What’s the relationship between aneurysm, thrombosis, and stenosis?

I got this really great question from one of my students, and it got me thinking about how important it is to have really clear definitions of pathologic conditions. These three conditions – aneurysm, thrombosis, and stenosis – are totally different things. And yet they can sometimes co-occur, or one can cause another – so it can become confusing!

I thought I’d share the question and my answer here, because I’m sure there are other students who are having trouble understanding these disorders.

Here’s the question:

I was reviewing the Blood Vessel Pathology lecture notes from this past week and was having a bit of trouble differentiating between aneurysm, thrombosis and stenosis. I’ve written what I believe to be the differences, but would you mind giving me some feedback on if this is correct?

“An aneurysm is when a clot occurs, widening the blood vessel to unhealthy proportions due to high blood pressure and or atherosclerosis, and it may rupture with no warning signs, leading to internal bleeding. The difference between aneurysm and thrombosis is that aneurysm causes damage to the lining wall of the blood vessel. Thrombosis is clotting of a blood vessel without damage to the walls. Stenosis is narrowing of the artery to cause clotting, and it comes with the warning sign of severe chest pain.”

Great question!! You’re on the right track – but there are some things in your statement that aren’t quite right – so I’ll give you my definitions and then comment on what you wrote.

Aneurysm

An aneurysm is an abnormal widening (or dilation, or outpouching) of a blood vessel. It’s focal in nature, which means that it’s just in one place; you can point to where it is (it’s not like the entire vessel is just a little bit wider). Here’s an image of a normal vessel and a vessel with an aneurysm:

Aneurysms can be caused by lots of things (like trauma and atherosclerosis), or they can be congenital. Sometimes aneurysms just sit there and never cause any problems. But sometimes they get larger and larger, and the vessel wall weakens to the point where it eventually ruptures.

Thrombosis

A thrombosis (or thrombus) is an abnormal blood clot. It’s not just a normal little blood clot formed to repair a hole in a vessel – it’s a blood clot that’s been made when it isn’t needed. The most common place for a thrombus is in the deep veins of the legs – but you can form a thrombus anywhere in the body.

It’s not good to have a thrombus for a few reasons:

  • If it’s big enough, the thrombus can block blood flow through the vessel, and the tissues fed by that vessel can be damaged or even die as a result.
  • Thrombi can weaken and damage the vessel wall, leading to other problems (like aneurysms, or even rupture of the vessel if it gets weak enough).

Here’s a related term: embolus. An embolus is a blood clot that’s floating in the blood (maybe it broke off from a thrombus in the leg, or maybe it formed on its own somewhere). The point is that it is mobile, and it’s going to move with the blood until it gets to a vessel that’s too small for it to pass through, and it will lodge there. If the embolus is tiny, you may not notice anything clinically. But if the embolus is big enough to block off an important vessel (say, one of the vessels in the brain), that means that the tissue fed by that blood vessel won’t get blood, and it will die.

Stenosis

Stenosis just means “narrowing.” It can be used to describe abnormal narrowing of lots of different structures in the body (like heart valves and the spine). When a blood vessel is stenotic, that means its lumen is smaller than normal.

There are many possible causes of stenosis in vessels. Here are some common ones: atherosclerosis (formation of plaques that take up space and narrow the lumen), thrombosis (formation of an abnormal clot that takes up space within the vessel lumen), and vasculitis (inflammation of the vessel).

Like the other abnormalities we talked about above, stenosis can be asymptomatic if it is mild. But if a vessel is very stenotic (for example, if the vessel lumen is only 20% of its normal diameter), that can impair blood flow enough to cause serious problems to the tissue downstream. This is particularly a problem if the vessel feeds the heart or the brain; in these places, restriction of blood flow can cause severe symptoms (or even death).

Why these things are confusing

These three conditions are distinct and separate entities – but they can occur together, and they can also occur sequentially – and this can be confusing. For example, if you have a thrombus in a vessel, that can weaken the vessel wall enough to cause an aneurysm. Or you can have a thrombus that simply sits there and takes up space in the vessel lumen, causing stenosis of the vessel.

So the best way to approach this is to make sure you understand what each of these disorders is – and then once you have that down, you can go on to learn about what causes them and what they can lead to.

Back to the statement part of the question – my comments are in blue.

An aneurysm is when a clot occurs, widening the blood vessel to unhealthy proportions due to high blood pressure and or atherosclerosis, and it may rupture with no warning signs, leading to internal bleeding. You’re correct in saying that an aneurysm is a widening of a blood vessel that may be caused by high blood pressure or atherosclerosis, and that it may rupture. And it’s true that aneurysms can be caused by abnormal blood clots (thrombosis) – but just to clarify – not all aneurysms are caused by clots. The main point is that an aneurysm is an abnormal widening of a blood vessel – and there are many potential causes. The difference between aneurysm and thrombosis is that aneurysm causes damage to the lining wall of the blood vessel. Thrombosis is clotting of a blood vessel without damage to the walls. No; the difference between aneurysm and thrombosis is that an aneurysm is an abnormal dilation/widening of a blood vessel, whereas a thrombosis is a blood clot that forms within a blood vessel. Both aneurysms and thromboses can damage the vessel wall. Stenosis is narrowing of the artery Yes! to cause clotting Not exactly. Stenosis is just the narrowing of a vessel lumen; it doesn’t necessarily cause the formation of a blood clot. However, thrombosis (abnormal clotting) can lead to stenosis (narrowing of the vessel lumen)! This is where you have to be really strict about your definitions, otherwise it gets confusing! and it comes with the warning sign of severe chest pain Sometimes! If the stenotic vessel is one that supplies the heart, and if the stenosis is moderately severe (meaning that the lumen is narrowed enough to decrease the amount of blood that can flow through the vessel), then the patient will experience chest pain (because there’s less blood flow to the heart than usual). This is a warning sign – it tells you that the tissue isn’t getting quite enough blood flow, and you better go see a cardiologist and get those vessels looked at. However, if the stenosis is really severe (like if the lumen is only 10% of its normal diameter), then almost no blood is getting through, and that may be enough to actually cause tissue death (myocardial infarction, or heart attack). In this case, the chest pain the patient experiences isn’t just a warning sign – it’s a sign that the tissue is actually dying right now.

Is Factor V Leiden a Mendelian Disorder?

Here is a great question I got from a student about the genetics of Factor V Leiden.

Q. Factor V Leiden is autosomal dominant – but it doesn’t seem to follow Mendel’s laws. Would you say it shows incomplete dominance?

A. This is such a good question! Factor V Leiden is an autosomal dominant disease – and you’re right: it does NOT follow Mendelian laws. However, the non-Mendelian pattern it follows is not incomplete dominance, but incomplete penetrance.

First, here’s why Factor V Leiden is a non-Mendelian disorder.

Factor V Leiden is an autosomal dominant disease. If it followed Mendel’s laws, everyone who inherited ether one or two copies of the Factor V Leiden gene (which is the dominant gene) would display the same phenotype (in this case, they’d all have the same exact amount of abnormal clot formation). But that’s not how it works in this disease.

Patients with factor V Leiden have an increased risk of developing abnormal clots. But not everyone with an FVL gene (or even with two FVL genes) develops a clot! Some do, and some don’t. So the phenotype is not the same in everyone with the FVL gene.

So how would you describe this non-Mendelian weirdness?

This weird phenomenon is called incomplete penetrance.

In Mendel’s experiments, his dominant alleles showed complete penetrance. In other words, every plant with a genotype containing a dominant allele (or two!) always displayed the same phenotype.

But in real life, that’s not always the case – sometimes penetrance is not complete, and factor V Leiden is a good example. As we mentioned above, the factor V Leiden gene confers an increased risk of abnormal clotting – but that’s all it is, just a risk, not a certainty. So some patients with the FVL gene display the disease phenotype, and some do not.

Incomplete dominance is also a non-Mendelian pattern of gene expression – but it’s different than incomplete penetrance.

In Mendelian dominance, there are two alleles and two phenotypes. In the left image below, the two phenotypes are purple and white flower colors – and as long as you have at least one dominant allele (in this case, P), you’ll get a purple flower.

In incomplete dominance, there are two alleles and three phenotypes. In the right image below, the phenotypes are red, white, and pink flower colors. If you are homozygous for either the R or the W allele, you’ll get a red or a white flower. But if you have both the R and the W allele, you’ll get a “blend” of the two other phenotypes – a pink flower!

Mendelian dominance

Incomplete dominance

Snapdragons actually display this incomplete dominance pattern! Good thing Mendel happened to use sweet peas in his experiments.

What’s up with factor XII?

XIIbHere’s a great coag question from a Path Student reader:

Q. I am wondering why Factor VII deficiency causes significant bleeding problems but Factor XII deficiency does not. One source I found stated that this is because the extrinsic pathway is the primary pathway in vivo and that the intrinsic pathway is of lesser importance.

However, the more I thought about it, I then wondered why Hemophilia A and Hemophilia B are so severe since they are involved in the intrinsic pathway. Why doesn’t the extrinsic pathway just pick up the slack and allow the patient to remain asymptomatic as it seems to with Factor XII deficiency?

A. It turns out that factor XII is pretty important in vitro, but not in vivo. In the test tube, XII is activated by contact factors (like HMWK), and then XIIa catalyzes the conversion of XI to XIa. In the body, though, the main thing that converts XI to XIa is thrombin (not XIIa). I don’t even include XII in my drawing of the cascade for my students, since it’s of no clinical consequence. The intrinsic side is complicated enough!

With regard to the extrinsic and intrinsic pathways: both are critical for fibrin formation in vivo. I wouldn’t say that either one is of lesser importance – they just do different things.

In vivo, the cascade starts on the extrinsic side with TF showing up and binding to VIIa. The TF-VIIa complex converts X to Xa, and things proceed from there. The weird thing is that as soon as a little Xa is made, the extrinsic pathway is turned off (by tissue factor pathway inhibitor, or TFPI)!

So then what? By this point, you already have a little thrombin around – and that thrombin goes and kicks off the intrinsic pathway. Thrombin converts XI to XIa, which converts IX to IXa, which – together with VIIIa – converts X to Xa.

Bottom line: the cascade starts with the extrinsic pathway, but that pathway gets shut off very quickly. Thrombin activates the intrinsic pathway, which proceeds to convert fibrinogen to fibrin until you need to turn it off.

What does phospholipid do in the PT and PTT?

phospholipid

Q. I have a quick question about coag lab tests. In the tests that you are adding phospholipid (like the PTT), what exactly is the phospholipid doing?

A. It’s just providing a surface for the coagulation factors to sit on! Many of the coagulation factors need a phospholipid surface to sit on in order to work.

Normally, the platelets provide that surface (they have phospholipids in their membranes) – but you’ve taken the platelets out of the test tube before you do the coagulation lab tests – so you need to add them back in if you want the whole cascade to run.

You also add phospholipid in the PT (INR)! It’s part of the thromboplastin molecule. Thromboplastin is just a tissue-factor-like substance plus phospholipid, all wrapped up in one reagent.

A few of the coag tests don’t require a phospholipid surface. The TT, for example, doesn’t need phospholipid; you’re just adding thrombin and seeing how fast it can convert fibrinogen to fibrin – and that single reaction doesn’t need phospholipid to work. Also, the fibrinogen assay doesn’t require phospholipid because it just measures the amount of fibrinogen.

Why do the INR and PTT measure different pathways?

test tubeCoagulation questions seem to come up all the time! Here’s a good one from one of our readers.

Q. In both the PT and PTT we add thromboplastin, right? So how come the PT measures the extrinsic pathway and the PTT measures the intrinsic pathway”

A. This is a great question because it really gets at the underlying concepts of the PT (INR) and PTT. When I was a medical student, I never really thought about why the INR only measured the extrinsic pathway and the PTT measured only the intrinsic pathway. I just memorized the substance added to the test tube in each test, and the pathway the test measured. Later on, though, I realized I didn’t have a clue as to why the tests measured the pathways they did.

Before we get into the reasoning behind the tests, a quick correction is in order. We don’t add thromboplastin in both the INR and PTT. In the INR, you add thromboplastin, and in the PTT you add phospholipids (not thromboplastin). It turns out thromboplastin is a substance that contains both phospholipids AND a tissue-factor-like substance. That’s why they call the assay the “partial thromboplastin time” – because you only need to add part of the thromboplastin reagent (the phospholipid part) to get this test to run.

To understand why the PT measures just the extrinsic pathway and the PTT measures just the intrinsic pathway, you need to know what activates these pathways in the body. The extrinsic pathway is activated by tissue factor. The intrinsic pathway can be activated by a bunch of things, the most important of which is thrombin.

Why the INR measures the extrinsic pathway
To get blood in a test tube to form fibrin along the extrinsic pathway, you need to add some tissue-factor-like substance. Also, since you removed the platelets and calcium before running the test, you need to add those things back into the test tube (the coagulation system needs a phospholipid surface, normally provided by platelets, and calcium to run). Thromboplastin is a substance that contains both phospholipids and a tissue-factor-like substance. Add thromboplastin and some calcium, and the blood in the test tube will form fibrin via the extrinsic pathway.

Why the PTT measures intrinsic pathway
To get blood in a test tube to form fibrin along the intrinsic pathway, you don’t need to add any tissue-factor-like substance (if you do, the extrinsic pathway will be activated!). All you need to do is add back what you took out of the blood (phospholipids and calcium), as well as something like silica or kaolin to activate the intrinsic pathway (normally, thrombin does this job in vivo), and you’ll form fibrin along the intrinsic pathway. This is actually why the intrinsic pathway was named the way it was: everything you need to get the pathway to run is “intrinsic” to the blood. The extrinsic pathway requires something “extrinsic” to the blood (tissue factor) for it to run.

Bottom line
The INR activates the extrinsic pathway because in this test you add thromboplastin (which contains both a tissue-factor-like substance and phospholipids) to the test tube. The PTT activates the intrinsic pathway because in this test you add just phospholipids to the test tube – and without tissue factor around, fibrin is formed along the intrinsic pathway.