16th September 2017
Beginning at the end.
Whilst there is significant controversy about how atherosclerotic plaques may start, and grow, the final event in cardiovascular disease is, in most cases, pretty much accepted – even by me. The formation of a blood clot. Yes, there are many caveats here, and also a number of different processes that can occur, but I am not covering them in this blog. I am using the simple ending. The obstructive blood clot.
If a blood clot forms in the coronary arteries – blood vessels supplying blood to the heart – it can fully block the artery, jam up blood flow, vastly reduce oxygen supply, and cause a myocardial infarction (MI). The clot usually forms on the surface of a pre-existing atherosclerotic plaque.
If a blood clot forms in the carotid arteries – main blood vessels supplying blood to the brain – it can then break off, travel up into the brain where it gets stuck, jams up blood flow, reduces oxygen supply, and cause a cerebral infarction (ischaemic stroke). Again, blood clots in the carotid arteries almost always form on the surface of atherosclerotic plaques formed earlier.
What this means is that reducing the formation of blood clots will, or definitely should, reduce the risk of heart attacks and strokes. And, of course, it does. Aspirin, for example, has anticoagulant action, and it lowers the risk of CVD, although not by a huge amount.
However, recently, a study was published in the New England Journal of Medicine which demonstrated that if you add rivaroxaban – an anticoagulant, primarily used to prevent strokes in patients with Atrial Fibrillation – to aspirin, this further reduces the risk of CVD1.
The trial was reported thus, in the Daily Mail on the 11th of September:
‘Phenomenal’ pill slashes the risk of death from heart disease by 22% and could save millions of lives, ‘ground-breaking’ trial finds.’
Oh yes, we do like a phenomenal pill, do we not. Mockery of such ridiculous hype aside, this was an impressive result. Far more impressive than any statin trial, it must be added – with no impact on LDL levels at all. Only one slight problem, it would be rather expensive to add rivaroxaban to everyone taking aspirin. Minimum cost, about £6Bn/years ($8Bn/year) in the UK alone.
Of course, there are other things that can reduce the risk of blood clotting. Omega 3 fatty acids, for example which reduce ability of platelets to stick together2 – an action almost identical to aspirin. Then there is Von Willibrand disease – a condition where people lack a key blood clotting element called the Von Willebrand factor. Patients with this condition have a 60% reduction in the risk CVD.
Those with haemophilia had – prior to the development of clotting factors to replace those that were missing –around 20% the risk of CVD of the surrounding population.
On the other hand, there are situations where the risk of blood clotting increases. Use of non-steroidal drugs e.g. brufen, naproxen, diclofenac etc. These increase the risk of clotting, and CVD. There are conditions, such as Hughes syndrome and Factor V Leiden where the risk of blood clotting goes up, and so does the risk of CVD and so on, and so forth.
In fact, I think it can be stated with complete confidence that any drug, condition, or anything else that reduces the risk of blood clotting, also reduces the risk of CVD, and vice-versa. Of course, if you reduce the risk of blood clotting, you can also increase the risk of serious bleeding. So, it is not all positive. All is balance. Yin and Yang, and suchlike. Even the relatively benign aspirin, in low doses, can lead to chronic blood loss, anaemia, and, in extreme cases, death.
What does this prove. Well it certainly proves that blood clotting and CVD are intimately related. So much so that the word ‘atherothrombosis’ is often used to describe the processes of CVD. ‘Athero-‘ = the atherosclerotic plaque growing then ‘-thrombosis’, the clot that forms top of the plaque that then kills you. That, at least, is the official Soviet party line.
However, I never liked the idea that we have two almost completely different processes going, that are linked together, but only at the final event. I wanted to explore the idea that a single process – blood clotting – could be responsible for plaque starting, growing and then ‘rupturing’ causing the whole spectrum of atherothrombosis. Blood clots, from start to finish.
This took me on a pretty amazing journey, a long and winding route indeed. I have come to believe that the system of blood coagulation must be, just about, the most complex physiological system in the body. It is beyond mind-boggling. Just when you think you have read about every factor involved, another one pops up. Indeed, I think I am forgetting facts about blood clotting faster than I can learn them. My brain is full.
However, the other day, I came across an expression that captured something about blood clotting that I have always struggled to put into words. It described the coagulation system as ‘idling’, as in sitting with the engine running. The blood coagulation system is never ‘off’ it is always turning over in the background, constantly producing small combination of substances that make up a full blood clot.
I suppose this is because, if you suffer a significant wound, or damage to a large blood vessel, the coagulation system cannot hang about. It must accelerate from zero to one hundred in the blink of an eye. Bang, go, stamp on the accelerator. At the same time, if it accelerates out of control, the clot will be too big, it will spread too rapidly, blocking blood vessels all over the place.
So, almost the moment you stamp on the accelerator, you are hammering on the brake. Accelerate, brake, accelerate, brake. Build up the clot, break down the clot. A fantastically dynamic system with feedback loop upon feedback loop. Too little clotting, you die. Too much clotting, you die. This is going on, all the time, in your body. A system constantly hunting, and hunting, to find equilibrium.
What is the greatest, the most powerful trigger, for a clot to form? It is a substance called Tissue Factor (TF). It is found almost everywhere in the body, but it is found in the highest concentrations within the walls of the larger arteries and veins. This, of course, makes perfect sense. If an artery, or vein, is damaged, the place you want a blood clot to form is exactly at that point. Bang, go.
Tissue factor is sometimes called extrinsic factor. It is called this because it does not float about (freely) in the bloodstream, it sits ‘externally/extrinsically’ to the blood. [In fact, platelets and white blood cells also contain TF, but it is inactive/not expressed unless other things are triggered first].
Other parts of the clotting system are often referred to as intrinsic factors that trigger the ‘intrinsic clotting system’. Factors you may have heard of, such as factor VIII, or factors IX and X and Xa etc. The intrinsic system tends to operate more slowly, and less powerfully, than the extrinsic (massive over-simplification warning).
Normally, the ‘intrinsic’ clotting factors, and the extrinsic system operate together to drive and amplify the clotting response once it is triggered. All of which means that, normally, you want to keep the blood well away from contact with TF, because the moment there is contact, all hell breaks loose and a blood clot will form, instantly, at that point.
The single most important barrier that keeps the blood separated from TF is the endothelium. Which means that an intact and healthy endothelium is the best protection against accidental blood clots forming. Yes, blood clots can form with no TF contact. A deep vein thrombosis (DVT) can develop in veins with intact endothelium. The process is different, the blood clot formed is also very different. It is mainly an intrinsic process.
Forgetting other types of blood clot that can form elsewhere in the body, the only way a clot will form in the larger arteries is due to endothelial damage. No endothelial damage, no clot. Once a blood clot has formed, then stabilised, what happens?
Well, normally the clot will not have been allowed to get too big, because all the feedback loops will kick into action to slow things down. So, most clots will not fully block an artery, nor even half block an artery. They also get shaved down in size quickly. Primarily through the action of Tissue Plasminogen Activator (TP(a)).
TP(a) is an enzyme floating about in the bloodstream that converts plasminogen into plasmin. Plasminogen is an inactive enzyme that is incorporated into all blood clots as they form. When TP(a) converts plasminogen to plasmin, it slices fibrin apart, chopping blood clots into small pieces. A process known as fibrinolysis. Two of the major components of a blood clot are platelets – small sticky cells that coordinate the clotting response – and fibrin – long sticky strands of protein that binds the clot together.
However, there will be always be a part of the clot that remains clamped to the artery wall. Because if all the clot was fully broken down/fibrinolysed, the bloodstream would be exposed to TF again, and the entire blood clotting process would simply kick off…. again.
Which means that once a clot has been formed, a part of it will always be left stuck to the artery wall. This then needs to be got rid of. How does this happen? Well, it is not like scratching your skin, whereby a clot (scab) forms, the endothelium re-grows underneath it, then the scab falls to the ground. If this were the process that happened in an artery, where do you think that clot would go? Down the artery, to get stuck where it narrows, to cause an infarction. Not a very good design feature, I would argue.
So, what happens is something far cleverer. A replacement endothelial layer is created from Endothelial Progenitor Cells (EPCs). These are synthesized in the bone marrow, and float about in the bloodstream. Chemicals released, when endothelium is damaged, attract EPCs to the area of damage/blood clot.
Once they arrive they stick to the surface of any remaining clot, then they grow into fully mature endothelial cells, forming a new endothelial layer. What this means is that any remaining blood clot now sits beneath the new endothelial layer, and within the artery wall itself. It cannot now break off and get stuck somewhere else in the body.
Even more clever is the fact that EPCs have the capability, to become something other than mature endothelial cells. They can travel down another road in the developmental pathway, to become monocytes. Monocytes, in turn, mature into macrophages.
Macrophages are white blood cells whose job it is to clear up all alien materials in the body. Dead cells, invading bacteria, any damaged tissue. They squirt nitric oxide out, oxidise dead and damaged material, such as anything found in a blood clot, then engulf it, before travelling off to the lymph glands. Here, the dead, damaged and alien materials are further broken down, before excretion from the body.
Thus, with EPCs, you have the entire repair and clearance system all in one package. Some of the EPCs that arrive on the scene, form the new endothelial layer. The rest turn into monocytes, then macrophages, which clear away the remnant blood clot.
This process of repair and clearance is what I call ‘healing’. Others choose to call it inflammation, and claim it is the underlying cause of CVD. Good for them. I suspect it may not be a fertile route to travel down.
The other thing to note here is that the substance which is most intimately bonded to the exposed endothelium, at least in humans, is lipoprotein (a) (LP(a). Lipoprotein (a) is Low Density Lipoprotein (LDL) with an extra protein attached to it. A protein called apolipoprotein A. This protein is fascinating, because it has an almost identical structure to plasminogen. Identical apart from a single amino acid.
However, this difference, though very slight, is critical, because it means that TP(a) cannot have any effect on apolipoprotein A. There can be no conversion to plasmin. Thus, any blood clot, or part of the blood clot, containing Lp(a) is extremely resistant to fibrinolysis. It cannot be broken apart, and so remains attached to the artery wall, and will be a major component of the remnant blood clot that is then drawn into the artery wall – and then broken down by macrophages.
This is where Linus Pauling, Mattias Rath, vitamin C, and guinea pigs come into play. I have discussed this area before, but I am going to discuss it again…. Soon.
Before fully signing off on this blog I shall leave you with another thought, which is this. Lp(a) is identical to LDL ‘bad cholesterol’ – apart from a single attached protein – apolipoprotein A. So, if you were closely studying the contents of an atherosclerotic plaque, it would be quite easy to think you were looking at LDL, when you were actually looking at Lp(a)?
Of course, what I have done here is to describe a process of clot formation, and repair, that is probably happening all the time. The next question is obvious. When, and how, can this process become ‘abnormal?’ When, and how, does it lead to CVD?
P.S. those interested in a great deal more complexity, this paper is a belter. http://onlinelibrary.wiley.com/doi/10.1111/j.1538-7836.2007.02515.x/full
Here is one section that explains a great deal in a few words. ‘Recent evidence suggests that ECs [endothelial cells] in regions of disturbed flow in arteries are primed for activation (they have increased levels of NF-κB in their cytoplasm) and that systemic imbalances (e.g. associated with sepsis or cardiac risk factors) may result in the translocation of NF-κB to the nucleus and increased expression of procoagulants such as tissue factor (TF) and adhesion molecules. TM, thrombomodulin; t-PA, tissue-type plasminogen activator; EPCR, endothelial protein C receptor; TFPI, tissue factor pathway inhibitor; VWF, von Willebrand factor.’ And there, I think you have it, in a nutshell. Although I realise that most people have never heard of any of those things.