chapter xviii a cardiovascular system the blood in this chapter we will discuss the characteristics of blood and what we find inside blood particularly the blood cells the red blood cells and white blood cells how we formed those blood cells the cellular fragments called platelets how we're going to maintain the blood inside the blood vessels in a process called hemostasis finally we will discuss the blood typing system called blood typing characteristics of blood blood if you recall is a connective tissue we have about four to six liters depending on your body size of blood volume or plasma volume and it has three main functions for transportation we're going to be transporting around gases like carbon dioxide and oxygen nutrients like amino acids fatty acids vitamins many hormones and waste products waste products come in a lot of forms things such as creatinine excess hydrogen ions for example blood is for regulation regulation of body temperature we distribute blood to different parts of our body to help maintain body temperature more to the surface when we're hot to cool the body more to the core when we're cool to keep the body warm blood is going to help us maintain our osmotic pressure the components of blood can move from one compartment to another so that affects how your cells function and also pH is regulated in your blood quite tightly between 7.35 and 7.45 blood helps protect our body it protects itself through the process of clotting to maintain hemostasis so we can keep the blood inside the blood vessels our white blood cells help us for our immune system as we have those cells to help fight infection and proteins inside the blood add to the osmotic but also we have immune proteins and clotting proteins that are going to help protect us from hemorrhage and infection respectively two components of blood blood being a connective tissue contains the cells and surrounded by the extracellular matrix liquid connective tissue like blood does not have the same type of extracellular matrix as other connective tissues the cells in that does not secrete the matrix unlike tissues like our areolar connective tissue bone and cartilage blood plasma is a liquid portion and it contains it contains these cellular parts like the white blood cells and red blood cells and also formed elements called platelets if we look at whole blood that has been spun down into such a fuge we see the heaviest parts or the erythrocytes the red blood cells that's sink to the bottom and the lighter portion is a blood plasma about 55% of the whole blood depending on the individual and at the interface the junction between the plasma and the erythrocytes we have what is called the Buffy coat the buffy coat contains the leukocytes which are white blood cells and the platelets out of your whole body fluids your whole blood is only about 6% and within the blood plasma after it's separated from the cellular components we have it containing mostly water proteins and electrolytes some of the proteins that are in the plasma that we will come back and talk about our out boomin which is same type of protein that we find in egg white fibrinogen which is a clotting factor immunoglobulins which are going to be antibodies and help us fight infection when we look at the cellular components the white blood cells and the red blood cells and platelets which are cellular fragments we see that the blood is mostly red blood cells we also have quite a few white blood cells and fewer platelets we will get to learn all of the different types of white blood cells so to introduce them here we see that in whole blood most of the white blood cells are neutrophils and then we have lymphocytes monocytes Jacinta fills and basophils so if you'll notice there's quite very few numbers of eosinophils and basophils there's not very many of them if we looked at a hundred white blood cells we might see one percent of them being basophils or one beza fill in a hundred the formed elements of blood we call the components of blood formed elements because not all of them are cells the white blood cells and red blood cells are different than the platelets which are cellular fragments in this picture we see a diagram as well as what we call a blood smear of whole blood showing that most of cells visible are those little red disks called red blood cells also known as erythrocytes the white blood cells are stained and visible here as well as the platelets because we use a stain called the Wrights stain right as in W righ T that causes the nuclei to have a purple color and the cytoplasm to be more pinkish the tiniest cellular fragments that you see are platelets they are much smaller than the red blood cells whereas the white blood cells are all larger than the red blood cells we can see the five types of white blood cells on the diagram we have monocytes lots of neutrophils eosinophils which are more of a reddish color and the lymphocytes and basophils on the blood smear you can see red blood cells the cellular fragments called platelets three neutrophils and one monocyte the formation of blood cells is called hemopoiesis or hematopoiesis we have to produce as many red blood cells that are destroyed when blood cells are created most of them will never undergo mitosis again so they have a certain lifespan and have to be replaced the main site for production of blood cells is the red bone marrow recall that the red bone marrow is at the ends of long bones and in the middle of flat bones and that spongy bone with the holes contains spaces for the red bone marrow in a fetus the spleen can also produce blood cells the red bone marrow and the spleen and the fetus contain stem cells that can do many different things so they are called pluripotent the potential so we have potent and pleura for plural having many jobs the stem cells can make all of the blood cells stem cells remember have the ability to undergo mitosis so they can replace themselves and proliferate make a lot of each other and some of them have the ability to differentiate become specialized for example pluripotent stem cells for white blood cells will be able to make lymphocytes and monocytes compared to a regular cell which can only reproduce itself in hemopoiesis we have two stem cell lines this just means two basic categories of stem cells that produce different types of blood cells the myeloid stem cell is responsible for making all of the blood cells and platelets except for the lymphocytes so that would be the red blue cells platelets monocytes neutrophils eosinophils and basophils so the myeloid stem cell line is for producing most of the blood cells and the platelets whereas a lymphoid stem cell line like the name implies is always only going to produce lymphocytes there are actually three types of lymphocytes T cells B cells are natural killer cells they can also be called T lymphocytes or B lymphocytes and natural killer cells are NK cells once the blood cells are produced in the red bone marrow they have to have a way to get out of the red bone marrow and into the bloodstream so the special blood cells that go over blood vessels that go around and throughout the red bone marrow are sinusoidal capillaries and sinusoidal our capillaries that have pretty big holes in them generally capillary walls are continuous so there's no big gaps but in this case the sinusoid are going to allow the blood cells that are produced in the red bone marrow to enter into the general blood stream all of our blood cells in formed elements except for lymphocytes are not able to undergo mitosis again once they leave the red bone marrow that means that they are terminally differentiated they are as specialized as they're going to be they have their final job and they don't need to undergo mitosis anymore they will go into circulation do their job and then they will die lymphocytes are a little bit different because lymphocytes will go and populate a lymphatic tissues where they can remain and can be stimulated to undergo mitosis again for example if you need to fight off an infection there are plenty of growth factors that are going to stimulate hemopoiesis so they're going to affect the production of your blood cells many of them are civic so our worth repeatin will stimulate the production of erythrocytes which are known as red blood cells thrombopoietin is going to stimulate the production of thrombocytes known as platelets and we have different types of stimulating factors and growth factors that can affect white blood cell production in general or in specific so for example colony colony stimulating factor or CSF and interleukins are family of hormones that are responsible for helping to determine when white blood cells should be produced if you think about it when you get an infection you may need to increase the production of white blood cells to help fight that off and those will come from the bone marrow as well as they can be affected affecting lymphocytes for red blood cells red blood cells are also known as erythrocytes erythro referring to the red color their main job is to produce haemoglobin and therefore carry oxygen when we think about why we are breathing it is to get the oxygen onto the red blood cells so that that oxygen can be delivered to our tissues this will be a recurring theme what are we going to use that oxygen for what how do we get it to the tissues the blood cells the red blood cells are going to be carrying it on a molecule called hemoglobin which we'll discuss in the following slide in order to carry enough oxygen we need to have enough red blood cells the production of red blood cells has to equal how quickly they're being destroyed so when they come out of the red bone marrow they are mature they're going to circulate around in the blood vessels for about a hundred and twenty days before they die we have to keep pushing out new red blood cells as the old ones get old and die in terms of structure they are a biconcave disk so a disk with two kind of dimples in the middle so that the center part is a little bit than the outside sort of like a tire where the whole doesn't go all the way through the surface materials on the red blood cell are going to determine the blood type which we'll be talking about later and those surface materials are glycolic lipids remember that's a lipid with a sugar attached to it red blood cells do not have a nucleus so that's why we see the mature red blood cells not having any little purple circle in the middle with the staining because there is no nucleus they don't need a nucleus they're not going to divide again they're really doing they're doing no transcription and they can do some translation based upon the mRNA that's present with inside the cell but they are so specialized they're full of hemoglobin they don't really need to have any mitochondria remember mitochondria make ATP but their metabolic needs are so low that they can just make enough ATP to survive using anaerobic metabolism so that means not using oxygen if you think about it that makes a lot of sense because we don't want the cells responsible for carrying oxygen to use all of it their job is just to float around and carry oxygen we'll see they have a few other little functions that they do but this is their main job on the bottom here in the figure we can see how a red blood cell is produced you do not need to memorize the names of any of the individual precursor cells but just notice we have a pluripotent stem cell that's going to be the myeloid stem cell it's going to produce a cell that then goes on to change in its shape and structure as it becomes mature from the colony forming unit to the erythroblast to the reticulocyte to the erythrocyte notice the use of the word a retro blast a blast cell usually denotes shows that that cell is not mature yet whenever you're here at the ending blast on this the erythrocyte is a mature sell it's lost its nucleus it has that biconcave shape it's full of hemoglobin and the hemoglobin when it binds to oxygen gets this reddish color that's what gives the erythrocyte its color and the blood its color hemoglobin we said that the red blood cell is full of hemoglobin we can see the shape of a mature red blood cell here see how its biconcave which means concave or dented on two sides by and they're quite small being between 5 & 7 micrometer micrometer is one millionth of a meter so point zero with six zeros at it added to it with the one very thin only two micrometers thick and we see below the construction of the hemoglobin hemoglobin is AK ordinary structure of a protein remember we had primary secondary tertiary and quarternary structures ordinary structures are we have when we have more than one polypeptide associated with one another and in hemoglobin we have four globin peptides attached to one another forming this hemoglobin and inside each of the globins proteins we have the heme portion which we can see the chemical formula of below in that blue box so two alpha globin chains in the blue two beta globin chains in the yellow and then four hemoglobins one for each of the Gloam it's four teams sorry one for each of the globin polypeptides and we look down into the blue box where we can see the heme molecule notice how Fe is in the middle Fe is the chemical symbol for iron it's the iron inside the heme which binds the oxygen we always associate hemoglobin with binding oxygen but it can also it does also help us carry around our carbon dioxide that we need to transport as well and we'll get into much more detail about how carbon dioxide is transported but for now just remember that red blood cells contain hemoglobin for binding and transporting oxygen around as an aside nitric oxide and O also binds to hemoglobin and nitric oxide is a vasodilator so it's going to cause blood vessels to dilate which makes them enlarged and allows more blood to flow through we'll see how this is used later on in the cardiovascular system red blood cells red blood cells can live about 120 days in circulation as we see from the diagram figure 18.9 vitamins minerals and other nutrients used to produce red blood cells in the red bone marrow allow mature erythrocytes to leave the red bone marrow and enter into circulation where they live about 120 120 days when they die they get broken down by the liver and the spleen all the cellular fragments can then be phagocytized by different cells to remove the debris in terms of breaking down the red blood cells the globin portion of the hemoglobin is very easy to reuse we just break them down into amino acids those amino acids then can be used to make new proteins but the heme portion is a little bit more problematic having that iron in there requires it to be broken down in very specific ways we don't want to lose the iron so we will remove the iron and transport that around we have a few molecules that help us hold and transport iron transferrin is for transferring it through the blood stream so that it can then be stored and held in with another protein called ferritin the non iron portion of the heme also has to be processed properly so the liver and spleen can help process that the products that come out of the spleen go into the blood get filtered to the kidney and come out in the urine and part of the yellow portion of the urine is due to breakdown of the heme the liver is going to break down non iron team as well and secrete it into the bile no bile is used for a couple of different purposes it's excretory for those products of the heme but also helps break down fats and absorb fats in our small intestine so file goes into the small intestine from the liver and that's how those breakdown products of the heme get into the feces as it goes through the small intestine large intestine and then is excreted and the stair Co billon gives the urine its brown color like the uro billon gives the urine its yellow color hemostasis in terms of erythrocytes is going to obviously want to keep up with red cell death so we want to produce as many as we destroy so that we can maintain a constant oxygen binding capacity of the blood what can stimulate production of red blood cells clearly if we don't have enough red blood cells we're not going to carry enough oxygen so if the body detects that the oxygen levels are too low that's going to stimulate erythrocyte production the liver and the kidneys are responsible for helping to detect how much oxygen is in our blood when we have hypoxemia which is low oxygen in the blood compared to high Baja hypoxia which is when a tissue has low oxygen hypoxemia stimulates our kidney to produce erythropoietin erythropoietin we said is a hormone and that's going to activate the stem cells in the red bone marrow to secrete and create more mature red blood cells so we can speed up mitosis in the red bone marrow so that we could get more red blood cells produced faster we can increase the amount of red blood cells in about 3 or 4 days when erythropoietin is produced so we see from our diagram low oxygen levels stimulate the liver and the kidneys to produce erythropoietin the hormone that hormone goes to the red bone marrow we're looking at example of the pelvis here but the red bone marrow is going to be stimulated to produce more red blood cells specifically as more red blood cells get produced and put into the bloodstream that's going to increase the red blood cell count and that's going to increase the oxygen binding capacity of the blood so that will alleviate the hypoxemia things that can cause hypoxemia include lung diseases so not enough oxygen can get even passed into the blood high-altitude where we don't have as much oxygen because the air is lower can cause hypoxemia when you increase the amount of exercises use you do that increases the amount of oxygen used and that can cause hypoxia so anything that's going to trigger hypoxemia will stimulate red blood cell production how do we evaluate the oxygen carrying capacity of the blood there are several ways to do that we can directly look at the amount of red blood cells we can do a red blood cell count RBC's tend to be a higher number in males compared to females so it's easier for females to become having reduced number of red blood cells like anemic for example men have about 5 to 6 million per microliter which is a tiny little millionth of a liter and women have between four and five and a half million red blood cells per microliter not only do we need to look at the number of red blood cells we can actually look at how many red blood cells or what percentage of red blood cells do we have within the blood and that's done through hematocrit as we saw in our previous picture we can spin down the blood using a centrifuge and we're expecting to have a certain portion of that volume be packed red blood cells in men because they have a higher red blood cell count we have a greater number or greater percentage of hematocrit so about 42 to 52 percent in males is normal whereas women we're going to have fewer red blood cells so that hematocrit that percentage is going to be the last 37 to 48 percent red blood cells where the rest is going to be plasma and a small amount the buffy coat so red blood cell is a direct count of the number of red blood cells hematocrit is an indirect measure of how many red blood cells we have then we can directly look at hemoglobin because even though we might have a lot of red blood cells it's really the amount of hemoglobin we have overall that determines how much oxygen carrying capacity we can have red blood cells can be produced with low levels of hemoglobin if we don't have enough iron for example so we can have iron deficiency anemia where we have appropriate red blood cell count and not or more appropriate red blood cell count and but still not enough hemoglobin so hemoglobin is a direct more direct measure of how much oxygen binding capacity one can have whole blood can be measured for hemoglobin content we'd expect to be higher in males and females again 13 to 18 grams per deciliter we're expecting for hemoglobin and men 12 to 16 micro grams grams per deciliter is what we're expecting for women different types of anemia affect different measurements pernicious anemia is going to prevent production of enough red blood cells so you would see RBC count hematocrit and hemoglobin decline whereas if you have iron deficiency anemia you may have normal numbers of red blood cells but reduced hemoglobin content number five white blood cells let's look at all the different white blood cells that we have and we'll go over their basic functions white blood cells or WBC's are also known as leukocytes leuco for the white color in fact they're clear until we stain them with dyes so all of the blood smear slides we're looking at are stained with rights dye that's a right stain as we talked about previously w righ t none of the white blood cells contain hemoglobin it's not their job or function to carry the oxygen like the red blood cells which is why they look completely different than the RBC's we can categorize the white blood cells as being granular meaning having lots of granules in their cytoplasm or a granular having fewer or no visible granules in their cytoplasm the granular leukocytes include the neutrophils eosinophils and basophils and help you remember that you can just remember nib and EB neutrophil using a Phillips basal film the a granular leukocytes are the remaining two types monocytes and lymphocytes and their cytoplasm is much more smooth looking compared to the granules we can see in the white and the granular white blood cells here we can see micrographs of right stained blood smear and literally the blood is kind of smeared on a slide dried and then stained and two of the dyes that are used in it right stain include hematoxylin and eosin eosin is a reddish color so when one of the cells started you know binds to the eosin a lot it was called an eosinophil because it's philic loving for eosin so the eosinophil has the bright red large granule sets that can be stained we see that in box a it has this sort of by lobed nucleus we haven't really encountered any cells with these strange nuclear shapes before but white blood cells many of them do not have a round nucleus the only one that does is a lymphocyte we can see down in D very little cytoplasm with a ring of a ring of cytoplasm surrounding more of a circular nucleus and not much larger than a red blood cell but the lymphocyte you see has a round nucleus whereas eosinophils has these two lobes and that is characteristic of an eosinophil and it can kind of sometimes look a bit like a pac-man and that will help you identify the white blood cell yes NFL you will need to be able to identify by looking at all of the white blood cells look at the Bay's of fill in letter B basophils again one of our granular lymphocytes basophils have so many dark granules that are pretty large you really can't see a nucleus at all this cytoplasm is completely filled with our granules the neutrophil on the far right letter C has a multi lobed nucleus and that's what a mature neutrophil looks like when neutrophils are a little bit younger the nucleus is attached and not lobed and looks more like a mono site which is down on the bottom in E monocytes have au shaped or kind of a heart-shaped nucleus they tend to be slightly larger than neutrophils the cytoplasm is less granular because they're a granular leukocytes and they can stain more of a blue compared to a pink or purple neutrophil if you recall when we talked about how frequent we have these cells in the blood most of the white blood cells we see when we look at a blood smear are neutrophils letter C and if you see a cell that kind of looks like you know the globe with the continents that is a mature neutrophil then our most our second most common lymphocyte is a cell is going to be our lymphocyte about 20% of the white blood cells are lymphocytes compared to maybe 65% of the white blood cells are neutrophils lymphocytes very common monocytes we might get eight to ten percent of our white blouse white blood cells being monocytes they can be confused with neutrophils so I encourage you to look at a lot of different pictures of neutrophils versus monocytes and we'll do some of those activities in our laboratory activities as well then we have eosinophils and basophils those are not very common so if you look at a hundred white blood cells you might just see a few eosinophils and just maybe one beza fill so that's what we're looking at in terms of the frequency of our white blood cells here receive figure eighteen point eighteen describing luka Poe Isis the production of white blood cells as erythropoiesis was the production of red blood cells you can see the two stem cell lines that we talked about the myeloid and lymphoid stem cell line the myeloid is responsible for our red blood cells and platelets red blood cells being erythropoiesis but all the other white blood cells except for lymphocytes are made through the myeloid stem cell line as well as I described previously you do not need to know the names of all the intermediate cell types as the white blood cells mature just make sure you know the mature names of the Olympic leukocytes eosinophils basophils neutrophils and monocytes all come from the myeloid stem cell whereas the lymphocytes the B lymphocytes are b-cells T lymphocytes or T cells and the natural killer cells are NK cells all come from the lymphoid stem cell line and they are the only ones that can undergo mitosis after they leave the red bone marrow the function of the white blood cells are known to be for immune system function and fighting pathogens most of the white blood cells only live for a few days when they're active acceptable lymphocytes which can live for years within the lymphoid tissues like lymph nodes and tonsils and the appendix we have way fewer white blood cells than we do red blood cells but their job is to help us fight infection when we have an increased number of white blood cells it is called leukocytosis so a normal number is going to be about 10,000 cells per microliter we see an increased number of white blood cells when we have an infection or just after fought an infection off so it is a sign that the immune system is active and so that's a normal response leukopenia on the other hand is when we have fewer white blood cells so fewer than the 10,000 per microliter that we'd expect and leukopenia is never beneficial because it implies that your immune system is not going to be able to function properly what do white blood cells do to fight off the invaders they're going to either under be able to undergo phagocytosis if you recall what that is that's cell eating to remove the pathogens directly or and/or they stimulate other immune responses to help the body fight off infections we created our blood cells inside the red bone marrow they got into blood vessels through the large gap II sinusoid capillaries inside the red bone marrow now they're circulating through the blood stream and these white blood cells have to be able to get to a site of infection we never want to have the infection actually be in the blood that is usually indicating that our immune system could not fight off that infection when infection gets in the blood so we have to get these white blood cells out to the tissues where we have infection where are some of the very most common places to get infections think about that a cold the flu those are going to be respiratory infections urinary tract infection open body cavities right so the skin when the skin gets broken we know that's very easily to get an infection because your skin is one of your first barriers to infection so if we need to get our white blood cells from the blood to that area of infection they have to get out of the bloodstream and we'll learn a lot about the inflammatory response once we get to the immune system but in general what's going to happen is white blood cells that normally just flow by through our blood capillaries will detect an area of infection because chemicals released at the site of infection caused the lining cells within the blood vessel to secrete proteins they're called selectins think about selecting for something so these selectins are going to attach to the red blood cells the white blood cells as they try and go by and sort of catch them so that Flags them down stops them instead of flowing by they stop and as they start to catch they do this little rolling action and they roll along the endothelium finally come to a stop at an area of infection endothelial cells in the capillary get larger spaces than normal and that helps cells and defense of chemicals to allow to get through out of the bloodstream into the intercession where the cells are located so once those white blood cells stop rolling that diaper deesis action they will then squeeze between the endothelial cells in those gaps and now they're out of the bloodstream we call that process immigration right leaving from one place and going to another so they emigrate and that's also called extra vacation meaning they're going outside the blood vessel let's look at some of the jobs for our white blood cells that were now familiar with neutrophils and macrophages both are strong phagocytes macrophages come from monocytes so once monocytes leave the bloodstream and get into the tissues they change their shape they change their morphology and they become very very good macrophages they actually can destroy way more bacteria than neutrophils but neutrophils are quite effective because there's so many of them we said 65% of white blood cells are going to be neutrophils so they come first and they start breaking down all of these materials through phagocytosis and then the monocytes come second there's not as many of them they transform into macrophages and they take over the job of just getting rid of a lot of those pathogens like bacteria basophils and eosinophils are not known for the phagocytic activity they have their functions more by releasing chemicals although some studies have shown asana feels to have small amounts of phagocytic ability but basophils and eosinophils remember our granular they have lots of these cytoplasmic granules and these granules contain chemicals and these chemicals are going to be active in the immune response one of the main jobs of basophils are to intensify inflammation so those chemicals that get released cause more white blood cells to come to the area tell them where to go it's going to stimulate the increased blood flow through blood vessels help make the blood vessels gappy so that the cells can get through heparin that basophils produced naturally is an anticoagulant so that prevents chemicals coming in from the blood from coagulating too much close to the area of infection is we want our white blood cells to be able to get those bacterial histamine as I said helps dilate the blood vessels and bring more blood to that area and that's why you have an area of infection or even allergy that gets inflamed red puffy swollen itchy eosinophils their job is a little bit different the chemicals that that really they release can actually help kill pathogens and as well activate secondary immune responses so those are responses involving lymphocytes which we'll talk about in a minute eosinophils we see most commonly elevated or coming to areas of infection with parasites or allergic infections one of the chemicals that eosinophils releases histamine ace so it has the opposite effects of histamine but they can phagocytize some antigens some chemicals of pathogens that can be that are targeted by antibodies from our immune system so once they're told what to do they can do some phagocytosis but one of their main jobs is to release defensive chemicals let's look at our lymphocytes we said lymphocytes are a granular along with the monocytes the lymphocytes come in three types and these are basic types we'll see in the immune system that there are subtypes to our B and T cells but B lymphocytes are known as b-cells and their job is to produce antibodies so we mentioned antibodies or immunoglobulins a couple of times immunoglobulin is a fancy name for the antibody and B cells are what create antibodies we haven't learned how antibodies work yet but we will antibodies are proteins that attach to specific things your body has told them are foreign so they don't belong and once anybody's can stick to a foreign material called an antigen then that tells you and helps your immune system to destroy it T cells are T lymphocytes have a couple of jobs we have different types of teas but they are going to be effective in activating immune responses as well as we have t-cells jobs whose job is to go and kill infected body cells directly these cells are the ones that can potentially also remove some self cells so maybe removing cancer cells that can be detected as not being as close to the original body cells as they should be both T and B cells are very specific they can't just attack anything they have to be triggered by particular pathogen parts called antigens and that's opposite compared to the natural killer cells natural killer cells are lymphocytes that are more general they're not specific so they're looking for anything that does not belong and so they can be effective against tumor cells as well as bacteria and other microbes platelets as we had special names for our red blood cells erythrocytes and our white blood cells leukocytes we also call platelets thrombocytes thrombocytes are fragments of a cell and I really like this picture figure 18 point 20 where we see the red bone marrow and all the little developing white blood cells and red blood cells and as giant Omega carrier site we all know what mega means right mega means really large Carrio refers to a nucleus if you remember mitosis is made of two phases karyokinesis then usually followed by cytokinesis so breaking up of the nucleus and then division of the cytoplasm well cario refers to the nuclear material so this megakaryocytes has this huge nucleus and look at the size of this cell it's probably almost as big as an ovum which is the largest cell we have so these cells the megakaryocytes do not leave the red bone marrow they stay there but they have these little cytoplasmic extensions that goes the sinusoid holds right remember sinusoids are capillaries with larger gaps in them and the megakaryocytes is constantly shedding pieces of itself and those are platelets now platelets are not cells their cellular fragments which is why we can't call all the things inside the blood blood cells we have to call them form elements what do the job of platelets platelets have the job of stimulating coagulation they're very very sticky so anything that's going to trigger platelets to stick will first form a ball of platelets called the platelet plug and then stimulate the coagulation process which we'll talk about later so platelets have all these little granules inside them and their job is to cause blood clot platelets being sticky means that the insides of blood vessels need to be extremely smooth so anytime we have an irregularity maybe a lipid plaque or maybe a cut in the vessel and expose collagen fibers then we can have platelets stick stem cell transplants when someone receives transplanted tissue usually the issue is having the body reject that tissue as it is recognized as foreign when stem cells for immune cells are transplanted into the body for example with bone marrow transplants we now have to worry about those transplanted immune cells essentially rejecting and a chat attacking the new host body this is called graft-versus-host disease and it takes time for rejection to occur but it's kind of the similar case but in this sense graft-versus-host disease we have the new T cells and B cells from the transplanted bone marrow attacking the host body one of the things you often hear about in terms of stem cell transplants is the idea of saving cord blood umbilical cord blood does have stem cells in it that can be true frozen at birth and the idea behind keeping these stem cells is that perhaps later the stem cells can be used to treat diseases in that you know what was the baby when they grow out in this case those stem cells would be self cells and therefore there would be no chance of having rejection or graft-versus-host disease whenever one somebody transplants tissues from yourself to yourself like for example a skin graft that's called an auto transplant so that ensures that there's no chance of graft-versus-host disease or rejection number eight hemostasis hemostasis is the process of making sure that the blood stays within the vasculature you want the blood to stay in the blood vessels what happens if somebody has too much bleeding too much hemorrhaging well we know that they die absolutely but we need to remember why is it someone dies from a hemorrhage the function of the blood from a minute-to-minute basis is to deliver oxygen and if there's not enough blood not enough blood pressure to deliver the oxygen the first tissue that suffers is the brain a lot of the other tissues in the body are much more resilient to reduce oxygen levels the brain and the heart are the two most sensitive organs so we must maintain that circulation of blood to bring the oxygen blood also does carry a lot of other nutrients it removes waste like carbon dioxide which are very very important but we know with just a brief interruption of blood flow to the brain that causes us to lose consciousness so hemostasis is a process to make sure that if there's a rupture or a break in a blood vessel that we try and block that off so that we don't lose the blood so that the blood can continue to transport the oxygen to the brain there are three mechanisms of hemostasis to reduce blood loss vascular spasm platelet plug formation and blood climb like it sounds vascular spasm will cause a quick contraction of the smooth muscle in the walls of the arterial you can have Vino constriction as well so constriction of the veins because they do have muscular walls what stimulates the vascular spasm is an irritation to the lining of the wall of the vessel this could be due to a cut it could be due to a crushing injury it can be due to foreign objects or materials inside the vessel wall the platelet plug formation just like it sounds forms a mass of platelets to try and block off the flow if the hole is very small then a platelet plug can be enough to block the blood loss platelet plug formation also activates coagulation the third step in hemostasis which we think about as blood climb we'll go through the process of blood clotting in detail in the following slides here we see in figure 18 point 2 1 a and C a to see that we have the three mechanisms of hemostasis showing a very small blood vessel this is a tiny arterial so vascular spasm will cause constriction of the smooth muscle in the lining here we see a hole in the vessel exposed collagen fibers from the connective tissue that causes the muscle to contract when the muscles contract inside the smooth inside the smooth muscle wall of the tunica media of a blood vessel that is now going to make the opening or the lumen smaller and you can see in this picture the very tip of the blood vessel is kind of tightened it's small and that reduces the amount of blood that can flow through that hole because now the hole is smaller and could potentially stop blood flow all together and that will reduce or stop hemorrhaging in the center picture B we see the platelets forming a mass that's called a platelet plug platelet plugs are fairly loose and not that strong so platelet plugs can't really do a good job at blocking larger holes very very small hole but one of its major job is is to lead to coagulation in the third stage this isn't the greatest picture of coagulation but the process of blood clotting is going to create chemical signals so that plasma proteins present in the blood as soluble materials become insoluble turn into fibers from these long fibrin strands that will help reinforce the platelet plug as we see in this picture but also the fibrin fibers catch the red blood cells as they try to exit out of the hole and that's why blood clots appear red because they capture the red blood cells stuck in these fibrin fibers the second stage in hemostasis platelet plug formation has three main stages adhesion release reaction and aggregation an order to remember the names of these stages let's make sure we can understand what adhesion release reaction and aggregation mean just in terms of the words adhere means to stick to so in the adhesion stage we're having the platelets stick to what ever is a regular inside the blood vessel platelets we said are already pretty sticky so if there's anything that's not smooth lining of the endothelium layer inside the blood vessel then platelets can get activated and get sticky once they activate they will start to release their cytoplasmic granules much like some of the white blood cells platelets are full of granules full of chemicals and some of those chemicals are going to activate other platelets around them so after the release reaction we now have all these chemicals floating around in that area where the platelet plug is forming and some of the chemicals include ATP and serotonin and those chemicals activate adjacent platelets and when more platelets continue to get activated and stick together we call this aggregation an aggregate is when you have a bunch of things in one area aggregation is going to be when we actually form the platelet plug so if we look at the diagram we see in the first part we have the platelets and the bloods cells kind of floating through the bloodstream properly but some of the platelets have detected an irregularity and that causes them to stick so that's the adhesion stage in this case they're detecting exposed collagen fibers because there's damage to the blood vessel so even if blood is not leaving a blood vessel platelets can get activated and this is how individuals get blood clots from reduced blood circulation because now the platelets kind of swirl around and get a little bit sticky it could be problem with a valve a valve that doesn't function correctly can stimulate platelets to start activating if you have an artificial valve inside the heart that is a foreign object and that can cause platelets to stick if someone has a thorough sclerotic plaques so fat deposits inside the blood vessels that's an irregularity that can cause platelets to activate so those are all ways we can get clots starting from platelet activation in an intact vessel so when we're starting platelet plug formation those little platelets detect something they activate and stick during adhesion then they will de granulate they'll release all their cytoplasmic granules contents and those chemicals signal other platelets to come D granulate activate stick and they form this ball called a platelet plug it's not a blood clot yet because blood clotting is the third stage but this mass of platelets is a platelet plug this could be useful if there is an actual tear inside the blood vessel lining to help eliminate or reduce blood loss sometimes this happens when the vessels intact and may just have something irregular inside it and that will start to cause a blood clot or thrombus the process of coagulation is a series of chemical reactions that is going to take soluble proteins inside the blood we talked about fibrinogen being inside the blood and form it into insoluble fibers so if you look at the diagram on the bottom 18 point 2 3 we see that there's a list of all of these individual factors starting from the top leading down to production of fibrin we can see fibrin being produced and catching red blood cells in the series of pictures on the right hand side the red fibrin fibers are attaching to platelets they're capturing red blood cells they form the tight mass called a blood clot how are we going to get to form v and fibers is the series of chemical reactions I'm referring to we do not have to know all of these reactions I will point out to you which particular enzymes and products that you should know but we do need to remember that as a series of chemical reactions one of the most important cofactors we need is calcium ions in the blood and you probably remember how we talked about how calcium in the blood is important we regulate blood calcium using PTH in calcitonin though two hormones if we don't have adequate calcium in the blood we cannot clot these chemical reactions won't occur so essentially what your body is going to do is make sure we have enough calcium in the blood we're going to take it out of the bone whenever necessary the stages of blood clotting there are two pathways that are going to initiate blood clotting those are called the extrinsic pathway and the intrinsic pathway they most both meet in a third pathway called the common pathway so no matter how blood clotting is initiated they're both going to trigger the last series of reactions that are going to lead to the fibrin fibers extrinsic means coming from outside intrinsic means coming from the inside and so understanding what these two words means will help you remember what is going to initiate the clotting process let's think about the intrinsic pathway which is shown in the yellow and as I told you you don't have to remember or memorize all of the individual clotting factors and reactions but just the ones that I'm going to point out to you anything that initiates platelet degranulation is going to initiate the intrinsic pathway of coagulation so you see up in the yellow this is the intrinsic pathway and we said what types of things can initiate platelets sticking a break to the blood vessel exposure of collagen fibers something irregular inside the blood vessel like a artificial valve a plaque from from lipid deposits a valve that's not working properly that causes reduced blood flow and the platelets kind of swirl around and have the opportunity to activate once platelets do granulate not only do they form their own little platelet plug but that leads to clotting factors being activated that's going to lead to our common pathway most the clotting factors that are found in your blood and would be considered part of your plasma proteins are made by your liver never forget your liver has many functions one of them is to make most of your clotting factors so anything that impaired liver function can impair coagulation we'll look at a couple little of these chemical reactions that the intrinsic pathway starts right we activate factor 12 we're going to work our way down and number in terms of the clotting factors see how calcium is used in the third pathway third chemical reaction and that's going to lead us to a chemical that will help us get to the common pathway you don't have to know all the intermediate stages on the left-hand side here in the orange we have the extrinsic pathway so extrinsic means outside right so the factors that initiate this pathway do not have to be in direct contact with the blood like we did have for the intrinsic pathway we can have external trauma trauma to the tissues around the blood vessel those are called peri vascular tissues tissues around the blood vessel peri vascular and maybe the blood vessel itself isn't disrupted yet but the the idea is that if you have an injury to the area we might have a break in the blood vessel so those injured tissues release a hormone called tissue factor and tissue factor is abbreviated TF it's also called thromboplastin it has a few names a lot these clotting factors have multiple names so we're gonna try and keep it very simplified but notice how when we do trauma to the peri vascular tissue the tissue releases tissue factor there's only one reaction shown here still requiring calcium ions to lead us to the common pathway so looking at the two pathways at the top the extrinsic pathway in the orange the intrinsic pathway in the yellow which one do you think is faster correct the extrinsic pathway is faster because there are fewer reactions so there can work simultaneously if you have a trauma to the body that has caused perivascular dish peri vascular tissue trauma or damage or we have a break to the blood vessel so those can happen at the same time or they can be independent of one another so it's kind of as if we have two mechanisms to make sure this gets done once we have activated either the intrinsic or extrinsic pathway that's going to lead us to the ability to create this enzyme called prothrombin ace it's also called prothrombin active or ik activator because of its job of activating prothrombin prothrombin ace tells you it's an enzyme ase at the end of the name of protein means it's an enzyme the extrinsic and intrinsic pathways are both going to lead to production of prothrombin ace and prothrombin ace is actually what we call a complex several proteins coming together once they've been activated to form this active enzyme prothrombin activator is going to require also calcium ions in these series of chemical reactions in the common pathway the function of prothrombin e's is to take the plasma protein prothrombin and verse it into thrombin when you see pro on the front of a protein it means that that protein is not mature yet it is not finished being altogether in its final format so prothrombin gets converted into thrombin usually by cutting off some amino acids or by adding on a chemical that changes its folding thrombin can now is now a mature protein and thrombin is actually another enzyme even though its name does not end in ASE thrombin job is to convert fibrinogen which we said is another plasma protein made by the liver into fibrin when you see Oh Jen on the end of a protein usually an enzyme it means that it's in its inactive form we often don't want enzymes to be doing things all the time just when we tell them to so they can be secreted and produced in inactive forms and we'll see the same thing happen when we get to the digestive system so fibrinogen is a soluble plasma protein when thrombin converts it into fibrin fibrin is now not soluble anymore so it turns into a solid and using other chemicals that are found in the blood fibrin sticks to itself to form long fibrin polymers remember the idea of a polymer is when you have many monomers stuck together with covalent bonds so these long fiber and polymer strands stick to that platelet plug catch the red blood cells as they try to pour out of the opening in this blood vessel which we don't want we don't want all the blood to go out that forms the big clot the mass of the red blood cells and the fibrin and the plate plug all stuck together so overall you need to remember that we have these two pathways that initiate blood clotting they both lead to production of prothrombin 'is the enzyme that's going to finish the common pathway prothrombin is converts prothrombin to thrombin thrombin is an active enzyme that converts fibrinogen into fibrin fibrin produces the threads of the clot that holds everything together in a mass and that's going to block blood flow to reduce blood loss just to recap we said that blood clotting has two pathways of initiation the extrinsic pathway is initiated from damage to barrett peri vascular tissue that tissue outside the blood vessel when it is damaged damaged releases a hormone known as tissue factor also called thromboplastin that then leaks from the peri vascular tissue inside the blood and can lead to the chemical reactions that form prothrombin ease in the intrinsic pathway that is initiated by damage and factors within the blood itself only for example anything that's going to activate platelets will trigger the intrinsic pathway that series of chemical reactions takes longer than the extrinsic pathway because there are more reactions so it's a bit slower but also leads to the formation of prothrombin ease let's think about how the liver is making some of these clotting factors that are all going to be present in the blood at all times in case you need them for hemostasis vitamin K which you may have heard of is which is important in blood clotting is important because vitamin K is used to make factors 2 7 9 and 10 you don't have to memorize that but you should know that vitamin K is necessary to make some of our client's so what do you think could happen if you're deficient in vitamin K that's right that could prevent your your liver from producing the correct amount of clotting factors and either your clotting time could be increased the time at which it takes your body to clot from a cut or it may be compromised all together where you cannot coagulate at all blood groups and blood types red blood cells have many surface molecules that identify them particular severe transfusion reactions when transplanted into another person have been identified for the blood typing system something that attaches to an antigen that causes clumping of the cells is called an agglutination agglutination is the clumping of cells due to an antibody and antigen reaction so the agglutinins on the surface of the red blood cells are dependent upon every individual person's genetics but when we think about how we're going to determine if one person can receive blood from another we have to consider those surface markings that are individual to the person the blood typing is based upon two main antigens also of lutein agents a and B and that those are very similar to environmental antigens that we are exposed to when we are very young so people who don't have those chemicals as self will make antibodies for the immune system against them and those antibodies can target those cells so red blood cells have many many many surface molecules many blood groups have been identified but we're using the a B and Rh antigens for our blood typing system because they can cause the most severe transfusion reactions when they are mistyped here we have the different blood types or blood groups that we could potentially have they are based on the a and B antigen we'll talk about Rh factor next which is known as D antigen if the red blood cells only have a antigen on the surface of their red blood cells then they're called Type A if the blood cells have only B antigens on their surface they're called type B and if they express both a and B antigens we call the blood typing a B a person who has neither a nor B antigen on the surface of their red blood cell is called Type O now remember the blood cells still have many many other groups and antigens on their surface but we're just looking at the presence or absence of type of a B antigens when we have those antigens react with antibodies which are immunoglobulins found in the blood of a person first those antibodies stick to the antigen which causes them to a gluten eight so the cells all clump together and that targets those cells for destruction through hemolysis hemolysis or hemolysis lysis is the break up of the cell membrane and hemo refers to the red blood cells specifically so hemolysis is the destruction and breaking up of red blood cells and that's what occurs during a transfusion reaction so we cannot give somebody who's got type A blood and red blood cells that have type B so we'll see why in the next slide here's a picture looking at the red blood cells for all the four blood types type a has a Agence type B has B antigens type a B expresses both of them and Type O has neither now because we said a and B antigens are similar to environmental antigens your body will start to make antibodies against them as being foreign if you do not have those as self antigens so for example we see in the type a person they will never make antibodies against type a tense against a antigen normally because that's a self antigen but if we look below and we see that little snowflake shaped antibody those will be detecting non-self antigens so things that maybe the body thinks is going to be foreign could be a pathogen we want to get rid of for some reason the a and B antigens the body detects as foreign so someone who's Type A will automatically start making anti B antigens from a young age you have to be exposed to an antigen in order for your immune system to make an antibody towards it type B red blood cells Express B antigen on the surface but their plasma the blood has anti a antibodies again they're not going to make antibodies against B antigens because that's a self antigen and would cause agglutination in Humala hemolysis someone who's type a B does not make either A or B antigen or a or b antibody because both a and B are self antigens so you see that there's no antibodies in their blood for a or B that's what makes type a B of universal recipient because they don't have antibodies to interact they can receive from type a Type B type a B or oh let's look at Type O Type O individuals have neither a nor B antigen so both a and B antigens are considered formed by the body and you will find anti a and anti-b antibodies in the plasma we draw the antibodies like this as a little snowflake because this is the type of antibody that causes the most severe transfusion reactions each of those little Y shaped structures on the snowflake combine to two antigens at a time so we can have ten antigens bound and potentially ten red blood cells bound attached every time we have interaction so that's what causes the clumping the agglutination process in Type O we can see that because we have the presence of both an T a and anti-b antibodies that person cannot receive blood from a person of type a Type B or type a B they can only receive from o looking at Type O with none of the surface antigens that were interested in on the on the present on the surface of the red blood cell they can be donated to all the other blood types because they aren't recognized by any antibodies in the plasma so Type O is a universal donor they can give to a B type B type a and type O when you transfuse blood from one person to another you have to be considerate of the antigens on the red blood cells we do not have to worry about the plasma antibodies because they're in such small amounts in that transfuse blood that it won't have any effect so we're just considering for the transfusion the recipients antibodies and the donated bloods antigens during the blood typing process were utilizing the presence of the antigens and the interaction between antigen and antibody causing agglutination to detect the presence of a or b antigens remember if someone has a antigens their type a if they have B antigens or type B and if they have both a and B antigen on their red blood cells or type a B and if they have neither their Type O we can synthesize antibodies towards a and B antigens in the laboratory and then utilize them on blood to determine what blood type the person is when we add anti a and anti-b antibodies to a blood sample and it causes agglutination with type A that means they have a antigens and no B antigens so their blood type is egg if the agglutination occurs with anti-b antibodies but not with anti a it means those red blood cells have only B antigens and so are type B if we see clumping or agglutination with both antisera anti a and Aunty B antibody that means the cells have both a and B antigens and so our type a B if there's no reaction with either antibody it means that there's neither antigen and therefore they're Type O so this is not the same as the transfusion reaction but we're utilizing the antibody antigen interaction causing agglutination to detect the blood type so here we're just worried about understanding which antigen is present because the antigen that's present determines the blood type a for a B for B a and B for both a B and neither for Type O lastly we will talk about Rh factor and Rh incompatibility normally a person does not make antibodies to an antigen until it enters the body then it is detected as foreign and your immune system particularly or lymphocytes your B lymphocytes are going to make antibodies towards that antigen when the antibody contacts the antigen it causes an Raye of effects one of them being to clump up that antigen and flag it for removal by your immune system the a and B antigens are special on your red blood cells because we said they're very similar to environmental antigens so we make antibodies towards them early on in childhood most other antigens have to be directly in contact or enter the body in some other manner you get infected with chickenpox virus so your body will make antibodies towards chickenpox virus you get injected with the booster shots when you're a child and that forces your body to make any bodies towards measles mumps rubella for example Rh factor is another surface antigen on your red blood cells but we normally do not make anybody's towards it until we're exposed to it once then that stimulates the immune system as a non self antigen Rh factor is also known as D antigen so when we think about the possibility of having blood transfusions we will typically match the Rh factor as well Rh positive means the presence of D antigen Rh negative blood means there's no D antigen on the surface someone with no D antigen on the surface of their red blood cells can detect and create antibodies against D antigen if it enters the body so someone who's o+ receipt o negative sorry receives o+ blood for the first time that's going to stimulate their immune response because we don't know what antibodies are in the plasma of somebody when they come in to the ER for example we don't make the assumption that they have no aunty D antigens so will tend to type the blood specifically that's why own a it is truly the universal donor neither a nor B nor D antigen so having said that when a mother is Rh negative and has a baby with a father who is Rh positive that can lead to the potential of having an Rh positive baby we now have to think about what can happen when the mom gets in contact with the blood from the baby normally during pregnancy there is no mixing of the blood between the mom and the fetus the blood vessels in the placenta come very close to one another so materials and nutrients can move by diffusion but there's no mixing what happens is when a first Rh positive baby is born the placenta has to detach and that tears a lot of blood vessels at the time of birth so fetal blood can now mix with maternal blood and that will stimulate the mom to make antibodies toward Rh factor anti D antibodies so the first baby is not going to have any problem with Rh incompatibility because the mom does not have any antibodies yet against Rh factor it's the second baby we have to be concerned with if the mom has another Rh positive baby then that potentially those antibodies could cross the placental barrier and attack the fetal red blood cells and that's called hemolytic disease of the newborn the reason why it tends to affect a late gestation baby or an older fetus is because the type of antibodies that moms make the first antibodies that a person makes are always those big snowflake shaped ones those have ten antigen binding regions they're too big to cross through the placenta so we don't have to worry about that but later on the ones that we make the first ones are called IgM the second ones we make in larger amounts are IG g IG g are small enough there are v is size IG m to cross the placental barrier so you see in our picture the first time an Rh positive baby is created by an Rh negative mom when the baby's born she can get inoculated essentially with the baby's blood that's Rh positive she makes and develops antibodies against that Rh factor they draw them here incorrectly they would be IgM s the next baby could be attacked by the moms antibodies and that would have the same effect as a transfusion reaction where the red blood cells first get a gluten Aidid and then get hemolyzed and a baby who's born with hemolytic disease of the newborn or hemolytic anemia would have to have a total blood transfusion how do we prevent this this is one of the reasons why we think look at the blood types of the mom and the father's if the mom is Rh positive we don't have to worry she will never normally make antibodies against her own antigens it's only Rh negative mom we have to worry about if the father is Rh positive if there's two rh negative people having a child the baby will automatically be Rh negative due to the genetics we haven't covered genetics but we'll talk about that and the chapters way down the road so we only have to worry about this for an Rh negative mom with potentially Rh positive dad and potentially Rh positive baby what they can do is usually before birth they're going to start treating the mom as well as after birth with an anti RH antibody essentially what it does is it's an antibody called gamma globulin that's going to attach to that Rh factor it finds if it gets in the mom's bloodstream and what that will do is give them mom what we call passive immunity so she doesn't have to make her own immune response to it and that way we won't develop the ability to make her own antibodies ones that she are given will just be destroyed when they get old because they're just proteins gamma globulin is globulin is given before and after birth and for every subsequent pregnancy for an Rh negative mom that's it for chapter 18