Blood PDF

# Blood ## Physical characteristics of * Fluid connect sue composed of: * Liquid extracellular matrix - "plasma" with dissolved cells & cell fragments - "formed elements". * Interstitial fluid - Fluid that bathes the body cells. | Feature | Value | |---|---| | PH | 7.35-7.45 | | Temperature | 38°C | | Body weight | 8% | | Volume | 5-6 liters (1.2 gal.) | * Blood plasma (55%): * Contains: * Water (91.5%) * Proteins (7%) * Albumin, immunoglobulins, fibrinogen, complement factors, clotting factors * Transport proteins (e.g. transferrin, ceruloplasmin) * Other solutes (1.5%) * Ions (potassium, sodium, chloride.), enzymes, hormones, vitamins * Waste products, e.g. urea, inactivated toxins. ## Functions of Blood 1. **Transportation:** * Oxygen and carbon dioxide transport to and from the tissues. * Transport of food molecules and hormones (bound or unbound) * Transport of body heat and metabolic wastes away from the cells and tissues. 2. **Regulation:** * Dissolved carbonate and proteins, e.g. albumin, helps to buffer and regulate the pH of the body fluids. * Variable flow rate helps to adjust body temperature and supply of nutrients to the cells. * Of osmotic pressure of cells and tissues. 3. **Protection:** * Contains the components, i.e. coagulation factors, of the blood coagulation system. * Contains the components, i.e. complement factors, of the blood complement system. * Carries major non-cell and cell components of the body's immune system e.g. antibodies, white blood cells, monocytes, T-cells, B-cells, NK cells. ## Composition of Blood * 55% Plasma – liquid component of blood. * 45% Formed elements – cells/cellular fragments * Erythrocytes – red blood cells (RBCs) * Leukocytes – white blood cells (WBCs) * Platelets - (thrombocytes) ## Plasma ### Components of plasma **Plasma Proteins** | Protein | Function | |---|---| | Albumins (60%)| Major contributors to osmotic pressure of plasma; transport lipids, steroid hormones | | Globulins (35%)| Transport ions, hormones, lipids; immune function | | Fibrinogen (4%) | Essential component of clotting system; can be converted to insoluble fibrin | | Regulatory proteins (<1%) | Enzymes, proenzymes, hormones | **Other Solutes** | Solute | Function | |---|---| | Electrolytes | Normal extracellular fluid ion composition essential for vital cellular activities. Examples Na+, K+, Ca2+, CI-, HCO3 | | Organic nutrients | Used for ATP production, growth, and maintenance of cells. Examples: Fatty acids, glucose, amino acids | | Organic wastes | Carried to sites of breakdown or excretion. Examples: Urea, bilirubin | ## Formed Elements | Element | Function | |---|---| | Platelets (0.1%) | | | White blood cells (99.9%) | | | Red blood cells | | **Sample of Whole Blood** The formed elements of blood consist of: * Red blood cells * White blood cells * Granular: * Neutrophils (50-70%) * Eosinophils (2-4%) * Basophils (<1%) * Agranular: * Lymphocytes (20-30%) * Monocytes (2-8%) * Platelets ## Erythrocytes (RBCs) * Biconcave shape, flexible cells * Around 5 million RBCs per mm3 blood * Average "life span" of 120 days * Cells contains cytosol, no nucleus/organelles; filled with Hemoglobin (Hb) * Red blood cells - highly specialized for oxygen transport function. Mature RBCs have no nucleus, all their internal space is available for oxygen transport. * RBCs lack mitochondria and generate ATP anaerobically so they do not use up any of the oxygen they transport. * Shape of an RBC facilitates its function- biconcave disc has a much greater surface area for the diffusion of gas molecules. * Each RBC contains about 280 million hemoglobin molecules. ## Hemoglobin * A hemoglobin molecule consists of a protein called globin, composed of four polypeptide chains (two alpha and two beta chains); a ringlike nonprotein pigment called a heme is bound to each of the four chains. * At the center of each heme ring is an iron ion (Fe+2) that can combine reversibly with 1 O2 molecule, allowing each Hb molecule to bind 4 O2 molecules. * Each oxygen molecule picked up from the lungs is bound to an Fe+2. As blood flows through capillaries, tissthe reaction reverses. Hemoglobin releases oxygen, which diffuses first into the interstitial fluid and then into cells. * Hemoglobin also transports about 23% of the total carbon dioxide, a waste product of metabolism. Blood flowing through tissue capillaries picks up carbon dioxide, some of which combines with amino acids in the globin part of hemoglobin. As blood flows through the lungs, the carbon dioxide is released from hemoglobin and then exhaled. * In addition to its key role in transporting oxygen and carbon dioxide, hemoglobin also plays a role in the regulation of blood flow and blood pressure. The gaseous hormone nitric oxide (NO), produced by the endothelial cells that line blood vessels, binds to hemoglobin. Under some circumstances, hemoglobin releases NO. The released NO causes vasodilation, an increase in blood vessel diameter that occurs when the smooth muscle in the vessel wall relaxes. Vasodilation improves blood flow and enhances oxygen delivery to cells near the site of NO release. * As RBCs get damaged/worn out, they must be removed from circulation & replaced. * About 1% of the circulating RBCs are replaced each day, at a rate of about 3 million RBCs per second. * Worn out RBCs are removed by phagocytic cells in the liver, spleen & bone marrow ## RBC Life Cycle 1. Macrophages in the spleen, liver, or red bone marrow phagocytize ruptured and worn-out red blood cells. 2. The globin and heme portions of hemoglobin are split apart. 3. Globin is broken down into amino acids, which can be reused to synthesize other proteins 4. Iron is removed from the heme portion in the form of Fe+3, which associates with the plasma protein transferrin (trans-FER-in; trans- = across; ferr- = iron), a transporter for Fe+3 in the bloodstream.. 5. In muscle fibers, liver cells, and macrophages of the spleen and liver, Fe+3 detaches from transferrin and attaches to an iron-storage protein called ferritin. 6. Upon release from a storage site or absorption from the gastrointestinal tract, Fe+3 reattaches to transferrin. 7. The Fe+3-transferrin complex is then carried to red bone marrow, where RBC precursor cells take it up through receptor-mediated endocytosis for use in hemoglobin synthesis. Iron is needed for the heme portion of the hemoglobin molecule, and amino acids are needed for the globin portion. Vitamin B12 is also needed for the synthesis of hemoglobin. 8. Erythropoiesis in red bone marrow results in the production of red blood cells, which enter the circulation. 9. When iron is removed from heme, the non-iron portion of heme is converted to biliverdin (bil'-i-VER-din), a green pigment, and then into bilirubin (bil'-i-ROO-bin), a yellow-orange pigment. 10. Bilirubin enters the blood and is transported to the liver. 11. Within the liver, bilirubin is released by liver cells into bile, which passes into the small intestine and then into the large intestine. 12. In the large intestine, bacteria convert bilirubin into uro-bilinogen (ur-o-bi-LIN-ō-jen). 13. Some urobilinogen is absorbed back into the blood-converted to a yellow pigment called urobilin (ur-6-BI-lin), and excreted in urine. 14. Most urobilinogen is eliminated in feces in the form of a brown pigment called stercobilin (ster'-ko-BI-lin), which gives feces its characteristic color. ## Hemoglobin Recycling The process of recycling Red Blood Cells: * **Macrophage** - Ruptured red blood cells are broken down by macrophages. * **Globin** - The globin protein is broken down into amino acids. * **Heme** - the heme group is split. * **Iron** - Iron is bound to transferrin and transported via circulation. * **Biliverdin** - The remaining heme is converted to biliverdin and bilirubin. * **Liver** - Stored iron is used to create new hemoglobin. Bilirubin is released into the bloodstream. * **Small Intestine** -Bilirubin travels from the liver to the small intestine. * **Large intestine** - Bacteria convert bilirubin to urobilinogen, which is then converted to stercobilin for excretion in feces. * **Kidney** - Some urobilinogen can be absorbed into the bloodstream and excreted in urine. New red blood cells are released back into the circulation. ## Haematopoiesis Hematopoiesis is the formation of blood cells. Pluripotent stem cells in red bone marrow produce two further types of stem cells, which have the capacity to develop into several types of cells. These stem cells are called myeloid stem cells and lymphoid stem cells. **Myeloid stem cells** begin their development in red bone marrow and give rise to red blood cells, platelets, monocytes, neutrophils, eosinophils, and basophils. **Lymphoid stem cells** begin their development in red bone marrow but complete it in lymphatic tissues; they give rise to lymphocytes. ## Hematopoiesis During hemopoiesis, some of the myeloid stem cells differentiate into progenitor cells. Other myeloid stem cells and the lymphoid stem cells develop directly into precursor cells. Progenitor cells are no longer capable of reproducing themselves and are committed to giving rise to more specific elements of blood. Some progenitor cells are known as colony-forming units (CFUs). Following the CFU designation is an abbreviation that indicates the mature elements in blood that they will produce: * **CFU-E** ultimately produces erythrocytes (red blood cells) * **CFU-Meg** produces megakaryocytes, the source of platelets, and * **CFU-GM** ultimately produces granulocytes (specifically, neutrophils) and monocytes. In the next generation, the cells are called precursor cells, also known as blasts. Over several cell divisions they develop into the actual formed elements of blood. For example, monoblasts develop into monocytes, eosinophilic myeloblasts develop into eosinophils, and so on. Several hormones called hemopoietic growth factors regulate the differentiation and proliferation of particular progenitor cells. * **Erythropoietin or EPO** increases the number of red blood cell precursors. EPO is produced primarily by cells in the kidneys that lie between the kidney tubules (peritubular interstitial cells). With renal failure, EPO release slows and RBC production is inadequate. * **Thrombopoietin or TPO** is a hormone produced by the liver that stimulates the formation of platelets (thrombocytes) from megakaryocytes. * **Several different cytokines** regulate development of different blood cell types. Cytokines are small glycoproteins that are typically produced by cells such as red bone marrow cells, leukocytes, macrophages, fibroblasts, and endothelial cells. They generally act as local hormones. Cytokines stimulate proliferation of progenitor cells in red bone marrow and regulate the activities of cells involved in nonspecific defenses (such as phagocytes) and immune responses (such as B cells and T cells). * **Two important families of cytokines** that stimulate white blood cell formation are colony-stimulating factors (CSFs) and interleukins. ## Erythropoiesis During erythropoiesis, immature red blood cells go through several developmental stages: 1. **Proerythroblast** – immature red blood cells with a high nuclear-to-cytoplasmic ratio. 2. **Basophilic erythroblast** – a smaller cell with a more condensed nucleus. 3. **Polychromatophilic erythroblast** – cytoplasm is grayish due to synthesis of hemoglobin. 4. **Orthochromic erythroblast** - cytoplasm is reddish. 5. **Reticulocyte** – the nucleus is extruded. 6. **Mature Red Blood cell** – The cell no longer has a nucleus. ## Regulation of erythropoiesis Lower oxygen content of air at high altitudes, anemia, and circulatory problems may reduce oxygen delivery to body tissues. *The main stimulus for erythropoiesis is hypoxia, a decrease in the oxygen-carrying capacity of the blood.* 1. **Receptors** - Kidney cells that secrete erythropoietin detect low oxygen levels. 2. **Control center** - Erythroblasts in red bone marrow mature more quickly into reticulocytes. Reticulocytes enter the blood stream. 3. **Effectors** - More reticulocytes enter the bloodstream. This increases the number of red blood cells in circulation leading to increased oxygen delivery to tissues, restoring normal oxygen levels in the blood. ## Erythropoiesis This illustration shows multiple steps involved in the production of red blood cells (erythropoiesis): * The **formation of RBCs** begins with a *Proerythroblast* from a bone marrow stem cell. * **Increased mitotic rate** – proerythroblasts divide rapidly. * **Accelerated maturation** – The proerythroblasts become **erythroblasts** and then **reticulocytes**. * **Reticulocyte** becomes biconcave shaped. * **RBC maturation** – the reticulocyte matures and enters the bloodstream. * **Release of erythropoietin (EPO)** - The **kidney hormone erythropoietin (EPO)** triggers the production of red blood cells. This hormone is secreted in response to low oxygen levels in the blood. * **Tissue oxygen levels decline** – the kidneys sense low oxygen levels in the bloodstream. * **Tissuer oxygen levels rise** – EPO enters the bloodstream and stimulates the bone marrow to produce red blood cells. * **Increased numbers of circulating RBCs** - The increased number of red blood cells improves the oxygen-carrying capacity of the blood; correcting the initial low oxygen levels, restoring normal oxygen levels in the blood. # Blood Typing The surfaces of erythrocytes contain a genetically determined assortment of antigens composed of glycoproteins and glycolipids. These antigens, called agglutinogens occur in characteristic combinations. ## ABO Blood Typing * Based on the presence or absence of various antigens, blood is categorized into different blood groups. Within a given blood group, there may be two or more different blood types. * There are at least 24 blood groups and more than 100 antigens that can be detected on the surface of red blood cells. Here we discuss two major blood groups - ABO and Rh. Other blood groups include the Lewis, Kell, Kidd, and Duffy systems. * The ABO blood group is based on two glycolipid antigens called A and B. * People whose RBCs display only antigen A are type A blood. * People who only have antigen B are type B. * Individuals who have both A and B antigens are type AB. * Those who have neither antigen A nor B are type O. * Blood plasma usually contains antibodies called agglutinins that react with the A or B antigens if the two are mixed. * Anti-A antibody, which reacts with antigen A, * Anti-B antibody, which reacts with antigen B. * You do not have antibodies that react with the antigens of your own RBCs, but you do have antibodies for any antigens that your RBCs lack. * People with type AB blood do not have anti-A or anti-B antibodies in their blood plasma. They are sometimes called **universal recipients** because theoretically they can receive blood from donors of all four blood types. * People with type O blood have neither A nor B antigens on their RBCs and are sometimes called **universal donors** because theoretically they can donate blood to all four ABO blood types. ## Rh Blood Typing * The Rh blood group is so named because the antigen was discovered in the blood of the Rhesus monkey. * People whose RBCs have Rh antigens are designated Rh+ (Rh positive); those who lack Rh antigens are designated Rh-(Rh negative). * Normally, blood plasma does not contain anti-Rh antibodies. If an Rh person receives Rh+ blood transfusion, however, the immune system starts to make anti-Rh antibodies that will remain in the blood. If a second transfusion of Rh+ blood is given later, the previously formed anti-Rh antibodies will cause agglutination and hemolysis of the RBCs in the donated blood, and a severe reaction may occur. ## Summary of Blood Typing * **Type A** blood has **A antigens** on the red blood cells and **anti-B antibodies** in the plasma. * **Type B** blood has **B antigens** on the red blood cells and **anti-A antibodies** in the plasma. * **Type AB** blood has **both A and B antigens** on the red blood cells and **neither anti-A or anti-B antibodies** in the plasma. * **Type O** blood has **neither A or B antigens** on the red blood cells and **both anti-A and anti-B antibodies** in the plasma. * **Rh-positive** people have the **Rh factor** on their red blood cells, while **Rh-negative** people do not. **When you combine the information from the AB & Rh antigens, the possible blood types will be:** * A+/A- * B+/B- * AB+/AB- * O+/O- ## Leukocytes (WBCs) * More like "typical cells" with single nucleus, organelles. * 5 types of WBCs characterized as granular or agranular. * Granular - Neutrophils, Eosinophils & Basophils * Agranular - Lymphocytes & Monocytes * All function in defense * Average 6000-9000 WBCs/mm3 of blood (total WBC count) * Variable "life" span depending on type of WBC- days (neutrophils) to decades (lymphocytes); in sick person, some WBCs live minutes to hours ## Leukocytes (WBCs) * WBCs exhibit common characteristics: * Amoeboid movement * Diapedesis * Positive chemotaxis ## Differential Count & Functions of WBCS * "WBC differential count” – normal range (in percentage) of WBCs in the peripheral circulation. * Differential count will vary during specific types of disorders, depending on which type of WBC responds. * During a period of infection, phagocytic WBCs may live only a few hours. WBCs are far less numerous than red blood cells; at about 5000-10,000 cells per L of blood, they are outnumbered by RBCs by about 700:1. * WBC response based on functions of specific type. ## Differential Count & Functions of WBCS * **Neutrophils - 50-70%** * Function in acute bacterial infections; phagocytic * **Lymphocytes – 20-30%** * Function in "immunity” – specific resistance to disease. * **Monocytes – 4-8%** * Function in chronic bacterial infections; migrate into tissues to become "wandering macrophages". * **Eosinophils – 2-4%** * Active against parasites & elevated in allergic reactions; destroy antibody-coated antigens by phagocytosis * **Basophils - <1%** * Release chemicals (histamine, heparin) during tissue ## Platelets (Thrombocytes) * Under the influence of hormone thrombopoietin, myeloid stem cells develop into megakaryocyte-colony-forming cells that in turn develop into precursor cells called megakaryoblasts. * Megakaryoblasts transform into megakaryocytes, huge cells that splinter into 2000 to 3000 fragments. Each fragment, enclosed by a piece of the plasma membrane, is a platelet (thrombocyte). * Platelets break off from the megakaryocytes in red bone marrow and then enter the blood circulation. * Between 150,000and 400,000 platelets are present in each L of blood. * Each is disc-shaped, 2–4 μm in diameter, and has many vesicles but no nucleus. * Platelets circulate for 9-12 days before being removed from circulation. * Platelets function in “hemostasis” – the processes that stop bleeding from damaged blood vessels. ## Hemostasis * Hemostasis is a sequence of body responses that stops (internal or external) bleeding when blood vessels have been injured, by trauma, infections, etc. * A successful hemostasis prevents hemorrhages ("bleedings") in the human body. ### Three Mechanisms of Hemostasis: 1. **Vascular spasm** * Shortly after injury or damage, the inner diameter of blood vessels in the injury site become more narrow due to a process called vasoconstriction. * Many phospholipid-derived molecules, called prostanoids, such as TXA2, play an important role in triggering this blood loss-preventing event. 2. **Platelet plug formation** * Injury of blood vessels caused by, e.g. by a traumatic event (thorn, scratch), invaded microbes, viruses or "shear stress", triggers a series of events, which are summarized as platelet plug formation. * Platelets make contact with the endothelial cells or exposed proteins of the extracellular matrix (ECM), e.g. collagen, fibronectin, at the injury site. * Platelets become activated and begin to release molecules such as thrombin, thromboxanes (TXA₂), histamines and others at the injury site, contributing to vasoconstriction. * Platelets become sticky and plug together in a process called platelet aggregation. 3. **Blood clotting (blood coagulation)** * Injury also triggers the activation of the blood coagulation cascade or reaction, which is a complex series of proteaseenzyme and coagulation factor (“clotting factors”) interactions. * At the end of the coagulation reaction the blood plasma protein fibrinogen has been converted into insoluble protein fiber-forming protein fibrin. * Fibrin plus aggregated platelets form a dense meshwork called a blood clot. * In the final stage the formed blood clot formed at the injury site seals off the damaged site and prevents further blood loss. * A blood clot is a gel-like structure that contains formed elements of the blood,mostly RBCs and platelets, entangled in a network of fibrin threads ... * Clot retraction and blood vessel repair by endothelial cell and fibroblasts-the fibrin threads attached to the damaged blood vessel site contracts and retracts slowly ### Steps of the Coagulation Cascade: 1. Platelet adhesion 2. Platelet release reactions 3. Platelet aggregation & clot formation ### Blood Coagulation * Blood clotting (blood coagulation) is a complex series of proteaseenzyme and coagulation factor ("clotting factors") interactions. * At the end of the coagulation reaction the blood plasma protein fibrinogen has been converted into insoluble protein fiber-forming protein fibrin. * Fibrin plus aggregated platelets form a dense meshwork called a blood clot. * In the final stage the formed blood clot formed at the injury site seals off the damaged site and prevents further blood loss. * A blood clot is a gel-like structure that contains formed elements of the blood,mostly RBCs and platelets, entangled in a network of fibrin threads ... * Clot retraction and blood vessel repair by endothelial cell and fibroblasts-the fibrin threads attached to the damaged blood vessel site contracts and retracts slowly ### Components of Blood Coagulation * **Clotting factors** are several substances known as clotting (coagulation) factors. These factors include calcium ions, several inactive enzymes that are synthesized by hepatocytes & released into the bloodstream, and various molecules associated with platelets or released by damaged tissues. * **Clotting factor activation** – Clotting is a complex cascade of enzymatic reactions in which each clotting factor activates many molecules of the next one in a fixed sequence. Finally, a large quantity of product (the insoluble protein fibrin) is formed. ### Blood Clotting Pathways: * **Extrinsic pathway** * Begins with damage to surrounding tissues & BV endothelium which cause the release of "tissue factors" * Eventually results in the formation of an enzyme ("Factor X activator") capable of activating Factor X * Shorter, quicker pathway for initiation of coagulation * **Intrinsic pathway** * Begins with the release of "platelet factors" * Eventually results in the formation of "Factor X activator" * More complicated, slower pathway of coagulation ### Common Pathway * The **common pathway** is initiated by either the extrinsic or intrinsic pathways. * Both the *intrinsic pathway* and the *extrinsic pathway* result in the activation of **Factor X (10)**. * **Activation of Factor X** begins the **common pathway**. * **All 3 pathways** require **the presence of Ca2+ & vitamin K**. ## Extrinsic Pathway * The extrinsic pathway begins with the release of *tissue factor*. * This pathway results in the activation of **Factor X**. ## Intrinsic Pathway * The intrinsic pathway begins with the release of *platelet factor*. * This pathway results in the activation of **Factor X**. ## Coagulation Cascade: * The extrinsic pathway and intrinsic pathway converge to activate **Factor X** by the production of **Factor X activator**. * This activation leads to the formation of **prothrombinase**. * **Prothrombinase** converts **prothrombin** (a clotting protein) into **thrombin** (an enzyme). * **Thrombin** converts **fibrinogen** (soluble protein) into **fibrin** (insoluble protein threads) that create the actual clot (a network of fibrin, platelets, and red blood cells). ## Clot Retraction, Repair & Removal * Once the clot has begun to form, the fibrin threads & trapped platelets cause the edges of the damaged vessel to pull together causing **clot retraction**. * Repair to the damaged vessel & surrounding tissues occur as fibroblasts invade the area & endothelial cells regenerate. * Eventually the clot gets removed by the enzyme “plasmin” in a process known as **fibrinolysis**. * A clot which remains present in an intact vessel is known as a **thrombus**. Thrombi can block blood flow & pieces can dislodge creating an **embolism**. ## Hematopoiesis * To form blood cells, pluripotent stem cells in red bone marrow produce 2 types of stem cells: myeloid & lymphoid stem cells * **Myeloid** - develop in RBM & give rise to RBCs, platelets, monocytes, neutrophils, eosinophils & basophils. * **Lymphoid** stem cells start development in RBM but complete it in lymphatic system & give rise to lymphocytes. * Some myeloid cells differentiate into progenitor cells while some directly develop into precursor cells. Progenitor cells-not capable of reproducing & give rise to more specific blood elements. * Some are called colony forming units (CFUs). * **CFU-E** produces erythrocytes, * **CFU-Meg** produces megakaryocytes, source of platelets & * **CFU-GM** produces granulocytes & monocytes. * Next generation are called precursor cells also known as blasts. Over several cell division they develop into actual formed blood elements. * Precursor cells have recognizable microscopic appearances while progenitor cells do not. ## Anemia * Anemia is a condition in which the oxygen-carrying capacity of blood is reduced. All of the many types of anemia are characterized by reduced numbers of RBCs or a decreased amount of hemoglobin in the blood. * In most anemias, erythropoietin production & erythropoiesis are increased, causing erythroid hyperplasia. ## Classifications of Anemia * **I. Blood Loss Anemia- Hemorrhage:** * **Acute:** * **Trauma -** Immediate threat is hypovolemia i.e. shock rather than anemia. Hemodilution begins, achieves full effect in 2-3 days. * **Anemia** is normocytic and normochromic. * **Chronic:** * **Lesions of GI tract, gynaecologic disturbances** - With chronic blood loss, iron stores are gradually depleted resulting in iron deficiency anemia. * **II. Increased rate of destruction - Hemolytic anemia** - May be due to inherent defects in erythrocyte (intracorpuscular haemolytic anemia) which are usually inherited or to external influences (extracorpuscular haemolytic anemia) which are usually acquired. * **Marked Hypercellularity** within the marrow owing to increase in erythropoiesis. * **Destruction of red cells** may occur within vascular compartment (intravascular hemolysis) or within cells of mononuclear phagocyte or reticuloendothelial system (extravascular hemolysis). * The pathways for excretion of excess iron are limited so there is tendency for abnormal amts of iron to accumulate. ### Intrinsic Abnormalities of Red Cells * **Hereditary:** * **Disorders of red cell membrane cytoskeleton**-Eg. Spherocytosis, Elliptocytosis * **Red cell enzyme deficiencies** * **Glycolytic enzymes** - Hexokinase * **HMP shunt enzymes**- G6PD * **Disorders of Hb synthesis** * **Deficient globin synthesis**- Thalassemia syndrome * **Structurally abnormal globin synthesis**- Sickle cell anemia. * **Acquired:** * **Membrane defect:** Paroxysmal nocturnal hemoglobinuria * **Extrinsic Abnormalities:** * **Ab mediated:** * Isohemagglutinins: Transfusion reactions, Erythroblastosis fetalis * Autoantibodies: Idiopathic, SLE * **Mechanical trauma to red cells** * Microangiopathic haemolytic anemia- Thrombocytopenic purpura * Cardiac traumatic haemolytic anemia * **Infections- Malaria** * **III. Impaired red cell production** * **Disturbance of proliferation & differentiation of stem cells:** Aplastic anemia, Pure red cell aplasia * **Disturbance of proliferation & differentiation of erythroblasts:** * **Defective DNA synthesis:** Deficiency or impaired utilization of Vit B12 & folic acid- megaloblastic anemia * **Defective Hb synthesis:** * **Defecient heme synthesis:** Iron deficiency * **Defecient globin synthesis:** * Thalassemias Unknown or multiple mechanisms ## Types of Anemia * **Iron deficiency anemia** - the most common type of anemia. * Causes: Inadequate absorption of iron, excessive loss of iron, increased iron requirement, or insufficient intake of iron causes iron deficiency anemia. * Risk factors: Women are at greater risk for iron-deficiency anemia due to menstrual blood losses and increased iron demands of the growing fetus during pregnancy. Gastrointestinal losses, such as those that occur with malignancy or ulceration, also contribute to this type of anemia. * **Megaloblastic anemia** * Causes: Inadequate intake of vitamin B12 or folic acid causes megaloblastic anemia in which red bone marrow produces large, abnormal red blood cells (megaloblasts). * Risk factors: Can be caused by drugs that alter gastric secretion or are used to treat cancer. * **Pernicious anemia** * Causes: Insufficient hemopoiesis resulting from an inability of the stomach to produce intrinsic factor, which is needed for absorption of vitamin B12 in the small intestine. * **Hemorrhagic anemia** * Causes: Excessive loss of RBCs through bleeding resulting from large wounds, stomach ulcers, or especially heavy menstruation. * **Hemolytic anemia** * Causes: RBC plasma membranes rupture prematurely in hemolytic anemia. The released hemoglobin pours into the plasma and may damage the filtering units (glomeruli) in the kidneys. The condition may result from inherited defects such as abnormal red blood cell enzymes, or from outside agents such as parasites, toxins, or antibodies from incompatible transfused blood. * **Thalassemia anemia** * Causes: Deficient synthesis of hemoglobin occurs in thalassemia, a group of hereditary hemolytic anemias. The RBCs are small (microcytici), pale (hypochromic), and short-lived. Thalassemia occurs primarily in populations from countries bordering the Mediterranean Sea. * **Sickle cell anemia** * Causes: The hemoglobinopathies are a group of hereditary disorders characterized by presence of structurally abnormal Hb. The most prevalent prototype results from mutation in the gene coding for ẞ globin chain that causes the formation of sickle Hb. Substitution of valine for glutamic acid at the sixth position of ẞ globin chain produces HbS. hbS molecules undergo polymerization- change in physical state- assume an enlongated cresentic or sickle shape due to deoxygenation. Susceptible to sequestration & hemolysis within spleen. Mostly reversible. * **Aplastic anemia** * Causes: Destruction of red bone marrow results in aplastic anemia. It is caused by toxins, gamma radiation, and certain medications that inhibit enzymes needed for hemopoiesis. ## Thrombotic thrombocytopenic purpura (TTP or Moschcowitz syndrome) * Thrombotic thrombocytopenic purpura (TTP or Moschcowitz syndrome)-is a rare disorder of the blood-coagulation system, causing extensive microscopic clots to form in the small blood vessels throughout the body. These small blood clots, called thromboses, can damage many organs including the kidneys, heart and brain. * Red blood cells passing the microscopic clots are subjected to shear stress which damages their membranes, leading to intravascular hemolysis and schistocyte formation. * Reduced blood flow due to thrombosis and cellular injury results in end organ damage. * Current therapy is based on support and plasmapheresis to reduce circulating antibodies. ## Aplastic Anemia * Aplastic anemia is a condition where bone marrow does not produce sufficient new cells to replenish blood cells. The condition, as the name indicates, involves both aplasia and anemia. * Typically, anemia refers to low red blood cell counts, but aplastic anemia patients have lower counts of all three blood cell types: red blood cells, white blood cells, and platelets, termed pancytopenia. * Causes: In many cases, the etiology is considered to be idiopathic (without a known cause), but one known cause is an autoimmune disorder in which white blood cells attack the bone marrow. Aplastic anemia is also sometimes associated with exposure to toxins such as benzene, or with the use of certain drugs, including chloramphenicol, carbamazepine. * Exposure to ionizing radiation from radioactive materials or radiation-producing devices is also associated with the development of aplastic anemia. * Medical therapy of aplastic anemia often includes a short course of antithymocyte globulin (ATG) or antilymphocyte globulin (ALG) and several months of treatment with a cyclosporin to modulate the immune system. * Mild chemotherapy with agents such as cyclophosphamide and vincristine may also be effective. * Antibody therapy, such as ATG, targets T-cells, which are believed to attack the bone marrow. * Steroids are generally ineffective, though are often used to combat serum sickness caused by ATG use. ## Megaloblastic Anemia * Megaloblastic anemia (or megaloblastic anaemia) is an anemia (of macrocytic classification) that results from inhibition of DNA synthesis in red blood cell production. * When DNA synthesis is impaired, the cell cycle cannot progress from the G2 growth stage to the mitosis (M) stage. This leads to continuing cell growth without division, which presents as macrocytosis. * The defect in red cell DNA synthesis is most often due to hypovitaminosis, specifically a deficiency of vitamin B12 and/or folic acid. * Vitamin B12 deficiency alone will not cause the syndrome in the presence of sufficient folate, for the mechanism is loss of B12 dependent folate recycling, followed by folate-deficiency loss of nucleic acid synthesis (specifically thymine), leading to defects in DNA synthesis. * Folic acid supplementation in the absence of vitamin B12 prevents this type of anemia. * The pathological state of megaloblastosis is characterized by many large immature and dysfunctional red blood cells (megaloblasts) in the bone marrow [3] and also by hypersegmented neutrophils (those exhibiting five or more nuclear lobes ("segments"), with up to four lobes being normal). These hypersegmented neutrophils are found in the "peripheral blood" (i.e., a diagnostic smear of a blood-sample taken from the circulation). ## Iron-Deficiency Anemia * Iron-deficiency anemia (or iron-deficiency anaemia) is a common anemia (low

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