Fibrinolytic System in Diabetes Mellitus Plasminogen Activator Inhibitor

PAI-1, one of the inhibitors of the fibrinolytic system, is synthesized by hepatocytes, fibroblasts, adipocytes, and ECs and is stored within the platelet granules.

Elevated PAI-1 levels have been noted in patients with CAD and are strongly correlated with components of cardiometabolic syndrome (CMS) such as BMI, blood pressure, and triglycerides (2, 27). Festa et al. examined the relationship between new-onset diabetes and dynamic changes of PAI-1 and fibrinogen (39, 40). In nondiabetic, healthy individuals, increasing PAI-1 levels were associated with new cases of diabetes. Both fibrinogen and PAI-1 levels are elevated in prediabetic subjects; however, only PAI-1 levels further increased with rising glucose levels and the development of diabetes (40). These investigators suggested that the findings in the Insulin Resistance Atherosclerosis Study (IRAS) population indicate that healthy individuals who have a hypofibrinolytic, proinflammatory, and procoagulant state as evidenced by high levels of PAI-1 and fibrinogen are at increased risk for development of diabetes (40). Increases in both of these coagulation factors appear to be very early markers for the development of diabetes.

Clinical studies have shown that nonpharmacological and pharmacological interventions including diet, lifestyle, and weight reduction, as well as treatment with Metformin and ACE inhibitors, have been associated with reductions in PAI-1 levels (41). Further prospective clinical trials are needed to prove if decreasing PAI-1 levels will prevent or delay the progression of diabetes (Fig. 2).

Tissue Plasminogen Activator t-PA is a serine protease synthesized and secreted by the ECs. The majority of t-PA circulates in the plasma bound to PAI-1. In the presence of a fibrin clot, t-PA and plasminogen bind to fibrin enhancing the formation of fibrin degradation products. Numerous studies have shown an association of insulin resistance and elevated PAI-1 and decreased t-PA activity. Furthermore, elevated PAI-1 levels may indicate long-standing EC damage as is commonly seen in insulin resistance (27).

Alterations in Clotting Factor Levels

Fibrinogen

Fibrinogen is a heterodimer synthesized by the liver. It is involved in thrombogenesis and platelet aggregation. Several prospective epidemiological studies and clinical observations have shown that elevated fibrinogen is a risk factor for CVD (42). There are several potential pathophysiological mechanisms by which elevated fibrinogen levels increase CVD risk. Fibrinogen is the substrate for thrombin and represents the final step in the coagulation cascade; it is essential for platelet aggregation, modulation of endothelial function, promotion of VSMC proliferation and migration, and interaction with the binding of plasmin to its receptor. In addition, it represents a major acute-phase protein. Elevated fibrinogen levels, as discussed earlier, can predict the development of DM2 in healthy individuals (40).

Contradictory results regarding various diabetes treatment strategies and their impact on fibrinogen levels have been obtained. In the Veterans Affairs Cooperative Study in DM2, intensive insulin therapy transiently increased fibrinogen levels (43). This increase in fibrinogen levels may have resulted from direct stimulation of fibrinogen synthesis by insulin. On the other hand, in another study, Metformin therapy resulted in a reduction of fibrinogen levels (44).

Fibrin > degradation products Fig. 2. Fibrinolytic pathway (Source: Created by Dr. Reddy).

Factor VIIc

Factor VIIc is a protein synthesized in the liver, which has been associated with increased cardiac incidents (27). The Prospective Cardiovascular Munster (PROCAM) study revealed a trend toward significance of higher factor VIIc levels in subjects who had fatal cardiovascular events (45). In concert with these data, another study of circulating tissue factor procoagulant activity found elevated factor VIIc, tissue factor, and thrombin complexes in patients with DM2 (46).

Von Willebrand Factor and Factor VIII

Von Willebrand Factor (VWF) is synthesized and secreted by vascular EC. It functions in primary hemostasis by forming an adhesive bridge between platelets and vascular subendothelial structures as well as between adjacent platelets at sites of endothelial injury. It also serves as a carrier protein for factor VIII, which has a greatly shortened half-life unless it is bound to VWF (27). Elevated levels of VWF may be a surrogate for endothelial dysfunction. Some studies have reported an association between elevated VWF and factor VIII and CVD (27). Elevated levels of factor VIII with hyperglycemia accelerate the rate of thrombin formation, which may contribute to occlusive vascular disease (3).

Thrombin-Antithrombin Complex

Thrombin plays a pivotal role in the coagulation system with multiple effects that result in formation of fibrin. Once activated, free thrombin is rapidly inactivated by combination with antithrombin. Thrombin-antithrombin complexes (TAT) subsequently circulate and are removed by the liver. Thus, elevated TAT levels are indicators of coagulation system activation. Multiple studies have documented elevated TAT in diabetes (2, 38).

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