How does an infection cause a thrombosis?

[scilearner]

Hello everyone,

 

I saw this in something I read recently. The infection could cause thrombosis. Ok my question is if thrombosis is a blood clot that occludes a vessel, how does infection create one. If the blood vessel is damaged some how it is possible. Are they saying bacteria or something from the infection can damage blood vessels, how by their toxins? or is this caused by swelling? Also how does a thrombosis occur. I mean in animations I have seen when a vessel is damaged, fibrin and all close the gap nicely, what makes them overdo their stuff. Also this is just another general question, in infections is it mostly the bodies immune response (swelling) that is damaging more than the infection? Thanks a lot

[Greippi]

Atherosclerosis is one disease that can cause thrombosis. Incidentally, I have an exam tomorrow on atherosclerosis so I've just been reading about this!

 

Atherosclerosis basically occurs when damage to the arterial endothelial cells provokes an immune response, causing inflammation. This can lead to the formation of a plaque covered by a fibrous cap - if the cap breaks, the contents of the plaque is released, causing thrombosis. If you look up atherosclerosis, e.g. the wikipedia page basically explains how slight damage to the artery wall can lead to thrombosis.

 

As for infection: the classical view would be that an infection, or some sort of trauma lead to the production of cytokines by the endothelial cells of an artery and thus inflammation, plaque formation, thrombosis etc. There was evidence that Chlamydia pneumoniae and cytomegalovirus (CMV) were triggers for provoking this response. The infectious agents could be circulating in the blood then infect the endothelial cells maybe. However, more recent research shows that you're just as likely to get atherosclerosis if you don't have an infection - infection isn't necessary for initiation or progression of the disease.

 

Infectious agents may have a part to play in exacerbating the atherosclerotic process. Chlamydia pneumoniae can infect the various immune cells involved in the inflammation response. It can also promote the expression of adhesion molecules on cells, meaning that immune cells are more likely to bind to the endothelial cells on an artery and cause an immune reaction. There are various viruses that can make atherosclerosis worse, including the herpes viruses.

 

Source: Cytokines in Atherosclerosis: Pathogenic and Regulatory Pathways. ALAIN TEDGUI AND ZIAD MALLAT Physiol Rev 86: 515–581, 2006; doi:10.1152/physrev.00024.2005.

Edited May 23, 2010 by Greippi

[scilearner]

 

Atherosclerosis basically occurs when damage to the arterial endothelial cells provokes an immune response, causing inflammation. This can lead to the formation of a plaque covered by a fibrous cap - if the cap breaks, the contents of the plaque is released, causing thrombosis. If you look up atherosclerosis, e.g. the wikipedia page basically explains how slight damage to the artery wall can lead to thrombosis.

 

As for infection: the classical view would be that an infection, or some sort of trauma lead to the production of cytokines by the endothelial cells of an artery and thus inflammation, plaque formation, thrombosis etc.

 

Thanks Grieppi. I appreciate your detailed response So even if there is no blood vessel cut, say from a physical wound, when inflammation occurs does everything occur. I mean if an infectious agent get it even if it doesn't attack blood vessel do platelets begin to aggregate and stuff. Also let's say they say a particular cell is infected. If it is a virus it would probably have gone inside the cell and then lyse destroying it. If the cell is infected by bacteria, what do they exactly mean. Do bacteria live inside cells, or are they saying bacteria outside the cell using the resources of the cell. My question is not related to artherscelrosis, although I know a bit about with formation of foam cells. Thanks again

[Greippi]

So even if there is no blood vessel cut, say from a physical wound, when inflammation occurs does everything occur

Yup

 

As for bacteria, I assume it's just floating around free in the blood stream. But I am not entirely sure about that one. Maybe it produces toxins that irritate the artery wall.

 

Yah, I know your question wasn't specifically related to atherosclerosis, but it's one way in which a thrombus can form. And the only way I know much about

---

Merged post follows:

Consecutive posts merged

Here's something else:

 

Cytokines, such as TNF are secreted in response to infection (innate immune system, many cell types can recognise infection and release cytokines). Resident macrophages recognise LPS (bacterial lipopolysaccharides) and can release TNF alpha. One local effect of TNF is the influx of platelets to cause blood clotting in capillaries as a barrier to prevent spread of infection. This can produce a microthrombus, and sometimes this can lead to coronary thrombosis.

[CharonY]

I am actually not sure whether a mechanism is known. Bacterial infections have been implicated in atherosclerosis, but I cannot recall how strong the link was, never mind the actual mechanism.

[Greippi]

I am actually not sure whether a mechanism is known. Bacterial infections have been implicated in atherosclerosis, but I cannot recall how strong the link was, never mind the actual mechanism.

 

If you check the review I cited:

Cytokines in Atherosclerosis: Pathogenic and Regulatory Pathways. ALAIN TEDGUI AND ZIAD MALLAT Physiol Rev 86: 515–581, 2006; doi:10.1152/physrev.00024.2005.

 

There's a good section there, along with references to other papers.

[scilearner]

Yup

 

As for bacteria, I assume it's just floating around free in the blood stream. But I am not entirely sure about that one. Maybe it produces toxins that irritate the artery wall.

 

Yah, I know your question wasn't specifically related to atherosclerosis, but it's one way in which a thrombus can form. And the only way I know much about

---

Merged post follows:

Consecutive posts merged

Here's something else:

 

Cytokines, such as TNF are secreted in response to infection (innate immune system, many cell types can recognise infection and release cytokines). Resident macrophages recognise LPS (bacterial lipopolysaccharides) and can release TNF alpha. One local effect of TNF is the influx of platelets to cause blood clotting in capillaries as a barrier to prevent spread of infection. This can produce a microthrombus, and sometimes this can lead to coronary thrombosis.

 

Hey that is a very interesting piece of information. Thanks for that However I mean there is no full proven explanation for this yet right?

[Ardyen]

I'd like to add something here. The mechanism of thrombus formation is essentially the same(through the cytokines and other inflammatory mediators), though the stimulating insult may vary. Every infection dosen't cause a thormbus.

 

Atherosclerosis is something that happens innately, and its related to ageing and LDL/cholesterol levels. It makes certain arteries(cornary and the cerebral) more prone to occlusion, but it itself doesn't cause thrombosis as previously suggested.

 

I know someone's then gonna say that thrombi in infective endocarditis, are essentially from plaqes, which are a result of inflammation itself, but we'll take it as a one off. (What actually happens is that the palque acts as a platform of sort for the bacteria to develop and produce blood clots).

 

I guess a part of the answer to this question must be through sepsis. This is when the bacteria overwhelm the humoral immunity, which was lacking in that individual for a large number of reasons(the cell mediated immunity is still intact but overworked as well), and start multiplying rapidly.

 

One of the manifestations of this is that toxins are released at a higher rate than in an uncontrolled infection and this is what predisposes to microthrombi in capillary circulation. Also some bacteria possess Hemagglutination receptors, and they cause clotting in vitro( i'm not sure whether its in vivo as well).

 

So, lets say someone has uncontrolled pneumonia, and if untreated can cause microthromi in pulmonary circulation apart form the pathological process of consolidation.

 

And Scilearner, you're right in the opening post that inflammation itself causes more tissue harm than the bacteria themselves. But in the long-term outcome is going to be much adverse, maybe death. So, you could consider it as some sort of collateral damage!!

[Greippi]

 

Atherosclerosis is something that happens innately, and its related to ageing and LDL/cholesterol levels. It makes certain arteries(cornary and the cerebral) more prone to occlusion, but it itself doesn't cause thrombosis as previously suggested.

 

Confused here. If an atherosclerotic plaque ruptures, it can cause a thrombus. How can you then say it's not related to thrombosis?

 

The idea of atherosclerosis primarily being caused by aging and LDL levels is a little out-dated.

[Ardyen]

The idea of atherosclerosis primarily being caused by aging and LDL levels is a little out-dated.

 

Unless you know something I don't, Its still caused by lipoproteins/LDL/Cholesterol.

 

I quote abstract texts from Harrison's Principles of internal medicine. 17th edition. Pages 1501-1505:

 

"The early lesions most often seem to arise from focal increases in the content of lipoproteins within regions of the intima......."

 

"Lipoproteins sequestered from plasma anti-oxidants in the extracellular space of the intima, become particularly susceptible to oxidative modificatins, giving rise to hydroperoxides......" which is essentially ageing.

 

I don't think we need to debate on the molecular mechanisms or specific pathological processes in the formation or re-organizatinon of a plaque, because the inciting factors remain the same: Higher Lipoprotein levels and oxidants. NO other etiological cause: bacterial/infective, genetic, or immune mediated disorder has been PROVED to cause it, though there are a number of hypotheses for the same.

 

If an atherosclerotic plaque ruptures, it can cause a thrombus. How can you then say it's not related to thrombosis?

 

And if you read my entire post, I said that atherosclerosis PREDISPOSED to formation of a thrombus.

 

It makes certain arteries(cornary and the cerebral) more prone to occlusion, but it itself doesn't cause thrombosis as previously suggested.

 

A thrombus is formed on a plaque when it ruptures. But it doesn't arise from within the plaque or the original cellular/endothelial defect/mass.It dosen't have to always form when a plaque ruptures as well. Procoagulant factors in blood come in contact with exposed plaque collagen, can cause thrombosis. Rupture of an atherosclerotic plaque causes predisposition to thrombsis.

 

Normal plaques DO NOT cause thrombosis. They occlude the lumen, so that an emboli may get lodged here and subsequently cause infarction. So Plaques predispose to thrombosis when they rupture, which is NOT a normal outcome of re-organization of an atherosclerotic lesion.

Edited May 27, 2010 by Ardyen

[Greippi]

 

"The early lesions most often seem to arise from focal increases in the content of lipoproteins within regions of the intima......."

 

"Lipoproteins sequestered from plasma anti-oxidants in the extracellular space of the intima, become particularly susceptible to oxidative modificatins, giving rise to hydroperoxides......" which is essentially ageing.

 

 

I'm sorry I phrased the cholesterol thing wrong really. Yes, it's a major factor in many cases, but there are other factors that come in to play in the initiation and progression of atherosclerosis, and research has moved on from primarily focusing on cholesterol.

 

Also, cholesterol increases expression of VCAM-1 (I'll find the reference for that later) integrin molecule. Meaning that inflammatory cells are more likely to adhere to the vessel wall and start the whole process.

 

While they seem to arise at increases in LDL content (i.e. fatty streaks), most patients with atheroscleorisis have cholesterol levels within the normal range (the Nature paper I cited above). These fatty streaks tend to develop in children. What is universally acknowledged is that they are more prone to developing in areas of sher stress and lower blood flow (making it easier for the adhesion of leukocytes I assume).

 

Really interesting review, if you're interested I suggest you read it if you have time:

Inflammation in atherosclerosis. Peter Libby NATURE VOL 420 19/26 DECEMBER 2002

 

Hemodynamic parameters regulating vascular inflammation and

atherosclerosis: A brief update

Ridgers et al Biomedicine & Pharmacotherapy 62 (2008) 536e540

 

 

But I LIKE debating. Debate is good, I wanna share ideas! It's interesting because you're from a medical background and I'm a biochemist.

[Ardyen]

I like a debate as well!

 

I did read similar views a while ago(I will read the paper's you've quoted sometime today), but I don't think they have been incorporated into mainstream clinical/medical literature. Part of the reason for that may be that, if we acknowledge that vascular/hemodynamic fators (yes, the sheer stress and non-laminar blood flow causes the initial damage to vascular endothelium, and hence increased leukocyte adherence) are a significant etiology, then atherosclerosis will then have to be considered Idiopathic, rather than related to measurable biochemical parameters. And the normal LDL/cholesterol levels causing fatty streaks in some individuals, may well be related to their inherent responses(What's normal for most, may not be normal for a small subset, like Blood Pressure, Leukocyte count...etc).

 

I think that the current clinical view is that its multifactorial, and that we have established a major portion of what we presume to be the etiological factors, and reluctant to add the others without conclusive proof, because that would then make the current stress on lowering lipid levels(with statins, modified diets, finding ways to decrease oxidative stress and ruling genetic/familal causes for isolated hyperlipidemias) , pretty much redundant.

 

 

Also with epidemiological evidences for the older beliefs as with the Framingham Heart Study (one of the classical longitudial studies, I'm sure you'd have heard of it: http://en.wikipedia.org/wiki/Framingham_Heart_Study, and many such in the late 80's to 90's) I think the medical community will find it hard to disregard these factors.

 

Maybe, just maybe a few decades later, we'd come to think of our current views as pretty outdated:-p.