The development of atherothrombotic arterial disease is dependent on complex interactions between a variety of inflammatory, thrombotic and classical risk markers over the lifetime of the individual [1]. This process leads to the development of chronic atheroma formation secondary to vascular damage which culminates in plaque instability and rupture with occlusive thrombus formation. Clinically, these changes most commonly present as acute coronary syndromes/myocardial infarction, ischemic cerebrovascular disease and ischemic peripheral vascular disease. Perhaps one of the more plausible explanations for the huge burden of atherothrombotic disorders in the last century is provided by the very tight association that exists between diabetes and other dysglycemic states and vascular disease [2]. Over the last 15 years there has been an increasing awareness of the pivotal role of insulin resistance in the pathogenesis of Type 2 diabetes and of insulin resistance-associated risk clustering in the development of cardiovascular disease. This has led to the concept of the common soil hypothesis tightly linking diabetes and cardiovascular disease as one condition with common antecedents [3]. Within the insulin resistance risk cluster lie both atherogenic (dyslipidemia, dysglycemia, hypertension, obesity) and thrombotic (increased plasminogen activator inhibitor-1 (PAI-1), fibrinogen, factor VII, activation of platelets) risk that associate with insulin resistance [4, 5]. In addition, increasing awareness of the potential role of inflammatory pathways in the pathogenesis of both coronary artery disease and diabetes means that insulin-resistant subjects cluster all the factors necessary for plaque formation, plaque instability and a hypercoagulable state. It is not difficult to hypothesize that this combination could be responsible for a significant proportion of the atherothrombotic disorders, although it does not confirm the role of the hypercoagulable state in these conditions. Central to concepts regarding the role of hypercoagulability in relation to arterial disease is a meaningful definition of the term. Views on this differ. Some observers have opined that it is difficult to define, whilst others see levels of activation markers as a clear indicator of hypercoagulability. In addition, popularly, the presence of increased levels of clotting factors is often taken to indicate a hypercoagulable state. Personally, I prefer the rather more clinical definition which states that ‘a hypercoagulable state is one in which there is a greater prevalence of thrombosis for a given stimulus than in the normal population’. Employing this definition it becomes clear that protein C/S, and antithrombin III deficiency, and possession of factor V Leiden all fulfil these criteria. Biochemical measures support this observation. However, these comments apply only to venous thrombosis, whilst the evidence that this is the case in relation to arterial disease needs examination. Employing the model of cardiovascular disease in relation to insulin resistance and diabetes tells us a great deal about the role of hypercoagulability. First of all, there are undoubtedly a greater number of atherothrombotic events that occur at an earlier age than in the non-diabetic population. Second, patients with insulin resistance generally have elevated clotting factors, inhibitors of fibrinolysis and altered platelet function. This fulfils two of three necessary requirements for the definition of a hypercoagulable state, but what of the third, are there more thrombotic events for a given stimulus? One way of answering this is to consider the vascular tree of such patients. Diabetes subjects with coronary artery disease tend to have multiple lesions in affected vessels [6] and there is evidence that the extent of coronary artery disease is related to the degree of insulin resistance [7]. In the coronary circulation, diffuse distal disease further complicates this condition. Such patients therefore have disseminated disease with earlier, more frequent plaque rupture. Is that it, or does hypercoagulability have a role as well? The answer to this question can be derived from three important areas of study. 1. Pathology of the coronary artery in diabetic subjects. Work from Moreno and colleagues [8] on the composition of atherectomy specimens from the coronary arteries of diabetic and non-diabetic subjects reported a greater volume of lipid-rich atheroma, with a greater degree of macrophage infiltration and thrombosis in diabetic subjects. It was concluded that these results supported the concept that diabetic subjects had more unstable plaques and a greater propensity to thrombosis. The observation that individual lesions are more commonly associated with thrombosis in diabetic subjects is strong circumstantial evidence for the influence of hypercoagulability under these conditions. 2. The effect of increased clotting proteins on thrombin generation. Elegant studies from Mann et al. have convincingly demonstrated that elevated levels of clotting factors are associated with increased thrombin generation in vitro[9]. Clearly, deficiencies of clotting factors lead to a variety of bleeding disorders. These data imply that regulation of the coagulation cascade in either direction alters our ability to generate thrombin, which should, theoretically, indicate a potential hypercoagulable state in the context of elevated coagulation factors. In addition, a twin study indicates that there is a heritable basis to the variability in activation peptide levels in plasma [10]. Taken together, these findings indicate that elevated levels of coagulation factors enhance the rate of thrombin generation and that there may be a genetic basis for a component of this. 3. The effect of diabetes on thrombus formation. Two important studies of ex-vivo thrombus formation in diabetic subjects help to shed further light on these issues. Using the Badimon chamber it has been reported that poor glycemic control is associated with enhanced tissue factor release and increased thrombus formation [11, 12]. Both models have platelets in the system, making it difficult to tease out the effects of coagulation alone, although the overall implication of these studies is that hypercoagulability is having an effect on size of thrombus formation. In summary, pathologically and biochemically, there is evidence to support the existence of a hypercoagulable state that contributes to arterial risk in diabetic patients. Such individuals have a greater prevalence and severity of coronary artery disease, with higher rates of atherothrombotic vascular disease. Biochemically, there is evidence of a hypercoagulable state with elevated levels of coagulation factors, the fast acting inhibitor of fibrinolysis (PAI-1) and platelets that have lost some of the inhibitory mechanisms that regulate platelet activation. The atherothrombotic risk cluster that occurs around insulin resistance appears to be one of the commonest and most potent causes of cardiovascular disease, with evidence to suggest that this cluster also exists in the insulin-resistant prediabetic state, totalling in all around 25% of the population. Everything that is taking place in this large group of individuals suggests that risk factors accelerate the rate and extent of atheroma formation to generate inflammatory plaques that are more vulnerable to rupture. As this occurs, a hypercoagulable state associated with activation of coagulation pathways and platelets with inhibition of fibrinolysis leads to the formation of a more extensive thrombus resistant to physical and chemical degradation. If this hypothesis is true, we would expect patients with diabetes to have bigger myocardial infarcts with worse outcomes—exactly what is seen in practice. Why does this happen? One plausible explanation is that, biologically, we store fat and activate inflammatory and hemostatic mechanisms to prepare for hibernation in winter. In western societies with a constant food supply this hibernation is no longer necessary, with the net effect that we continue to put on 1–2 kg in weight each year and maintain the metabolic changes associated with, what becomes, a permanent insulin-resistant state. These chronic changes lead to the syndrome of atherothrombosis with what is biologically beneficial in evolutionary terms becoming harmful in a modern setting. It seems biologically implausible that we generate large quantities of excess coagulation proteins in such circumstances for no reason and equally implausible that in the modern context of plaque rupture these proteins do not contribute to the infarction phenotype. Does hypercoagulability contribute to the development of cardiovascular disease? Biochemically, clinically and philosophically, yes.
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Apr 16, 2024
Li-Ding Bai + 2
