Abnormal endothelial release of fibrinolytic activity and fibronectin in diabetic microangiopathy

Abstract

Endothelial cell function in Type 1 (insulin-dependent) diabetic patients, both with and without retinopathy, was assessed by measuring the plasma fibrinolytic activity and fibronectin after 10 min venous stasis induced by a sphygmomanometer cuff. After venous stasis, diabetic subjects with proliferative retinopathy had fibrinolytic responses (median 0.13 increasing to 0.26 U/ml) in the low normal range, which were significantly less (p less than 0.005) than control subjects (0.17-0.68 U/ml) and diabetic patients with minimal retinopathy (0.16-0.68 U/ml; p less than 0.01). Plasma fibronectin levels were similar in the different groups, but after venous stasis, rose significantly in the diabetic patients, both in those with proliferative retinopathy (mean 317-399 micrograms/ml; p less than 0.002) and without retinopathy (312-371 micrograms/ml; p less than 0.05) but not in normal subjects (304-333 micrograms/ml). These changes in fibrinolytic activity and fibronectin were independent of blood glucose, glycosylated haemoglobin, or indices of sensory or autonomic nerve function. These disturbances of endothelial function, together with known abnormalities of haemostatic variables and microvascular reflexes, might convert a usually temporary obstruction of capillary blood flow into a pathological capillary closure, and might contribute to the inexorable progression of advanced diabetic microangiopathy in spite of good diabetic control.

Does chronic smoking influence fibrinolytic potential in Type 1 diabetes mellitus?

“…24,28,29,32 Our findings suggest that smoking does not significantly compromise non-specific endothelial cell function in diabetes prior to the development of advanced complications.…”

“…In this context it is reassuring that evidence exists to support the prolonged maintenance of normal fibrinolysis in the setting of uncomplicated disease. 24,31 It seems safe to conclude that the impairment of fibrinolysis associated with smoking is circumvented in Type 1 DM; that levels of the principal activator and inhibitor of fibrinolysis are normal in uncomplicated Type 1 DM, and that breakfast and exogenous insulin do not significantly alter t-PA or PAI-1 levels.…”

“…A previous study has described significantly elevated PAI activity in smokers with much longer histories of diabetes, many of whom had varying degrees of diabetic complications 23 which may have affected fibrinolysis. [24][25][26] Moreover, in that study, 23 as with several previous studies on fibrinolysis and diabetes, blood was collected onto citrate alone, raising the possibility that some of the measured PAI in plasma had leaked from platelets in vitro. 19 The current study was designed to minimize the 25,[27][28][29] although one group has described significantly reduced t-PA and PAI-1 antigen levels in uncomplicated diabetes.…”

Detection of Prethrombotic States in Patients with Atherosclerotic Lesions

“…A diminished fibrinolytic activity, especially in patients with angiopathy, was described 223 ' 226 ' 228 and also after venous occlusion. 229 Although the fibrinolytic activity was increased after venous occlusion, high molecular weight fibrinogen split products were found by Gurewich et al 224 in patients with diabetic macro-and microangiopathy. In another study, the tissue plasminogen activator of the vessel wall was reduced.…”

Genetics of diabetic retinopathy

“…3-q22. Previous studies in subjects with type 1 diabetes have shown an enhanced fibrinolytic activity and lower levels of PAI-1 with diabetic retinopathy. 95,96 Altered PAI-1 expression, through its effect on plasmin production and tissue proteolysis, may alter the endothelial extracellular matrix composition and accumulation seen in diabetic microvascular disease. 97 The Pima Indians of Arizona have an extremely high incidence of diabetes which is exclusively non-insulin-dependent and complications of diabetes are similar in nature to those seen in other populations with type 2 diabetes.…”