactions and paroxysmal nocturnal hemoglobinuria).
- Infections (such as malaria and Clostridium perfringens infections).
- Mechanical trauma (e.g., from heart valves).
- Oxidative damage (e.g., from drugs like dapsone and maloprim).
- When intravascular red cell destruction occurs, free hemoglobin is released into the plasma.
Red Cell Membrane Defects
- Hereditary spherocytosis
- Hereditary elliptocytosis
Red Cell Enzymopathies
- Mature red cells produce energy through ATP to maintain homeostasis and protect against oxidative stress caused by oxygen transport.
- Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common human enzymopathy, affecting 10% of the global population.
- The geographical distribution of this deficiency mirrors malaria prevalence, as heterozygotes are protected from malarial parasitization.
Glucose-6-Phosphate Dehydrogenase Deficiency (G6PD): Clinical Features
- Acute drug-induced hemolysis, triggered by analgesics (e.g., aspirin, phenacetin), antimalarials (e.g., primaquine, quinine, chloroquine, pyrimethamine), antibiotics (e.g., sulphonamides, nitrofurantoin, ciprofloxacin), and other substances.
- Chronic compensated hemolysis.
- Infection or acute illness.
- Neonatal jaundice.
- Favism (acute hemolysis after broad bean consumption).
Glucose-6-Phosphate Dehydrogenase Deficiency (G6PD): Laboratory Features
- Bite cells
- Blister cells
- Irregularly shaped small red blood cells
- Polychromasia (reflecting reticulocytosis).
- Heinz bodies (denatured hemoglobin within red blood cells).
- G6PD levels can be assessed indirectly through screening or directly.
- Increased reticulocytes may cause a false normal G6PD result, particularly in acute hemolytic episodes.
Pyruvate Kinase Deficiency
- Second most common red cell enzyme defect.
- Results in ATP deficiency, causing chronic hemolytic anemia.
- Inherited as an autosomal recessive trait.
- Anemia severity varies.
- Enzyme activity is 5-20% of normal.
- Transfusion support may be necessary.
Autoimmune Hemolytic Anemia
- Increased red cell destruction due to red blood cell autoantibodies.
- Antibodies may be IgG, IgM, or less commonly IgE or IgA.
- Strong complement fixation by the antibodies leads to intravascular hemolysis.
- Mild complement activation leads to extravascular hemolysis.
- Antibody-coated red cells are phagocytosed by macrophages in the spleen, causing spherocytes to form.
Warm Antibodies
- Optimal activity at 37°C.
- Account for approximately 80% of cases.
- Primarily IgG.
- Incidence: 1/100,000 population per year; more common in middle-aged females.
- May be caused by unknown factors in up to half of the cases, or result from other conditions in the other half.
Cold Antibodies
- Optimal activity at 4°C but capable of binding at temperatures up to 37°C in certain cases.
- Accounts for 20% of the cases.
- Predominantly IgM.
- Often binds to complement.
Warm Autoimmune Hemolysis: Investigations
- CBC, RETICS, LFTS
- Diagnosis confirmed by the direct Coombs (antiglobulin) test.
- Patient's red cells are mixed with Coombs reagent (containing antibodies against human IgG, IgM, and complement).
- Agglutination indicates antibody coating in vivo.
- About 10% of warm autoimmune hemolytic anemias are Coombs test-negative.
Warm Autoimmune Hemolysis: Management
- Treat the underlying cause (if applicable) and discontinue implicated drugs.
- Initial treatment is prednisolone (1 mg/kg orally).
- Response seen within 70-80% of cases, potentially exceeding 3 weeks.
- Hg rise parallels a decrease in bilirubin, LDH, and reticulocyte levels.
- Reduce corticosteroid dose gradually over 10 weeks.
- Corticosteroids decrease macrophage destruction of antibody-coated red cells and antibody production.
- Transfusion may be necessary in life-threatening situations such as heart failure or acute hemoglobin drops.
- Splenectomy can be considered if corticosteroids are ineffective or necessitate high doses to manage the disease.
- Alternatives include immunosuppressives (azathioprine or cyclophosphamide), but these may be less suitable for younger patients due to the risk of secondary neoplasms. Rituximab, an anti-CD20 monoclonal antibody, is sometimes used.
Cold Agglutinin Disease
- Due to IgM antibodies binding to red cells at low temperatures causing agglutination.
- Intravascular hemolysis can occur if complement fixation occurs.
- Any underlying lymphoma should be treated.
- Patients should maintain warm extremities, especially during the winter months.
- Treatment may involve corticosteroids and blood transfusions.
- All individuals will require folic acid supplementation.
Paroxysmal Nocturnal Hemoglobinuria (PNH)
- Rare, acquired, life-threatening disease of the blood.
- Characterised by destruction of red blood cells, blood clotting in unusual areas, and impaired bone marrow function.
- Leads to intravascular hemolysis and anemia due to the increased sensitivity of red cells to complement-mediated lysis.
- Hemoglobinuria (red-brown urine) occurs in the early morning, resulting from intravascular hemolysis episodes.
PNH: Management
- Supportive care including transfusions and treatment of thrombosis.
- Eculizumab, an anti-complement C5 monoclonal antibody, has been shown to effectively reduce hemolysis.
Hemoglobinopathies
- Caused by mutations affecting globin gene sequences within the hemoglobin molecule.
- Normal hemoglobin comprises HbA (α2β2).
- Alpha-globin chains are continuously produced throughout life, including in the fetus, meaning severe mutations may lead to intrauterine fetal death.
Fetal Hemoglobin
- Has two gamma chains (HbF α2γ2).
- Predominant adult hemoglobin (HbA) has two beta chains (HbA α2β2).
Sickle Cell Anemia
- Results from the single glutamic acid to valine substitution at position 6 of the beta globin polypeptide chain.
- Inherited as an autosomal recessive trait.
- Homozygotes produce abnormal beta chains, forming HbS (SS), thus causing sickle cell disease.
- Heterozygotes have a mixture of normal and abnormal beta chains, creating HbA and HbS (AS), hence the clinically asymptomatic sickle-cell trait.
Sickle Cell Anemia: Clinical Features
- Sickling is triggered by hypoxia, acidosis, dehydration and infection.
- Irreversibly sickled cells compromise microcirculation, causing acute crises and chronic organ damage.
- Painful vaso-occlusive crisis is the most frequent complication.
- Bone marrow infarction may lead to fat emboli in the lungs causing further sickling and infarction, potentially leading to respiratory failure if untreated.
- Sequestration crisis involves dead tissue detached from healthy tissue.
- Venous outflow thrombosis within an organ may block function.
- The spleen is most commonly affected in children.
Sickle Cell Anemia: Investigations
- Compensated anemia (usually 60-80 g/L)
- Sickle cells, target cells and features of hyposplenism.
- Increased reticulocytes.
- Hb electrophoresis confirms the presence of HbS and the absence/minimal presence of HbA, HbF (2%-20%)
- Both parents of an affected individual will have a sickle-cell trait.
Sickle Cell Anemia: Management
- Daily folic acid prophylaxis.
- Vaccination against pneumococcus, meningococcus, Haemophilus influenzae B, hepatitis B, and seasonal influenza
- Aggressive rehydration, oxygen, adequate analgesia (opiates often needed). and antibiotics to treat vaso-occlusive crises.
- Transfusion, particularly in life-threatening conditions.
- A high HbF level inhibits HbS polymerization and reduces sickling, hence a milder clinical course with fewer crises.
- Some agents increase HbF synthesis, reducing severe crisis frequency.
- Hydroxycarbamide (an oral cytotoxic agent) demonstrates clinical benefit in children and adults with frequent severe crises.
- HLA-matched sibling allogeneic stem cell transplantation may be curative.
- Priapism, a prolonged, firm erection, is a potential complication; treatment includes oxygenation, analgesics, IV fluids, and transfusion, with aspiration as a critical step.
Thalassemias
- Group of autosomal recessive hemoglobin disorders characterized by reduced or absent beta or alpha globin chain synthesis.
Alpha Thalassemia
- Caused by defects in the alpha globin genes.
- Reduced or absent alpha-chain synthesis is common in Southeast Asia.
- There are two alpha gene loci on chromosome 16, meaning each individual carries four alpha gene alleles.
- If one alpha chain is deleted: no clinical effect.
- If two alpha chains are deleted: mild hypochromic anemia.
- If three alpha chains are deleted: hemoglobin H disease.
- If all four alpha chains are deleted: Hydrops fetalis, often fatal, and hemoglobin Barts.
Beta Thalassemia
- Failure to synthesize beta chains (beta-thalassemia) is the most common type.
- Most prevalent in the Mediterranean area.
- Heterozygotes (thalassemia minor): mild microcytic anemia, little to no clinical disability.
- Homozygotes (thalassemia major): profound transfusion-dependent hypochromic anemia developing in the first 4-6 months of life.
Thalassemias: Clinical Aspects
- Classical presentation: Anemia, jaundice (varying degrees), failure to thrive, bone malformations (primarily skull), hepatosplenomegaly, hemosiderosis, recurrent infections, and heart failure.
- Mild to moderate symptoms (beta thalassemia intermedia): growth problems, delayed puberty, bone abnormalities (e.g., osteoporosis), and an enlarged spleen.
- Severe Symptoms (hemoglobin H disease or beta thalassemia major): severe symptoms that often manifest at birth; severe lifelong anemia, poor appetite, pale or yellowish skin, dark or tea-colored urine, and irregular facial bone structure.
Thalassemias: Diagnosis and Tests
- Complete blood count (CBC): Lower hemoglobin and RBC count than normal, and sometimes smaller than normal RBCs.
- Reticulocyte count: May indicate insufficient RBC production from the bone marrow.
- Iron studies: Assess whether iron deficiency or thalassemia is the reason for anemia.
- Hemoglobin electrophoresis: Used to diagnose beta thalassemias.
- Genetic testing: Used to diagnose alpha thalassemias.
Thalassemias: Management
- Regular blood transfusions to maintain adequate hemoglobin levels.
- Chelation therapy (e.g., desferrioxamine or deferiprone) to remove excess iron.
- Splenectomy to reduce the workload on the spleen.
- Bone marrow transplantation is a potential cure in some cases.
- Folic acid supplementation reduces the need for blood transfusions in some conditions.
Thalassemias - Prevention
- Health education about the genetic nature of the condition.
- Population screening.
- Genetic counseling.
- Prenatal diagnosis.
Conclusion
- Thalassemias are hereditary diseases characterized by chronic, often severe anemia; the severe form is now well-recognized through its clinical presentation.
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Description
This quiz explores the mechanisms and consequences of hemolytic anemia. It covers red blood cell destruction, compensatory bone marrow response, and key biochemical markers associated with hemolysis. Test your understanding of the physiological processes involved in this condition.
