Transcription
Let's continue our series about bleeding and coagulation disorders. In the previous two videos, we have talked about the platelet and its structure. Today, let's talk about the arachidonic acid, one of the most important pro-inflammatory substances in your body. So let's get started. [Music]
First, let me just clarify one thing. I've told you before that the first cell here is the multipotent stem cell. I don't think this is exactly correct. It's the pluripotent stem cell that starts everything. After the pluripotent stem cell comes the multipotent. But Guyton says pluripotent stem cell is the mother cell here. So let's go with Guyton. So where's the platelet? It's a myeloid of myeloid origin. We have the megakaryoblast, promegakaryocytes, then the megakaryocytes. The glorious megakaryocyte will give us platelets. Platelets are not cells; they are just pieces of the magnificent megakaryocyte. And here are the previous two videos, so make sure to subscribe and save the playlist. The playlist is called "Bleeding and Coagulation Disorders."
Arachidonic acid: where does it come from? From the cell membrane, specifically from the lipid bilayer plasma membrane. As you know, the lipid bilayer plasma membrane, or cell membrane, is composed of proteins, lipids, and carbohydrates. Lipids such as phospholipids, cholesterol, and other lipids such as the sphingolipids, especially in nerve cells. The phospholipids form the arachidonic acid. So the arachidonic acid comes from the phospholipid, which are part of the cell membrane. The cell membrane is made of proteins, carbohydrates, and lipids: the lipids, phospholipids, and cholesterol, and others. Each phospholipid has a head and two tails. The head is probably phosphate, and the tails are free fatty acids. Not exactly that, but I just want to make it simple. The phosphates are negatively charged. We call this the amphipathic, like the amphibian, because they have one face pointing to the outside world, which is water, and one face pointing to the inside, which is lipid.
Dr. Arachidonic acid, which comes from the phospholipids of the lipid bilayer plasma membrane, is a polyunsaturated omega-6 fatty acid. Chemically, it's a carboxylic acid, which means it has 20 carbons present in the phospholipid portion of the lipid bilayer plasma membrane. Yes, indeed, it's a very important inflammatory mediator, and it mediates lots of stuff such as vasodilation, also vasoconstriction. So let's add it here: and vasoconstriction. But beware: in inflammation, you need vasodilation, but in blood coagulation, you need vasoconstriction. So the arachidonic acid is captured in the phospholipid. Who does free the arachidonic acid from the phospholipid? It's the great enzyme phospholipase A2. It's inhibited by steroids. So steroids inhibit phospholipase A2. In other words, steroids inhibit the formation of arachidonic acid. Since arachidonic acid is inflammatory, steroids are the ultimate anti-inflammatory. Makes perfect sense.
Arachidonic acid is not an essential fatty acid, except when linoleic acid is deficient. What does essential fatty acid mean? Essential fatty acid means that you have to eat it in the diet because your body doesn't make it. So ironic, as it is not that. However, when linoleic acid, the father of arachidonic acid, is deficient, arachidonic acid becomes an essential fatty acid. So we call arachidonic acid conditionally essential or semi-essential fatty acid because normally you don't have to have it in the diet, but under certain situations, you have to eat it in the diet. Conditionally essential. By using the great Aristotelian method: two premises and conclusion. One: arachidonic acid is pro-inflammatory. Two: steroids prevent arachidonic acid formation. Therefore, steroids are anti-inflammatory. Bahahahaha. So logical.
So here are the membrane phospholipids, which are part of the lipid bilayer plasma membrane. Phospholipase A2 will free the arachidonic acid from the membrane phospholipids. Now we have our arachidonic acids. Then we have two pathways: the prostaglandins pathway and the leukotrienes pathway. The enzyme that makes the arachidonic acid be converted into prostaglandins is the cyclooxygenase. The enzyme that makes the arachidonic acid go this way is the lipoxygenase. Some authors say 5-lipoxygenase. I couldn't care less. Let the phospholipase A2 enzyme speak about himself: "Dear, you have the microphone. I set the arachidonic acid free from the tyranny of phospholipids. I let arachidonic acid loose to promote my agenda, i.e., inflammation. However, steroids can send me to the cleaners."
Membrane phospholipids, through the great enzyme phospholipase A2, said the arachidonic acid free. By the cyclooxygenase enzyme, give us the prostaglandin. By the lipoxygenase enzyme, give us the leukotrienes. Let's go to the prostaglandins. It depends on the tissue type. If you are in the platelets, let's form thromboxane A2. Thromboxane A2 is pro-coagulation. However, if you are in the endothelium, let's form prostaglandin I2, also known as prostacyclin. Prostacyclin is anticoagulation. Believe it or not, both the thromboxane A2 and the prostacyclin have the same route. Both the pro-coagulatory and the anticoagulant mediators come from the same route, which is an ingenious method. Why? Let's say you need more coagulation: convert all of your arachidonic acid into thromboxane A2 and at the same time decrease the conversion of arachidonic acid into prostacyclin. Okay, you are in the endothelium; everything is nice and smooth and rosy. Let's do anticoagulation; let's convert all of the arachidonic acid to the prostacyclin and inhibit the formation of thromboxane A2. By the same token, it's really genius. It's like water pipes: you have a pipe, and it has two branches to house number A and house number B. This guy's using the shower; convert all of the water here and decrease it from here. This guy is using the shower; go to hell, and let's get the water to this guy. But nowadays, since they can both have their shower at the same time, we invented new stuff such as water pumps. But in your body, since pro-coagulation and anticoagulation should not be happening simultaneously, it's a very good method to have platelet thromboxane and the endothelium prostacyclin coming from the same route. That's how you regulate them and focus on one thing at a time.
Let's make it more complicated: membrane phospholipid to arachidonic acid, thanks to the glorious phospholipase A2. What does the arachidonic acid come from? From the linoleic acid. That's why arachidonic acid by itself is not an essential fatty acid; it comes from the linoleic acid. Your body can synthesize linoleic acid and then convert linoleic acid into arachidonic acid. But when you are deficient of the linoleic acid, arachidonic acid becomes essential. Okay, let's go to the prostaglandins: cyclooxygenase, prostaglandin, specifically prostaglandin G2. How about the lipoxygenase? Leukotrienes, and we have different types of leukotrienes: leukotriene B4, C4, D4, F4. Whoever invented these names were in like first what, kindergarten or something? Come on, scientists, you can do better. Prostaglandin G2 is converting to prostaglandin H2, ABCDEFGH. Then after prostaglandin H2, depends on the tissue. If you are in the platelets and you need coagulation, let's synthesize the thromboxane A2 through the thromboxane synthase. If you're on the endothelium and you need blood flowing smoothly, let's have that prostacyclin through the prostacyclin synthase. Thromboxane: it's called thromboxane, so it promotes thrombosis, but it has many functions. First: vasoconstriction. Why? Because when you're losing blood and bleeding and you want to coagulate, the first thing to do is vasoconstrict the vessel to decrease the surface area, to decrease the surface area from which the blood is lost. Makes perfect sense. It promotes platelet aggregation to start the thrombus, and it's also a bronchoconstrictor. Let's go to the prostacyclin in the endothelium. Then the endothelium is smooth and nice and acting in its self-interest, which is to leave the blood flowing in a nice laminar flow. So prostacyclin will keep the blood cycling flowing smoothly. Prostacyclin will promote vasodilation, and it will inhibit platelet aggregation. It's the exact opposite to thromboxane A2.
Let's go to the leukotrienes. Leukotriene B4 is a chemotaxis agent—chemo, which means chemical, and taxis—so it will recruit the neutrophil through some chemicals. Then how about that leukotriene C4, D4, and E4? They are bronchoconstrictors; they make the life of an asthmatic patient hell. Let's make it even more complicated. We start with a membrane phospholipid. Thanks to phospholipase, we have arachidonic acid, which comes also from the linoleic acid. Through the cyclooxygenase, I'm going to have the prostaglandin G2. After G comes H2. H2 can give us prostaglandin D2 and prostaglandin E2. Prostaglandin E2, E2 promotes pain, which is even worse, it hurts. And prostaglandin F2 alpha. Then the prostaglandin H2, depending on the tissue, will give us thromboxane A2 and prostacyclin. Thromboxane A2 has three functions: number one, it's a vasoconstrictor; number two, it increases platelet aggregation; number three, it's a bronchoconstrictor. How about the prostacyclin? It keeps the blood cycling, so it's a vasodilator; it's also decreasing the platelet aggregation.
Let's make it more complicated by adding some drugs: pharmacology, baby. Membrane phospholipid by the enzyme phospholipase A2, we have arachidonic acid. Who inhibits the phospholipase A2? Steroids. That's why steroids are the best anti-inflammatory ever invented, ever known to mankind, because they inhibit the prostaglandins and leukotrienes, and all of these are inflammatory mediators. Thank you, steroids. That's why when your doctor is stupid and he doesn't know how to treat you, probably he will give you steroids, and probably you'll be fine because there is a very good chance one of those crazy guys is involved in your disease. So what inhibits the phospholipase A2 is the steroid. What promotes and activates the phospholipase A2? Tissue injury. Yes, because it's pro-inflammatory. Tissue injury means we need an inflammation to fight all of the bad stuff that's happening: clotting, the bacteria, thrombin. Yeah, baby, thromboxane. We need thrombosis through thrombin. Makes perfect sense to promote this agenda of coagulation: bradykinin, because bradykinin also stimulates pain; angiotensin 2, because angiotensin 2, let's say you have hypotension or you have sepsis, so we need to vasoconstrict; epinephrine, sympathetic fight-flight-fright mechanism; you're bleeding to death; epinephrine is high; stimulates phospholipase A2; arachidonic acid is converted into prostaglandin G2, which is converting to prostaglandin H2, converted into thromboxane A2 by the thromboxane synthase. Thromboxane A2 will vasoconstrict and increase platelet aggregation until we form a thrombus and prevent you from bleeding to death. Amazing.
Let's go to the leukotrienes. We have the leukotriene B4, chemotaxis; C4, D4, and E4. How to inhibit the leukotrienes? We have a leukotriene inhibitor called zileuton. Zileuton will inhibit this conversion from arachidonic acid into leukotrienes. Okay, let's say that zileuton didn't work, or we are not using zileuton. We have another chance at the receptor level. These leukotrienes will act on the receptor causing bronchoconstriction and making the asthmatic patient's life worse. So let's block the receptor by receptor leukotriene receptor inhibitors such as the great montelukast, the montelukast. Let's go to the cyclooxygenase: inhibited by aspirin and non-steroidals. That's why aspirin is a famous antiplatelet drug; it inhibits the thromboxane A2. Okay, how's aspirin antiplatelet? If aspirin will also inhibit the prostacyclin that will keep the blood cycling, we have two theories here: one, yes, in the beginning it inhibits the prostacyclin, but just give it time, and it will release the inhibition of prostacyclin, and it will only inhibit thromboxane A2. That's why it's an antiplatelet. There is another theory that aspirin does not inhibit the formation of prostacyclin; somehow the tissue knows how to escape and bypass this crazy nonsense. So aspirin, famous antiplatelet. The difference between aspirin and non-steroidals is that aspirin is an irreversible platelet inhibitor while non-steroidals are reversible. That's very important. So if you are taking aspirin, and you are taking aspirin, and you take another aspirin, and you take another aspirin for a long time, I guarantee you your platelets are all screwed irreversibly. The only way to stop it is to stop aspirin and give the bone marrow some time to produce extra megakaryocytes, and they will produce new platelets that didn't know aspirin, and they will function normally. Another thing: aspirin in low dose is antiplatelet. That's why grandpa takes baby aspirin. You might be surprised. Why does grandpa, the old guy, takes baby aspirin? Shouldn't aspirin be like baby aspirin before babies? No, aspirin is never for babies; it can cause Reye's syndrome. We never use aspirin for babies; we only use baby aspirin for grandpa. Baby means small dose because aspirin in low dose is antiplatelet; in high dose, it's analgesic, anti-inflammatory, and antipyretic. Aspirin's just genius. How's aspirin genius? By blocking the cyclooxygenase. What is the most famous side effect of aspirin? Guess what? Bleeding. Now we understand why.
We use inhaled steroids for asthmatics because steroids inhibit the formation of the arachidonic acid, and arachidonic acid is going to be converted into the leukotrienes B4, C4, and D4. C4, D4, and B4 are bad for asthmatics. So steroids will inhibit the arachidonic acid formation. We used leukotriene inhibitors for asthmatics? Yeah, absolutely; they are bronchoconstrictors. Asthmatics need bronchodilation, not bronchoconstriction. Aspirin is antiplatelet; yeah, it inhibits the cyclooxygenase, so now we don't have prostaglandins such as the ugly thromboxane A2. Steroids are the most powerful anti-inflammatory ever because they inhibit both pathways: the cyclooxygenase and lipoxygenase, by inhibiting the root, which is the arachidonic acid formation by the phospholipase A2 enzyme. Platelets are the only cells in your body that possess the thromboxane synthase, so which makes them mostly the only cell that forms thromboxane. This may not be 100% true, but I like to make things easy. Thromboxane A2: bronchoconstrictor, vasoconstrictor, platelet aggregator. How about the prostacyclin, also known as prostaglandin I2? It's a vasodilator, and it inhibits platelet aggregation. Well done.
In the next video, we'll talk about thrombocytosis, about grandma who has a high platelet count, and we will learn when to reassure her and send her home and when to give her medicine. It all depends. I'll see you in the next video. That's why you need to subscribe and hit the bell to get notified when I release new videos. And please consider supporting this channel on Patreon. I have more than 60 notes only for Patreon subscribers. Go to patreon.com/mindykosis. Anyways, thank you so much for watching, and as always, be safe, stay happy, and study hard. It's Medicosis Perfectionalis. Elsewhere, medicine makes perfect sense.