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Role of coagulation and anti-thrombotic treatment

  1. Top of page
  2. Role of coagulation and anti-thrombotic treatment
  3. References

As indicated more comprehensively elsewhere in this Forum, the metabolic syndrome is a common phenotype characterized by the coalition of multiple cardiovascular risk factors, particularly that of raised blood pressure, central obesity, abnormal glucose and lipid metabolism [1,2]. This clinical syndrome is associated with the development of diabetes and increased cardiovascular mortality [3,4]. While insulin resistance, broadly defined as impaired biological response to insulin, is widely regarded as the primary abnormality [5], others have proposed that the overt manifestations of this clinical syndrome may be consequences of endothelial damage/dysfunction in small vessels of different vascular beds [6], although there are few data examining the temporal relationship between the development of components of metabolic syndrome and endothelial damage/dysfunction. Similarly, epidemiological studies indicate higher coronary heart disease (CHD) risk (as calculated, for example, by the Framingham equation) in patients with metabolic syndrome [7], but there are no prospective data examining the relationship between CHD risk and the development of metabolic syndrome.

Despite these lacunae, it seems plausible, if not probable, that the final pathophysiological events in the metabolic syndrome, obesity and diabetes share common ground, i.e. atherothrombosis. Accordingly, we presume that the etiology of this process involves the inappropriate platelet activation and/or dysregulation of the coagulation system. For example, is there a linear progression from obesity or other isolated risk factors, via their coalition into the metabolic syndrome, and thence into diabetes? The theory is certainly attractive. A corollary of this is that these abnormalities in coagulation are also present in the precursors of metabolic syndrome and/or obesity, although possibly to a lesser degree than in full-blown diabetes. But is this view justified?

The literature, of course, identifies and/or implicates numerous components of the coagulation pathway and platelet activity that may be targets in reducing the risk of atherothrombosis in clear diabetes (Table 1). However, taking evidence-based medicine as the yardstick, there are precious few clear indications that intervention to reduce the risk of atherothrombosis in the metabolic syndrome and obesity would be valuable. Indeed, it could be argued that any such intervention in subjects with the metabolic syndrome and/or obesity, but not diabetes (or even the insulin resistance syndrome), is unwarranted in the absence of good trial data. For example, firm and conclusive evidence in favor of a clear and unambiguous hypercoagulable state in subjects with the metabolic syndrome or obesity, whilst free of diabetes and/or overt cardiovascular disease, is lacking, although some limited data do exist (Table 1).

Table 1.  Abnormalities in coagulation and platelet indices in diabetes, the metabolic syndrome, and in obesity
  1. * Data pooled from [8–11] and elsewhere. †Data pooled from [12–19] and elsewhere. NB: This list is not intended to be exhaustive.

Diabetes*
Coagulation
Soluble thrombomodulin, fibrinogen, von Willebrand factor, factor VII, factor VIII, fibrinopeptide a, plasminogen activator inhibitor, prothrombin fragments 1+2, antithrombin, tissue factor, tissue plasminogen activator
Platelets
Soluble P-selectin, platelet microparticles, expression of CD62P, expression of CD63
β-Thromboglobulin, platelet factor 4, spontaneous and agonist-induced aggregation
The Metabolic Syndrome and/or obesity
Coagulation
Von Willebrand factor, fibrinogen, plasminogen activator inhibitor, tissue plasminogen activator, protein C, protein S, factor VIII, factor VIIc, activated factor XII
Platelets
Agonist-induced aggregation

Despite this, if an individual with the metabolic syndrome and/or obesity is considered to be at high risk of atherothrombosis, then prophylaxis can consider only the staples of oral anticoagulation with warfarin (or analog) and/or the antithrombotic properties of aspirin. Data on the use of clopidogrel under these conditions do not exist. Agents designed to inhibit high levels of plasminogen activator inhibitor (consistently raised in both the metabolic syndrome and in obesity [17–19]) are in development but seem unlikely to be licensed for metabolic syndrome or obesity during this decade. The literature on the value of standard anticoagulant and antiplatelet agents in active cardiovascular disease is unquestioned, but in isolated diabetes data are poor. Nevertheless, there is a growing view that all patients with Type 2 diabetes should receive aspirin [20], although current treatments are aimed not at hypercoagulability but at hypertension and hypergylcemia. However, other strategies exist: perhaps unsurprisingly, adherence to a Mediterranean-style diet by subjects with the metabolic syndrome results in improved endothelial function [21], as does calorific-restricted weight loss in the normotensive and hypertensive obese [22]. Despite consistent epidemiological reports (and a plausible mechanism) that poor endothelial function and raised fibrinogen predict adverse outcome [23–26], these effects are not yet considered strong enough to warrant targeting, and in any case there are no pharmacological agents demonstrated specifically to improve endothelial function and concurrently reduce the risk of thromboembolism. Nevertheless, several trials of antihypertensive and/or antihyperlipdemic agents have demonstrated improved endothelial function alongside a reduced rate of cardiovascular events, although the precise mechanism(s) responsible for these improved outcomes are impossible to dissect.

In conclusion, although obesity and the metabolic syndrome are recognized clinical syndromes and precursors of diabetes, the data on abnormalities in hemostasis are weak and in need of confirmation. Until such time, and following data on the rates of cardiovascular events in these groups, anticoagulation and antithrombotic treatments are not warranted.

References

  1. Top of page
  2. Role of coagulation and anti-thrombotic treatment
  3. References
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