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Mechanism of Antiplatelet Interaction

by Carlo Raj, MD
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    00:01 Hi there, my name is Dr. Raj and let's take a look at what happens when you have damage taking place within your blood vessel, a process called hemostasis.

    00:12 The primary cell responsible for hemostasis would be what you're seeing here.

    00:17 Now what are you seeing here? Take a look at the arrows.

    00:22 Those are your platelets.

    00:23 Would you be able to tell me as to what the normal count of the platelets are? At least 150,000 to maybe approximately 400,000.

    00:33 That's a lot of platelets that we have circulating and therefore, this picture here is a peripheral blood smear.

    00:39 If you were to take a look at platelet before it matured, that would be way back in the bone marrow.

    00:47 So what we're not seeing here is a bone marrow aspirate and you can tell because around the platelet the cells that you're seeing there are your RBCs.

    00:58 Notice the central pallor, right? Normal.

    01:01 This is a peripheral blood smear of your platelet.

    01:03 So that baby or immature platelet way back in the bone marrow is then known as your megakaryocyte.

    01:09 And one of the things that you need to know at your point in medical education is being able to identify a megakaryocyte in your bone marrow.

    01:17 Now why is it important that we have to have so many platelets? The weakest point and you and I right now is at the junction between this picture, between the capillary and the venule.

    01:29 So as blood is moving from the capillary into the venule at that junction, it's the weakest point.

    01:33 We need to make sure that at all times we have enough platelets so that we fill up that particular hole that you and I normally.

    01:42 What will happen if the cells of a blood vessel know as your endothelial cells would then get injured? When does endothelial cells become injured? Due to? You and I right now, maybe a blood pressure rise as you go to bed, maybe we bumped our arms into something or maybe listening to me got bored you fell asleep and you fell of your chair and then you caused damage to your endothelial cell and when you do you're then going to express a particular ligand from the subendothelial collagen.

    02:14 Remind me what that collagen is made up of? Collagen making up your basic membrane is of the type IV type.

    02:21 It is then expressing a particular ligand called von Willebrand factor.

    02:25 There you go.

    02:26 And what does that von Willebrand factor going to bind to? And that'll come up next.

    02:31 What I'm gonna show you is a picture of where we're headed and then we'll go into details and then as you shall see we're gonna make this clot stronger and stronger and stronger.

    02:42 You notice this is a temporary hemostatic plug.

    02:47 You'll notice at the very bottom, I want you to have this picture in your head as we move through the next few discussions.

    02:56 At the very bottom here is your von Willebrand factor, do you see that? Huh, that von Willebrand factor was being expressed by the subendothelial collagen.

    03:05 How did that happen? The endothelial cells then became damaged, didn't they? How? Maybe hypertension, smoking, what have you.

    03:13 When does endothelial cells become damaged? Express von Willebrand factor and then von Willebrand factor as you see here has to then bond to a receptor.

    03:22 The receptor that you're seeing that it binds to is then called glycoprotein Ib.

    03:28 While all of these, of course, a central point of all these would be then your platelet.

    03:33 At this point, the only hemostatic factor that we brought in is your platelet.

    03:39 It is not your clotting factors yet or your coagulation cascade factors.

    03:44 I will tell you when we will transition from our platelet plug which is temporary here in which we will then notice, you see the beads called fibrinogen? What is the suffix ogen mean to you? It means weak.

    04:01 You've heard of trypsinogen, you've heard of pepsinogen, you've heard of angiotensinogen.

    04:07 In order for something to become strong, what has to happen? Oh, the ogen has to be cleaved up and once the ogen has been cleaved it becomes strong, but at this point notice we're only in the form of fibrinogen.

    04:18 So therefore, this is a weak temporary hemostatic blood but yet we did form a plug.

    04:25 Now, subsequently now we'll have discussions about how this platelet gets activated and then it'll aggregate and as we move further we will then take the fibrinogen and you should rather be thinking of the enzyme that cleaves up your ogen which is then called you got this, what is it? Thrombin.

    04:49 So at that point we'll get into our coagulation cascade.

    04:55 Let's go and activate that platelet, shall we? Now, that platelet will get activated.

    05:01 There's a particular receptor on that platelet, it's called P2Y12.

    05:10 When that P2Y12 receptor gets activated, you have a dense granule within your platelet.

    05:17 That dense granule is then going to release ADP and all that platelet then gets activated and then inside the platelet you have a particular arachidonic acid metabolite called thromboxane, TXA2.

    05:31 And thromboxane, obviously, is going to take the platelet and it will help you facilitate further aggregation.

    05:38 In the mean time, remember, all of these is hemostasis.

    05:42 In other words, what are we trying to do? Well, let's say that you got to a big picture, you got a paper cut or you nicked yourself with a knife in the kitchen because, whatever, you're cutting carrots and when you do when you cut yourself you gotta stop that bleeding, don't you? Well, you have the process of inflammation.

    05:59 That discussion we've had before and that will be neutrophils and then here you have to stop the bleeding so obviously, platelets.

    06:07 So vasoconstriction is also part of the protocol.

    06:10 Remember the beads that I showed you in the previous discussion? Those beads represent a fibrinogen.

    06:17 Those fibrinogen then bind to particular receptors on the platelet.

    06:21 The name of those receptors are glycoprotein IIb/IIIa.

    06:27 Now, how important are these receptors? Oh my goodness! Really important.

    06:32 So by the time we've gone through the normal and then we start integrating our pathology and start integrating our pharmacology, then you'll have a firm understanding of these glycoproteins.

    06:42 The GP stands for glycoproteins.

    06:45 For example, a condition in which you're missing glycoprotein Ib is called Bernard-Soulier.

    06:51 A condition in which you're missing glycoprotein IIb/IIIa is called Glanzmann thrombasthenia or management, pharmacology, a particular drug that is a monoclonal antibody, Fab fragment, that targets that glycoprotein IIb/IIIa, you must know it's called abciximab, isn't it? These are things to come but I'm just trying to give you little bits of appetizers so that you know as to why it's important.

    07:19 Ultimately, we need to make sure that the platelet has now come together and you form what kind of plug again? Temporary.

    07:28 Why do we say temporary? Because the fibrin is in a form of fibrinogen.

    07:32 We haven't cleaved it yet, we haven't brought in our discussion of coagulation factors.

    07:36 The only thing we've discussed so far is the activation of platelet in forming a temporary hemostatic plug.

    07:43 Let's take a look at this picture now in greater detail.

    07:47 So where we left off was where von Willebrand factor was being expressed by the endothelial cell disrupted endothelial surface.

    07:55 This was a ligand that bound to which receptor please? Glycoprotein Ib.

    08:01 Memorize that.

    08:03 This process is called what? Is this aggregation or adhesion? That's important.

    08:08 It's adhesion.

    08:10 The platelet that firmly not that firmly but it is adhering to the subendothelial collagen via von Willebrand factor.

    08:20 Next, you see the beads again.

    08:23 These beads are the fibrinogen.

    08:27 -Ogen means what to you? Weak.

    08:31 The fibrinogen binds to what receptors? Uh-oh, glycoprotein IIb/IIIa, you see that? Also very importantly, that glycoprotein IIb/IIIa receptor was being expressed by the platelet with the help of whom? ADP.

    08:50 Why is that important? Oh, how about some drugs called clopidogrel, prasugrel? You know about those drugs.

    08:58 You may have heard of trade name called Clavix and such.

    09:03 The point is these are drugs that will then inhibit ADP, therefore, not release or express IIb/IIIa and therefore you would not be able to then bind the fibrinogen with the other platelet.

    09:17 In other words, you wouldn't be able to properly aggregate or maybe perhaps you're deficient of IIb/IIIa and there'll be symptoms like Glanzmann thrombasthenia or maybe, maybe there was a type 2 hypersensitivity reaction in which a patient developed these autoantibodies of IgG type which will then be attacking IIb/IIIa.

    09:37 You see what I'm trying to get at? You must realize at this point that IIb/IIIa is the receptor responsible for aggregation.

    09:45 Now ultimately, as we move forward we'll talk about that coagulation cascade.

    09:51 We're then going to bring in the thrombin, you see that thrombin, that's factor II.

    09:57 Now, big picture, please close your eyes and think about factor II.

    10:01 Factor II is activated by the combination or the convergence of both what's known as the extrinsic and the intrinsic branch of the coagulation cascade which we haven't discussed yet.

    10:13 And ultimately that thrombin will take the ogen and cleave it off the fibrinogen to form a stable fibrin clot as we shall see.


    About the Lecture

    The lecture Mechanism of Antiplatelet Interaction by Carlo Raj, MD is from the course Hemodynamics.


    Included Quiz Questions

    1. Glycoprotein 1b
    2. Glycoprotein 1a
    3. Von Willi brand factor
    4. Factor 8
    5. Factor 9
    1. Bleeding time
    2. D- dimers
    3. Thromboplastin time
    4. Prothrombin time
    5. International normalisation ratio
    1. Platelets adhesion
    2. Endothelial rupture
    3. Solubility in lipids
    4. Solubility in polar solvents
    5. Fibrin activation
    1. Aspirin sensitivity
    2. Widespread skin necrosis
    3. Warfarin sensitivity
    4. Heparin sensitivity
    5. Cloumadin sensitivity

    Author of lecture Mechanism of Antiplatelet Interaction

     Carlo Raj, MD

    Carlo Raj, MD


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