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.

Does pyknosis occur in necrosis or apoptosis?

Q. Would a pyknotic cell be a form of necrosis or apoptosis? Or am I totally off base here?

A. No you’re totally not off base – that’s a really good question!!

We typically use the word “pyknosis” to mean one of the three nuclear patterns seen in necrotic cells…but pyknosis can also occur in apoptosis! I’ll explain a bit more.

When cells undergo necrosis, they show a lot of different morphologic abnormalities. Overall, necrotic cells appear enlarged and more eosinophilic, and their nuclei look abnormal due to breakdown of DNA. There are three specific patterns of nuclear change in necrosis, which are:

  • Pyknosis (the nucleus shrinks and becomes dark blue/black)
  • Karyorrhexis (the nucleus breaks apart, or fragments, like a cookie crumbling into bits)
  • Karyolysis (the nucleus just fades away)

Here’s a nice diagram I found (I modified it a bit from the original) showing these changes:
When cells undergo apoptosis, they also show a lot of different morphologic features. Overall, apoptotic cells appear shrunken, with really dense, dark, eosinophilic cytoplasm, and the chromatin in the nucleus aggregates into a dense mass which can fragment. Here’s a photo from Robbins showing an apoptotic cell:

The word “pyknosis” isn’t typically used when describing an apoptotic cell – but Robbins does say that pyknosis can be a feature of apoptotic cells, so there you go.

So…the bottom line is that pyknosis is a nuclear change in which the nucleus shrinks and becomes dark blue/black. Typically, we associate the word “pyknosis” with necrotic cells – but apoptotic cells can show pyknosis too.

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 does megaloblastic mean?

Here are a few great questions about megaloblastic anemia I received by email.

Megaloblastic vs. macrocytic

Q. Do I have to say “megaloblastic macrocytic” anemia? Aren’t megaloblastic and macrocytic the same thing?

A. Macrocytic refers to the size of the mature red cells in the blood. It means that the red cells are big. Normal is 80-100 femtoliters. If the red cells are over 100, they’re macrocytic; if they’re under 80, they’re microcytic.

Megaloblastic refers to the weird morphologic changes (immature nucleus, mature cytoplasm, large overall size) you see in red cell precursors (and, to some extent in neutrophil precursors), in patients who are B12 deficient. So the term is really referring to the cells in the bone marrow, not mature, circulating red cells. However, you can also see changes in the blood that indicate megaloblastic anemia, the most common of which is hypersegmented neutrophils (like the one above).

So the terms are not equivalent.

That being said, you don’t need to say both terms if you have a megaloblastic anemia, because all megaloblastic anemias are also macrocytic. You just say “megaloblastic anemia.”

Conversely, if you just say “macrocytic anemia,” that doesn’t say anything about whether there are megloblastic changes present or not! It just says: there’s an anemia, and the red cells are big.

Non-megaloblastic anemia

Q. What really is non-megaloblastic anemia? Because my lectures have mentioned it but I’m not sure what it really is.

A. Non-megaloblastic anemia just means an anemia without megaloblastic changes – and technically, that encompasses every single anemia except megaloblastic anemia! But really, when people say non-megaloblastic anemia, they’re usually referring to a macrocytic anemia (one in which the red cells are large, over 100 femtoliters) without megaloblastic changes (funny looking red cells). This type of anemia can be seen in liver failure and in myelodysplasia.

Pernicious anemia and megaloblastic anemia

Q. I don’t understand the difference between pernicious anemia and megaloblastic anemia. Pernicious anemia is just a deficiency in intrinsic factor that helps with absorption of B12…so patients have low B12 levels. But how is that different from megaloblastic anemia?

A. The best way to think about these two terms is: pernicious anemia is one cause of megaloblastic anemia.

Megaloblastic anemia is a type of anemia in which you get weird morphologic changes (megaloblasts, hypersegmented neutrophils, oval macrocytes) due to a lack of B12 and/or folate. There are lots of things that can cause a lack of B12 and/or folate…so when you see a case of megaloblastic anemia, you have to investigate to find out what the cause is.

Pernicious anemia (in which patients can’t absorb B12 due to a lack of intrinsic factor) is one cause. Another cause is folate-depleting drugs (like chemotherapy drugs); another is dietary deficiency.

It’s kind of confusing because they put the term “anemia” in pernicious anemia – so it makes it sound like pernicious anemia is a category in and of itself. It’s not – it just falls under the heading of megaloblastic anemia.

 

 

 

 

 

 

What’s the difference between an aortic dissection and a false aneurysm?

 

 

Q. I’m a little confused about the difference between an aortic dissection and a false aneurysm.

In diagrams of aortic dissection, it looks like all three layers of the vessel have been damaged and blood is leaking out of the vessel BUT still contained by connective tissue etc. Isn’t that what a false aneurysm is? So what’s the difference between the two?

A. I can see what you mean – diagrams of aortic dissections can be misleading!

Diagrams of aortic dissection (like this one above, from Wikipedia) often focus on the three types of dissections. The point of these diagrams is just to show the place in the aorta where the dissection begins (near the heart vs. more distally). They can be kind of misleading, though, if they don’t clearly depict how the blood tunnels through the wall of the aorta. Like you described, it can look more like the aorta has actually ruptured all the way through, and the blood is collecting outside the aorta.

So let’s quickly review the definitions of false aneurysm and dissection.

In a false aneurysm, all three walls of the vessel have been broken through, and blood collects just outside the vessel. It doesn’t tunnel down or up into the wall of the vessel at all. After some time, the blood organizes and becomes firm – kind of like a blood clot – and it prevents further blood from escaping the damaged vessel.

In a dissection, only the inner portion of the vessel wall is damaged. Blood enters into that damaged area, and tunnels up or down within the wall of the vessel. Unlike a false aneurysm, in which blood bursts through all three layers of the vessel, in a dissection, the outer layers of the vessel are still intact, and blood forms a channel within the vessel wall itself.

So you had the right idea! It was just the diagram that threw you off. In the diagram above, the arrangement of the two little white arrows incorrectly implies that blood is busting all the way through the aorta at a single point – but the rest of the aortic wall looks intact. To really show what’s happening in an aortic dissection, the wall of the aorta should be more clearly depicted, and the second arrow should point up or down within the wall itself, showing the path of blood as forms a tunnel within the vessel wall.

 

What does “differentiation” mean?


Q. I have Googled and YouTubed this thing to death, and I still can’t grasp the meaning of “differentiation.” It seems the opposite of its definition. To “differentiate” means to recognize what makes something different. But according to your post on tumor differentiation, well-differentiated tumors resemble (don’t look different from) their tissue of origin. I would think if something is well-differentiated, it would look very different from the thing it’s being compared to. Why is the use here opposite of its meaning?

A. I totally get where you’re coming from. It’s REALLY frustrating in pathology when things are described in terms that don’t seem to make sense. You are not alone in questioning the use of this term!

The problem is that the word in question – differentiation – has a specific meaning in the real world. You’re exactly right in your definition: to differentiate between two things means to recognize what’s different or unique.

So you’d think that “differentiation” in the pathology world would mean the same thing: the recognition of things that are unique, different, or not the same. By logical reasoning, then, a “differentiated” tumor would be one that looked different from its cell of origin. And you’d think a “well-differentiated” tumor would be one that looked very different from its cell of origin.

Unfortunately, “differentiation” doesn’t have the same definition in the pathology world. So we have to put aside our logic and knowledge of vocabulary for a moment, irritating as that may be, and learn a new definition for this word.

The definition of “differentiation” in pathology-speak.

When we’re talking about tumors, the definition of “differentiation” is simply this: the degree to which tumor cells resemble their cell of origin. A well-differentiated tumor is one in which the tumor cells look very much like their cell of origin. A poorly-differentiated tumor (like the poorly-differentiated squamous cell carcinoma shown above) is one in which the tumor cells barely resemble their cell of origin.

That’s it. Yes, it’s an annoying word choice, because it is used here in a way that seems counterintuitive. But maybe it’s not as far off as it seems.

Maybe this will help.

I think about it (okay, rationalize it) this way. When cells are really immature, they don’t have a lot of features that make them look different from other cells. Myeloblasts don’t look very different than lymphoblasts, for example. So we could say that these immature cells are undifferentiated; it’s hard to tell what kind of cell they really are, and hard to tell them apart from other cells.

The same thing is true of the cells in poorly-differentiated tumors! The cells show practically no features that give away their identity; it’s hard to even tell what kind of cells they are. They are, in effect, undifferentiated.

If you think about “differentiation” this way (undifferentiated cells lack identifying features; it’s hard to tell what kind of cell they are), then the concept of tumor differentiation is a little easier to swallow. A little.

Do all leukemias arise from hematopoietic stem cells?

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Q. I have a quick question on the cell of origin in leukemia. In our pharmacology class, we went through a section on cancer. There was a slide that said leukemia is a tumor of hematopoietic stem cells. But leukemia involves more than just hematopoietic stem cells, right? (more…)

Tumor invasion and metastasis: are they the same thing?

Here are a couple great questions from one of my lovely students regarding invasiveness and metastasis.

Q. I have a quick question on today’s lecture. There is a slide near the end that has a picture of non-invasive carcinoma. For a tumor to be malignant, should it not be invasive?

A. Great question! I think you may be referring to the image above, which shows a gland with either severe dysplasia or carcinoma in situ.

Cancers are usually invasive, as opposed to benign tumors, which grow with pushing borders and are typically encapsulated.

However, very early cancers are called “carcinoma in situ”, which means they have not broken through the basement membrane yet (and thus are non-invasive). Every cancer has to start somewhere!

The only really definitive quality of malignancy is metastasis. If a tumor has metastasized, that is definite evidence of malignancy.

Q. But is invasiveness different from metastasis? That is, can a cancer metastasize without first invading tissue? Or are we talking about a tumor that has the ability to metastasize, but has not yet metastasized?

A. I’ll answer your questions separately.

1. Yes – invasiveness is different than metastasis.

  • Invasiveness is the ability of a tumor to extend into the surrounding tissue, and it is almost always a sign of malignancy. Benign tumors (with very few exceptions), are encapsulated and grow simply by expanding and pushing the surrounding tissue aside. Malignant tumors (with very few exceptions), are unencapsulated and grow by reaching into the surrounding tissue.
  • Metastasis is the ability of the tumor to move to a different location in the body and set up shop (start growing) there. Benign tumors NEVER metastasize. Malignant tumors usually do, although if detected early, they may be removed before they have the chance.

2. No: a cancer cannot metastasize without first invading tissue. In order to metastasize, tumor cells must first invade tissue, then make their way into vessels (either blood vessels or lymphatics), and then make their way out of those vessels and into new tissue.

3. Yes, the image above shows a non-invasive malignancy (carcinoma in situ), which is a malignant tumor that has not yet metastasized (or even invaded) yet. Left to its own devices, carcinoma in situ almost always becomes invasive carcinoma. As the tumor grows, some cells will most certainly develop the ability to become metastatic. So it’s way better to detect a carcinoma when it is in the carcinoma in situ stage rather than the invasive stage.