Transcription
Let's resume our discussion of bleeding and coagulation disorders. In the previous videos, we have talked about primary hemostasis, secondary hemostasis, and the coagulation cascade, as well as high molecular weight kininogen. Today, let's dig deeper into the chelicerin kinin system, and let's get started.
Believe me when I say there are only two ways to coagulate, but there are several ways to bleed. What are the two ways to coagulate? The intrinsic and the extrinsic pathways.
The intrinsic pathway has four members, and they revolve around factor 10. So they are eight, nine, eleven, twelve. 11 and 12 are called contact group because they get activated by coming in contact with the subendothelial collagen in the basement membrane of the blood vessel or the negative charges in the wettable surface of the glass of the gray test tube. And when the test tube continues its education, it becomes a graduated cylinder.
To understand the coagulation cascade, go from the bottom up. Fibrin comes from fibrinogen. Thrombin comes from prothrombin. What activates it? The prothrombinase complex, and there is a committee of two words and two numbers: five, ten, calcium, and phospholipid; they activate this prothrombin. They are the prothrombinase complex; activate the prothrombin and thrombin, then fibrinogen into fibrin.
We have two pathways. Extrinsic, which is very fast but less efficient because it only has one factor, which is factor seven, activates on seeing an evident of trauma like the tissue factor coming in contact with the blood. Cool.
Let's move to the intrinsic pathway. It starts with the contact group. The contact group has to come in contact with the subendothelial collagen. 12 becomes active. 11 becomes active. Skip 10 because it's the most important member of the common pathway; it's in the committee, then go to nine and then go to eight. Slow, more efficient; fast but less efficient. What activates the intrinsic pathway? We have the subendothelial collagen. What else? We have the high molecular weight kininogen. What else? We have the plasma chelicerin. If you are in vitro, add the charged wettable surface of the glass of the test tube.
Don't forget that you are to stabilize the fibrin that you have created by cross-linking it and forming a stable fibrin meshwork. Thanks to factor 13, also known as the fibrin stabilizing factor.
The extrinsic pathway needs something from the extrinsic, from outside the blood, such as the tissue factor. It has less steps; it's a shorter cascade. That's why it's less efficient; start with factor seven; has only one factor, which is seven. Pt will measure the extrinsic and the common; Pt being the prothrombin time.
Intrinsic pathway, on the other hand, is intrinsic to the blood; depends on factors from within the blood such as the subendothelial collagen, the platelet factor three, the high molecular weight kininogen, etc. More steps; longer cascade. That's why it's stronger and more efficient, but yet it's slower. So with factor 12, we have factors eight, nine, eleven, twelve. PTT measures the intrinsic and the common; PTT means or a PTT activated partial thromboplastin time.
Here is the intrinsic pathway. We have twelve, twelve, eleven, nine, eight. High molecular weight kininogen activates both twelve and eleven; plasma colicrin activates only factor 12, which returns the favor in a positive feedback loop. Then we have the high molecular weight kininogen being converted into bradykinin thanks to plasma colicrin. Plasma colicrin is present in a precursor, in activated form, called prekallikrein. This is called plasma kallikrein because high molecular weight kininogen is in the plasma, not to be confused with low molecular weight kininogen, which is in the tissue. That's why I always say plasma kallikrein.
Here is the positive feedback loop: high molecular weight kininogen into bradykinin, who helps this kallikrein. Kallikrein also activates factor 12; factor 12 returns the favor by activating the inactive prekallikrein into active plasma kallikrein. Plasma kallikrein will activate factor 12, and so on and so forth. This is a positive feedback loop. Kallikrein converts high molecular weight kininogen into bradykinin. What does bradykinin do? Causes vasodilation. What else? It increases vessel permeability, leading to inflammation and pus. What else? It triggers pain. What else? It constricts your bronchioles, leading to bronchoconstriction, leading to dry cough. And last but not least, remember natriuresis: increased sodium excretion in the urine. This will lead to hypotension together with the vasodilation. And please don't forget that the increased vessel permeability will lead to not only pus but also angioedema.
Quick question for you: Is angioedema a medical emergency? Oh, yeah. It could be an emergency. Why? Because it's swelling of structures in the head and neck. You know what's in your neck? Yes, your upper airways. You can choke to death.
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High molecular weight kininogen is kind of an active member, or it will be active. And so this is it; it's a protein. It's an alpha globulin. Inactive, activated by coming in contact with the basement membrane, subendothelial collagen, and produces kinin. That's why we call it that kallikrein-kinin system. What kind of kinin? Bradykinin. What does bradykinin do? Contraction of nonvascular smooth muscles such as your bronchus, leading to bronchoconstriction and dry cough; increased vessel permeability, which will lead to pus. Is pus pitting edema or non-pitting edema? And the answer is it's non-pitting edema. It's an exudate; it's not a transudate; pain. What kind of pain is it? Is it acute pain? No; chronic pain due to chronic inflammation; also vasodilation will lead to hypotension; increased vessel permeability will lead to the ugly, dreaded angioedema.
If you are talking in vitro, you are outside of your body. You don't have subendothelial collagen. Can you still activate the intrinsic pathway? Yes, I can. I still have high molecular weight kininogen. I still have kallikrein; I still have platelet factor three, and I have the wettable surface, guys.
It's called Kallikrein-Kinin system. We start with high molecular weight kininogen. Thanks to kallikrein, we have bradykinin. So Kallikrein-kinin system produces kinin. Kinin such as what? Just bradykinin and kallidin. This kallidin is also known as lysyl bradykinin. What does bradykinin do? Contraction of nonvascular smooth muscle; increase vessel permeability into pus and angioedema; increase pain; vasodilation and natriuresis into hypotension; and don't forget the bronchoconstriction will lead to dry cough.
Okay, plasma kallikrein versus tissue kallikrein. It's the kallikrein-kinin system either way. In the plasma, high molecular weight kininogen thanks to kallikrein have bradykinin; in the tissue, low molecular weight kininogen thanks to tissue kallikrein, we have kallidin or lysyl bradykinin. Bradykinin and lysyl bradykinin are very similar. This is produced in the plasma; that's produced in the tissue thanks to plasma kallikrein; thanks to tissue kallikrein, respectively.
Some etymology, please. "-ogen" means it will genesis; it will generate kinin such as the bradykinin; such as fibrinogen. Remember fibrinogen ends in "-ogen"; it will generate fibrin. Same thing here. Kininogen, it will generate kinin such as bradykinin or the ugly lysyl bradykinin, which is produced in the tissue. "-Kallikrein" means protein. If it's active, it's protein. It doesn't have to be a protein; could be a peptide. I mean, I don't know; I care. It's a protein for me. And then "-kinin" from kinetic, to set in motion, because bradykinin is very active; it it's it goes crazy. It's similar to histamine; does all of the crazy stuff such as increased vessel permeability; increase contractions smooth muscle; increase pain; increase vasodilation; increase natriuresis; very active; it it sets in motion. That's why it's a kinin.
Let's take it to the next level: high molecular weight kininogen into bradykinin. What activates this step is the plasma kallikrein; what inhibits this step is the great ACE enzyme, angiotensin-converting enzyme. This stimulates and this inhibits this pathway. Okay, even if you succeeded in reducing bradykinin, neglecting the ACE, the ACE will still take you to the cleaner by converting the bradykinin into inactive metabolites. The angiotensin-converting enzyme hates bradykinin; it can't stand its butt. ACE takes bradykinin literally to the cleaner. That's why we call angiotensin-converting enzyme a kinase because it gets rid of the kinin. High molecular weight kininogen by kallikrein goes into bradykinin. Plasma kallikrein stimulates the step, but ACE hates the step; it inhibits the step; and even if you succeed in producing some bradykinin, I will convert them into inactive metabolites. In other words, I will degrade them. ACE takes bradykinin to the cleaners; never ever forget this.
What if you're taking ACE inhibitors as a medicine? ACE is gone; bradykinin is left free to do all of the crazy butt stuff. You have increased bradykinin because you have decreased ACE because you are on the stupid ACE inhibitors, which is any drug that ends in "-pril," such as lisinopril, enalapril, etc. This will lead to bronchoconstriction and dry cough. That's why ACE inhibitors cause dry cough big time. This dry cough, by the way, is refractory, which means it doesn't respond to medicine. So if your doctor says, "My honey, I'm sorry that the ACE inhibitors that I prescribed are causing you dry cough. Let's give you an antitussive medication," he's a stupid idiot. The cough is caused by the ACE inhibitor. This cough is refractory. In order to cure this cough, maybe you should stop this stupid medicine and switch them to the angiotensin receptor blocker or the ARBs. Very important. Don't give an antitussive. Don't put the patient on two freaking medicines when you can just use one. Use your gut-given brain.
What else will happen when you are on ACE inhibitors? Increased vessel permeability; increased natriuresis; vasodilation leading to hypotension, which makes ACE inhibitor an excellent hypertensive medication; it manages hypertension. Don't forget ACE inhibitors also lead to increased vessel permeability, which will lead to angioedema. If your patient complains of angioedema, stop the ACE inhibitors immediately and switch them to ARBs. Angioedema is a medical emergency. It's a swelling of the head and neck structures. What's in your neck? The upper airways. You can die of hypoxia while your doctor is sitting on his theory.
So what are the adverse effects of ACE inhibitors? ACE inhibitors: you have decreased ACE; when you have decreased ACE, bradykinin is free to do all of the crazy butt stuff, including dry cough, natriuresis, increased vessel permeability into angioedema. You have vasodilation; natriuresis leading to hypotension; but ACE inhibitors have a whole other set of side effects leading or induced by the inhibition of ACE in the angiotensin I to angiotensin II in the renin-angiotensin-aldosterone system. So ACE, the angiotensin-converting enzyme, is called angiotensin-converting, so it converts angiotensin I to angiotensin II. Angiotensin II is too powerful, and it does two main functions such as vasoconstriction and aldosterone secretion. What does vasoconstriction do? It increases the blood pressure and increases the GFR, which makes ACE inhibitors excellent antihypertensive medications. But as you know, every drug has desired effects and adverse effects. ACE inhibitors will harm your kidney, leading to renal impairment because angiotensin II, may it rest in peace, used to constrict the efferent arteriole. So here is your efferent arteriole; here is your nice glomerulus; and here is your efferent arteriole; and here is your kidney tubules. When the angiotensin II constricted this efferent arteriole, it forced all of the filtrate into the tubule. This is called increased GFR. The kidney loves it; loves it when you have increased GFR, but now you're taking ACE inhibitor and your angiotensin II is history; increasing the GFR is history. The GFR is decreased. ACE can harm your kidney. What else? The angiotensin II, may it rest in peace, used to activate or secrete aldosterone. Aldosterone reabsorbs sodium and secretes potassium; reabsorbs sodium and secretes hydrogen ions. But now aldosterone is history because you are taking ACE inhibitors. What will happen to the sodium? It's gonna decrease. What will happen to potassium? It's gonna increase, leading to hyperkalemia. What's gonna happen to the hydrogen ions? They are increased, leading to acidosis. Is it metabolic or respiratory? It's related to the kidney, so it's metabolic.
So here are your adverse effects of the ACE inhibitor: you have the dry cough; you have the hypotension; the increased vessel permeability will lead to angioedema, which is an emergency; the vasodilation; the natriuresis; the inhibition of the angiotensin II will lead to hypotension; the decrease of the GFR will lead to renal impairment; the increased loss of sodium in the urine will lead to natriuresis, maybe hyponatremia; the increased potassium level in the blood will lead to hyperkalemia and muscle problems and EKG changes. Cool. This decrease in hydrogen excretion will lead to acidosis; and in pharmacology, when you are asked about the side effects of any drug, just add nausea, vomiting, diarrhea; in ninety-nine point nine percent of cases, you'll be correct. So just mention all of this and add nausea, vomiting, diarrhea, some dizziness, blah blah blah. You are perfectly fine.
Now let me ask you a question, not about the ACE inhibitors, but about the angiotensin receptor blockers. Will angiotensin receptor blockers lead to dry cough? Very unlikely. Why? Because they don't inhibit ACE; they don't increase bradykinin level in your blood. There is no dry cough. How about angioedema when you're taking ARBs? No angioedema. Forget it. Very unlikely. But ARBs still acts on the angiotensin II receptor. Will ARBs lead to hypotension? You bet. That's why they are antihypertensive medications. Will they lead to renal impairment? They could. How about acidosis and hyperkalemia? ARBs certainly could lead to this stuff, but the good news is very unlikely you get dry cough; very unlikely you get angioedema, which is an emergency, which makes ARBs very good drugs. And ARBs, if ACE inhibitors end in "-pril," ARBs have "-sartan," such as losartan, valsartan, telmisartan, whatever.
So here is your renin; here is the angiotensin-aldosterone system. We start with the renin from the kidney; angiotensinogen from the liver is converted to angiotensin I thanks to renin; angiotensin I is converted into angiotensin II thanks to ACE, produced mainly, or not mainly, in the lungs, among other places. Angiotensin II will bind to the receptor; when angiotensin II binds to the angiotensin receptor, it leads to vasoconstriction, aldosterone release, increased thirst and ADH release, increased sodium-potassium exchange in the proximal tubule of the nephron; and as you know, aldosterone will increase sodium reabsorption, increase potassium secretion, increase hydrogen ion secretion.
What happened when you are on ACE inhibitors? When I'm on an ACE inhibitor, angiotensin II is gone, and ACE is gone here; bradykinins are high, leading to many things including dry cough and angioedema. How about angiotensin receptor blockers? I didn't increase bradykinin; very unlikely I'm getting dry cough or angioedema. However, I still can get hyperkalemia, acidosis, renal impairment, hypotension, etcetera, etcetera.
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