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 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.

 

 

 

 

 

 

Blood cookies!

I’ve been really busy teaching this fall, so I haven’t been posting nearly as much as I’d like. I will be back to normal (ha) soon – but until then, I thought I’d share what we did in class yesterday. We’ve been learning about hematopathology (my favorite) – so I made cookies depicting some of the diseases we covered.

It’s super geeky, but I’m okay with that. It’s really fun to combine path knowledge with something that’s actually creative and pretty. And it’s sort of educational for my class…at the very least, they get a well-deserved break from the HOURS of lecture they have to sit through. Here are the end results (with a few high-yield things about each cell).

Sickle cells

Sickle cells are seen, of course, in sickle cell anemia. They’re abnormally shaped because when sickle hemoglobin deoxygenates, it polymerizes, contorting the red cell into a sickle shape.

Reed-Sternberg cell

Reed-Sternberg cells are the malignant cells in Hodgkin lymphoma. They’re gigantic, and typically they have two nuclei with prominent nucleoli, giving the cell an “owl’s-eye” appearance.

Neutrophil with Dohle body

In some cases of bacterial infection, neutrophils develop little blue cytoplasmic inclusions, called Döhle bodies, which are chunks of revved-up rough endoplasmic reticulum.

Butt cell

No, I didn’t make this up! Follicular lymphoma is made up, in part, of small cleaved cells – and when these get out into the blood, their nuclei totally look like butts. Adorable.

Faggot cell

Faggot cells contain TONS of Auer rods (faggot means bundle of sticks). They’re pathognomonic of acute promyelocytic leukemia, which has a t(15;17) that you should stick in your head somewhere.

Blast with Auer rod

Auer rods are only seen in malignant myeloblasts. So if you see one, you know you’re dealing with acute myeloid leukemia. Not all AMLs have Auer rods, though – so the absence of Auer rods doesn’t rule out AML.

Platelets

These could be normal platelets…but since we’re talking about diseases, let’s say they’re platelets from essential thrombocythemia, which is one of the four chronic myeloproliferative disorders (it’s the one in which the blood has an extremely high platelet count).

Do all leukemias arise from hematopoietic stem cells?


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…)

What the H is HLH?

Hemophagocytic lymphohistiocytosis is not easy to pronounce. That’s why it is often abbreviated HLH, which is a lot kinder on both the tongue and the keyboard.

The “hemophagocytic” part of the name, which means “blood + eat + cell,” comes from the observation that the immune activation in HLH often results in hemophagocytosis, in which blood cells are engulfed by histiocytes (macrophages in the tissue) in a very cannibalistic way. Check out the histiocyte in the center of this image (can you see the red cells inside?).

This activation of macrophages is why the disease has also been called macrophage activation syndrome in the setting of juvenile rheumatoid arthritis. The “lympho” part comes from the increase in lymphocytes that happens in HLH. Even though this disease has a complicated name and several different triggers, the symptoms have one common cause: Cytokine Storm.

What causes HLH? Cytokines and hit men.

Cytokines are important molecules in inflammatory signaling in the body, and when not properly regulated they can cause a lot of destruction. if you want a mini-review on cytokines check out all about cytokines in less than 400 words.   

HLH happens when something triggers an over-activation of cytotoxic T and natural killer (NK) cells, which are cells responsible for quickly recognizing and destroying cells which have been infected, usually by viruses. Cytotoxic T cells and NK cells are specialized lymphocytes which are kind of the hit men of the immune system. When they detect cells presenting viral antigens via major histocompatibility complexes, they release perforins to punch holes in the cells and cytokines to signal other inflammatory cells to rush in and finish the job.

This immune over-activation turns on lots and lots of cytokine-producing macrophages. The massive cytokine release causes fever. The huge numbers of activated macrophages end up “eating” or destroying the patient’s own blood cells as well as doing damage to many organs, such as the bone marrow, lungs, and liver. The damaged blood cells get trapped in the spleen, causing splenomegaly. HLH can also kick off other problems in blood regulation, such as disseminated intravascular coagulation (DIC).

Primary vs. Secondary HLH

HLH can be genetic (“primary”) or acquired (“secondary”). Genetic cases usually appear in early childhood and are associated with a mutation affecting cytotoxic cell function, or with an immunodeficiency state such as Chediak-Higashi syndrome. Acquired forms of HLH can occur at any age – but often affect adults (although some adults are later found to have a predisposing mutation). Adult cases are hard to recognize, because they happen in the setting of other serious illnesses and can present with non-specific symptoms.

Acquired HLH can be triggered by any event provoking an immune response. Usually, though, it occurs in the setting of infection or malignancy, when the immune system is already compromised. Infectious triggers are usually viral, most commonly Epstein-Barr virus (EBV) and human immunodeficiency virus (HIV). Exactly why adult HLH happens in these settings is still poorly understood, although it is thought that underlying genetic susceptibility could play a role in some cases.

Diagnosis

Despite the name of the disease, hemophagocytosis is not necessary to diagnose HLH. It can be helpful  – but it isn’t specific for HLH, and can be found in a lot of other inflammatory conditions. So to diagnose HLH, you need either an established molecular abnormality consistent with an HLH mutation, or 5 of the following clinical criteria:

  1. Fever
  2. Splenomegaly
  3. Cytopenias in at least 2 blood cell lineages (indicating that the blood cells are being eaten up)
  4. High triglycerides and/or low fibrinogen (the latter is involved in the clotting cascade)
  5. Hemophagocytosis
  6. Low or absent NK-cell activity
  7. High ferritin (which transports iron and is also a marker of acute stress in the body)
  8. Elevated soluble CD25 (also called soluble IL-2 receptor alpha. Remember, IL-2 tells lymphocytes to proliferate and differentiate)

Treatment

It is very important to recognize HLH quickly so treatment can be started – but diagnosis can be tricky since many of the symptoms overlap with sepsis or malignancy. Treatment includes chemotherapy, immunosuppression, supportive care, and sometimes bone marrow transplant (mostly in genetic cases). Untreated, HLH is nearly universally fatal.

Bottom Line

The lesson here? Never underestimate the power of cytokines…and think about the possibility of HLH in a very sick patient with the appropriate clinical warning signs.

For more about HLH, read Robbins 9e., pages 585-586

Reference:
Jordan, M. B., Allen, C. E., Weitzman, S., Filipovich, A. H. & McClain, K. L. How I treat hemophagocytic lymphohistiocytosis. Blood 118, 4041–4052 (2011).

A huge thanks to Michelle Stoffel, MD PhD, PGY3 Pathology Resident at the University of Wisconsin, for yet another informative and fun post! Check out her other awesome posts here , here and here. 

More student questions on heme

questionI get so many really good questions from my students. I post them for our class – and from time to time I post them here, too, so everyone can benefit. (more…)