Haemostatic factors in diabetes mellitus with particular reference to thrombotic disease
Paton, Robert Colin
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The aim of this Thesis was to investigate haemostatic function in diabetes mellitus and to relate abnormalities to the presence of micro- and macrovascular disease. Since poor metabolic control appears to favour the development of diabetic vascular complications, the influence of hyperglycaemia on haemostatic function was also studied. In Part I, evidence that thrombosis is involved in the pathogenesis of micro- and macroangiopathy was discussed and the physiology of platelets and of the coagulation and fibrinolytic systems, with particular reference to their respective roles in thrombus formation, was reviewed. In Part II, platelet aggregation and a battery of tests of coagulation and fibrinolysis were performed on 3^ patients attending a diabetic out-patient clinic. Compared with non-diabetic controls, significantly higher levels of fibrinogen, factors II, V, VII, VIII:C, OC^-macroglobulin and c^-esterase inhibitor and lower levels of factor XI and antithrombin III were found, though the threshold concentrations of ADP, adrenaline and collagen required to produce second phase platelet aggregation were similar in diabetics and controls. The refinement of a new, non-radioisotopic method for the measurement of platelet survival was described in Part III. Using this method, platelet survival of 12 diabetics was found to be significantly shorter than that of 12 controls. Diminished platelet survival may result from alterations in the platelet membrane; further evidence for membrane abnormalities in platlets from diabetic subjects was provided by the observation that platelets from 8 patients with severe retinopathy had significantly increased "^I-fibrinogen binding compared with 9 non-diabetic controls, fibrinogen binding of platelets from 8 diabetics with slight retinopathy being intermediate between the two groups. Similarly, ADP-induced first phase platelet aggregation was found to be significantly increased in the group with severe retinopathy compared with the controls. Sensitivity of the platelets to ADP was found to be significantly correlated with the HbA^ concentration, but not with the degree of fibrinogen binding, suggesting that platelet aggregation and fibrinogen binding were related to the extent of microvascular disease, but that aggregation may also be increased by poor metabolic control. In Part IV, the effect of diabetic serum on the production of PGI^ by thrombin stimulated cultured human vascular endothelial cells was assessed. Both PGI -like activity and 6-keto-PGFT concentrations were significantly lower in cells cultured in 20% serum from diabetics with proliferative retinopathy compared with non-diabetic controls, with a significant correlation between the depression in 6-keto-PGF^ production and the concentration of HbA-. Production of I 6-keto-PGFTla was not affected by changes in glucose concentration in the culture medium, and there were no significant differences when cells cultured in serum from well controlled diabetics were compared with serum from poorly controlled diabetics in the absence of vascular disease. In Part V, effects of metabolic control on haemostatic function were studied. Compared with the results after stabilization of the diabetes, II patients with ketoacidosis had significantly raised levels of factors VIII:C and VIIIRrAg and fibrin degradation products, a shorter partial thromboplastin time and reduced concentrations of antithrombin III. These changes may indicate vascular damage and intra¬ vascular fibrin deposition. Out of three deaths, two diabetics with the hyperosmolar syndrome had evidence of disseminated intravascular coagulation. In a second study, the effect of control of hyperglycaemia on haemostatic function was observed in IA- non-insulin dependent diabetics. After 2 months treatment with diet alone, II were given the sulphonylurea gliclazide, the others remaining on diet only. Compared with pretreatment values, significant reductions in platelet retention, factors VIIIjC and VIIIR:Ag and plasma heparin neutralizing activity accompanied a fall in the plasma glucose concentration due to diet alone or diet plus gliclazide. This Thesis has shown that diabetes mellitus is associated with a number of alterations of the haemostatic system. These changes appear to indicate tissue, and particularly vessel wall, injury and may in part be reversed by improved metabolic control. It remains uncertain whether such alterations predispose to diabetic vascular disease, though clinical trials of antithrombotic drugs during diabetic coma and in the long term prevention of micro- and macroangiopathy in diabetic patients may be indicated.