Abnormalities in the fibrinolytic system

The fibrinolytic system controls the patency of the vascular tree and is likely a critical regulator of thrombosis. One hypothesis is that small amounts of fibrin are constantly deposited on the endothelium and that these fibrin deposits are continually dissolved, resulting in a dynamic balance between coagulation and fibrinolysis. The generation and activity of plasmin, the enzyme responsible for the degradation of fibrin deposits and thrombi, are regulated mainly by the production of two critical proteins by the vascular endothelium, tissue-plasminogen activator (t-PA) and the main inhibitor of t-PA, PAI-1. t-PA converts inactive plasminogen into plasmin at the site of fibrin formation.

Impaired fibrinolytic activity is characterized by low t-PA activity and high PAI-1 antigen and activity. Studies in man have shown that t-PA antigen concentration (associated with high PAI-1 and low basal or stimulated t-PA activity) may be high in subjects with preclinical atherosclerosis and a marker for the development of coronary and cerebrovascular events (276,277). Furthermore, t-PA antigen has been found to have a higher predictive value for mortality in patients with established CAD than cholesterol, triglycerides, fibrinogen, blood pressure, diabetes, or smoking (278). Like in nondiabetic subjects, impaired fibrinolysis is an independent risk factor for MI in diabetic subjects (279,280).

Decreased fibrinolytic function in type 2 diabetes correlates with the presence and severity of angiopathies (281). In patients with type 1 diabetes, increased PAI-1 activity has been observed in association with microalbuminuria (282). Regulation of PAI-1 gene expression and protein synthesis in HepG2 cells seems to be controlled by insulin alone (283,284) or insulin in association with VLDL (284). Increased concentrations of free fatty acids in diabetes may account for the insulin and VLDL-mediated augmentation of PAI-1 synthesis and therefore normalization of elevated concentrations of free fatty acids by improvement of glycemic control may normalize or near-normalize the fibrinolytic system activity in type 2 diabetes. Some studies examining this issue in vivo (285) confirmed this postulate (286). This observation is consistent with the favorable effects induced by sulfonylureas, metformin, and the two in combination in normalizing the fibrinolytic system activity in type 2 diabetes (287).

Lipoproteins are also able to regulate t-PA and PAI-1 release, as demonstrated by in vitro studies using cultured endothelial cells. VLDL isolated from normal individuals induce the release of t-PA and PAI-1 from cultured endothelial cells, whereas VLDLs from hypertriglyceridemic individuals are unable to do so (288). Endothelial production of PAI-1 is also increased by incubation with VLDL obtained from hyperglycemic patients (289). In vivo evidence to support the "in vitro" studies showing increased PAI-1 activity in type 2 diabetes was provided by studies showing an abnormal response to the administration of desmopressin acetate in type 2 diabetic patients with hypertriglyceridemia. Plasma t-PA activity was frankly decreased and PAI-1 activity frankly increased when compared to the activity levels obtained in normal controls (290). Recently it has been reported that lipoprotein [Lp](a) also attenuates fibrinolysis as a result of the interaction of apo(a) with the ternary complex of t-PA, plasminogen and fibrin (291). Lp(a) species containing smaller apo(a) isoforms bind more avidly to fibrin and are better inhibitors of plasminogen (292).

Another well-recognized contributor to augmented activity of PAI-1 in diabetes is the adipocyte. PAI-1 may be released directly from an increased mass of adipose tissue, particularly visceral fat, and that may account, in part, for the association between obesity and impaired fibrinolysis (293-295). However, abnormal concentrations of cytokines such as TGF-P and TNF-a, may also contribute to augment PAI-1 expression in adipocytes (296). Other cytokines including IL-1 and -6 have also been implicated as agonists for PAI-1 synthesis (297). Another factor likely to influence PAI-1 expression in diabetes is the renin-angiotensin system (RAS) because PAI-1 synthesis is augmented by the binding of angiotensin II to the ATI receptor (298). As earlier work has shown the RAS is activated in patients with type 2 diabetes. In fact, the American Diabetes Association has recommended the use of angiotensin receptor blockers alone or in combination with angiotensin-converting enzyme inhibitors in diabetes not only for treatment of hypertension but also to attenuate microalbuminuria. Angiotensin-converting enzyme inhibition has also the advantage of attenuating hypofibrinolysis not only in blood but also in tissues including the heart (299).

Diabetes 2

Diabetes 2

Diabetes is a disease that affects the way your body uses food. Normally, your body converts sugars, starches and other foods into a form of sugar called glucose. Your body uses glucose for fuel. The cells receive the glucose through the bloodstream. They then use insulin a hormone made by the pancreas to absorb the glucose, convert it into energy, and either use it or store it for later use. Learn more...

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