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BLOOD AND ITS CONSTITUENTS
18.INTRODUCTION TO BLOOD AND PLASMA PROTEINS
Blood as a Transport Medium: Blood serves as the primary medium for transporting oxygen, nutrients, hormones, and waste products throughout the body. It also plays a central role in maintaining homeostasis, regulating pH, temperature, and osmotic pressure. Composition of Blood: Blood is composed of two major components: Plasma (55% of blood volume): A straw-colored fluid containing water, electrolytes, proteins, hormones, nutrients, and waste products. Formed Elements (45% of blood volume): Includes red blood cells (RBCs), white blood cells (WBCs), and platelets. Plasma Proteins: Plasma contains various proteins, each serving specific roles: Albumin (60% of plasma proteins): Maintains colloid osmotic pressure and acts as a transport protein.
Globulins (35%): Includes alpha, beta, and gamma globulins, with roles in immunity, transport, and enzymatic activity. Fibrinogen (4%): Essential for blood clotting, forming fibrin strands during coagulation. Other proteins, such as enzymes, hormones, and complement proteins, are also present in smaller amounts. Functions of Plasma Proteins: Colloid Osmotic Pressure: Maintains fluid balance between blood vessels and interstitial spaces. Transport: Many plasma proteins bind and transport hormones, lipids, vitamins, and ions. Immunity: Gamma globulins (immunoglobulins) are key components of the immune response. Blood Clotting: Fibrinogen and clotting factors are essential for hemostasis. Buffering Capacity: Proteins contribute to pH regulation by acting as buffers. Physiological Regulation: The liver is the primary site of synthesis for most plasma proteins, except immunoglobulins, which are produced by plasma cells. Plasma protein levels are tightly regulated, as imbalances can lead to conditions like edema, infections, or clotting disorders. Clinical Significance: Abnormalities in plasma protein composition or concentration are associated with various diseases, including liver dysfunction, nephrotic syndrome, and immunodeficiencies.
Maximizes surface area-to-volume ratio for efficient diffusion of gases. Enhances flexibility for passage through narrow capillaries. Lack of Organelles: No nucleus or mitochondria, providing more space for hemoglobin. Energy production occurs via anaerobic glycolysis. Hemoglobin: A tetrameric protein consisting of globin chains (α and β) and heme groups. Each heme contains an iron atom that binds one molecule of oxygen. Functions : Oxygen transport from lungs to tissues. Carbon dioxide transport from tissues to lungs (as carbaminohemoglobin or dissolved bicarbonate). Functions of Erythrocytes Gas Transport: Oxygen: Delivered to tissues via hemoglobin. Carbon Dioxide: Transported back to lungs via bicarbonate buffering or binding to hemoglobin. Buffering Role: Hemoglobin acts as a buffer, maintaining blood pH by binding and releasing hydrogen ions. Erythropoiesis (Production of Erythrocytes) Location: Fetal Life: Yolk sac, liver, spleen. Post-Birth: Bone marrow of flat bones and the proximal ends of long bones. Stages of Development:
Hematopoietic stem cell → Myeloid progenitor → Proerythroblast → Basophilic erythroblast → Polychromatic erythroblast → Orthochromatic erythroblast → Reticulocyte → Erythrocyte. Regulation by Erythropoietin (EPO): EPO is a hormone secreted by the kidneys in response to hypoxia. It stimulates red blood cell production in the bone marrow. Nutritional Requirements: Iron: Essential for hemoglobin synthesis. Vitamin B12 and Folic Acid: Required for DNA synthesis during RBC production. Proteins and Amino Acids: For globin synthesis. Iron Metabolism Absorption: Dietary iron is absorbed in the duodenum, facilitated by gastric acid and vitamin C. Transport: Iron binds to transferrin, a plasma protein, for delivery to bone marrow. Storage: Stored in liver, spleen, and bone marrow as ferritin and hemosiderin. Utilization: Incorporated into hemoglobin during erythropoiesis. Lifespan and Destruction of Erythrocytes Lifespan: ~120 days. Destruction (Erythrophagocytosis): Senescent RBCs are removed by macrophages in the spleen, liver, and bone marrow.
Jaundice: Excessive RBC destruction (hemolysis) or impaired bilirubin metabolism causes yellowing of skin and eyes. Sickle Cell Disease : Genetic mutation in hemoglobin leads to abnormal RBC shape, causing blockage in capillaries and hemolysis. Thalassemias : Inherited disorders resulting in reduced or defective globin chain synthesis. Adaptations and Disorders High Altitude Adaptation: Hypoxia triggers increased erythropoiesis via erythropoietin production. Leads to polycythemia to enhance oxygen transport. Hemoglobinopathies: Structural abnormalities in hemoglobin (e.g., HbS in sickle cell disease).
20.ERYTHROPOESIS
Definition of Erythropoiesis Erythropoiesis is the process by which erythrocytes (RBCs) are produced in the body. It ensures a constant supply of RBCs to replace those that are destroyed and to meet the body's oxygen transport demands.
Sites of Erythropoiesis During Fetal Development: Yolk Sac (1st Trimester): Hematopoiesis begins here. Liver and Spleen (2nd Trimester): These organs take over RBC production. Bone Marrow (3rd Trimester): Becomes the primary site. After Birth: Children: Active red bone marrow in all bones. Adults: Restricted to flat bones (e.g., sternum, ribs, pelvis) and the proximal ends of long bones. Stages of Erythropoiesis Hematopoietic Stem Cell (HSC): Pluripotent stem cells in the bone marrow give rise to all blood cell lineages, including RBCs. Differentiates into myeloid progenitor cells under specific growth factors. Proerythroblast: The first committed erythroid precursor. Large nucleus and basophilic cytoplasm (due to high RNA content). Basophilic Erythroblast: Hemoglobin synthesis begins. Cytoplasm remains deeply basophilic due to ribosomes. Polychromatic Erythroblast:
Increases the rate of hemoglobin synthesis. Reduces the maturation time of erythroid precursors.
2. Hypoxia-Inducible Factor-1 (HIF-1): A transcription factor activated during hypoxia. Upregulates EPO production in the kidneys. 3. Nutritional Requirements: Iron: Essential for hemoglobin synthesis. Absorbed in the duodenum and jejunum. Transported in blood by transferrin. Vitamin B12 (Cobalamin): Required for DNA synthesis and cell division. Absorbed in the ileum with the help of intrinsic factor. Folic Acid: Also necessary for DNA synthesis. Deficiency causes impaired cell division and megaloblastic anemia. Proteins and Amino Acids: For globin chain synthesis. 4. Other Factors Influencing Erythropoiesis: Thyroid Hormones: Enhance metabolism and erythropoiesis. Androgens: Stimulate RBC production. Cytokines: IL-3 and GM-CSF promote stem cell proliferation. Iron Metabolism in Erythropoiesis Iron is a critical component of heme in hemoglobin.
Storage: Stored as ferritin and hemosiderin in the liver, spleen, and bone marrow. Recycling: Macrophages in the reticuloendothelial system recycle iron from senescent RBCs. Regulation: Hepcidin, a liver-produced hormone, regulates iron absorption and release from stores. Lifespan and Destruction of RBCs RBCs have a lifespan of ~120 days. Aged RBCs are destroyed in the spleen, where hemoglobin is broken down: Heme: Converted to bilirubin and excreted via bile. Globin: Broken down into amino acids. Iron: Recycled or stored. Clinical Disorders Related to Erythropoiesis
1. Anemias: Iron-Deficiency Anemia: Microcytic, hypochromic RBCs due to inadequate iron. Megaloblastic Anemia: Caused by vitamin B12 or folic acid deficiency, leading to large, fragile RBCs. Aplastic Anemia: Bone marrow failure resulting in reduced erythropoiesis. Hemolytic Anemia: Increased destruction of RBCs leads to increased demand for erythropoiesis. 2. Polycythemia: Primary Polycythemia (Polycythemia Vera): Overproduction of RBCs due to a bone marrow disorder. Secondary Polycythemia: Caused by chronic hypoxia (e.g., high altitude, chronic lung disease). 3. Pernicious Anemia: Caused by the failure to absorb vitamin B12 due to lack of intrinsic factor.
21.HEMOGLOBIN
Overview of Hemoglobin Hemoglobin (Hb) is a specialized protein in red blood cells (RBCs) responsible for the transport of oxygen (O₂) from the lungs to tissues and carbon dioxide (CO₂) from tissues to the lungs. It also plays a crucial role in buffering blood pH. Structure of Hemoglobin Protein Composition : Hemoglobin is a tetramer, consisting of four polypeptide chains. Two types of globin chains combine to form hemoglobin: Adult Hemoglobin (HbA): 2 alpha (α) and 2 beta (β) chains (most abundant). Fetal Hemoglobin (HbF): 2 alpha (α) and 2 gamma (γ) chains (higher oxygen affinity, replaced after birth). Other forms include HbA₂ (α₂δ₂) and embryonic hemoglobin. Heme Group: Each globin chain contains one heme group. Heme Structure: Porphyrin ring with a central iron (Fe²⁺) atom that binds one molecule of oxygen. Four heme groups allow each hemoglobin molecule to carry four oxygen molecules. Iron in Hemoglobin:
The ferrous form (Fe²⁺) of iron is essential for oxygen binding. Oxidation of iron to the ferric form (Fe³⁺) results in methemoglobin, which cannot bind oxygen. Synthesis of Hemoglobin Site: Occurs in the bone marrow during erythropoiesis. Stages of Hemoglobin Synthesis: Heme Production: Takes place in the mitochondria and cytoplasm of erythroblasts. Succinyl-CoA and glycine combine to form δ-aminolevulinic acid (ALA). ALA undergoes a series of reactions to form protoporphyrin IX. Protoporphyrin IX binds iron (Fe²⁺) to form heme. Globin Chain Production: Synthesized by ribosomes in the cytoplasm of erythroblasts. Controlled by genes specific to α, β, γ, and δ globin chains. Regulation: Controlled by oxygen levels, erythropoietin, and availability of iron. Functions of Hemoglobin Oxygen Transport: Hemoglobin binds oxygen in the lungs (oxyhemoglobin) and releases it in tissues. Each hemoglobin molecule can carry four oxygen molecules. The binding of oxygen is cooperative, meaning the binding of one oxygen molecule increases the affinity for subsequent molecules (sigmoidal O₂ dissociation curve). Carbon Dioxide Transport: Hemoglobin transports CO₂ in three ways:
Increased CO₂ or H⁺ reduces oxygen affinity, facilitating oxygen release in metabolically active tissues. Haldane Effect: Deoxygenation of hemoglobin increases its affinity for CO₂, aiding CO₂ transport to the lungs. Hemoglobin Variants Normal Variants: HbA: Predominant in adults (96-98%). HbA₂: Minor component in adults (~2-3%). HbF: Predominant in the fetus, replaced by HbA after birth. Abnormal Variants (Hemoglobinopathies ): Sickle Cell Hemoglobin (HbS): Mutation in the β-globin chain leads to polymerization under low oxygen, causing RBC deformation. Thalassemias: Defective production of α or β chains results in imbalanced globin synthesis. Hemoglobin Disorders Anemia: Iron Deficiency: Impaired hemoglobin synthesis leads to microcytic, hypochromic anemia. Megaloblastic Anemia: Vitamin B12 or folic acid deficiency affects DNA synthesis, resulting in large, fragile RBCs. Aplastic Anemia: Reduced RBC production affects hemoglobin levels. Polycythemia: Excess RBC production leads to elevated hemoglobin levels. Can be primary (polycythemia vera) or secondary (high altitude, chronic hypoxia).
Methemoglobinemia: Oxidation of iron to Fe³⁺ impairs oxygen binding and release. Can be congenital or acquired (e.g., due to certain drugs). Carbon Monoxide Poisoning: CO binds to hemoglobin with ~250 times the affinity of oxygen, preventing oxygen transport. Clinical Correlations Jaundice: Excessive RBC breakdown releases heme, leading to increased bilirubin levels. Blood Doping: Artificially increasing hemoglobin levels (via EPO or transfusion) to enhance oxygen delivery in athletes. Hemoglobin Testing: Measured in routine blood tests (normal range: 13.5–17.5 g/dL in males, 12.0–15.5 g/dL in females). Assesses oxygen-carrying capacity and helps diagnose anemia or polycythemia. 22.ANEMIA AND POLYCYTHEMIA Anemia Anemia is defined as a reduction in the total number of red blood cells (RBCs), hemoglobin concentration, or hematocrit, resulting in decreased oxygen-carrying capacity of the blood. Causes of Anemia
Causes: Vitamin B12 deficiency (pernicious anemia due to lack of intrinsic factor). Folic acid deficiency. Alcoholism or liver disease. Characteristics: Large, immature RBCs with defective DNA synthesis.
3. Normocytic, Normochromic Anemia: Causes: Acute blood loss. Hemolytic anemia. Anemia of chronic disease. Characteristics: Normal-sized RBCs but reduced in number. Physiological Effects of Anemia Reduced Oxygen Delivery: Tissue hypoxia leads to fatigue, pallor, dyspnea, and impaired physical performance. I ncreased Cardiac Output: To compensate for reduced oxygen, the heart pumps more blood, potentially causing tachycardia and heart failure. Compensatory Mechanisms: Increased 2,3-BPG production shifts the oxygen-hemoglobin dissociation curve to the right, promoting oxygen unloading to tissues.
Increased erythropoietin (EPO) secretion stimulates RBC production in bone marrow. Specific Types of Anemia Iron-Deficiency Anemia: Most common cause of anemia. Symptoms: Fatigue, pallor, spoon-shaped nails (koilonychia), pica. Pernicious Anemia: Autoimmune destruction of gastric parietal cells leads to vitamin B12 deficiency. Neurological symptoms: Peripheral neuropathy, ataxia. Hemolytic Anemia: Increased RBC destruction results in elevated bilirubin levels and jaundice. Reticulocyte count is elevated as bone marrow compensates. Aplastic Anemia: Bone marrow failure results in pancytopenia (low RBCs, WBCs, and platelets). Causes include radiation, toxins, and autoimmune disorders. Diagnosis of Anemia Laboratory Tests: Hemoglobin and hematocrit levels. RBC indices (MCV, MCH, MCHC). Reticulocyte count. Peripheral blood smear. Serum iron, ferritin, and total iron-binding capacity (TIBC) for iron status. Vitamin B12 and folic acid levels.
