Chapter 13, Alterations in Oxygen Transport. So in this chapter, we'll talk about the composition of blood, we'll introduce adult hemoglobin, and then the process of making red blood cells, so urethropoiesis. Then we'll talk about anemia, thalassemia, sickle cell anemia, and then we'll end with fetal hemoglobin.
So what is blood made up of? So total blood volume is about 75 milliliters per kilogram in men, 66 and a half in women. So about 7 to 8% of your body weight is from your blood. So in terms of how many liters, we have about 5 to 6 liters. Now your blood is divided into the cellular components and plasma.
So the blood cells make up about 45% of your blood volume. And your blood cells would include things like your red blood cells, your white blood cells, and your platelets. Plasma makes up the rest, about 55% of your blood volume. and plasma is made up of 92% water and then 7% plasma proteins.
So what are some of the organic and inorganic components of your plasma? So the plasma proteins are formed in the liver, and they really help contribute to osmotic pressure. There are three general types.
We have our albumin, our globulin, and fibrinogen. So for instance, when albumin levels fall, we change the osmotic pressure within our blood. And so we start to lose water out of the circulatory system into the extracellular space or interstitial space. We also have some regulatory proteins in the plasma like hormones and enzymes. And then organic constituents like products of tissue metabolism and the nutrients.
and other particles related to that, and then inorganic constituents like electrolytes and ions. Electrolytes like ions and then things like iron as well. So what about the cellular components? So we said our blood cells including urethrocytes, red blood cells, leukocytes, white blood cells, and platelets.
So our red blood cells are important for the transport of oxygen from our lungs to our tissues. The red blood cells will also help remove carbon dioxide from our tissues, deliver it to our lungs so we can breathe it out. And another function of red blood cells is that it acts as a buffer.
So it can actually bind up hydrogen ions and help buffer changes in pH. Our leukocytes are white blood cells. They act primarily in tissues, but they circulate obviously in the bloodstream and the lymphatic system. And again, we talked about white blood cells already, but they really help protect our body from invaders as well as from our own cells. And then we have platelets.
Platelets are formed from fragments that kind of break off from these really big cells called megakaryocytes. And they help with clotting. So these platelets are really important so that we don't bleed out.
About a third of our body's platelets are found in the spleen. So let's move on to specifically our adult red blood cell, so adult hemoglobin. So hemoglobin is what's found inside your red blood cell.
It's made up of two alpha chains and two beta chains, and we can see that over here. So the alpha chains are shown in purple, the beta chains are shown in yellow. Now within each hemoglobin chain, we have an iron-containing heme group.
So this iron-containing heme group shown here is what actually carries oxygen. So this is one red blood cell. So this one red blood cell has one, two, three, four iron-containing heme groups. So it has the potential to carry up to four oxygen molecules.
The average person has about 15 grams of hemoglobin per deciliter of blood. So let's make some red blood cells. So the process of making red blood cells is called urethropoiesis and You're going to be stimulated to make red blood cells when your body senses oxygen levels are low.
Now, obviously, when oxygen levels are low, you'll have other responses like increased respiratory rate. But one of the things that it will also do is stimulate more red blood cell production. Why?
Because we carry oxygen in our red blood cells. So it's a way to make sure we have more red blood cells to carry more oxygen. So when our body's chemosensor sense that oxygen levels are low, we are going to release a hormone. that stimulates red blood cell production.
That hormone is released by the kidney, so it will secrete urethropoietin. So urethropoietin is the hormone that stimulates urethropoiesis, which is the production of urethrocytes, our red blood cells. So the urethropoietin that's released in the kidneys will circulate through our bloodstream, make its way to our bone marrow, and stimulate our bone marrow to make new red blood cells. So then why would a man that's receiving chemotherapy for cancer possibly develop anemia? So we talked about cancer previously.
We talked about how chemotherapy and kind of other treatments might target dividing cells. So now here I have radiation damage, but chemotherapy as well targets dividing cells. So because when you're trying to make new red blood cells, they are dividing, these cells might be targeted and selected for, and as a result, you may not make as many red blood cells and that may lead to anemia.
Why would a man with renal failure possibly develop anemia? Well, take a look. Our kidneys make urethropoietin.
It secretes it here. So when you have renal failure, your renal system fails to do its job, including not just keeping blood composition normal, but another function is to make urethropoietin. So that would also be compromised.
And so if you don't make the hormone urethropoietin, you won't be stimulating your bone marrow to make new red blood cells. So let's continue on with this cycle of urethropoiesis. So we've made some new red blood cells. They're going to mature, and our mature red blood cells will circulate for about 120 days.
And after about 120 days, they are sufficiently damaged. Now, our red blood cells don't have a nucleus, so they cannot repair its membrane when it gets damaged as it's circulating through our bloodstream. So after about 120 days, it's been sufficiently damaged.
So what do we do with these red blood cells that we need to kind of get rid of? Well, they break in capillaries of the spleen. Now, when you break in capillaries of the spleen, the spleen has a lot of white blood cells.
And so when these red blood cells break, the hemoglobin inside the red blood cells gets released, and the white blood cells are there to eat up. that hemoglobin. Now, the spleen is a normal place for red blood cells to break. So is the liver, the bone marrow, and lymph nodes. And I want you to notice all of these places we have a lot of white blood cells to eat up the hemoglobin that is now released from our red blood cell.
And that hemoglobin will get processed by our white blood cells into something called bilirubin. Now, right now, this bilirubin is unconjugated, which basically means it's not bound to anything. An unconjugated bilirubin building up in your blood can be toxic.
So let's ask a question. Why would a man with defective red blood cells develop hepatosplenomegaly, which is enlargement of the liver and the spleen? Well, if you have defective red blood cells, they're going to be destroyed much quicker. So they're not going to live a whole 120 days. They might only live 60 days.
And so you're going to have greater activity within the liver and the spleen. And so your white blood cells might multiply to try to deal with all of this red blood cell destruction and all of this hemoglobin that's getting released, and as they multiply, it will enlarge your liver and enlarge your spleen. So now let's continue on. We have our hemoglobin that processed into bilirubin, and like I said, that is unconjugated bilirubin. Now, unconjugated bilirubin is toxic.
So if that bilirubin just builds up in the blood, we have bilirubin. So it's basically bilirubin in the blood. And bilirubinemia, one of the signs of that is jaundice, and that's that yellowing of the skin.
Now another thing that we would actually like to do with that unconjugated bilirubin is we're going to conjugate it. We're going to link it to glucuronic acid, and the liver will do that. And now we have conjugated bilirubin, and the liver will then use that conjugated bilirubin to make bile. So that's it. but conjugated bilirubin is a component of bile.
And then you'll store that bile in the gallbladder, and then you'll release that bile to help digest fat in your GI tract. So basically, this is an example of your body kind of recycling itself. So why would a man with liver failure develop jaundice?
Well, if your liver fails, your liver can't link our unconjugated bilirubin, so then bilirubin starts to build up in the blood, and that's how you get jaundice. because he's unable to remove it from the body. So this is a figure from your book that kind of goes over another way of looking at the life cycle of a red blood cell.
So we have our bone marrow making our urethrocytes. Our red blood cells live for about 120 days. Now they're damaged.
We will destroy them. Hemoglobin gets released. It'll get converted into bilirubin.
The liver will link it into conjugated bilirubin, making bile with it, and then we'll release the bile into our small intestine. Alright, so let's say things don't go exactly the way they should, and now instead of our red blood cells being destroyed in the spleen, or the bone marrow, or the liver, remember those are all normal places, let's say it just breaks outside of those areas. So right now I just said the spleen here, but it really is outside of all those other areas that we mentioned.
Well then what happens is that hemoglobin is just getting released into the blood. Normally white blood cells, we have a lot of them. ready and waiting to digest that hemoglobin and turn it into bilirubin.
But now that it's being broken in other areas where we don't have all of these white blood cells ready and waiting, the hemoglobin just gets released into the blood. So now we have hemoglobinemia. So that is a buildup of hemoglobin in the blood. And when you have hemoglobinemia, that really turns the plasma red. And things in the blood, a lot of the times, you will filter in your kidneys and it'll show up in your urine.
including hemoglobin. So then you start to see hemoglobin in your urine, and that's called hemoglobin urea, hemoglobin in your urine, and that will turn your urine a dark brown color. So here I've described it as it looks like Coca-Cola. So then why do you think malaria was called black water fever? Well, people who had malaria, basically that parasitic infection causes red blood cells to be destroyed.
They're being destroyed kind of anywhere and not just in the spleen, the bone marrow, etc. And so now you start to have hemoglobin just building up in the blood, eventually showing up in your urine, and people were urinating urine that was very, very dark. So they called it blackwater fever. All right, so now that we talked about the process of urethropoiesis and the life cycle of a red blood cell, let's discuss an issue with red blood cells, and that would be anemia.
So anemia is an abnormally low hemoglobin level or a low number of circulating red blood cells or bull. But whatever the case, it is having a lower oxygen carrying capacity than normal. So your capacity to carry oxygen is less than it should be. It could be because you don't have enough hemoglobin. It could be because you don't have enough red blood cells or a combination of Now, why is this a problem?
Well, our tissues need oxygen. It needs oxygen because we use oxygen to do aerobic metabolism to make energy. So if we don't have enough oxygen, we will suffer from tissue hypoxia.
Our tissues won't get enough oxygen. Anemia itself is not a disease, but it is an indication that there's some disease process or alteration in the body going on. Now, our body is really good at compensating, and so we have compensatory mechanisms to try to get more oxygen to our tissues. So it's an emergency.
So think of turning on the GAS, the General Adaptation Syndrome, or symptoms. So we're going to activate our sympathetic nervous system. We're going to increase our heart rate, increase cardiac output, increase contractility. We're going to get increased circulatory rate.
So more blood is getting delivered to our vital organs. So even though there's less blood within a, I'm sorry, even though there's less oxygen within a volume of blood. We're going to try to send more blood to our tissues so that it's compensating and getting as much oxygen as possible. Another way you can compensate is by increased levels of 2,3-DPG. Now, 2,3-DPG, when it increases, it causes the affinity between hemoglobin and oxygen to reduce.
So again, our red blood cells have the potential to carry up to four oxygen molecules. And what happens is when a red blood cell goes to our lungs, it'll get saturated. It'll carry all four.
When that same red blood cell goes to our tissues, it will actually only release one oxygen molecule to our tissues. It doesn't give it all four. And why is that? Think of physiologic reserve. So then let's say for some reason we need more oxygen in our tissues.
Let's say we're exercising and our tissues need more oxygen. Well, Because in normal situations, we only give one of our four oxygens to our tissues. When our tissues need more, now we have three more we could give.
That's our physiologic reserve. What 2,3-DPG does is it reduces the affinity so that when these red blood cells comes to our tissues, instead of just giving away one oxygen, it causes it to give away two. So even though you may have less red blood cells, because each red blood cell is releasing more oxygen molecules, it is a way to compensate.
Okay, so what causes anemia? Well, blood loss. So when you're bleeding whole blood, you're just losing red blood cells, so your capacity to carry oxygen will be reduced.
Or maybe there's hemolysis going on. There's red blood cells that are being destroyed, maybe again because of malaria. Or it could be you have impaired red blood cell production. So remember, your red blood cells have a life cycle.
They live for about 120 days. So literally every day you're making new red blood cells and you're breaking down red blood cells. And that level should stay constant so your red blood cell count really doesn't change.
So if you are losing more red blood cells than normal, you'll get anemia. or if you're not making them at the same rate that you should, and that's where the impaired red blood cell production comes into play. Now, that could happen for several reasons.
One would be you have issues with a lack of nutritional elements. For example, you need iron to make red blood cells, because remember, we have an iron-containing heme group in our red blood cells. So if you don't have iron, you don't have the nutrients, the elements necessary to make red blood cells. We also have folate and vitamin B12.
These are necessary for DNA synthesis, so these are also required. This is why women who are pregnant tend to take extra folic acid. Or maybe there's just something wrong with your bone marrow.
It's depressed, and so that can also impair red blood cell production. So if you do have anemia, how does it manifest? What does it look like? So normal levels were about 15 grams per deciliter, so anything that's Eight grams and above would be considered mild anemia, so you have some mild symptoms. Below eight grams per deciliter, you'll have more moderate to severe symptoms, and that includes things like a drop in blood pressure, hypotension, pallor, paleness, rapid breathing.
Again, that would be a way to compensate. We have headaches, lightheadedness, fainting. Again, that's because your brain isn't getting enough oxygen.
Tachycardia, palpitations. Again, think of compensation. Our body is increasing our heart rate. trying to send more blood to our tissues. So that can lead to angina.
Your heart is working harder, but your blood has less oxygen, so the oxygen demand might not be met by the oxygen supply causing chest pain. And it can even lead to heart failure. You can also have some nighttime leg cramps. You'll have fatigue, because you don't have enough energy, and so you'll be weak.
The red blood cells can also change in terms of what they look like. So here, On the far right, we have what normal red blood cells look like. So I have this biconcave shape. Here's what sickle cell looks like.
So we have these sickled red blood cells. And that's, I will talk more about sickle cell anemia. We have megaloblastic anemia. This is an inhibition of red blood cell DNA production.
And it causes these like kind of big red blood cells. And here we have iron deficiency anemia. So you don't have enough iron to make hemoglobin.
So you have reduced hemoglobin. And so your red blood cells look pale. So we have a man who had severe anemia and he developed weakness, angina, fainting. He has tachycardia, sweating and pallor, and he has pain in his bones, including his sternum.
So looking at his signs and symptoms, we're going to go over which are caused by just a decrease in red blood cells and a decrease in oxygen, which are caused by your body compensating by turning on the GAS, and then which are caused by your body's attempt to try to replace. red blood cells. So he has severe anemia. So what do you think happened to his red blood cell count?
It probably went down. It reduced. Now if his red blood cell count reduces, his skin is going to look pale because there's not a lot of blood. If he has a lower red blood cell count, what would that do to his oxygen levels?
His capacity to carry oxygen will also be reduced. and that means your tissues will become hypoxic. They're not gonna get as much oxygen as they should, all of your tissues, but let's talk about three of them. So what would that do to your muscles?
It'll make them weaker. What will it do to your brain? You'll have lightheadedness, you might faint. What will it do to your heart?
It might cause chest pains, angina. And then number five, is the GAS activated? And the answer is yes, it'll be activated. It's an emergency, we're gonna try to compensate. And when the GAS is activated, what will your blood vessels do?
Well, your blood vessels will vasoconstrict. And when your blood vessels vasoconstrict, especially in your skin, it'll cause even more paleness. And what will your heart rate do when you turn on the GAS? Well, the sympathetic will increase heart rate. So your heart will beat faster.
You'll have tachycardia. And then what will your kidneys do? So you have low red blood cell count and low oxygen. Didn't we say when your body senses a drop in oxygen, your kidneys will secrete a hormone? Which hormone?
Your erythropoietin, which will go to your bone marrow, so they will make more red blood cells. Your bone marrows, as they're working more, may expand, and that expansion is what's leading to bone pain. So in the previous slide, I asked, well, which signs and symptoms are due to just low oxygen and low red blood cell count? That would be everything in red here. Which are due to your body trying to compensate by turning on the GIS?
And that would be everything in yellow. And then which are due to your body trying to replace the red blood cell that was lost? That would be everything in green. All right, so let's take a look at anemias where it's particularly or specifically due to deficient red blood cell production.
You're just not making them like you should. So again, we said nutrients, your nutritional elements, having a lack of them plays a role. So iron deficiency anemia is the most common diet deficiency in the world. So you need that iron.
So if you're not getting it, you'll have iron deficiency anemia. We have megaloblastic anemia. Again, this is inhibition of DNA synthesis. And so things like vitamin B12 and folic acid, remember these are required for DNA synthesis.
So when you have a deficiency in these nutrients, that will lead to megaloblastic anemia. Now I wanna briefly mention pernicious anemia. Pernicious anemia is where you don't have enough vitamin B12 in your blood, but it's not necessarily because you are not ingesting it, it's because the vitamin B12 isn't getting absorbed into your body. And in order to absorb vitamin B12, you need something called intrinsic factor that's released by the parietal cells in your stomach.
So if your parietal cells aren't making the intrinsic factor, the vitamin B12 isn't getting absorbed like it should. And so it leads to pernicious anemia. So it's a specific type.
Aplastic anemia is just things like stem cell disorders due to just depressed bone marrow, maybe caused by toxins, radiation, immunologic injuries. So you It's just the bone marrow, it just isn't working. And then we have some chronic disease anemias like chronic inflammation or chronic renal failure. Remember, if you have chronic renal failure, you're not gonna make urethrapoetin and so you won't stimulate urethrapoesis.
So you're not gonna produce it like you should. So for instance, people who are getting dialysis, they also need to make sure they're getting administered urethrapoetin. So here's another scenario.
We have a boy. who is pale, he's weak, he has increased respiratory rate and increased heart rate, his spleen and his liver are enlarged, he has yellow skin, so he has jaundice, he has that dark brown urine, and his red blood cell count is low. So we have a lot of signs and symptoms here. Now, looking at his signs and symptoms, does he have a deficiency anemia or a hemolytic anemia? Okay, so if you take a look, Anemia is anemia.
So whether it's deficiency anemia or hemolytic anemia, you're gonna have a lot of the same signs and symptoms because they are both anemic. But when you have a hemolytic anemia, remember, this is the anemia where you're breaking red blood cells. And so you will have additional signs and symptoms because you are breaking red blood cells and you're gonna see the signs and symptoms of all of that broken red blood cell and all of that waste. So we know he has hemolytic anemia.
Why? Because he has that jaundice. He has that dark brown urine.
He has that enlarged spleen and liver. And notice all of those things are caused because we are breaking red blood cells more. So we're dealing with that and the waste that's produced from that.
Okay. So which signs and symptoms are caused by decreased red blood cell count and hypoxia? Again, it's the same as the previous flow chart, everything in red. So Having hemolysis, broken red blood cells will obviously still decrease your red blood cell count. That leads to pallor and low oxygen levels.
Your tissues are hypoxic. Here we only see the muscle, but the brain, the heart, all of those are still impacted. And yes, it's still an emergency. So our GAS will be activated.
So we'll vasoconstrict, we'll increase heart rate, we'll increase respiratory rate. So everything in the blue background is due to our body trying to compensate by turning on the GAS. But because he has hemolytic anemia, everything over here are the additional things that he has to deal with.
So I asked here, is hemoglobin being released? And the answer is yes, hemoglobin is being released because the red blood cells are being broken down. Now if we go over here, we're going to, this is if they break outside the spleen.
So if the hemoglobin is being released outside the spleen, we will eventually see it in our urine, that's hemoglobin urea, and that will cause our urine color to be dark. If it breaks in the spleen or the liver or the bone marrow, then we're going to make bilirubin. Our liver will then convert it into conjugated bilirubin.
And if it doesn't, we may have jaundice. All right. So let's talk a little bit more about hemolytic anemia. This is where we are breaking down red blood cells.
So it could be due to a membrane issue. So we have things like hereditary spherocytosis. This is where your red blood cells, instead of being that biconcave shape, they're spherical.
And so when they're spherical, they can't really deal with the stress and strain of flowing through red blood cells and bumping into the walls, et cetera, like a biconcave red blood cell. And so these red blood cells, there's just more wear and tear on the membrane. So they tend to break down.
This is an autosomal dominant trait, so it's inherited. So if you inherit at least one deficient or mutated chromosome, then you will have the disease. We also have acquired hemolytic anemia.
That just means you're born normal and then you acquired it, maybe through an infection. And then we have hemolytic disease of the newborn. This is where we have a the mother's red blood cells and the fetal hemoglobin mixing, and then the mother making antibodies against the fetal hemoglobin, and then attacking the fetal hemoglobin.
So we talked about this in the immune chapter. There's also hemoglobinopathies. These are inherited disorders of red blood cells.
We have sickle cell and thalassemia. We're going to talk about both, starting with thalassemia. So thalassemia is a genetic defect that results in a reduced rate of synthesis of one of your globin chains.
So remember, adult hemoglobin is made up of two alpha and two beta. So if you have alpha thalassemia, you are not able to make alpha. You have a reduced rate of synthesis of your alpha chains.
So people who have alpha thalassemia will actually make hemoglobin that's made up of four beta chains. People who have beta thalassemia, they don't make their beta chains like they should, so they might have red blood cells that are made up of four alpha chains. Now, fetal hemoglobin, I haven't mentioned this yet, but you might remember, instead of being made up of two alpha and two beta chains, it's made up of two alpha and two gamma chains.
So what that means is fetuses can have alpha thalassemia because they're supposed to make alpha. So if there's an issue or if they have alpha thalassemia, they won't make that alpha. Fetuses cannot have beta thalassemia because they don't make beta anyway. All right, now let's talk about sickle cell disease.
So sickle cell is due to a point mutation. That means one DNA nucleotide happened to be the wrong one. And this is only in the gene that codes for the beta chain of your hemoglobin. And so that one DNA error leads to one amino acid being the wrong one. So your beta chain is made up of 146 amino acids stuck together.
The sixth one is supposed to be glutamate, but it's replaced with the amino acid valine. And just because of that one little error on the sixth amino acid out of the 146, we have sickle cell. So it's an example of how important it is for your DNA to be copied correctly.
Now, what happens? Well, essentially, these beta chains can become sticky. So when your red blood cells are fully saturated, meaning they're carrying all four oxygen molecules, then your red blood cells will stay nice and biconcave.
So just because someone has sickle cell doesn't mean that all of their red blood cells are sickle. They can have normal looking red blood cells, normal function red blood cells circulating in their body. But when these same red blood cells go into a deoxygenated environment, where oxygen you don't have as much, Then what happens is our red blood cells start to lose oxygen, right?
Remember how when we have low oxygen environment, our red blood cells might give away more oxygen to our tissues, for example. And so now instead of losing one out of the four, we might lose two. And when our beta chains aren't holding on to oxygen, essentially they become sticky and they kind of stick to each other.
And that's why that biconcave red blood cell starts to look like a sickle. Now, why is that a problem? Well, Think of sickled red blood cells circulating through your bloodstream.
It's going to cause clots. It's going to block your vasculature, and that can lead to acute pain. And then by blocking these capillaries, we'll have consequences depending on which capillaries are blocked. So if it's in the heart, it can lead to a heart attack.
If it's in the lungs, it can lead to chest pain and chest breathing issues. If it's in the blood supply going to the brain, it can lead to a stroke. So it really just depends on where the blockages are happening.
Also, sickle-bred blood cells are more likely to be destroyed, and so that can also lead to jaundice. What is the treatment of choice? Well, we have stem cell transplant.
So replace the stem cells so that you're not making sickle-bred blood cells anymore or blood cells with... the wrong beta chain. But another thing that we can do with sickle cell disease is, remember, in sickle cell, it's only the beta chain that's the problem. Keep in mind, fetal hemoglobin does not have beta chains. They have 2-alpha and 2-gabba.
So you can try to reactivate, pharmacologically reactivate fetal hemoglobin in adults as a way to also treat sickle cell. All right, so this is just an image. So we have our...
point mutation. So here I see guanine adenine guanine has been replaced with guanine thymine guanine. So one little nucleotide is the wrong one.
That causes our amino acid glutamate to be replaced with valine. And again, when our red blood cells are oxygenated, they look normal, they function just fine, but it's only when they get into a deoxygenated environment that they will sickle. Good news is this is reversible.
The bad news is sometimes it's not. And the more you go back and forth between normal, sickle, normal, sickle, that's going to, again, cause your membrane to get damaged quicker. And sickle red blood cells, notice, instead of nicely and easily flowing through our blood stream, can cause occlusions and blockages.
All right, so let's take a look at how you inherit sickle cell disease. So sickle cell anemia is a recessive disorder. which basically means you have to inherit the sickled allele from both your mother and your father for you to have sickle cell disease.
If you only have one sickle disease but have one normal, I'm sorry, one sickled allele and one normal allele, then you will only be considered a carrier. You have the sickle trait. You don't actually express the sickled phenotype. Okay, so in this example, a man has the sickle trait. So I know what that means because I know that sickle cell is a recessive disorder.
So he has a sickle trait, which means he has heterozygous for sickle cell. So one of his alleles is normal. One of his alleles is sickled. Remember, your chromosomes are all paired.
You got one copy from mom and one copy from dad. The wife has the sickle disease. The only way for her to have the disease is for both of her alleles to be the diseased allele.
So she is homozygous for sickle cell. So she has sickled sickle. Okay. Now the question is what percentage of their children will have this disease? It's not really worded well.
It should be, what is the likelihood the next generation will have the disease? So all you're going to do is you're going to create a little square, and you might've done this in previous classes, and you're going to figure out what are all of the possible combinations between sperm and eggs meeting. So if we take a look.
We can inherit a sickled allele from mom and a normal allele from dad. Or we can inherit this sickled allele from mom with this normal allele from dad, S and N. Or we can get this S from mom and this S from dad, and that's how we got this box.
Or we can get this S from mom and this S from mom. Do you see how these are all the possible combinations? Now, the question is, who will... What's the likelihood the next generation will have the disease? The only way you can have the disease is if both of the alleles are sickled.
And only two out of four are sickled, sickled. And so it is a 50% chance that you will pass on the disease to your next generation. Now, there's also a 50% chance that your kids will have the sickle trait.
But none of your offspring will be completely normal. Meaning they will... none of them will have both normal alleles.
So they'll either be a carrier or they will have the disease. Now, instead of talking about a mother and a father, let's talk about a population. So in a population, let's say the gene frequency for sickle cell allele is 10%.
So that means 10% of the alleles are sickle, 90% are normal. So assuming the gene is equally common in males and females and it doesn't affect reproduction, What percentage of the next generation is likely to have the sickle trait? So we have to first understand what are we looking for? We're not looking for the sickle disease. We're looking for the sickle trait.
So we're looking for one S and one N. So in women, we said about 10% are sickle, 90% are normal. Same thing with men. 90% are normal, 10% are sickle. We're going to do all of our possible combinations.
So a sickle here, a normal here. That's one combination. A normal and a normal. Do you see how we're just looking at all of the possible combinations?
Sickled, sickled, sickled, and a normal. Now, because it's a population and it's not a 50-50, we have 10% sickled and 90% normal in the population, the percentage here is different. So to get the percentage of this possible combination. We take the nine from 90% and multiply it with the one from the 10%.
So nine times one is 9%. So the likelihood of this combination happening is a 9% chance. What's the likelihood that a normal mother and a normal father's allele will meet?
Well, there's a 90 and a 90% for each of those. So nine times nine is 81. For this combination, 10 times 10 or one times one is a 1% chance. And then for this, it's a nine times one or 9%. Because we're looking for the sickle trait, we're looking for SN. So a 9% chance of this guy happening, a 99% chance of this happening, so nine plus nine is 18. So there's an 18% chance the next generation will have the sickle trait.
Okay, so let me quickly talk about polycythemia. Polycythemia, poly means many, so this is actually an increase in red blood cells. It's the opposite of anemia where you had a decrease.
Here we have a lot. Now this is not a good thing either. So when you have too many red blood cells, what does it do to your blood? It makes it really, really thick.
So it increases blood viscosity. And when your blood is thicker, it's going to take more work for you to move the blood throughout your body. And so you'll see symptoms of hypertension, high blood pressure. Now polycythemia can be caused by polycythemia vera. secondary or relative.
So let's briefly talk about each. Polycythemia vera is like having true polycythemia. Your bone marrow has just transformed, and so it's just making too many red blood cells.
So it's a neoplastic transformation of the bone marrow. So the bone marrow is the issue. In secondary polycythemia, something else is the issue outside of the bone marrow. Like maybe you have chronic hypoxemia.
Maybe you have a respiratory disorder. That causes you to not bring in as much oxygen as possible. And so when you are not able to bring in as much oxygen as possible, what happens?
Your kidneys will make your urethra poetan and stimulate more red blood cell production. And that's why you have too much red blood cell. It's not an issue with the bone marrow. It's an issue with your lungs. So it's a secondary problem.
And then we have relative polycythemia. So relative is relative to something in comparison. So remember, Your blood is cells and plasma, and plasma is mostly water.
So if you are dehydrated, you haven't changed the number of red blood cells, but now I'm dehydrated and I've reduced the amount of water, then that's going to increase our red blood cell count per volume. So it's going to increase our viscosity. All right, and then finally, we're going to end with fetal hemoglobin.
Fetal hemoglobin, I already mentioned, is made up of 2 alpha and 2 gamma. It does not have a beta chain. So not only can fetal hemoglobin not have beta thalassemia, they also cannot sickle because they don't have a beta chain to sickle.
Now, obviously, once the baby is born and they make adult red blood cells, then they will sickle, but fetal hemoglobin cannot. This is, again, why one of the ways we can try to treat sickle cell anemia is to try to pharmacologically reactivate the production of fetal hemoglobin in adults. And then I have a flow chart that goes over the life cycle of a red blood cell. So here's the word bank, and here is the flow chart.
Again, you can pause it here, try it on your own, but I'm going to kind of show it all. So we have our decreased oxygen. Our kidneys will secrete urethra poetin in response to low oxygen.
That will stimulate our bone marrow to make more red blood cells. Some of our red blood cells might be immature. Some of them might be reticulocytes, but hopefully we will make mature red blood cells.
They circulate for 120 days, now they're damaged, and if everything goes right, they're going to break in places like the spleen, the liver, the bone marrow, the lymph nodes. And when they break in those areas, white blood cells will eat the hemoglobin, turning the hemoglobin into bilirubin. Now right now that bilirubin is unconjugated. So if we look here, I see bile on this side, I'm going to do the left side first. So the unconjugated bilirubin might just build up in the blood that leads to bilirubinemia, and that can lead to jaundice.
or that unconjugated bilirubin will become conjugated by the liver, and that conjugated bilirubin will be used to make bile. Now, if we go over here, that damaged hemoglobin can break in the spleen, or it can break outside in other areas, and if that happens, hemoglobin just gets released in the blood, leading to hemoglobinemia, and that can eventually show up in your urine, leading to hemoglobinuria, all stuff that we already did. Now, a couple of quick questions.
Why do hemolytic anemias cause jaundice and splenomegaly, whereas aplastic and deficiency anemias do not? Remember, anemia is anemia, so you'll see similar signs and symptoms, but in hemolytic, you'll have extra signs and symptoms because you have to deal with the broken red blood cells. So it says in aplastic and deficiency anemias, there aren't many urethrocytes produced.
But since jaundice and splenomegaly have to do with increased urethrocyte breakdown, they occur in anemias in which the urethrocytes are still being made effectively, but are being destroyed too quickly. So you're seeing the signs and symptoms of all that broken red blood cell. Sorry, this is kind of, oh no, this is fine. Okay, so a man is homozygous for hereditary spherocytosis. So hereditary spherocytosis is an autosomal dominant disease.
That means even if you have one... of the hereditary spherocytosis, one of that allele, you're going to have the disease. And he is homozygous part.
So both of his alleles are the diseased allele. His wife does not have the disease. And the only way for her not to have the disease is for both of her alleles to be normal. What's the likelihood that their first child will have the disease? Well, if you even have just one of the diseased allele, you're going to have the disease because it's a dominant disease.
and you need to get one allele from your dad, and your dad has two alleles that are both diseased, so there's a 100% chance that the next generation will have the disease. Now, this man has gallstones. Why did this happen?
Well, if you recall, hereditary spherocytosis, the red blood cells are spherical in shape, and so what happens, they break down quicker, and so because there's increased red blood cell breakdown, that means there's more bilirubin, and remember, you use unconjugated bilirubin. to make bile. Now bile is made up of other things including like cholesterol. When you start to change and alter how much and the composition of bile, then the bile can start to precipitate and form clots. It's kind of like when you bake.
If you add too much dry to your wet ingredients, your dough is really, really thick and clumpy. And that's what's happening with your bile, which leads to the gallstones. Now, his doctor suggests removing his spleen if his disease worsens, and he doesn't understand why this would help his gallbladder.
How can you explain it to him? Well, keep in mind, the spleen is where we do a lot of our red blood cell destruction. So if we remove it, then fewer red blood cells might be destroyed, and so there's less bilirubin for your gallbladder to have to deal with.
Now, Kyle is five months old, and he has a respiratory infection, and he's had his first sickling crisis. His parents don't understand why he's in pain from a blood disease or why he only began to have crises now when he's had respiratory infections before. How are you going to explain it to him?
So first of all, why is he experiencing pain? So he has sickling. So when you have sickled blood, they may cause blockages. So if you block red blood cells and you don't have oxygen going to your tissues, it's going to cause pain. What's the significance of his respiratory infection and his sickling?
Why do they happen together? Remember, sickled red blood cells only sickle in a deoxygenated environment. So when he has a respiratory infection, he might not be getting as much oxygen as possible, and that's what's causing the deoxygenated environment and the sickling.
But then why does it happen at five months? Why didn't it happen earlier when he's had respiratory infections before? Because when he was younger, he still had some of his fetal hemoglobin. And so those fetal hemoglobin don't sickle because, again, they don't have a beta chain.
And that is it for this chapter. Thank you.