PHM 212 Lecture: Red Blood Cell & Hematopoiesis PDF

**PHM 212 LECTURE:** **Red blood cell (Erythrocytes): Structure and function** Red blood cells or RBCs are also called erythrocytes. They serve as the functional components in blood which is responsible for the transportation of gases and nutrients across the entirety of the human body. - - -...

**PHM 212 LECTURE:** **Red blood cell (Erythrocytes): Structure and function** Red blood cells or RBCs are also called erythrocytes. They serve as the functional components in blood which is responsible for the transportation of gases and nutrients across the entirety of the human body. - - - - - **Structure of Red Blood Cells (RBCs)** - - - - The structure of RBCs can be described as follows: 1. Deformability, allowing it to squeeze through narrow capillaries without disrupting its cell membrane. Enhances diffusion of gases into out of the cell by virtue of a greater surface area. Reduces wall tension as the cells swell after taking up carbon dioxide from the tissue. 2. 3. 4. **Formation of hemoglobin** - - - - - **The life cycle of erythrocytes comprises three phases:** 1. 2. 3. ### **1. Production** - - ### **2. Maturation** The maturation process involves several morphological changes to produce highly functional specialized cells. This process includes the expulsion of the nucleus and the loss of organelles, such as the smooth and rough endoplasmic reticulum, Golgi apparatus, and ribosomes, leading to the formation of mature biconcave RBCs. ### **3. Destruction** Mature RBCs have a lifespan of about 120 days. At the end of their lifespan, they are removed from circulation and destroyed, primarily by macrophages in the spleen and liver. **Functions of Red Blood Cells (RBCs)** - - - - - **HEMATOPOIESIS** Hematopoiesis is a continuous, regulated process of blood cell production that includes cell renewal, proliferation, differentiation, and maturation. These processes result in the formation, development, and specialization of all the functional blood cells. **The primary locations of hematopoiesis change throughout life**. During [fetal development], [hematopoiesis] progresses through the mesoblastic, hepatic, and medullary phases. Organs that function at some point in hematopoiesis include the liver, spleen, lymph nodes, thymus, and bone marrow. The bone marrow is the primary site of hematopoiesis at birth and throughout life. In certain situations, blood cell production may occur outside the bone marrow; such production is termed *extramedullary.* **Hematopoiesis** is the process that leads to the regulated formation of the highly specialized circulating blood cells from **[pluripotent hematopoietic stem cells (HSCs) in the bone marrow.]** The HSCs are the most primitive blood cells, and they have the ability for both self-renewal and pluripotency. - *The HSCs are derived from uncommitted, totipotent stem cells that can be stimulated to form any cell in the body. Adults have a few of these, but they are more readily obtained from the blastocysts of embryos.* The HSCs differentiate to more mature "committed" cells including the ***[common lymphoid progenitor (CLP)]*** and the ***common myeloid progenitor** (CMP).* - The CLP population produces dendritic cells and mature T or B lymphocytes. - CMP cells differentiate into **megakaryocyte--erythroid progenitors** (**MEP**), **granulocyte--macrophage progenitors** (**GMP**), mature mast cells, eosinophils and basophils. - The MEP cells eventually differentiate into functional red blood cells and platelets. - The GMPs give rise to either neutrophils or monocytes. - Differentiation toward monocytes is induced synergistically by interleukin (IL)-3, granulocyte colony-stimulating factor (G-CSF), and granulocyte macrophage colony-stimulating factor (GM-CSF). **Figure showing the Development of various formed elements of the blood from bone marrow cells** ***Kindly note that the use of CFU (colony forming units) in some text books is similar to the use of progenitors or precursors*** **Erythropoesis -- formation of Matured RBC** **„ SITE OF ERYTHROPOIESIS „** **IN FETAL LIFE** In fetal life, the erythropoiesis occurs in three stages: 1\. Mesoblastic Stage During the first two months of intrauterine life, the RBCs are produced from mesenchyme of yolk sac. 2\. Hepatic Stage From third month of intrauterine life, liver is the main organ that produces RBCs. Spleen and lymphoid organs are also involved in erythropoiesis. 3\. Myeloid Stage During the last three months of intrauterine life, the RBCs are produced from red bone marrow and liver **IN NEWBORN BABIES, CHILDREN AND ADULTS** In newborn babies, growing children and adults, RBCs are produced only from the red bone marrow. 1\. Up to the age of 20 years: RBCs are produced from red bone marrow of all bones (long bones and all the flat bones). 2\. After the age of 20 years: RBCs are produced from membranous bones like vertebra, sternum, ribs, scapula, iliac bones and skull bones and from the ends of long bones. After 20 years of age, the shaft of the long bones becomes yellow bone marrow because of fat deposition and looses the erythropoietic function. In adults, liver and spleen may produce the blood cells if the bone marrow is destroyed or fibrosed. Collectively bone marrow is almost equal to liver in size and weight. It is also as active as liver. Though bone marrow is the site of production of all blood cells, comparatively 75% of the bone marrow is involved in the production of leukocytes and only 25% is involved in the production of erythrocytes, Cells of CFU-E(GM-CSF) pass through different stages and finally become the matured RBCs. During these stages four important changes are noticed. 1. Reduction in size of the cell (from the diameter of 25 to 7.2 µ) 2\. Disappearance of nucleoli and nucleus 3\. Appearance of hemoglobin 4\. Change in the staining properties of the cytoplasm. **„ STAGES OF ERYTHROPOIESIS** **1Proerythroblast:** High nuclear to cytoplasmic ratio, immature nuclear chromatin,1-2 nucleoli, basophilic cytoplasm\ **2Basophilic erythroblast (Early** normoblast**):** High nuclear to cytoplasmic ratio, Chromatin condenses, no nucleoli, basophilic cytoplasm\ **3Polychromatophilic erythroblast(Intermediate** normoblast**):** Round nucleus with mature (clumped chromatin),no nucleoli, Cytoplasm is grayish in colour due to hemoglobin synthesis occurring at this stage.\ Cell division ceases at this stage\ **4Orthochromic erythroblast(late** normoblast**) :** Densly pyknotic nucleus with well hemoglobinized cytoplasm (reddish).\ **5Reticulocyte:** late erythroblasts extrude nuclei to become reticulocyte. Intermediate position between nucleated RBCs and mature red blood cells. Has bluish tinge due to RNAs **6. Matured RBC**  FACTORS NECESSARY FOR ERYTHROPOIESIS Development and maturation of erythrocytes require varie - ty of factors, which are classified into three categories: 1\. General factors 2. Maturation factors 3. Factors necessary for hemoglobin formation. GENERAL FACTORS General factors necessary for erythropoiesis are: i\. Erythropoietin ii. Thyroxine iii. Hemopoietic growth factors iv. Vitamins. i\. Erythropoietin Most important general factor for erythropoiesis is the hormone called erythropoietin. It is also called hemopoietin or erythrocyte stimulating factor. **Chemistry** Erythropoietin is a glycoprotein with 165 amino acids. Source of secretion Major quantity of erythropoietin is secreted by peritubular capillaries of kidney. A small quantity is also secreted from liver and brain. Stimulant for secretion Hypoxia is the stimulant for the secretion of erythropoietin. Actions of erythropoietin Erythropoietin causes formation and release of new RBCs into circulation. After secretion, it takes 4 to 5 days to show the action. Erythropoietin promotes the following processes: a. Production of proerythroblasts from CFU-E of the bone marrow b\. Development of proerythroblasts into matured RBCs through the several stages -- early normoblast, intermediate normoblast, late normoblast and reticulocyte c\. Release of matured erythrocytes into blood. Even some reticulocytes (immature erythrocytes) are released along with matured RBCs. Blood level of erythropoietin increases in anemia ii\. **Thyroxine** Being a general metabolic hormone, thyroxine accelerates the process of erythropoiesis at many levels. So, hyperthyroidism and polycythemia are common. iii\. **Hemopoietic Growth Factors** Hemopoietic growth factors or growth inducers are the interleukins and stem cell factor (steel factor). Generally these factors induce the proliferation of PHSCs. Interleukins (IL) are glycoproteins, which belong to the cytokines family. Interleukins involved in erythropoiesis: a. Interleukin-3 (IL-3) secreted by T-cells b. Interleukin-6 (IL-6) secreted by T-cells, endothelial cells and macrophages c. Interleukin-11 (IL-11) secreted by osteoblast. **iv. Vitamins** Some vitamins are also necessary for the process of erythropoiesis. Deficiency of these vitamins cause anemia associated with other disorders. Vitamins necessary for erythropoiesis: a\. Vitamin B: Its deficiency causes anemia and pellagra (disease characterized by skin lesions, diarrhea, weakness, nervousness and dementia). b\. Vitamin C: Its deficiency causes anemia and scurvy (ancient disease characterized by impaired collagen synthesis resulting in rough skin, bleeding gum, loosening of teeth, poor wound healing, bone pain, lethargy and emotional changes). c\. Vitamin D: Its deficiency causes anemia and rickets. d\. Vitamin E: Its deficiency leads to anemia and malnutrition „ **MATURATION FACTORS** Vitamin B12, intrinsic factor and folic acid are necessary for the maturation of RBCs. 1\. **Vitamin B12 (Cyanocobalamin)** Vitamin B12 is the maturation factor necessary for erythropoiesis. Source Vitamin B12 is called extrinsic factor since it is obtained mostly from diet. Its absorption from intestine requires the presence of intrinsic factor of Castle. Vitamin B12 is stored mostly in liver and in small quantity in muscle. When necessary, it is transported to the bone marrow to promote maturation of RBCs. It is also produced in the large intestine by the intestinal flora. Action ***[Vitamin B12 is essential for synthesis of DNA in RBCs.]*** Its deficiency leads to failure in maturation of the cell and reduction in the cell division. Also, the cells are larger with fragile and weak cell membrane resulting in macrocytic anemia. Deficiency of vitamin B12 causes pernicious anemia. So, vitamin B12 is called antipernicious factor. **2. Intrinsic Factor of Castle** Intrinsic factor of castle is produced in gastric mucosa by the parietal cells of the gastric glands. It is essential for the absorption of vitamin B12 from intestine. In the absence of intrinsic factor, vitamin B12 is not absorbed from intestine. This leads to pernicious anemia. Deficiency of intrinsic factor occurs in: i. Severe gastritis ii. Ulcer iii. Gastrectomy. **3. Folic Acid** Folic acid is also essential for maturation. It is required for the synthesis of DNA. In the absence of folic acid, the synthesis of DNA decreases causing failure of maturation. This leads to anemia in which the cells are larger and appear in megaloblastic (proerythroblastic) stage. And, anemia due to folic acid deficiency is called megaloblastic anemia. **FACTORS NECESSARY FOR HEMOGLOBIN FORMATION** Various materials are essential for the formation of hemoglobin in the RBCs. Deficiency of these substances decreases the production of hemoglobin leading to anemia. Such factors are: 1\. ***First class proteins and amino acids:*** Proteins of high biological value are essential for the formation of hemoglobin. Amino acids derived from these proteins are required for the synthesis of protein part of hemoglobin, i.e**. the globin.** 2\. ***Iron***: Necessary for the formation of heme part of the hemoglobin. 3\. ***Copper***: Necessary for the absorption of iron from the gastrointestinal tract. 4\. ***Cobalt and nickel***: These metals are essential for the utilization of iron during hemoglobin formation. 5. Vitamins: Vitamin C, riboflavin, nicotinic acid and pyridoxine are also essential for the formation of hemoglobin. **The Lymphatic System** The lymphatic system consists of a fluid (lymph), vessels that transport the lymph, and organs that contain lymphoid tissue. **Lymph** Lymph is a fluid similar in composition to blood plasma. It is derived from blood plasma as fluids pass through capillary walls at the arterial end. As the interstitial fluid begins to accumulate, it is picked up and removed by tiny lymphatic vessels and returned to the blood. As soon as the interstitial fluid enters the lymph capillaries, it is called lymph. Returning the fluid to the blood prevents edema and helps to maintain normal blood volume and pressure. „ **FORMATION OF LYMPH** Lymph is formed from interstitial fluid, due to the permeability of lymph capillaries. When blood passes via blood capillaries in the tissues, 9/10th of fluid passes into venous end of capillaries from the arterial end. And, the remaining 1/10th of the fluid passes into lymph capillaries, which have more permeability than blood capillaries. So, when lymph passes through lymph capillaries, the composition of lymph is more or less similar to that of interstitial fluid including protein content. Proteins present in the interstitial fluid cannot enter the blood capillaries because of their larger size. So, these proteins enter lymph vessels, which are permeable to large particles also. - **Addition of Proteins and Fats** Tissue fluid in liver and gastrointestinal tract contains more protein and lipid substances. So, proteins and lipids enter the lymph vessels of liver and gastrointestinal tract in large quantities. Thus, lymph in larger vessels has more proteins and lipids. Concentration of Lymph When the lymph passes through the lymph nodes, it is concentrated because of absorption of water and the electrolytes. However, the proteins and lipids are not absorbed. About 120 mL of lymph flows into blood per hour. Out of this, about 100 mL/hour flows through thoracic duct and 20 mL/ hour flows through the right lymphatic duct. **Factors Increasing the Flow of Lymph** Flow of lymph is promoted by the increase in: 1\. Interstitial fluid pressure. 2. Blood capillary pressure. 3. Surface area of lymph capillary by means of dilatation. 4. Permeability of lymph capillaries. 5. Functional activities of tissues. **FUNCTIONS OF LYMPH** 1\. Important function of lymph is to return the proteins from tissue spaces into blood. 2\. It is responsible for redistribution of fluid in the body. 3\. Bacteria, toxins and other foreign bodies are removed from tissues via lymph. 4\. Lymph flow is responsible for the maintenance of structural and functional integrity of tissue. Obstruction to lymph flow affects various tissues, particularly myocardium, nephrons and hepatic cells. 5\. Lymph flow serves as an important route for intestinal fat absorption. This is why lymph appears milky after a fatty meal. 6\. It plays an important role in immunity by transport of lymphocytes. Lymphatic Vessels Lymphatic vessels, unlike blood vessels, only carry fluid away from the tissues. The smallest lymphatic vessels are the lymph capillaries, which begin in the tissue spaces as blind-ended sacs. Lymph capillaries are found in all regions of the body except the bone marrow, central nervous system, and tissues, such as the [epidermis](https://api.seer.cancer.gov/rest/glossary/latest/id/546e03ece4b0d965832afe5c), that lack blood vessels. The wall of the lymph capillary is composed of endothelium in which the simple squamous cells overlap to form a simple one-way valve. This arrangement permits fluid to enter the capillary but prevents lymph from leaving the vessel.  The microscopic lymph capillaries merge to form lymphatic vessels. Small lymphatic vessels join to form larger tributaries, called lymphatic trunks, which drain large regions. Lymphatic trunks merge until the lymph enters the two lymphatic ducts. The right lymphatic duct drains lymph from the upper right quadrant of the body. The thoracic duct drains all the rest. ***What moves lymph in the absence of a pump structure like the heart? Like veins, the lymphatic tributaries have thin walls and have valves to prevent backflow of blood. There is no pump in the lymphatic system like the [heart](https://api.seer.cancer.gov/rest/glossary/latest/id/5502b492e4b0c48f31d64b2b) in the cardiovascular system. The pressure gradients to move lymph through the vessels come from the [skeletal muscle](https://api.seer.cancer.gov/rest/glossary/latest/id/5505629de4b0c48f31d6efd7) action, [respiratory](https://api.seer.cancer.gov/rest/glossary/latest/id/55337cb2e4b0e16303c9062c) movement, and contraction of smooth muscle in vessel walls***. Lymphatic Organs Lymphatic organs ***[are characterized by clusters of lymphocytes and other cells, such as macrophages, enmeshed in a framework of short, branching connective tissue fibers.]*** The lymphocytes originate in the red bone marrow with other types of blood cells and are carried in the blood from the bone marrow to the lymphatic organs. *[When the body is exposed to microorganisms and other foreign substances, the lymphocytes proliferate within the lymphatic organs and are sent in the blood to the site of the invasion.]* This is part of the immune response that attempts to destroy the invading agent. The lymphatic organs include: - Lymph Nodes - Tonsils - Spleen - Thymus Lymph Nodes =========== Lymph nodes are small bean-shaped structures that are usually less than 2.5 cm in length. They are widely distributed throughout the body along the lymphatic pathways where they filter the lymph before it is returned to the blood. Lymph nodes are not present in the central nervous system. There are three superficial regions on each side of the body where lymph nodes tend to cluster. These areas are the inguinal nodes in the groin, the axillary nodes in the armpit, and the cervical nodes in the neck. The typical lymph node is surrounded by a connective tissue [capsule](https://api.seer.cancer.gov/rest/glossary/latest/id/5522bcd7e4b0bc5c16c0437c) and divided into compartments called lymph nodules. The lymph nodules are dense masses of lymphocytes and macrophages and are separated by spaces called lymph sinuses. The afferent lymphatics enter the node at different parts of its periphery, which carry lymph into the node; entering the node on the convex side. The lymph moves through the lymph sinuses and enters an efferent lymphatic vessel, which, located at an indented region called the hilum, carries the lymph away from the node. Illustration of the structure of a lymph node Clinical correlate -- Swelling of Lymph Nodes ============================================= During infection or any other processes in a particular region of the body, activities of the lymph nodes in that region increase. This causes swelling of the lymph nodes. Sometimes, the swollen lymph nodes cause pain. Most common cause of swollen lymph nodes is infection. Lymph nodes situated near an infected area swell immediately. When the body recovers from infection, the lymph nodes restore their original size gradually, in one or two weeks. ================================================================================================================================================================================================================================================================================================================================================================================================================================================================== Causes for Lymph Node Swelling ============================== 1. Skin infection of arm causes swelling of lymph nodes in armpit. ================================================================== 2. Tonsillitis or throat infection causes swelling of lymph nodes in neck. ========================================================================== 3. Infection of genital organs or leg results in swelling of lymph nodes in groin. ================================================================================== 4. Viral infections such as glandular fever which affect the whole body cause swelling of lymph nodes in various parts of the body. =================================================================================================================================== 5. Cancer in a particular region may spread into the nearby lymph nodes causing the swelling. Examples: ======================================================================================================= i. Throat cancer may spread into lymph nodes in neck. ===================================================== ii. Lung cancer may spread into lymph nodes in chest. ===================================================== iii. Breast cancer may spread into lymph nodes in armpit. ========================================================= iv. Intestinal cancer may spread into lymph nodes in abdomen. ============================================================= v.. Lymphomas (cancer of lymphatic system) and leukemia cause swelling of lymph nodes in many parts of the body =============================================================================================================== Tonsils =======  Tonsils are clusters of lymphatic tissue just under the mucous membranes that line the nose, mouth, and throat (pharynx). There are three groups of tonsils. The pharyngeal tonsils are located near the opening of the nasal cavity into the pharynx. When these tonsils become enlarged they may interfere with breathing and are called adenoids. The palatine tonsils are the ones that are located near the opening of the oral cavity into the pharynx. Lingual tonsils are located on the posterior surface of the tongue, which also places them near the opening of the oral cavity into the pharynx. Lymphocytes and macrophages in the tonsils provide protection against harmful substances and pathogens that may enter the body through the nose or mouth. „ = Spleen ====== The spleen is located in the upper left abdominal cavity, just beneath the diaphragm, and posterior to the stomach. It is similar to a lymph node in shape and structure but it is much larger. The spleen is the largest lymphatic organ in the body. Surrounded by a connective tissue capsule, which extends inward to divide the organ into lobules, the spleen consists of two types of tissue called **[white pulp and red pulp]**. The white pulp is lymphatic tissue consisting mainly of lymphocytes around arteries. The red pulp consists of venous sinuses filled with blood and cords of lymphatic cells, such as lymphocytes and macrophages. Blood enters the spleen through the splenic artery, moves through the sinuses where it is filtered, then leaves through the splenic vein. The spleen filters blood in much the way that the lymph nodes filter lymph. Lymphocytes in the spleen react to pathogens in the blood and attempt to destroy them. Macrophages then engulf the resulting debris, the damaged cells, and the other large particles. The spleen, along with the liver, removes old and damaged erythrocytes from the circulating blood. Like other lymphatic tissue, it produces lymphocytes, especially in response to invading pathogens. The sinuses in the spleen are a reservoir for blood. In emergencies such as hemorrhage, smooth muscle in the vessel walls and in the capsule of the spleen contracts. This squeezes the blood out of the spleen into the general circulation. Thymus ====== Illustration of the thymus and its location in the human body The thymus is a soft organ with two lobes that is located anterior to the ascending aorta and posterior to the sternum. It is relatively large in infants and children but after puberty it begins to decrease in size so that in older adults it is quite small. The primary function of the thymus is the processing and maturation of special lymphocytes called T-lymphocytes or T-cells. While in the thymus, the lymphocytes do not respond to pathogens and foreign agents. After the lymphocytes have matured, they enter the blood and go to other lymphatic organs where they help provide defense against disease. The thymus also produces a hormone, thymosin, which stimulates the maturation of lymphocytes in other lymphatic organs.