Pathophysiology
Summary
In extravascular hemolysis, red blood cells (RBCs) are primarily destroyed in the spleen, leading to normocytic anemia (MCV 80-100). The misshapen RBCs become ensnared in the Cords of Billroth and are subsequently engulfed by splenic macrophages, part of the reticuloendothelial system. Unlike intravascular hemolysis, RBC digestion occurs intracellularly within splenic macrophages, thereby avoiding hemoglobinemia or hemoglobinuria.
The intracellular hemoglobin is metabolized into unconjugated bilirubin, causing symptoms like jaundice. Excessive bilirubin leads to increased levels of urobilinogen in both the urine and stool. This surplus bilirubin can also result in the formation of pigmented gallstones. Extravascular hemolysis is marked clinically by elevated serum lactate dehydrogenase (LDH), released from digested RBCs, and an increased reticulocyte count (>3%) due to compensatory RBC production by the bone marrow. Chronic extravascular hemolysis can result in the expansion of the red pulp in the spleen, leading to splenomegaly. Treatment for extravascular hemolysis often involves splenectomy, especially in refractory cases.
Hereditary spherocytosis is an autosomal dominant condition caused by mutations in membrane proteins like spectrin and ankyrin, which anchor the external phospholipid bilayer of the RBC cell membrane to its internal cytoskeleton. These mutations lead to weak, inflexible RBCs that are more likely to undergo phagocytosis in the spleen. In this condition, RBCs lose vesicles of membrane in the splenic cords, leading to smaller RBCs and an increased RBC distribution width (RDW). It can be diagnosed using the osmotic fragility test or the acidified glycerol lysis test and is associated with an increased mean corpuscular hemoglobin concentration (MCHC). Notably, hereditary spherocytosis can cause complications like hydrops fetalis and aplastic crisis due to Parvovirus B19 infection.
Hereditary elliptocytosis is another autosomal dominant condition causing extravascular hemolysis, often due to mutations in spectrin affecting the RBC cytoskeleton's elastic recoil. Interestingly, this condition offers increased protection against malaria.
Pyruvate kinase deficiency is an autosomal recessive disorder that results in extravascular hemolysis and normocytic anemia. The deficiency in pyruvate kinase, which converts phosphoenolpyruvate into pyruvate in glycolysis leads to inadequate ATP production, causing a loss of concentration gradients in the RBC membrane and a loss of potassium and water. The affected RBCs, known as burr cells or echinocytes due to their stiff architecture, are also phagocytosed in the spleen. Pyruvate kinase deficiency presents with hemolytic anemia in the newborn and splenomegaly later in life.
Lesson Outline
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FAQs
Extravascular hemolysis primarily takes place in the spleen, where misshapen red blood cells (RBCs) are trapped in specialized regions known as the Cords of Billroth. These trapped RBCs are then engulfed and destroyed by splenic macrophages, which are part of the reticuloendothelial system. In extravascular hemolysis, hemoglobin from RBCs remains intracellular, where it is converted to unconjugated bilirubin. This process leads to a normocytic anemia, characterized by a mean corpuscular volume (MCV) between 80-100, as the RBCs that are destroyed are typically of normal size.
Extravascular hemolysis can lead to several complications due to the accumulation of unconjugated bilirubin. This excess bilirubin can cause jaundice, elevate urobilinogen levels in urine and stool, and contribute to the formation of pigmented gallstones. Additionally, serum lactate dehydrogenase (LDH) levels may rise due to the release of this enzyme from the destroyed RBCs. Over time, chronic extravascular hemolysis can also result in splenomegaly due to the expansion of its red pulp.
Hereditary spherocytosis is an autosomal dominant condition that often leads to extravascular hemolysis and normocytic anemia. This disorder is caused by mutations in proteins like spectrin and ankyrin, which are important for anchoring the RBC membrane to its internal cytoskeleton, resulting in RBCs that are weak and inflexible. Such RBCs are prone to losing membrane vesicles when they pass through the Cords of Billroth in the spleen, making them susceptible to phagocytosis by splenic macrophages and subsequent extravascular hemolysis.
Diagnosis of hereditary spherocytosis often involves the osmotic fragility test, which assesses the RBCs' vulnerability to osmotic stress. The condition is also marked by an elevated mean corpuscular hemoglobin concentration (MCHC). Management may include addressing severe complications like hydrops fetalis and aplastic crisis, which can occur in hereditary spherocytosis. Splenectomy may be considered to alleviate the symptoms and complications of extravascular hemolysis.
Pyruvate kinase deficiency is an autosomal recessive disorder that disrupts glycolysis by impairing the conversion of phosphoenolpyruvate to pyruvate. This enzymatic deficiency results in inadequate ATP production, affecting the ionic balance across the RBC membrane leading to a loss of potassium and water. The altered membrane architecture makes these RBCs more susceptible to being trapped in the Cords of Billroth in the spleen, where they are phagocytosed by splenic macrophages, leading to extravascular hemolysis and normocytic anemia.
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