Twelve parts and not finished yet. Oh well.
At this point I have an admission to make – having recently been thinking about things in a different way. Up to now I have been using a model which I have called the ‘four step’ process of cardiovascular disease.
- Endothelial damage
- Clot formation/dysfunctional clot formation
- Clot repair/dysfunctional clot repair
- The final, fatal, blood clot
I still think that all the parts of the model are correct. However, it is probably best to look at this more as overlapping sets, rather than steps. Whilst it is true that, until the endothelium is damaged, nothing else can happen in the process of atherosclerotic plaque development. Once endothelial damage has occurred we are not looking at step 2, step 3, step 4 – as a linear process. After the first episode of endothelial damage, all the processes can be going on, virtually simultaneously (apart from the final, fatal clot obviously).
So, the thought I wish to make at this point, is that we are looking at a dynamic process, where all processes overlap and interconnect. Endothelial damage can be going on, whilst dysfunctional clot repair is also happening, in addition to further clot formation.
I was trying to think of a good analogy. The best I could come up with was rust on paintwork on a car. Before you can get rust, you need some damage to the paintwork. After that other factors can come into play. Water, salt…. Um, water and a bit more salt…um. Well, I am sure that other things can make cars rust more quickly, but hope you get the general idea.
Thus, I have decided not to call this the four step process anymore. I shall call it the four process process. No, that is rather clumsy. I shall call it the…not sure. The quadrilateral process. The ‘four process clotting’ hypothesis of heart disease. Anyway. I hope you know what I am going on about (those that have read the previous eleven blogs may do).
The role of lipoproteins
Now I am going to take this discussion in a direction those who have followed my writing thus far, may not quite expect. I want to look at the role of lipoproteins in blood clotting. Mea Culpa. I have spent a great deal of time telling people that lipoproteins have nothing to do with CVD. This is not entirely true. They can, and do, play a role.
The reality is that virtually every substance that can be found in the blood has some influence on blood clotting – and there are an enormous number of substances in the blood. So, it should come as no real surprise to find that high density lipoprotein (HDL), low density lipoproteins (LDL) and very low density lipoproteins (VLDL) are also involved.
Just to recap on one lipoprotein, namely lipoprotein (a) (Lp(a). As I have discussed earlier Lp(a), is produced by the body to plug areas of damage to artery wall. It is found in animals that cannot synthesize vitamin C – and are therefore at high risk of scurvy. Scurvy is, primarily, a disease of connective tissue e.g. collagen (which needs vitamin C for its synthesis).
Breakdown of collagen leads to cracks in blood vessels, and Lp(a) plugs the gaps. Thus, here is one lipoprotein, the entire function of which, is to help form very strongly bound blood clots. What I wish to highlight here is that Lp(a) could also be called LDL(a). Because Lp(a) is LDL which has one different protein attached to it.
With LDL and Lp(a) being virtually identical, it should come as no surprise that LDL itself also has an impact on blood clotting, through a number of different mechanisms. Indeed, the interaction between LDL and blood clotting is mind-boggling in its complexity. I am not going into things here in too much detail, and I will just highlight one study. It has the catchy title: ‘LDL receptor cooperates with LDL receptor–related protein in regulating plasma levels of coagulation factor VIII in vivo.’ Here we go:
‘High levels of FVIII in plasma (greater than 1.5 U/mL) constitute a major risk factor for arterial and venous thrombosis in humans. Our observation that the up-regulation of hepatic LDLR protein expression in mice by gene transfer accelerated FVIII clearance from the circulation may be of therapeutic interest for patients who have elevated plasma FVIII levels. In humans, the up-regulation of LDLR protein is achieved by treatment with 3-hydroxy-3-methylglutaryl co-enzyme A (HMG-CoA) reductase inhibitors, also called statins. Statins are widely recognized in the treatment of hypercholesterolemia in humans.’ 1
What is all this about? Basically if you have fewer LDL receptors (LDLR) there will be slower clearance of factor VIII (a key blood clotting factor) and the level in the blood rises. If you increase LDL receptors, by using statins, more factor VIII will be removed, and the risk of blood clotting will fall. So, here we have statins reducing the risk of cardiovascular disease by increasing the number of LDL receptors on the liver, which causes factor VIII (a blood clotting factor) to be removed from the blood.
In addition to this LDL interacts with platelets (the key blood cells involved in blood clotting) and the more LDL you have, the greater the tendency of platelets to clump together:
‘Platelets and lipoproteins are intimately involved in the pathogenesis of a wide variety of disease including atherosclerosis, thrombosis, and coronary heart disease. Evidence accumulated over the years suggests the possibility of a direct relationship between plasma lipoproteins and the hemostatic function of platelets. A number of studies demonstrated that native LDL enhanced the platelet sensitivity to stimulation and induced platelet activation.’2
In short, LDL activates platelets, and activate platelets are the starting point for blood clot formation.
The enormous complexity of the clotting system is further revealed when we look at High Density Lipoproteins (HDL) a.k.a. ‘good’ cholesterol. It is widely accepted that HDL is protective against death from CVD. It is generally believed that this protection comes through the process of reverse cholesterol transport i.e. HDL sucks cholesterol out of plaques. [Which I do not believe]
However, this is almost certainly not how HDL works. It has other important and potent effects on blood coagulation:
‘….Furthermore, HDL stimulates the endothelial production of nitric oxide and prostacyclin, which are potent inhibitors of platelet activation. Thus, HDL’s antithrombotic actions are multiple and therefore, raising HDL may be an important therapeutic strategy to reduce the risk of arterial and venous thrombosis.’3
Finally, for now, what to triglycerides do – with regard to blood clotting? More jargon here, but a very powerful statement linking VLDL/triglyceride levels to blood clotting.
‘Activation of platelets and the coagulation cascade are intertwined. VLDL and remnant lipoprotein concentrations are often increased with the metabolic syndrome. These lipoproteins have the capacity to activate platelets and the coagulation pathway, and to support the assembly of the prothrombinase complex. VLDL also upregulates expression of the plasminogen activator inhibitor-1 gene and plasminogen activator inhibitor-1 antigen and activity, a process accompanied by platelet aggregation and clot formation. The surface membrane of activated platelets also supports the assembly and activity of the prothrombinase complex, resulting in further thrombin generation and amplification of the coagulation cascade.’4
If you don’t like the jargon, I will simplify:
- High levels of LDL increase the risk of blood clots forming
- High levels of HDL reduce the risk of blood clots forming
- VLDL/triglycerides increase the risk of blood clots forming
To this, I will just add that ‘oxidised’ LDL is particularly pro-coagulant. It reduces Nitric Oxide synthesis in the endothelium, triggers platelet activation and damages the endothelium. Thus the condition known as ‘dyslipidaemia’ is particularly dangerous. Dyslipidaemia consists of low HDL, high VLDL and more ‘oxidised’ LDL. It is usually caused by insulin resistance a.k.a. the metabolic syndrome a.k.a. pre-diabetes.
So, ahem yes, blood borne lipoproteins do have a role to play in CVD. The role is not key, but it is there. I thought I should get that off my chest.
2: Yashika Gupta, V. Mallika* and D.K. Srivastava: ‘INTERACTION OF LDL AND PLATELETS IN ISCHAEMIC AND ISCHAEMIC RISK SUBJECTS’ Indian Journal of Clinical Biochemistry, 2005, 20 (1) 97 – 92