Protein C Deficiency in Insulin-Dependent Diabetes: A Hyperglycemia-Related Phenomenon

Summary

In 30 insulin-dependent diabetic patients protein C (PC) antigen and PC activity were significantly lower than those of matched control healthy subjects. An inverse correlation between fasting plasma glucose and both PC concentration and activity was present in diabetics, while a direct correlation between PC concentration and PC activity was observed. Induced hyperglycemia in diabetic and normal subjects was able to decrease both PC antigen levels and PC activity, and heparin reversed in part this effect.

In diabetic patients euglycemia obtained by insulin infusion restored to normal the depressed PC levels. Heparin did not alter both the basal PC concentration and activity in healthy controls.

These data stress the major role of hyperglycemia in determining PC decrease in diabetics, and suggest that PC reduction is probably associated to hyperglycemia-enhanced thrombin formation.

• References

• 1 Jones RL, Peterson CM. The fluid phase of coagulation and the accelerated atherosclerosis of diabetes mellitus. Diabetes 1981; 30 (Suppl. 02) 33-38
• 2 Ostermann H, van de Loo J. Factors of the hemostatic system in diabetic patients. A survey of controlled study. Haemostasis 1986; 16: 386-416
• 3 Clouse LH, Comp PC. The regulation of hemostasis: the protein C system. N Engl J Med 1986; 314: 1298-1304
• 4 Vukovich TC, Schemthaner G. Decreased protein C levels in patients with insulin-dependent type I diabetes mellitus. Diabetes 1986; 35: 617-619
• 5 Ceriello A, Dello RussoP, Zuccotti C, Florio A, Nazzaro S, Pietrantuono C, Rosato GB. Decreased antithrombin III activity in diabetes may be due to non-enzymatic glycosylation. A preliminary report. Thromb Haemostas 1983; 50: 633-634
• 6 Ceriello A, Giugliano D, Quatraro A, Stante A, Consoli G, Dello RussoP, D’Onofrio F. Daily rapid blood glucose variations may condition antithrombin III biologic activity but not its plasma concentration in insulin-dependent diabetes. A possible role for labile non-enzymatic glycation. Diab Metabol 1987; 13: 16-19
• 7 Ceriello A, Giugliano D, Quatraro A, Stante A, Consoli G, Dello RussoP, D’Onofrio F. Induced-hyperglycemia alters antithrombin III activity but not its plasma concentration in healthy normal subjects. Diabetes 1987; 36: 320-323
• 8 National Diabetes Data Group. Classification and diagnosis of diabetes mellitus and other categories of glucose intolerance. Diabetes 1979; 28: 1039-1057
• 9 Cerasi E, Luft R. What is inherited - what is added?. Hypothesis for the pathogenesis of diabetes mellitus. Diabetes 1967; 16: 615-627
• 10 Marciniak E, Gokerman JF. Heparin-induced decrease in circulating antithrombin III. Lancet 1977; 2: 581-584
• 11 Mallia AK, Hermanson GT, Krohn RS, Fujimoto EK, Smith PK. Preparation and use of a boronic acid affinity chromatography for separation and quantification of glycosylated hemoglobin. Anal Lett 1981; 14: 649-661
• 12 Boyer C, Rothschild G, Wolf M, Amiarl J, Meyer D, Larrien MJ. A new method for estimation of protein C by ELISA. Thromb Res 1984; 36: 579-589
• 13 Martinoli JL, Stocker K. Fast functional protein C assay using Protac, a novel protein C activator. Thromb Res 1986; 43: 253-264
• 14 Griffin GM, Mosher DF, Zimmermann TS, Kleiss AJ. Protein C, an antithrombotic protein, is reduced in hospitalized patients with intravascular coagulation. Blood 1982; 60: 261-264
• 15 Mannucci PM, Vigano S. Deficiences of protein C, an inhibitor of blood coagulation. Lancet 1982; 2: 463-467
• 16 Nossel HL. Radioimmunoassay of fibrinopeptides in relation to intravascular coagulation and thrombosis. N Engl J Med 1976; 295: 428-432
• 17 Jones RL. Fibrinopeptide A in diabetes mellitus: relation to levels of blood glucose, fibrinogen disappearance, and hemodynamic changes. Diabetes 1985; 34: 836-843
• 18 Ceriello A, Giugliano D, Quatraro A, Dello RussoP, Marchi E, Torella R. Hyperglycemia may determine fibrinopeptide A plasma level increase in man. Metabolism 1989; 38: 1162-1163
• 19 Delvos U, Meusel P, Preissner KT, Muller-Berghaus G. Formation of activated protein C and inactivation of cell-bound thrombin by antithrombin III at the surface of cultured vascular endothelial cells -A comparative study of two anticoagulant mechanisms. Thromb Haemostas 1987; 57: 87-91
• 20 Mannucci PM, Tripodi A, Mari D. Congenital deficiences of anticoagulant proteins (Antithrombin III and protein C). Haematologica 1984; 69: 730-746
• 21 Comp PC. Heparin-protein C interaction. Nouv Rev Fr Hematol 1984; 26: 239-242
• 22 Ceriello A, Giugliano D, Quatraro A, Stante A, Consoli G, Dello Russo P, D’Onofrio F. Heparin preserves antithrombin III biological activity from hyperglycemia-induced alterations in insulin-dependent diabetics. Haemostasis 1986; 16: 458-464