Factor VIIa and tissue factor procoagulant activity in diabetes mellitus after acute ischemic stroke: Impact of hyperglycemia

Summary

Alterations in blood coagulation may explain the poorer neurological outcome with diabetes mellitus and hyperglycemia after acute ischemic stroke. We studied the relationships between diabetes mellitus, hyperglycemia, whole blood tissue factor procoagulant activity (TF-PCA) and plasma Factor VIIa (FVIIa) in ten patients with type 2 diabetes mellitus and 11 non-diabetic patients at baseline and 6, 12, 24, and 48 hours (h) after presentation for acute stroke. In addition, we examined plasma prothrombin fragment 1+2 (F1.2) and thrombin-antithrombin complexes (TAT) as markers of thrombin generation. Stroke severity, assessed by National Institute of Health Stroke Scale (NIHSS), was similar at baseline (p=0.26) but worse in diabetic (8.20 ± 4.3) than nondiabetic patients (2.67 ± 2.1,p=0.023) at 48 h. At presentation, diabetic patients had higher FVIIa (p=0.004) and lower TF-PCA (p=0.027) than non-diabetic patients but both were higher than in normal control subjects. FVIIa levels remained higher in diabetic patients at 6, 12 and 24 h after stroke. In diabetic patients, FVIIa (r=0.40, p=0.02) and TF-PCA (r=0.50, p=0.02) correlated with blood glucose; and, FVIIa correlated with plasma F1.2 (r=0.34, p=0.002) and TAT levels (r=0.62, p<0.0001). In non-diabetic patients, TF-PCA, but not FVIIa, correlated with F1.2 (r=0.402, p=0.010) andTAT (r=0.39, p=0.011). Combining both groups, NIHSS scores were positively related to FVIIa levels (r=0.50,p=0.021) and inversely related toTF-PCA levels (r=-0.498, p=0.02). Acute ischemic stroke patients with diabetes and hyperglycemia have a more intense procoagulant state compared with nondiabetic patients. This is related to glucose levels and provides a potential mechanism for the observed worse prognosis in such patients after acute stroke.

Keywords

Stroke - diabetes - hyperglycemia - procoagulant state - tissue factor

• References

• 1 Williams LS, Rotich J, Qi R. et al. Effects of admission hyperglycemia on mortality and costs in acute ischemic stroke. Neurology 2002; 59: 67-71.
• 2 Bruno A, Levine SR, Frankel MR. et al. Admission glucose level and clinical outcomes in the NINDS rt- PA Stroke Trial. Neurology 2002; 10 (59) 669-674.
• 3 Gentile NT, Seftchick M, Chen T. et al. Decreased mortality with normalizing blood glucose after acute ischemic stroke. Acad Emer Med 2006; 13: 174-180.
• 4 Ceriello A. Coagulation activation in diabetes mellitus: The role of hyperglycaemia and therapeutic prospects. Diabetologia 1993; 36: 1119-1125.
• 5 Dunn EJ, Grant PJ. Type 2 diabetes: an atherothrombotic syndrome. Curr Mol Med 2005; 5: 323-332.
• 6 Leurs PB, Stolk RP, Hamulyak K. et al. Tissue factor pathway inhibitor and other endothelium-dependent hemostatic factors in elderly individuals with normal or impaired glucose tolerance and type 2 diabetes. Diabetes Care 2002; 25: 1340-1345.
• 7 Rauch U, Nemerson Y. Tissue factor, the blood, and the arterial wall. Trends Cardiovasc Med 2000; 10: 139-143.
• 8 Mackman N. Role of tissue factor in hemostasis, thrombosis, and vascular development. Arterioscler Thromb Vasc Biol 2004; 24: 1015-1022.
• 9 Wilcox JN, Smith KM, Schwartz SM. et al. Localization of tissue factor in the normal vessel wall and in the atherosclerotic plaque. Proc Natl Acad Sci USA 1989; 86: 2839-2843.
• 10 Giesen PL, Rauch U, Bohrmann B. et al. Bloodborne tissue factor: another view of thrombosis. Proc Natl Acad Sci USA 1999; 96: 2311-2315.
• 11 Key NS, Slungaard A, Dandelet L. et al. Whole blood tissue factor procoagulant activity is elevated in patients with sickle cell disease. Blood 1998; 91: 4216-4223.
• 12 Chou J, Mackman N, Merrill-Skoloff G. et al. Hematopoietic cell-derived microparticle tissue factor contributes to fibrin formation during thrombus propagation. Blood 2004; 104: 3190-3197.
• 13 Abdel-Hafiz E, Vaidyula VR, Bagga S. et al. Elevated whole blood tissue factor procoagulant activity in diabetes mellitus: vitamin E inhibits glucose induced tissue factor activity in vitro. Blood 2002; 100: 496a.
• 14 Sambola A, Osende J, Hathcock J. et al. Role of risk factors in the modulation of tissue factor activity and blood thrombogenicity. Circulation 2003; 107: 973-977.
• 15 Tutar E, Ozcan M, Kilickap M. et al. Elevated whole-blood tissue factor procoagulant activity as a marker of restenosis after percutaneous transluminal coronary angioplasty and stent implantation. Circulation 2003; 108: 1581-1584.
• 16 Rao AK, Vaidyula VR, Bagga S. et al. Effect of antiplatelet agents clopidogrel, aspirin, and cilostazol on circulating tissue factor procoagulant activity in patients with peripheral arterial disease. Thromb Haemost 2006; 96: 738-743.
• 17 Asakura H, Kamikubo Y, Goto A. et al. Role of tissue factor in disseminated intravascular coagulation. Thromb Res 1995; 80: 217-224.
• 18 Vaidyula VR, Rao AK, Mozzoli M. et al. Effects of hyperglycemia and hyperinsulinemia on circulating tissue factor procoagulant activity and platelet CD40 ligand. Diabetes 2006; 55: 202-208.
• 19 Smith FB. Hemostatic factors as predictors of ischemic heart disease and stroke in the Edinburgh Artery Study. Arterioscler Thromb Vasc Biol 1997; 17: 3321-3325.
• 20 Takano K. Hypercoagulability in acute ischemic stroke: analysis of the extrinsic coagulation reactions in plasma by a highly sensitive automated method. Thromb Res 1990; 58: 481-491.
• 21 He M, Wen Z, He X. et al. Observation on tissue factor pathway and some other coagulation parameters during the onset of acute cerebrocardiac thrombotic diseases. Thromb Res 2002; 107: 223-228.
• 22 Berge E, Friis P, Sandset PM. Hemostatic activation in acute ischemic stroke. Thromb Res 2001; 101: 13-21.
• 23 Soncini M, Gasparini P, Lorena M. et al. Prognostic significance of markers of thrombin generation in the acute and chronic phases of non cardioembolic ischemic stroke. Minerva Cardioangiol 2000; 48: 349-356.
• 24 Cote R, Wolfson C, Solymoss S. et al. Hemostatic markers in patients at risk of cerebral ischemia. Stroke 2000; 8: 1856-1862.
• 25 American Stroke Association.. Available at http://asa.trainingcampus.net
• 26 Conover WJ, Iman RL. Rank transformations as a bridge between parametric and nonparametric statistics. Am Statistician 1981; 35: 124-129.
• 27 Moreno PR, Foster V. New aspects in the pathogenesis of diabetic atherothrombosis. J Am Coll Cardiol 2004; 44: 2293-2300.
• 28 Martin A, Rojas S, Chamorro A. et al. Why does acute hyperglycemia worsen the outcome of transient focal cerebral ischemia?. Stroke 2006; 37: 1288-1295.
• 29 Meigs JB, Mittleman MA, Nathan DM. et al. Hyperinsulinemia, hyperglycemia, and impaired hemostasis: the Framingham Offspring Study. J Am Med Assoc 2000; 283: 221-228.
• 30 Ruddock V, Meade TW. Factor VII activity and ischaemic heart disease: fatal and non-fatal events. Quart J Med 1994; 87: 403-436.
• 31 Morel O, Hugel B, Jesel L. et.al Sustained elevated amounts of circulating procoagulant membrane microparticles and soluble GPV after acute myocardial infarction in diabetes mellitus. Thromb Haemost 2004; 91: 345-353.
• 32 Roberts HR, Hoffman M, Monroe DM. A cellbased model of thrombin generation. Semin Thromb Hemost 2006; 32: 32-38.
• 33 Van den Berghe G, Wouters P, Weekers F. et al. Intensive insulin therapy in the critically ill patients. N Engl J Med 2001; 345: 1359-1367.
• 34 Hansen TK, Thiel S, Wouters PJ. et al. Intensive insulin therapy exerts antiinflammatory effects in critically ill patients and counteracts the adverse effect of low mannose-binding lectin levels. J Clin Endocrinol Metab 2003; 88: 1082-1088.
• 35 Van den Berghe G, Wilmer A, Herman H. et al. Intensive Insulin Therapy in the Medical ICU. N Engl J Med 2006; 354: 449-461.
• 36 DeSantis AJ, Schmidt K, O’Shea-Mahler E. et al. Inpatient management of hyperglycemia: the Northwestern experience. Endocr Pract 2006; 12: 491-505.
• 37 Malmberg K. Role of insulin-glucose infusion in outcomes after acute myocardial infarction: the diabetes and insulin-glucose infusion in acute myocardial infarction (DIGAMI) study. Endocr Pract 2004; 10 (Suppl. 02) 13-16.
• 38 Cheung NW, Wong VW, McLean M. The Hyperglycemia: Intensive Insulin Infusion In Infarction (HI-5) Study: A randomized controlled trial of insulin infusion therapy for myocardial infarction. Diabetes Care 2006; 29: 765-770.
• 39 Berger L, Hakim AM. The association of hyperglycemia with cerebral edema in stroke. Stroke 1986; 17: 865-871.
• 40 Mohanty P, Hamouda W, Garg R. et al. Glucose challenge stimulates reactive oxygen species (ROS) generation by leucocytes. J. Clin. Endocrinol. Metab 2000; 85: 2970-73.
• 41 Tripathy D, Mohanty P, Dhindsa S. et al. Elevation of free fatty acids induces inflammation and impairs vascular reactivity in healthy subjects. Diabetes 2003; 52: 2882-2887.
• 42 Dhindsa S, Tripathy D, Mohanty P. et al. Differential effects of glucose and alcohol on reactive oxygen species generation and intranuclear nuclear factor-kappaB in mononuclear cells. Metabolism 2004; 53: 330-334.
• 43 Aljada A, Ghanim H, Mohanty P. et al. Insulin inhibits the pro-inflammatory transcription factor early growth response gene-1 (Egr)-1 expression in mononuclear cells (MNC) and reduces plasma tissue factor (TF) and plasminogen activator inhibitor-1 (PAI-1) concentrations. J Clin Endocrinol Metab 2002; 87: 1419-1422.