Diabetes and fibrinolysis

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Decreased fibrinolytic system capacity is observed consistently in blood from patients with DM, particularly those with type 2 diabetes (93,94). It has been known for many years that obesity is associated with impaired fibrinolysis (95); that elevated blood triglycerides and other hallmarks of hyperinsulinemia are associated with increased activity of PAI-1 (96); and that elevated PAI-1 is a marker of increased risk of acute MI as judged from its presence in survivors compared with age-matched subjects who had not experienced any manifestations of overt CAD (97). We found that impaired fibrinolysis in subjects with type 2 DM, not only under baseline conditions but also in response to physiological challenge, was attributable to augmented concentrations in blood of circulating PAI-1. Furthermore, obese diabetic subjects exhibited threefold elevations of PAI-1 in blood compared with values in nondiabetic subjects despite tissue-type plasminogen activator (t-PA) values that were virtually the same. The observation of an impairment of fibrinolysis not only under basal conditions but also in response to physiological stress implicates the pathophysiological import of the abnormality (94). Subsequently, we found that precursors of insulin including proinsulin (30,31) and desproinsulin (63,64) induced time- and concentration-dependent elevation in expression of PAI-1 by human hepatoma cells in culture (98). Additionally, we found that concentrations of PAI-1 can be elevated in blood in normal subjects rendered hyperglycemic, hyperinsulinemic, and hyperlipidemic (99). Furthermore, women with the polycystic ovarian syndrome, known to be associated with hyperinsulinemia, have increased concentrations of PAI-1 in blood that can be reduced by administration of troglitazone, an insulin sensitizer (100).

Thus, people with type 2 diabetes exhibit a decreased fibrinolytic system capacity secondary to increased PAI-1 in blood. Similar derangements are evident in association with other states of insulin resistance and compensatory hyperinsulinemia in conditions such as obesity (94,95), hypertension (101), and the polycystic ovarian syndrome (100,102,103).

Because the endogenous fibrinolytic system influences the evolution of thrombosis and the rapidity and extent of lysis of thrombi when vascular damage is repaired, overexpression of PAI-1 is likely to exacerbate development and the persistence of thrombi. Results in transgenic mice deficient in PAI-1 compared with wild type animals are consistent with this hypothesis. Thus, 24 hours after arterial injury, persistence of thrombosis and the residual thrombus burden were greater than in wild type mice that were not deficient in PAI-1 (104). Analogous observations have been obtained based on analysis of human tissues after fatal pulmonary embolism (105). Increased expression of PAI-1 in association with the pulmonary thromboembolism was evident. Thus, increased expression of PAI-1 typical of that seen in type 2 diabetes is likely to be a determinant of increased and persistent thrombosis.

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