Atherosclerosis and Atherothrombosis Pathophysiology

Deepak L. Bhatt, MD, MPH: Despite intensive antiplatelet therapy, patients with coronary and/or peripheral artery disease exhibit a high residual risk of atherothrombotic events. Evidence from anti-Xa therapy in addition to standard therapy supports the use of a direct, oral, factor Xa inhibitor in reducing mortality and morbidity in patients with acute coronary syndrome, when combined with antiplatelets.

Our discussion today focuses on the available factor Xa inhibitors and potential uses in cardiovascular disease.

I am Dr Deepak Bhatt, the executive director of Interventional Cardiovascular Programs and a professor of medicine at Harvard Medical School in Boston, Massachusetts. Joining me today are Dr John Eikelboom, a professor in the Division of Hematology & Thromboembolism of the Department of Medicine at McMaster University in Hamilton, Ontario; Dr Vamsi Krishna, an interventional cardiologist and endovascular specialist at Ascension Medical Group in Kyle, Texas; and Dr Manesh Patel, the chief of the Division of Cardiology and a member of the Duke Clinical Research Institute in Durham, North Carolina. Thanks for joining us. Let’s begin.

There’s a lot to talk about today on our plate, and it will hopefully be an interesting discussion for the audience. Maybe we can start off with the basics. In my introduction I was talking about atherothrombosis. I like the term, but maybe we can start off with a discussion of what the difference is between atherosclerosis and atherothrombosis. Is there meaning to those words?

Manesh Patel, MD: Yes, maybe I’ll start and I’m sure others can jump in, too, Deepak. I think we went through a period when we thought of everything as atherosclerosis. It’s important to remember that in medical school or even the earliest observations, it was pathology where we looked at the arteries and saw yellow streaky lipid content in people’s arteries. So that led to this idea of hardening of the arteries and atherosclerosis, where in fact the cells have some lipid material and a variety of other compounds laid down over a lifetime of exposure, but unfortunately this starts young in age.

The addition of thrombosis is really important because that’s how the pathology happens, in that atherosclerosis may be occurring. But most often, whether it’s a heart attack, stroke, or often even thrombosis in the limbs, there’s actually a disruption to that atherosclerosis that then starts to trigger the thrombotic events that lead to either a full occlusion of that vessel or at least downstream embolization. And so I think it’s a really nice way of thinking about both the biology of the underlying disease process, but also the acute manifestations. I don’t know, John, if that’s a good description. You’re the hematologist. That’s my interventional description.

John Eikelboom, MBBS, MSc, FRCPC: That’s a great description. If there is such a thing as elegant pathology, maybe atherothrombosis is the phrase to describe it. Because we have a pristine vessel, which is injured by some exposure to some injurious agent. As a response, the vessel gets damaged and then it exposes subendothelial proteins, it releases tissue factor, and it starts to stimulate coagulation. So even when you don’t have overt thrombosis sitting there, your coagulation system starts ramping up, your platelets start getting a bit fired up, and then there is a sequence of events that can lead to subclinical thrombosis to clinical thrombosis. It’s a continuum combining that response to injury with thrombus formation.

Deepak L. Bhatt, MD, MPH: Let me ask you, and you’re probably the most qualified here. What we learned in medical school was the coagulation cascade, and Vamsi is still having nightmares about that, by the way, so be gentle in your depiction of this. But there’s a coagulation cascade, there are the platelets, and they’re doing this there, and they’re doing this there. But they’re much more intermingled in real life, of course. How do they all interplay?

John Eikelboom, MBBS, MSc, FRCPC: That’s a terrific point because when we are taught this in medical school, we could be forgiven for believing that they’re totally disparate pathways, that are at some stage married together at critical moments. But it’s all happening at the same time. And I like to think of coagulation actually as incredibly simple. It’s like this “Y” of tubes, intrinsic, extrinsic, which already gives horrors to everyone. But then everything leads to a common pathway where thrombin is generated and thrombin leads to platelet activation and to fibrin formation, the two key components of every thrombus. You’ve always got fibrin, you’ve always got platelets. In fact, at no stage through this process do you independently activate platelets or independently generate thrombin. They’re very closely linked.

Deepak L. Bhatt, MD, MPH: I think that provides a good basis of how potentially antiplatelet and/or anticoagulant therapy can be useful in atherothrombotic conditions. Some people say, well, atherosclerosis, atherothrombosis, it’s all going away anyway. What do you think, Vamsi, what are you seeing out there on the front lines? Have we conquered atherosclerosis and atherothrombosis?

Vamsi Krishna, MD: I think we made good strides with statin and non-statin therapies to help control some of our cholesterol and new medications like Vascepa out there to help with triglycerides and other molecules out there. I think we’re making good strides. I do think it’s important that we use the word atherothrombotic because when we’re talking about continued residual risk, especially as interventionalists, we acutely fix an issue, we determine the duration of antiplatelet therapy, we do goal-directed medical therapy, and then patients are off their medications. But really the reality is that there is a constant diffuse state of disease going on, and that these end points of having a stroke, having a heart attack, or having some limb event are real. And what therapies are we really using, and how are we defining it in trials? I think using these atherothrombotic end points are really important for the community to understand.

Transcript edited for clarity.