The coagulation system and diabetes mellitus

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Activation of the coagulation system leads to the generation of thrombin and thrombin-mediated formation of fibrin from fibrinogen. The generation of thrombin depends on activation of procoagulant factors. It is limited by antithrombotic factors and inhibitors. Fibrinopeptide A (FPA) is released when fibrinogen is cleaved by thrombin. FPA has a very short half-life in the circulation and is cleared promptly by the kidneys. Elevated concentrations in blood are indicative of thrombin activity in vivo (70). Subjects with DM (both types 1 and 2) have increased concentrations of FPA in blood and in urine compared with corresponding concentrations in nondiabetic subjects (71-74). The highest concentrations are observed in patients with clinically manifest vascular disease (72,74).

The increased concentrations of FPA seen in association with diabetes reflect an altered balance between prothrombotic and anti-thrombotic determinants in subjects with DM favoring thrombosis. This interpretation is consistent with other observations suggesting that generation of thrombin is increased with diabetes resulting in increased concentrations in blood of thrombin-anti-thrombin complexes (75). The steady-state concentration of thrombin-anti-thrombin complexes in blood is a reflection of the rate of formation of thrombin being generated over time.

The increased generation of thrombin in people with diabetes is likely to be dependent on increased activity of factor Xa. This has been observed in patients with type 1 diabetes (76). Factor Xa, a major component of the prothrombinase complex, is formed from components including circulating coagulation factor X assembled on phospholipid membranes in association with the tissue factor VIIa complex. Thrombin is generated by the prothrombinase complex comprising factors Xa, Va, and II assembled on phospholipid membranes. The activity of this complex is reflected by prevailing concentrations in blood of prothrombin fragment 1 + 2, a cleavage product of factor II (prothrombin). Increased concentrations of prothrombin fragment 1 + 2 in blood from patients with type 1 diabetes have been observed, consistent with the presence of a prothrombotic state.

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