The final common pathway resulting from activation of the coagulation system is generation of thrombin and thrombin-mediated formation of fibrin from fibrinogen. Generation of thrombin depends on activation of procoagulant factors and is limited by antithrombotic factors and inhibitors. A marker of thrombin activity is fibrinopeptide A (FPA), released when fibrinogen is cleaved by thrombin. This peptide has a very short half-life in the circulation because it is cleared promptly by the kidneys. Elevated concentrations in blood are, therefore, indicative of thrombin activity in vivo. Subjects with diabetes mellitus (both types 1 and 2) have increased concentrations of FPA in blood and in urine compared with those in nondiabetic subjects.
The increased concentrations of FPA seen in association with diabetes reflect an altered balance between prothrombotic and antithrombotic phenomena in subjects with diabetes mellitus favoring thrombosis. Patients with diabetes mellitus have increased concentrations in blood of the prothrombotic factors fi-brinogen, von Willebrand factor, and factor VIIa coagulant activity. Among them, elevated concentrations of fibrinogen have been most strongly associated with an increased risk of development of cardiovascular disease. Although the mechanisms responsible for increased concentrations of fibrinogen and von Willebrand factor have not yet been fully elucidated, elevated concentrations in blood of insulin and proinsulin may be determinants in subjects with type 2 diabetes. This possibility is suggested by the close correlation between elevated concentrations of fibrinogen and hyperinsulinemia and hyperproinsulinemia in otherwise healthy subjects. Prediabetic subjects and patients in early stages of type 2 diabetes have marked insulin resistance reflected by a compensatory increase in the concentrations in blood of insulin and proinsulin. Thus, hyper(pro)insulinemia has been implicated in the evolution of concomitantly increased concentrations of fibrino- g gen. Improvement in metabolic control per se (euglycemia and amelioration of hyperlipidemia) has not been associated with normalization of the increased concentrations in blood of fibrinogen, von Willebrand factor, or factor VII coagulant activity.
First-degree nondiabetic relatives of subjects with type 2 diabetes exhibit increased concentrations of fibrinogen and factor VIIa coagulant activity in blood compared with values in age-matched controls. These are associated with other features indicative of insulin resistance. Thus, increased concentrations of pro-thrombotic factors seen typically in subjects with type 2 diabetes mellitus appear to be dependent on insulin resistance and hyperinsulinemia rather than to reflect the metabolic derangements typical of the diabetic state. Accordingly, hormonal abnormalities, particularly insulin resistance and hyper(pro)insulinemia, have been implicated as determinants of the prothrombotic state.
Decreased activity of antithrombotic factors in blood can potentiate thrombosis. Of note, concentrations in blood of protein C and activity of antithrombin are decreased in diabetic subjects. Unlike changes in concentrations of prothrom-botic factors, altered concentrations and activity of antithrombotic factors appear to be reflections of the metabolic state typical of diabetes such as hyperglycemia, regardless of whether type 1 or type 2 diabetes is responsible. In fact, decreased antithrombotic activity has been associated with nonenzymatic glycation of anti-thrombin.
To recapitulate, functional activity of the prothrombinase complex and of thrombin itself are increased consistently in blood of subjects with diabetes. The increased activity is likely to be a reflection of increased procoagulant activity of platelets and monocytes in association with increased concentrations of fibrin-ogen, von Willebrand factor, and factor VII. Diminished activity in blood of antithrombotic factors secondary to glycation of antithrombin (and also of protein C) may contribute to the prothrombotic state. To date, no anticoagulant pharmacological regimen has been identified that unequivocally decreases the intensity of the prothrombotic state in subjects with diabetes. To the extent that glycation of proteins contributes to a prothrombotic state, optimal glycemic control should attenuate it. Accordingly, an important approach to attenuation of a prothrombotic state is normalization of the metabolic abnormalities typical of diabetes. Results in the DCCT trial are consistent with this interpretation. Despite the fact that the trial focused on microvascular complications of diabetes, known to be influenced by hyperglycemia, a trend toward reduction of macrovascular events was seen with stringent glycemic control.
The potential value of improving metabolic control with specific regimens that are insulin sensitizing rather than insulin providing, thereby limiting -o hyper(pro)insulinemia while achieving metabolic (glycemic and lipidemic) control, has been recognized. With respect to cardiovascular events, this concept will £ be evaluated in the BARI 2D trial. BARI 2D is a study of patients with diabetes and cardiovascular disease, all of whom will be treated with an objective of optimal metabolic control (HbAlC < 7.0%). However, the approaches will differ. M Thus, patients will be assigned randomly to diverse regimens designed to achieve metabolic control with either insulin-providing or insulin-sensitizing agents.
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