Erythrocyte and Leukocyte Introduction

Gas Transport and Hemoglobin Characteristics

• Oxygen transport is facilitated by diffusion. When oxygen is inhaled into the lungs, it crosses the respiratory membrane, leaves the air, and binds to the blood flowing through pulmonary circulation.
• Oxyhemoglobin: Hemoglobin that has oxygen bound to it in the lungs. It is characterized by a bright scarlet red color.
• Unloading Oxygen: This occurs in the tissues where hemoglobin releases oxygen to cells for use in cellular respiration.
• Deoxyhemoglobin: Hemoglobin that has released its oxygen. This blood appears as a darker, maroon red color.
• Carbon Dioxide Transport: Hemoglobin also carries $CO_2$. It is loaded into hemoglobin in the tissues as a byproduct of cellular respiration and unloaded in the lungs to be exhaled.
• Binding Sites: Oxygen and carbon dioxide do not compete for binding sites within the hemoglobin molecule:   - Oxygen binds to the iron atom of the heme pigment.   - $CO_2$ binds to the globin chains (the polypeptide chains).

Erythropoiesis: The Production of Red Blood Cells

• Definition: Erythropoiesis translates literally to "red blood cell formation" or production ($poiesis$ means to make or form).
• Developmental Pathway:   - All formed elements begin with a stem cell called a hemocytoblast (also known as a hematopoietic stem cell).   - The cell then differentiates into the myeloid stem cell line.
• The Committed Cell Stage: For red blood cells, the committed cell is the proerythroblast. This is the "point of no return" because the cell now possesses receptors for specific regulatory chemicals.
• Stages of Development:   - Phase 1: Ribosome Synthesis: The cell makes ribosomes to facilitate protein synthesis. This follows the central dogma: DNA transcribes mRNA, which ribosomes translate into proteins.   - Phase 2: Hemoglobin Accumulation: Ribosomes build the protein hemoglobin. As the pigmented protein fills the cell, the color shifts from purple to a lighter pink.   - Phase 3: Ejection of Nucleus: The cell ejects its nucleus and most organelles degrade. This loss of internal structure causes the cell to collapse inward, becoming a biconcave shape.
• Reticulocyte: An immature (baby) red blood cell that is ejected from the red bone marrow into the bloodstream.   - It takes approximately $15$ days to go from the hematopoietic stem cell to the reticulocyte stage.   - Within $2$ days of entering the bloodstream, reticulocytes become mature erythrocytes as the remaining ribosomes degrade.
• Reticulocyte Count: A clinical measurement used to estimate the rate of red blood cell production in the bone marrow.

Regulation and Control of Erythropoiesis

• Homeostatic Balance: The body must balance RBC production and destruction.   - Too few RBCs: Leads to tissue hypoxia (low oxygen delivery).   - Too many RBCs: Increases blood viscosity (thickness), making blood flow like molasses and slowing oxygen delivery.
• Standard Values: On average, the body produces and destroys approximately $2,000,000$ red blood cells per second. Some estimates suggest up to $10,000,000$ are produced per second to maintain balance.
• Erythropoietin (EPO): An amino acid-based hormone that is the direct stimulus for erythropoiesis.   - Structure: It is water-soluble (not lipid-soluble) and cannot cross the plasma membrane; its receptors are located on the surface of proerythroblasts.   - Source: The kidneys are the primary source of EPO; the liver produces a smaller amount.   - Basal Rate: There is always a small, baseline concentration of EPO in the blood to maintain a steady rate of RBC production.
• Hypoxia Inducible Factor (HIF): An intracellular signaling molecule in kidney cells that detects oxygen levels.   - When oxygen is plentiful, HIF degrades.   - When oxygen is low (hypoxia), HIF accumulates and acts as a transcription factor, triggering the kidneys to synthesize and release more EPO.
• Indirect Stimulus: Hypoxia is considered the indirect stimulus that kicks off the process because kidney receptors detect low oxygen levels, not the number of red blood cells itself.
• Causes of Hypoxia:   - Decrease in RBC numbers (due to hemorrhage/bleeding or excessive destruction).   - Insufficient hemoglobin per RBC (e.g., iron deficiency).   - Reduced availability of oxygen (e.g., high altitudes like Denver, Colorado).

Dietary and Nutritional Requirements for RBC Formation

• General Nutrients: Amino acids, carbohydrates, and lipids are required to build the cell structures.
• Iron: Essential for synthesizing hemoglobin ($65\%$ of bodily iron is found in hemoglobin).   - Free iron is toxic. It is stored inside cells as ferritin or hemosiderin.   - It is transported in the blood bound to plasma proteins.
• Vitamin $B_{12}$ and Folic Acid: These are necessary for normal DNA synthesis and cell division during the development of red blood cell lines.

The Life Cycle and Destruction of Erythrocytes

• Lifespan: Red blood cells circulate for approximately $100$ to $120$ days ($3$ to $4$ months).
• Degradation: Lacking a nucleus, RBCs cannot repair themselves. Aging cells become rigid and fragile, eventually getting trapped in small vessels.
• The Spleen: Frequently called the "red blood cell graveyard."
• Salvage and Recycling:   - Macrophages in the spleen, liver, and bone marrow engulf and destroy dying RBCs.   - Globin: Broken down into amino acids, which are recycled for reuse.   - Iron: Salvaged from the heme and stored or reused.   - Heme Pigment: Degraded into bilirubin (a yellow pigment). The liver secretes bilirubin into the intestines via bile. Bacteria in the gut metabolize it into stercobilin, a brown pigment that gives feces its color.

Erythrocyte Disorders: Anemia

• Definition: Anemia is a condition where blood has an abnormally low oxygen-carrying capacity. It is a sign of a primary problem rather than a disease itself.
• Symptoms: Fatigue, paleness, shortness of breath, and feeling cold.
• Hemorrhagic Anemia: Caused by blood loss.   - Acute: Rapid blood loss (e.g., trauma/stab wound).   - Chronic: Slight but persistent loss (e.g., bleeding ulcers, hemorrhoids).
• Low RBC Production Anemias:   - Iron Deficiency Anemia: Caused by low iron intake or impaired absorption. Results in microcytes (small, pale RBCs because they aren't filled with hemoglobin).   - Pernicious Anemia: An autoimmune disease where the stomach fails to produce intrinsic factor, which is required for the small intestine to absorb Vitamin $B_{12}$. Results in macrocytes (large RBCs because cells cannot divide properly).   - Renal Anemia: Caused by lack of EPO due to damaged kidneys (treated with synthetic EPO).   - Aplastic Anemia: Failure, inhibition, or destruction of the red bone marrow. Affects all formed elements including WBCs and platelets.
• Hemolytic Anemias: Premature rupture ($lysis$) of RBCs.   - Thalassemia: Genetic disorder (common in Mediterranean ancestry) where one of the globin chains is absent or faulty, making RBCs thin and delicate.   - Sickle Cell Anemia: Genetic disorder (common in African American ancestry) caused by a single amino acid error in the hemoglobin chain (Hemoglobin S). Under low oxygen, RBCs become crescent-shaped, causing them to rupture easily or block blood vessels.

Polycythemia and Blood Doping

• Polycythemia: An excess of red blood cells leading to high blood viscosity.   - Polycythemia Vera: A bone marrow cancer resulting in hematocrit levels as high as $80\%$.   - Secondary Polycythemia: A natural response to high altitude.
• Blood Doping: Artificially induced polycythemia used by endurance athletes to increase oxygen-carrying capacity.   - Transfusion Method: An athlete stores their own packed RBCs and reinjects them a day or two before a competition, after the body has naturally replaced the missing cells.   - Synthetic EPO/Drugs: Use of lab-made EPO or HIF stabilizers to trick the body into producing more RBCs.   - Risks: Increased blood thickness leads to decreased cardiac output, heart attack, stroke, and pulmonary embolism. Risk is compounded by dehydration during competition.

Leukocytes: White Blood Cell Characteristics and Behavior

• Count: Leukocytes make up less than $1\%$ of total blood volume, with a healthy range of $5,000$ to $11,000$ cells per microliter ($\mu L$).
• Leukocytosis: An elevated WBC count above $11,000$, which is a normal homeostatic response to infection.
• Cell Structure: Unlike RBCs, WBCs are "true" cells with a nucleus and organelles.
• Migration Patterns:   - Positive Chemotaxis: WBCs follow chemical signals ("homing signals" or chemotaxis factors) released by damaged tissues or pathogens.   - Margination and Pavementing: Cells move to the margins (walls) of the blood vessels.   - Diapedesis: Translates to "leap across"; the process of WBCs leaving the bloodstream through vessel walls.   - Emigration: Moving through tissue spaces using amoeboid motion (pseudopods).

Classification and Types of Leukocytes

• Mnemonic for Abundance: "Never Let Monkeys Eat Bananas" (Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils).
• Granulocytes: Contain visible cytoplasmic granules that store chemicals.   - Neutrophils ($50-70\%$): The most abundant WBC and the primary "bacteria slayers." They have a multi-lobed nucleus ($3$ to $6$ lobes). Granules take up both acidic and basic stains, appearing lilac/pink. They contain defensins and hydrolytic enzymes.   - Eosinophils ($2-4\%$).   - Basophils ($0.5-1\%$).
• Agranulocytes: Lack visible cytoplasmic granules.   - Lymphocytes ($25-45\%$): The second most abundant; smallest WBC.   - Monocytes ($3-8\%$): The largest WBC.

Questions & Discussion

• Question: "Does anyone know what the chemical is that's going to bind to those receptors (on the proerythroblast)?"
• Answer: It is a hormone called EPO (erythropoietin), which forces the red blood cell pathway.
• Question: "What do ribosomes do in a cell?"
• Answer: They make proteins.
• Question: "Do you want too few red blood cells in your bloodstream?"
• Answer: No, that would lead to tissue hypoxia.
• Question: "When we use the words acute and chronic, what does that refer to?"
• Answer: Acute means rapid/short-term; chronic means gradual/long-lasting.