Hemolytic Anemia Overview

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.