Taking a Closer Look at Thrombin and Its Role in ACS CME
Jeffrey I. Weitz, MD
CME Released: 09/20/2012; Valid for credit through 09/20/2013
| Jeffrey I. Weitz MD: I am going to start off by focusing on thrombin and its role in acute coronary syndromes (ACS). |
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| Thrombin plays a critical role in ACS, where it serves as the link between vascular injury, coagulation, and platelet activation. Here we see the destructive atherosclerotic plaque. The exposed collagen and Von Willebrand factor provide a site onto which platelets adhere and become activated. The subendothelium is also rich in tissue factor and exposure of this tissue factor triggers coagulation. These activated platelets provide a surface on which the coagulation factors assemble to generate factor Xa, which then converts prothrombin to thrombin. Thrombin not only converts fibrinogen to fibrin, but also amplifies its own generation by feedback activation of factors V, VIII, and XI. Thrombin also activates ambient platelets, and induces them to aggregate. These platelet aggregates become enmeshed in the fibrin to form a platelet-rich thrombus at the site of injury. |
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| Now although only about 13% of patients who undergo angiography during their ACS with unstable angina (UA) might have angiographic evidence of thrombus, if you look on angioscopy about 94% of such patients have thrombi, so thrombus is a hallmark of ACS. These thrombi contain thrombin and this thrombin is the stimulus for thrombus expansion because 95% of thrombin generation occurs after clot formation. If you look here at what is happening on angioscopy, you can see this platelet-rich thrombus in the coronary artery. |
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| What is often underappreciated is the fact that if we trigger thrombin generation with tissue factor, and we monitor thrombin with a fluorogenic thrombin substrate, we have a lag phase, after which there is an exponential increase in thrombin generation. If you look at the blood, clotting occurs here so 95% of this thrombin generation occurs after clot formation. Thrombin amplifies its generation through feedback activation of coagulation. This thrombin burst, if you will, is important for solidifying that thrombus and also for activating platelets and inducing them to aggregate. |
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| Thrombin activates platelets via thrombin receptors known as protease-activated receptors (PAR). On human platelets, there are 2 PARs, PAR-1 and PAR-4. The major activator is PAR-1. PAR-1 is a transmembrane protein that has an extracellular domain which provides a thrombin-binding site. Thrombin docks on this extracellular domain, cleaves the receptor, and this creates a new end terminus which then folds back to interact with the body of the receptor. This causes outside/inside signaling, which then induces platelet activation and subsequent aggregation. This tethered ligand mechanism is unique to these PARs and a very potent mechanism for platelet activation. |
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If we look at the pathophysiology of atherothrombosis, such as occurs in ACS, you can see how the various treatments fit in. We get plaque disruption which, as I said, exposes collagen and Von Willebrand factor which interact with each other. This induces platelet adhesion and secretion. The activated platelets synthesize and release thromboxane A2 through cyclooxygenase-1 in a reaction that is inhibited by aspirin. Thromboxane A2 then recruits additional platelets and activates them.
The activated platelets also release adenosine diphosphate (ADP), which then interacts with the ADP receptor P2Y12 to additionally recruit and activate platelets. This interaction is the target of thienopyridines, ticlopidine, clopidogrel, prasugrel, and of course, it is also the target of ticagrelor. Platelet activation results in a conformational change in the glycoprotein (GP) IIb/IIIa receptor, which then ligates fibrinogen and Von Willebrand factor to mediate platelet aggregation and of course the GP IIb/IIIa of the antagonists, abciximab, eptifibatide, and tirofiban.
Plaque disruption also exposes tissue factor, which triggers thrombin generation. Thrombin activates platelets through PAR-1, and PAR-1 is the target for vorapaxar. Finally, this whole tissue factor pathway can be inhibited with anticoagulants and those anticoagulants can be multipurpose agents like heparin or low-molecular-weight heparin, or they can be targeted agents like rivaroxaban or apixaban. This pathway for atherothrombosis can be interrupted at many levels; combination therapy can be used to target multiple steps in this process. |
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| What I hope I have shown you in this brief introduction is that thrombin plays a critical role in ACS. Thrombin begets thrombin, and stopping thrombin generation or activity can attenuate atherothrombosis. Thank you very much. |
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