Mechanisms responsible for a prothrombotic state associated with diabetes

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Patients with DM have increased concentrations in blood of the prothrombotic factors fibrinogen, von Willebrand factor, and factor VII coagulant activity (77-79). Among the three coagulation factors, fibrinogen has been most strongly associated with the risk of development of CVD (80). 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 people with type 2 diabetes. This possibility is suggested by the close correlation between concentrations of fibrinogen with those of insulin and proinsulin in healthy subjects (81). Because prediabetic subjects and people with early stages of diabetes have marked insulin resistance that leads to a compensatory increase in the concentrations in blood of insulin and proinsulin (82-84), the hyper(pro)insulinemia of type 2 diabetes is likely to underlie, at least in part, the typically increased concentrations of fibrinogen. 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 (79). By the same token, the extent of elevation of concentrations in blood of prothrombin fragment 1 + 2 is not closely correlated with the concentration of HbA1c, a marker of glycation of proteins (85). First-degree nondiabetic relatives of subjects with type 2 diabetes exhibit increased concentrations of fibrinogen and factor VII coagulant activity in blood compared with values in age-matched controls (86). Thus, the increases in fibrinogen and factor VII-coagulant activity are associated with other, presumably independent features of insulin resistance. Accordingly, increased concentrations of prothrombotic factors seen typically in subjects with type 2 DM are not reflections of the metabolic derangements typical of the diabetic state but instead appear to be dependent on insulin resistance and hyperinsulinemia. In fact, hormonal abnormalities, particularly insulin resistance and hyper(pro)insulinemia, appear to underlie the prothrombotic state (81,86).

As mentioned in the preceding section on platelet function, procoagulant activity is increased in platelets from diabetic subjects. Procoagulant activity of monocytes is increased as well (87). The negatively charged phospholipid surface of platelets and monocytes catalyzes both formation and activity of the tenase and prothrombinase complexes. Thus, increased procoagulant activity of platelets and monocytes can potentiate thrombosis.

Decreased activity of anti-thrombotic factors in blood can potentiate thrombosis. Of note, concentrations in blood of protein C and activity of anti-thrombin are decreased in diabetic subjects (88-91), although not universally (75). Unlike changes in concentrations of prothrombotic factors, altered concentrations and activity of anti-thrombotic factors appear to be reflections of the metabolic state typical of diabetes, either type 1 or type 2, especially hyperglycemia. Thus, decreased anti-thrombotic 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 people 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 fibrinogen, von Willebrand factor , and factor VII. Diminished activity in blood of anti-thrombotic factors secondary to glycation of anti-thrombin and 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, the most effective mechanism available to attenuate a prothrombotic state is normalization of the hormonal and metabolic abnormalities in patients with diabetes. Results in the Diabetes Control and Complications Trial (DCCT) are consistent with this interpretation. Despite the fact that the DCCT focused on mi-crovascular complications of diabetes, known to be influenced by hyperglycemia, a trend toward reduction of macrovascular events was seen with stringent and glycemic control (92). This trend is consistent with reduction of the intensity of the prothrombotic state and hence attenuation of atherogenesis, determinants of its sequela, or both.

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