Interesting. Especially the riddle... Zee

IS HEART DISEASE ALL DUE TO BLOOD CLOTS?

If you want to understand coronary heart disease, you cannot ignore the
role of the humble blood clot.

by Malcolm Kendrick MD

Up to now I have resisted writing about this area, as blood clotting is
a mind-boggling and complicated area of human physiology. In the end,
however, if you want to understand coronary heart disease (CHD), you
cannot ignore the role of the humble blood clot.

For it is now accepted by everyone involved in CHD research that the
final event, the thing that kills you with CHD, is the formation of a
blood clot on top of an atherosclerotic plaque. If the blood clot is
big enough to completely block a critical artery, in a critical area,
you will die.

In the last few years medics have become increasingly expert at trying
to clear these potentially fatal clots. Aspirin is the first line of
defence, then the clot busters streptokinase, or tissue plasminogen
activator (tPA) are used.

Increasingly, cardiologists get to work with thin wires and balloons,
and stents, to remove the clot, prize the artery apart, and stick a
metal framework to keep the artery open after unblocking it. New drugs
have been developed to keep the artery patent. This is all great stuff,
and many thousands of people who used to die are now being saved.

So there is no argument from anyone about the final event in CHD.
It's a blood clot. It is also recognised that blood clots develop
over atherosclerotic plaques on quite a regular basis without causing
any symptoms at all, presumably because they are not big enough to
fully block the artery.

However, in these silent episodes, once the blood clot stabilises it
adds to the plaque size, and can lead to greater narrowing of the
artery. In this way, repeated blood clots forming over an area of
existing plaque cause atherosclerotic plaques to 'grow'. And if you
look at plaques closely, you can - in many plaques - clearly see
bands, with each band indicating an episode of plaque growth.

This is all agreed upon by almost everyone. And if you were a simple
soul, like me, you might argue that if plaques grow, and eventually
kill you due to clots forming on the artery wall, could this not be how
they start in the first place? Are atherosclerotic plaques not, in
fact, just the remnants of repeated blood clots, which are 'drawn
in' to the artery wall, in time turning into a form of scar tissue?

If you did think this, you wouldn't be the first. This hypothesis was
initially proposed by Karl Von Rokitansky in 1852. Although supporters
of Rudolf Virchow may argue that he said it first. Unfortunately,
therefore, I can hardly claim that this idea is either new, or mine.

Can it really be that simple? Surely there must be something wrong with
the hypothesis that atherosclerotic plaques are the remnants of
repeated blood clots? Where does this idea break down? I could say,
don't ask me, I happen to believe it's true. But I will attempt to
be a little more objective than this.

The key point of objection is that, whilst you can see how blood clots
can form over a 'damaged' artery wall, it is very difficult to see
how they form over a healthy artery wall. After all, a critical
function, perhaps the critical function of the lining of the artery
(the endothelium) is to prevent blood clots from forming. So how can
this process actually start? A good point from my learned friend.

But I put it to you, members of the jury, that every 'factor' that
has been identified as increasing the risk of CHD, has clearly
identifiable pro-coagulant activity. Equally, every factor that has
been identified as reducing the risk of CHD has clearly identifiable
anti-coagulant activity. Which, I would vouchsafe, is pretty
heavyweight proof.

Is this really true?

Well, yes. But you have to understand that there are three
interconnected factors at play here that can cause a clot to form over
the artery wall. Factor one, is 'damage' to the endothelium. Once
damaged, the endothelium stops acting as a non-stick anti-coagulant
surface. Indeed, if the endothelium is stripped away, it exposes the
middle layer of the artery, the media, to the blood, and the media
releases the most powerful pro-clotting factor known to man: Factor
VII, the 'extrinsic' factor.

The second factor is how pro-coagulant the blood is itself. There are a
multitude of clotting factors in the blood. Some of which you may have
heard of, such as factor XIII - the one that is missing in
haemophiliacs; some of which you probably haven't heard of e.g. Von
Willibrand factor. Increase a pro-coagulant factor, and you increase
the chance of clots forming.

The third factor is the structure of the blood clot itself. Some clots
are wobbly and weak; others are very tough, and difficult to break up.
For example, incorporated into all blood clots is a substance called
plasminogen. This is an enzyme which, when activated, chops the clot
into pieces. (Which is why tPA - tissue plasminogen activator - is
given to people having a heart attack) However, if you have a high
level of Plasminogen activator inhibitor - 1 (PAI - 1) in the
blood, plasminogen is less effective at breaking the clot up.

So, you have to look at three basic factors:

* The anti-coagulant status of the endothelium
* The pro-coagulant state of the blood
* The relative 'toughness' of the blood-clot once it is formed

Bearing this in mind, I think it is interesting to run through a few
factors known to alter the risk of CHD, and see how they fit:

Smoking:

Smoking creates free-radicals in the blood, these reduce nitric oxide
(NO) synthesis in the endothelium, and NO is the single most powerful
anti-coagulant factor in the body. Smoking also has pro-coagulant
effects in the blood; it raises fibrinogen levels. It also has
endothelium damaging effects. So, if you want to avoid CHD... STOP
SMOKING!

Drinking:

Ethanol, in moderate doses, reduces free-radical synthesis, reduces
clotting factors, such as fibrinogen, and reduces the blood clot
toughness. However, excess alcohol consumption creates rebound platelet
stickiness (platelets are hugely important in blood-clotting). Moderate
drinking protects against CHD, heavy drinking is a risk factor.

Diabetes:

A high blood sugar level leads to increased free-radical synthesis, see
above. A high blood sugar, independent of its effects on NO synthesis,
also causes endothelial 'damage.'

Haemophilia:

Not surprisingly, haemophilia reduces blood coagulability. Haemophilia
also reduces the absolute risk of CHD by 80%.

Statins:

Statins have strong anti-coagulant effects, they stabilise plaques and
increase NO synthesis.

Aspirin:

Aspirin reduces the stickiness of platelets (see alcohol). Platelet
aggregation is the first step in blood clotting.

Omega-3 fatty acids

Omega-3 fatty acids have strong anti-coagulant effects in the blood

Stress

Physical, or psychological stress causes the release of the stress
hormones: cortisol, adrenaline, growth hormone and glucagon. These
hormones all increase blood coagulabiltiy, raise the blood sugar level
(see above), and 'damage' the endothelium.

Raised blood pressure

I am a little ambivalent about this risk factor. I am unconvinced
that a raised blood pressure really is a 'cause' of plaque
development. However, it is possible to see how high pressure, and
turbulent blood flow, could strip away a layer of endothelium, exposing
the blood to the media, and thus factor VII, thus stimulating a blood
clot to form. It is certainly true that plaques don't form in low
pressure blood vessels (e.g. veins).

However, the clinical trials on blood pressure lowering are very
unconvincing when it comes to a correlation between the degree of blood
pressure lowering and the prevention of CHD.

HDL

HDL has strong anti-coagulant effects

LDL (Oxidised LDL)

This is a complex pathway. When platelets start to stick together,
they release free radicals. Free radicals oxidise LDL. Oxidised LDL is
a powerful blood clotting factor. LDL is also incorporated into the
blood clot as it forms, and provides a 'lipid' surface (along with
VLDL) for the construction of fibrin. Fibrin is the hugely strong
protein strand that binds a clot together and makes it 'tough.'

Frankly, I think that's enough. If you wish to, it is possible to
link every single factor known to have an impact on CHD rates to one of
three effects: endothelial damage, blood coagulation, or toughness of
the clot. If you don't affect any of these three things, then you
have no effect on CHD rates. If you manage to impact all three, then
it's time to increase the life insurance. (On a positive note you
won't need a big pension fund).

So, if it's that simple, then why have you never heard of this
before? Now that is another story altogether. But if enough people
think I am making all of this up, then I will provide a series of
references from prestigious journals to support every single fact that
I have presented.

To my mind, the answer as to the underlying cause(s) of CHD is not only
'out there,' it has been staring everyone in the face for the past
fifty years. Perhaps it is too obvious for anyone to see it.

To quote a riddle that my son came home with the other day:

What is greater than God
More evil than the devil
The poor have it
The rich need it
If you eat it you will die

Once you know the answer you cannot believe that you couldn't see it
straightaway.