Anatomy & Physiology II: BLOOD

Selected Blood Conditions

Anemia Anemia refers to an abnormally low number of circulating RBCs or level of hemoglobin or both. It results in diminished oxygen-carrying capacity. This can be due to such conditions as blood loss, inadequate dietary intake (of iron or vitamin B 12 or folate, all of which are needed to produce normal red blood cells), hemolysis or impaired RBC production. Symptoms include weakness, pallor and fainting. B. Polycythemia Polycythemia refers to excessive RBC numbers. This can be due to excessive plasma loss, in which the actual RBC numbers are normal, but since they are in a decreased volume of liquid, it appears that there is a greater concentration of RBCs. Also, the disorder called Polycythemia Vera is caused by excessive growth of bone marrow stem cells. Symptoms include increased blood viscosity (thicker blood) and hypertension. Polycythemia C. Neutropenia Neutropenia refers to low neutrophil numbers. It can be caused by bone marrow depression by viruses, drugs, chemotherapy agents or radiation. Symptoms include increased incidence of bacterial infections. D. Neutrocytosis Neutrocytosis, also called neutrophilia, refers to high neutrophil numbers in the blood. This is often due to the presence of a bacterial infection, as neutrophils are the white blood cells which fight off bacterial infections. It can also occur as a result of an inflammatory process in the body, such as occurs after a heart attack. E. Eosinopenia Eosinopenia refers to a low eosinophil count in the blood. This can be caused by excessive cortisol levels (cortisol, the hormone from the adrenal gland, causes immunosuppression) or acute infections or sepsis. F. Eosinocytosis Eosinocytosis, also called eosinophilia, refers to a high eosinophil count in the blood. This can occur as a result of allergic disorders or parasitic or fungal infections. G. Basopenia Basopenia refers to low basophil counts. It can be caused by hives, or can be an indicator of ovulation. It is difficult to detect because basophils are usually present in low numbers (they are the least numerous of the white blood cells). H. Basocytosis Basocytosis, also called basophilia, refers to high basophil counts. It is unusual to occur alone, but can be seen with a type of leukemia. I. Monocytopenia Monocytopenia refers to low monocyte counts. It can occur with acute infections, stress, or excessive cortisol levels. J. Monocytosis Monocytosis refers to high monocyte counts. It occurs with chronic inflammation or infection. K. Lymphocytopenia Lymphocytopenia refers to low lymphocyte counts. It can be caused by recent stress or infections. HIV (Human immunodeficiency virus) infection which causes AIDS causes low T lymphocyte counts. L. Lymphocytosis Lymphocytosis refers to high lymphocyte counts. This occurs with infections. M. Thrombocytopenia Thrombocytopenia refers to a low platelet count. It could be caused by autoimmune mechanisms, viruses (HIV, Epstein Barr), drugs (estrogen, heparin), chemotherapy, or toxins (cocaine). With thromobocytopenia, decreased ability to form blood clots occurs, and so hemorrhages occur, including petechiae (pinpoint hemorrhages), ecchymoses (large bruises), and possibly severe bleeding from GI tract, respiratory tract or CNS if platelets are very low. N. Thrombocytosis Thrombocytosis refers to high platelet counts. Often, this is not a concern. If platelet numbers are very high, as occurs along with increased red blood cells in the disorder polycythemia vera, there may be increased blood clots formed, causing strokes, heart attacks, and pulmonary emboli. O. Leukemia Leukemias are malignant disorders of the blood which cause increased leukocyte levels. Those increased white blood cells then crowd out the bone marrow so that other blood cells cannot be produced. They are classified by the cell affected, for example, lymphocytic leukemias involve the abnormal increased production of lymphocytes.

Clot Retraction

Clot retraction occurs when the platelets actin and myosin contract and pull the edges of the damaged vessel closer together. The fluid that is squeezed out is called serum, or a fluid from the blood that does not have fibrinogen and some of the clotting factors in it.

Clot Dissolution = Fibrinolysis

Fibrinolysis occurs within a few days after clot formation. Fibrinolysis is the breakdown of the clot, and it occurs to ensure that the clot does not remain after it is no longer needed. This is very important because if you had clots when you don't need them, they could block blood flow, or worse yet, a piece of them could break off, travel in the bloodstream and then get trapped in small blood vessels. If they get trapped in small blood vessels in the heart, they will cause a heart attack. And if it happens in the brain, it will cause a stroke. Fibrinolysis occurs as a result of plasmin, an enzyme that breaks down the insoluble fibrin threads. Plasminogen is activated into plasmin due to substances produced in the endothelial cells, called Tissue Plasminogen Activator (TPA) as well as factor XIIa and thrombin. Plasmin is the active form which will help dissolve or break apart the clot once it is no longer needed.

Vasospasm

The damaged blood vessel will constrict during this first phase of hemostasis - vasospasm or sometimes called the vascular spasm. Vasospasm is accomplished by contracting the smooth muscle of the damaged vessel. The significance of this is that it decreases blood flow to this area, or can even stop the flow of blood in very small blood vessels, so that blood loss is minimized. Vascular spasm can be continued during the next stage of hemostasis as a result of some of the chemicals released by the platelets

Plasma

The plasma is the liquid part of the blood The plasma functions to transport water, proteins, nutrients and waste products to and from the cells. These nutrients and waste products include small organic substances such as glucose, amino acids and urea and larger organic molecules such as plasma proteins and hormones. The majority of plasma is water. About 92 % of the plasma consists of water and it helps to maintain blood volume and as well as transport molecules. There are three major proteins in the plasma: albumin, globulin and fibrinogen. They are involved in several processes that maintain homeostasis. They also help maintain the pH of the blood by acting as buffers (or have the ability to take up or release hydrogen ions). The plasma protein Albumin helps maintain osmotic pressure in the blood. Osmotic pressure is the force caused by the difference in solute concentrations on either side of the membrane. Albumin is produced by the liver. Globulins, or specifically gamma globulins, are the antibodies secreted by lymphocytes in response to an antigen. These proteins help fight infection.

Eyrthropoietin (EPO)

is a hormone secreted from kidney. This hormone stimulates erythropoiesis, or RBC production The stimulus for production of erythropoietin is when levels of blood oxygen are low and this is detected in the low oxygen delivery to the kidneys. The EPO stimulates erythropoiesis in the bone marrow resulting in an increase in the number of circulating erythrocytes. Once more erythrocytes enter circulation, the oxygen carrying capacity increases and negative feedback will kick in and decrease the production of EPO and thus erythropoiesis overall.

Platelet Plug Formation

A platelet plug is an accumulation of platelets on the damaged collagen of the blood vessel. This happens when there is a small tear in blood vessels or capillaries throughout an average day or when greater, more significant damage has occurred. This plug will plug up those small holes in blood vessels, preventing blood loss from that torn blood vessel. The platelet plug occurs in 3 stages: platelet adhesion, platelet release reaction and platelet aggregation. The adhesion is when the platelets adhere to the underlying damaged collagen. The release reaction occurs when the platelets become activated and release ADP, thromboxanes and other chemicals to further attract more platelets to the area. Lastly, aggregation is when the platelet plug is formed, or the platelets pile up on one another to form a plug that plugs up the hole in the blood vessel. Cells lining the blood vessel, called endothelial cells, produce vonWillebrand factor (vWF) which is a protein that enhances platelet adhesion during the platelet plug formation. This plug and the following clot formation needs to be isolated so that it does not spread to adjacent, non- damaged areas of the blood vessel or through the entire circulatory system. There are several anti- coagulants or substances that prevent unwanted clots. One of these is called prostacyclin Endothelial cells produce substances such as nitric oxide, heparin and prostaglandin. These anti-coagulants inhibit the clot formation and vasodilate and inhibit the release of the clotting chemicals from the platelets.

Nutrients needed for Erythropoiesis

Although the hormone erythropoietin is necessary for erythropoiesis, proteins, vitamin B-12 and folic acid are also very important for the process to occur. Iron is essential for the hemoglobin formation as well as energy to fuel the process. Protein for the globin chains of hemoglobin (hemoglobin is the protein molecule inside the RBCs) Vitamin B-12 & Folic acid as coenzymes & building heme molecule (heme is a component of hemoglobin and the heme contains iron) Energy for formation - so enough calories must be consumed Iron - must be in the diet, since iron is a component of the heme portion of hemoglobin

Components of Blood

Blood is the only liquid connective tissue in the body and accounts for about 8% of one's total body weight or approximately 4-5 liters in females and 5-6 liters in males. Blood is a connective tissue and so contains both cells (called the formed elements) and the extracellular matrix (the plasma) The Formed Elements (cells) develop in bone marrow The formed elements include the erythrocytes (red blood cells), leukocytes (white blood cells) and the thrombocytes (platelets). The formed elements make up 45% of total blood volume. The formed elements include the Erythrocytes or Red Blood Cells (RBC's), the Leukocytes or White Blood Cells (WBCs) and the Platelets The plasma of the blood is the liquid portion of the blood that consists of water and dissolved substances such as gases (oxygen and carbon dioxide), nutrients (glucose, amino acids, fatty acids), waste products (urea, uric acid, ammonia, bilirubin, lactic acid), regulatory substances (hormones, enzymes) and proteins. Proteins in the plasma include albumin, globulins and fibrinogen. Albumin helps maintain blood osmotic pressure and helps with the transport of certain substances, globulins include antibodies and work within the immune system functions, and fibrinogen is involved in the formation of blood clots. The plasma makes up 55% of the blood.

Structure of Erythrocytes

Red blood cells have a biconcave shape, contain mostly the protein hemoglobin can fold or bend when traveling in very small spaces. They are about 7.5 microns in diameter. Shape of RBCs = biconcave disk The significance of the biconcave shape is that it allows for a greater surface area for gas exchange to occur. Red color due to hemoglobin filling their cytoplasm. Hemoglobin is a pigmented protein which consists of 4 polypeptide chains (2 short alpha protein chains and 2 long beta protein chains) and 4 heme groups surrounding an iron atom in the center. The hemoglobin occupies about 1/3 of the erythrocyte (RBC) cell volume and gives them their red color. Heme group on hemoglobin has a complex carbon, nitrogen & hydrogen ring structure and contains an iron (Fe) atom in the middle. The iron on the heme group binds to oxygen. One oxygen molecule can bind to each heme group. Globin portion of hemoglobin is a protein molecule. There are four globin or polypeptide chains in each hemoglobin - 2 alpha and 2 beta chains.

Sickle Cell Anemia

Sickle cell anemia is a genetic condition whereby the hemoglobin has an abnormal configuration. This causes the red blood cell to take on a "sickle" shape instead of the biconcave configuration These sickled cells are at much greater risk for lysis. This rapid breakdown of the RBC's leads to anemia since the production cannot keep up with the breakdown. General manifestations of anemia occur, which include weakness, pallor, and possibly fainting. Also, the spleen enlarges (that is, have splenomegaly), because the spleen is the site of RBC destruction. Also, jaundice is seen in these individuals due to high bilirubin levels that occur in the blood as a result of the excessive destruction of the RBCs.

Hematocrit

The hematocrit is the measurement of the proportion of red blood cells in a whole blood sample. This can be achieved by a centrifugation of a tube of blood that will allow the heavier components (the red blood cells) to settle to the bottom of the tube. Average hematocrit is about 38- 48% in females and 40-52% in males. Men have a slightly higher hematocrit in part to the fact that testosterone stimulates the production of erythrocytes (RBC's), so therefore they have a higher amount typically. When a sample of blood is centrifuged (or spun at high speeds in a test tube), the erythrocytes will fall to the bottom and the thrombocytes and leukocytes will form what is called the "buffy coat" or thin layer that sits between the erythrocytes and plasma. This is used clinically to ascertain conditions of anemia, blood loss or polycythemia (too many red blood cells). A low hematocrit is seen with anemia A high hematocrit is seen with polycythemia, dehydration or in persons living in high altitudes

Leukocytes

The main function of a Leukocyte or White Blood Cell (WBC's) is to protect the body against infection. These cells do have a nucleus and are therefore capable of cellular division. This becomes important when they need to replicate quickly when the body needs protection against a virus, pathogen or foreign substance.

Erythrocytes (Red Blood Cells) Development of Erythrocytes (Erythropoiesis)

The main function of erythrocytes or red blood cells (RBC's) is to transport oxygen. This is done due to the presence of a protein called hemoglobin that binds to the oxygen and helps transport it throughout the body. RBCs are produced in the red bone marrow. Erythrocytes do not have a nucleus, so they are not capable of cellular division and only circulate for approximately 120 days. Erythropoiesis is the process whereby red blood cells or erythrocytes are developed. It is stimulated by the hormone erythropoietin that is secreted from the kidneys in response to low blood oxygen levels. Erythropoiesis occurs in the red bone marrow. The entire process takes about 4 days to complete and on average 2.5 million cells are produced every second. This replenishment is necessary as a typical erythrocyte only lasts about 120 days and on average about 2.5 million cells are destroyed every second (hence the levels remain at homeostatic levels under normal conditions). The precursor stem cells from which erythrocytes develop are large nucleated cells called hemocytoblasts . This will mature into proerythroblasts. They will further mature and form erythroblasts. As these cells continue to mature, they shrink, extrude their nucleus and most of their organelles, and start to produce hemoglobin. Now they are known as reticulocytes, or immature RBCs The reticulocytes then leave the bone marrow, enter the blood stream and finish their maturation in the blood stream, to become mature red blood cells (a process that takes about 2 days).

Function of Erythrocytes

The main function of the RBC's is to transport the oxygen from the lungs so that it is available for cellular metabolism and the production of ATP (energy) throughout the body. About 97 - 98.5% of the oxygen in the blood is carried by hemoglobin with the remaining 1.5% dissolved in the plasma. Once a red blood cell ruptures or hemolysis occurs (remember they only live about 120 days) the hemoglobin becomes nonfunctional due to the reconfiguration of the heme that occurs at this point.

Breakdown (Hemolysis) of Erythrocytes

The term hemolysis means the rupturing or breakdown of the erythrocytes. When this happens the parts are "recycled" and reused to either create more erythrocytes or for other uses in the body. An average erythrocytes lives about 110 days in a male and 120 days in a female and remember they do not have a nucleus, so they are not capable of division. They are destroyed at a rate of about 2.5 million/second but fortunately erythropoiesis occurs at approximately the same frequency so levels are maintained at adequate levels in normal physiology. The cellular components degenerate, they are unable to carry as much oxygen and then the cell membranes will become fragile and rupture when they try to squeeze through a narrow vessel in circulation. Lifespan of a RBC is 120 days. During those 120 days, the red blood cell travels around in the bloodstream, carrying oxygen. As it passes into the small capillaries, it folds to fit through those small vessels. The red blood cell is able to do this because it is flexible. As the RBC gets toward the end of its life, it becomes less flexible, unable to fold itself to pass through small capillaries. RBCs are removed from the blood in small capillaries of the liver and the spleen. The red blood cell primarily contains hemoglobin, so we have to consider what happens to the hemoglobin as the red blood cell is broken down. The hemoglobin is broken down to heme and globin The globin is then broken down into amino acids that are then used to create new proteins. The heme part is broken apart into iron and biliverdin. Biliverdin breaks down into bilirubin which travels to the liver to help with the production of bile. Some iron stays in the liver and spleen for storage and some iron travels to the bone marrow where it is used in erythropoiesis to produce more erythrocytes. The non-iron part of heme is converted to biliverdin and then bilirubin. Bilirubin is taken to the liver, the liver then adds a molecule called to it and that bilirubin becomes a part of the bile that the liver produces. Bile is then released into the digestive tract and eliminated in the stool. If the bilirubin cannot be eliminated, or if you produce too much of it because you are breaking down too many RBCs, it will accumulate and cause jaundice.

Types of leukocytes

There are 2 different types of leukocytes: granular or agranular. The granulars include the leukocytes that contain chemical filled vesicles or granules that are made visible by staining. The agranular leukocytes lack these vesicles and are therefore called agranular. There are 3 granular leukocytes: The neutrophils, eosinophils and basophils. 1. Neutrophils - phagocytize pathogens (infectious agents, especially bacteria) 2. Eosinophils - phagocytize antigen-antibody complexes and allergens, destroy parasitic worms 3. Basophils - release histamine and heparin to promote blood flow to injured tissues, so they intensify the inflammatory response and are also involved in allergic reactions. 4. Monocytes - large wandering cells which phagocytize pathogens and cellular debris a. Macrophages - monocytes which have migrated from blood into tissue 5. Lymphocytes - specific immunity. These cells recognize specific pathogens or toxins and can also recognize and destroy cancer cells. a. Bursal derived lymphocytes (B cells) - involved in humoral immunity - they secrete antibodies against specific pathogens b. Thymal derived lymphocytes (T cells) - cell mediated immunity - they directly attack of specific pathogens

Hemostasis

Thrombocytes or platelets are the disc shaped formed elements that are involved in hemostasis or the process of clotting in the blood. These fragmented cells develop in the red bone marrow and have no nucleus. Therefore, they only live a short time and produced in very large quantities - about 200 billion r day. The process of hemostasis consists of 4 main phases: vasospasm, platelet plug formation, blood clotting and clot retraction/dissolution.

Blood Clotting = Coagulation

Vascular spasms and platelet plugs cannot close larger areas of a damaged vessel. Therefore, coagulation or blood clotting must occur. A blood clot is simply a network of protein fibers or threads that trap blood cells and fluid to seal off the area that is affected. This involves the activation of different clotting factors or coagulation factors that are normally inactive. There are two different ways in which clotting factors become activated - the intrinsic and extrinsic pathways. They both have a common end pathway which leads to the formation of a fibrin clot through activation of the plasma protein called fibrinogen. The intrinsic pathway is the pathway stimulated by chemicals found within the blood itself (hence the name). It takes longer than the extrinsic pathway since it requires more steps to activate factor X. When the blood vessel is damaged and the underlying collagen is exposed, it releases clotting factors. These clotting factors stimulate a cascade reaction where one stimulates another and eventually clotting factor X is activated. (This factor X activated is now the same for both extrinsic and intrinsic pathways). Activated factor X then forms prothrombinase or prothrombin activator. Prothrombinase converts prothrombin to thrombin. Thrombin continues to stimulate more thrombin in a positive feedback mechanism. Thrombin converts the inactive plasma protein fibrinogen into the insoluble protein fibrin. The extrinsic pathway is quicker than the intrinsic pathway and gets its name from the fact that it is activated by substances from outside the blood itself. Thromboplastin or tissue factor, also triggers the activation of factor X and now the pathway is the same as it is for the intrinsic above. The extrinsic pathway is stimulated when the damaged tissues release tissue factor or thromboplastin and leads to the formation of active factor X. Activated factor X then forms prothrombinase or prothrombin activator. Prothrombinase converts prothrombin to thrombin. Thrombin continues to stimulate more thrombin in a positive feedback mechanism. Thrombin converts the inactive plasma protein fibrinogen into the insoluble protein fibrin. Once the insoluble fibrin forms, the fibrin threads will trap red blood cells, platelets and fluid and form a clot. The platelets will form the clot through the process of clot retraction. The actin and myosin in the platelets contract and pull the damaged edges together. This clot retraction then makes the clot firmer, or more solid, and also gives you a smaller hole to heal up. Blood clots are controlled by the production of anticoagulants such as antithrombin and heparin. They inactivate thrombin so that clotting does not occur where it is not needed. This is very important because if you had clots where you don't need them, they could block blood flow, or worse yet, a piece of them could break off, travel in the bloodstream and then get trapped in small blood vessels. If they get trapped in small blood vessels in the heart, they will cause a heart attack. And if it happens in the brain, it will cause a stroke.