Transcription
Hey guys, it's Medicosis Peralis, continuing our bleeding and coagulation disorders playlist. In the previous video, we have talked about the kallikrein-kinin system. Today, let's talk about bradykinin, which comes from the high-molecular-weight kininogen, thanks to plasma kallikrein. Let's get started. This poor guy has angioedema.
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The coagulation cascade in brief: Here's fibrin, comes from fibrinogen; here's thrombin, comes from prothrombin; and here is the prothrombinase complex—it has four members: two numbers and two words. Let's go to the extrinsic pathway: tissue factor activating factor VII. Let's go to the intrinsic: the subendothelial collagen and the high-molecular-weight kininogen and the plasma kallikrein activate factor XII into XIIa, then XI, then IX, then VIII. This is slow but more efficient, while the extrinsic is fast but less efficient. Don't forget to stabilize the fibrin using the fibrin-stabilizing factor, AKA factor XIII.
The difference between the intrinsic and the extrinsic pathways is the intrinsic needs something from within, such as the subendothelial collagen, the platelet factor 3, the high-molecular-weight kininogen, the plasma kallikrein, and if you are in vitro, the wettable surface of the glass of the test tube. More steps, longer cascade; it's slower, but it's more efficient. It starts with factor XII; it has four members: 12, 11, 9, and 8. PTT measures the intrinsic and the common pathway. Extrinsic: we need something from outside, maybe from the tissue—the tissue factor. It's a shorter cascade; it's less efficient, but it's faster. It starts with factor VII; it only has one factor. PT measures extrinsic and the common pathway.
So, high-molecular-weight kininogen and plasma kallikrein activate the intrinsic pathway. High-molecular-weight kininogen can be converted into bradykinin thanks to plasma kallikrein. Bradykinin is the topic of today's video. High-molecular-weight kininogen activates factor XII and factor XI. Plasma kallikrein activates factor XII and converts the high-molecular-weight kininogen into bradykinin. High-molecular-weight kininogen is converted into bradykinin thanks to kallikrein. Kallikrein also activates factor XII. Factor XII returns the favor by activating prekallikrein into kallikrein. This is called a positive feedback. High-molecular-weight kininogen is a plasma protein; it's inactive; converted into the active form thanks to the contact; and produces kinins such as bradykinin. Confuse high-molecular-weight kininogen, which is in the plasma, with low-molecular-weight kininogen, which is in the tissue.
How do you activate the intrinsic pathway when you are outside the body, which means in vitro? I don't have subendothelial collagen in this tube yet; I still have high-molecular-weight kininogen, kallikrein, platelet factor 3, and the wettable surface of the glass. And that's why, my friends, deficiency of high-molecular-weight kininogen or kallikrein is not clinically significant because you still have platelet factor 3 and subendothelial collagen, and if you're in vitro, you have the wettable surface of the glass. So deficiency of one of them is not that important, clinically speaking. Let me remind you that I have 50 hematology cases on Patreon. Go to patreon.com/medcos, get those cases, answer them correctly, and make Grandma happy; otherwise, she will get thrombocytosis.
High-molecular-weight kininogen is converted into bradykinin thanks to plasma kallikrein; that's why we call it the kallikrein-kinin system. Bradykinin causes vasodilation, pain, increased vessel permeability, contraction of nonvascular smooth muscles such as the bronchi. Kinins are either bradykinin or kallidin, or also known as lysyl-bradykinin. Whether you are in the plasma or in the tissue, you can still produce kinin. If you're in the plasma, you produce bradykinin; if you're in the tissue, you produce kallidin. The difference is this is high-molecular-weight kininogen, this is low-molecular-weight kininogen; this needs plasma kallikrein; this needs tissue kallikrein. Kininogen—it means it will generate and cause genesis of kinins such as bradykinin. Kinin loves producing bradykinin, but angiotensin-converting enzyme just hates bradykinin; that's why we call the ACE kininase ACE because it destroys the kinin, which is bradykinin in this case. ACE takes bradykinin to the cleaners. We talked about the effects of ACE inhibitors in the previous video, but as you know, ACE inhibitors inhibit the ACE. When you don't have ACE, you have lots of bradykinin floating around, leading to bronchoconstriction and dry cough, increased vessel permeability, which will lead to angioedema, which is a medical emergency. You have pain; you have vasodilation. Vasodilation causes vasodilatory natures, which will lead to hypotension. And this, my friends, is why you get dry cough and angioedema when you take ACE inhibitors. It doesn't have to be 100% of cases, but it's a possible side effect. What happens when your patient who's on ACE inhibitors develops dry cough or angioedema? Stop the ACE inhibitor; switch them to an angiotensin receptor blocker such as losartan.
Side effects of ACE inhibitors: We divide them into two categories: first, due to increased bradykinin, and second, due to decreased formation of angiotensin II. Due to increased bradykinin, we have dry cough, we have angioedema, we have hypotension. Due to decreased formation of angiotensin II, we have hypotension, renal impairment, hyperkalemia, and metabolic acidosis. How about angiotensin receptor blockers? You don't get these side effects, but you absolutely can get these side effects. So, side effects of ACE inhibitors: dry cough, vasodilatory natures, increased vessel permeability and angioedema, pain, probably vasodilation leading to hypotension. You have hypotension, renal impairment; you can get angioedema, of course, and here we have hyperkalemia and acidosis. How about angiotensin receptor blockers? You don't get those, but you can get hypotension, renal impairment, hyperkalemia, and acidosis—absolutely yes.
Here is the famous renin-angiotensin-aldosterone system. We start with renin, which converts angiotensinogen into angiotensin I, thanks to ACE produced by the lungs. We convert angiotensin I into angiotensin II. Angiotensin II is too powerful and has mainly two functions: vasoconstriction of arterioles and aldosterone release. Aldosterone will reabsorb sodium, secrete potassium or hydrogen—cool. Don't forget bradykinin comes from the high-molecular-weight kininogen. Plasma kallikrein activates this step. ACE inhibits this step, and even if you form some bradykinin, ACE will take them to the cleaners and degrade them into inactive, ugly metabolites.
So here are the effects of bradykinin in one slide: You have bronchoconstriction and dry cough; you have increased vessel permeability leading to pus and edema; you have pain, especially chronic pain; you have vasodilation causing vasodilatory natures leading to hypotension. Remember, bradykinin can constrict your bronchioles and can cause angioedema, which can constrict your upper airways. So bradykinin is really not fun for your upper respiratory tract. In the next video, I have a crazy mnemonic about bradykinin, so make sure to subscribe. Thank you guys for watching. Subscribe to the channel and hit the bell. Subscription without hitting the bell doesn't mean anything anymore. Go to Patreon to get all of my notes and my 50 hematology cases. Thank you so much for watching. Until next time, be safe, stay happy, and study hard.