Transcription
You have platelets and coagulation factors in your blood right now, so how come you don't thrombose and die? What's your secret, my friend? Today we will learn about the anti-clotting mechanisms—how your blood just keeps flowing. So let's get started. [Music]
Here are my previous videos about bleeding and coagulation, especially this one. You must watch this; it was really awesome. This is Medicosis Perfectio, where medicine just makes perfect sense.
So why don't you just thrombose and die? What are the factors that prevent thrombus formation, also known as anti-clotting mechanisms?
First, the endothelium: it provides a smooth, non-thrombogenic surface so that the platelets cannot attach and go crazy. Vasodilation makes it harder for platelets to aggregate. The endothelium secretes endothelial-derived vasodilators such as nitric oxide; they will vasodilate and inhibit platelet aggregation. Endothelium secretes heparin-like molecules called heparin sulfate; it stimulates antithrombin 3—like father, like son—and it neutralizes the activated serine proteases such as prothrombin, factors 7, 9, 10, 11, and 12. The endothelium synthesizes prostacyclin and PGI2, which keeps the blood cycling by vasodilation and inhibiting platelet aggregation. This endothelium expresses thrombomodulin, which modulates thrombin from being pro-coagulation into being anti-coagulation. This is just amazing. Also, the tPA converts plasminogen to plasmin; plasmin destroys the clot and the clotting factors and restores normal function. This is called fibrinolysis. All of these mechanisms promote blood fluidity and inhibit coagulation. So we are done with the endothelium. What else prevents coagulation?
Heparin. Heparin and my body? Do I have heparin without taking it? Yes, indeed, you have heparin in your body right now, all of you, no exceptions. It's a glycosaminoglycan; it's in your body. It stimulates antithrombin 3. What does antithrombin 3 do? It inhibits the serine proteases: prothrombin, factor 7, 9, 10, 11, and 12. So actually, heparin is not the hero; the real heroes are antithrombin 3. Heparin just takes all of the credit. Heparin-like molecules such as heparin sulfate do the exact same thing.
Protein C and protein S. I think of this as the brakes, not the accelerator, but the brakes on coagulation; they stop coagulation. How come? They inactivate the accelerator—they inactivate the gas pedal—they inactivate factors five and eight. Protein C and S are vitamin K dependent, so when you have vitamin K deficiency or when you're taking warfarin to inhibit vitamin K dependent factors, you don't have protein C and S; you don't have the brakes. Also, when you're taking warfarin, you're inhibiting the other vitamin K dependent coagulation factors such as prothrombin, seven, nine, and ten. By the way, protein S is a cofactor of protein C, so it goes like this: we start with protein S. Actually, before protein S, there is the great vitamin K. Now protein S. Now we have protein C. Protein C is going to inactivate the accelerators of coagulation, which are factors five and eight. When factors five and eight are stopped and deactivated, you're not going to have the common pathway and the fibrin meshwork; it's not going to happen.
A quick review of the arachidonic acid pathway: we start with membrane phospholipids. Thanks to phospholipase A2, we have arachidonic acid. By cyclooxygenase, we have prostaglandin G2. Then we have prostaglandin H2. By thromboxane synthase, we have thromboxane. If you happen to be the endothelium and you hate coagulation, let's form prostacyclin to keep the blood cycling. How do you keep the blood cycling? By vasodilation and preventing platelet aggregation. If you are the platelets, how do you promote your agenda of coagulation? By secreting thromboxane, using thromboxane synthase. Thromboxane will cause thrombosis by vasoconstriction and increasing platelet aggregation. Thromboxane A2 is one of the pathogenesis factors of Prinzmetal angina, when your coronary vessels constrict and then you suffer.
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