Acute, short-term hyperglycemia enhances shear stress-induced platelet activation in patients with type II diabetes mellitus.

OBJECTIVES The aim of our study was to assess whether acute, short-term hyperglycemia affects platelet reactivity in patients with Type II diabetes mellitus (T2DM). BACKGROUND Hyperglycemic spikes are thought to precipitate ischemic events in T2DM. Previous studies have shown in vivo platelet activation in diabetes; however, no studies have assessed whether acute in vivo hyperglycemia induces further activation of platelets. METHODS In a cross-over, randomized, double-blind study, 12 patients with T2DM underwent 4 h of either acute hyperglycemia (13.9 mmol/l, 250 mg/dl) or euglycemia (5.5 mmol/l, 100 mg/dl). Shear stress-induced platelet activation, P-selectin and lysosomal integral membrane protein (LIMP) expression on platelets in the bleeding-time blood, urinary 11-dehydro-thromboxane B(2) (TxB(2)) excretion, von Willebrand factor:antigen (vWF:Ag), and von Willebrand factor:activity (vWF:activity) were measured before and after hyperglycemia or euglycemia. RESULTS Shear stress-induced platelet activation, P-selectin and LIMP expression on platelets in the bleeding-time blood, and urinary 11-dehydro-TxB(2) excretion increased significantly after hyperglycemic clamping, whereas no changes were observed after euglycemic clamping. Plasma vWF:Ag and vWF:activity increased strikingly in parallel fashion after hyperglycemic clamping, whereas no changes were observed after euglycemic clamping. CONCLUSIONS Our data demonstrate that acute, short-term hyperglycemia induces an increased activation of platelets exposed to high shear stress conditions in vitro (filtration method) or in vivo (bleeding time). In vivo platelet activation is reflected by an increased urinary excretion of 11-dehydro-TxB(2). The increased levels of vWF in the circulation correlate with the increase in platelet activation markers and may indicate some degree of causation. Acute, short-term hyperglycemia in T2DM may precipitate vascular occlusions by facilitating platelet activation.

[1]  S. Yusuf,et al.  The relationship between glucose and incident cardiovascular events. A metaregression analysis of published data from 20 studies of 95,783 individuals followed for 12.4 years. , 1999, Diabetes care.

[2]  Z. Ruggeri,et al.  Mechanisms of Shear-induced Platelet Adhesion and Aggregation , 1993, Thrombosis and Haemostasis.

[3]  G. Tjønnfjord,et al.  Reduced Effect of Aspirin on Thrombus Formation at High Shear and Disturbed Laminar Blood Flow , 1996, Thrombosis and Haemostasis.

[4]  J. Neaton,et al.  Diabetes, Other Risk Factors, and 12-Yr Cardiovascular Mortality for Men Screened in the Multiple Risk Factor Intervention Trial , 1993, Diabetes Care.

[5]  B. Howard,et al.  Diabetes and cardiovascular disease , 2000, Annual review of medicine.

[6]  P. Gresele,et al.  Role of proaggregatory and antiaggregatory prostaglandins in hemostasis. Studies with combined thromboxane synthase inhibition and thromboxane receptor antagonism. , 1987, The Journal of clinical investigation.

[7]  J D Hellums,et al.  Shear-induced platelet aggregation can be mediated by vWF released from platelets, as well as by exogenous large or unusually large vWF multimers, requires adenosine diphosphate, and is resistant to aspirin. , 1988, Blood.

[8]  M. Hanefeld,et al.  Postchallenge plasma glucose and glycemic spikes are more strongly associated with atherosclerosis than fasting glucose or HbA1c level. , 2000, Diabetes care.

[9]  G. FitzGerald,et al.  Analysis of prostacyclin and thromboxane biosynthesis in cardiovascular disease. , 1983, Circulation.

[10]  K. Pasi,et al.  Qualitative and quantitative abnormalities of von Willebrand antigen in patients with diabetes mellitus. , 1990, Thrombosis research.

[11]  A. Lazzarin,et al.  Interferon-Alpha Is Effective in the Treatment of HIV-1Related, Severe, Zidovudine-Resistant Thrombocytopenia: A Prospective, Placebo-controlled, Double-Blind Trial , 1994, Annals of Internal Medicine.

[12]  P. Reaven,et al.  Cardiovascular disease in diabetes mellitus type 2: a potential role for novel cardiovascular risk factors , 2000, Current opinion in lipidology.

[13]  G. Davı̀,et al.  In vivo formation of 8-iso-prostaglandin f2alpha and platelet activation in diabetes mellitus: effects of improved metabolic control and vitamin E supplementation. , 1999, Circulation.

[14]  D. Reed,et al.  Postchallenge Glucose Concentration and Coronary Heart Disease in Men of Japanese Ancestry: Honolulu Heart Program , 1987, Diabetes.

[15]  P. Halushka,et al.  Increased platelet thromboxane synthesis in diabetes mellitus. , 1981, The Journal of laboratory and clinical medicine.

[16]  H. Gerstein,et al.  Stress Hyperglycemia and Prognosis of Stroke in Nondiabetic and Diabetic Patients: A Systematic Overview , 2001, Stroke.

[17]  N. Savion,et al.  Shear-induced platelet adhesion and aggregation on subendothelium are increased in diabetic patients. , 1998, Thrombosis research.

[18]  A. Sala,et al.  Proteolysis of von Willebrand Factor and Shear Stress–Induced Platelet Aggregation in Patients With Aortic Valve Stenosis , 2000, Circulation.

[19]  Z. Ruggeri.  Mechanisms Initiating Platelet Thrombus Formation , 1997, Thrombosis and Haemostasis.

[20]  M. Kenward,et al.  Design and Analysis of Cross-Over Trials , 1989 .

[21]  C. Abrams,et al.  Direct detection of activated platelets and platelet-derived microparticles in humans. , 1990, Blood.

[22]  G. Davı̀,et al.  In Vivo Formation of 8-Iso-Prostaglandin F2α and Platelet Activation in Diabetes Mellitus , 1999 .

[23]  K. Polonsky,et al.  Abnormal patterns of insulin secretion in non-insulin-dependent diabetes mellitus. , 1988, The New England journal of medicine.

[24]  J. Schapiro,et al.  Platelet hyperreactivity and prognosis in survivors of myocardial infarction. , 1990, The New England journal of medicine.

[25]  Increased binding of fibrinogen to platelets in diabetes: the role of prostaglandins and thromboxane. , 1985 .

[26]  J. Willerson.  Conversion from chronic to acute coronary heart disease syndromes. Role of platelets and platelet products. , 1995, Texas Heart Institute journal.

[27]  D L Horwitz,et al.  Determination of Free and Total Insulin and C-Peptide in Insulin-treated Diabetics , 1977, Diabetes.

[28]  G. Davı̀,et al.  Platelet Activation Markers in Patients with Peripheral Arterial Disease , 1997, Thrombosis and Haemostasis.

[29]  F. Gries,et al.  Platelets in Diabetes: The Role in the Hemostatic Regulation in Atherosclerosis , 1993, Seminars in thrombosis and hemostasis.

[30]  J. O'brien,et al.  Shear stress activation of platelet glycoprotein IIb/IIIa plus von Willebrand factor causes aggregation: filter blockage and the long bleeding time in von Willebrand's disease , 1987 .

[31]  G. Davı̀,et al.  Thromboxane biosynthesis and platelet function in type II diabetes mellitus. , 1990, The New England journal of medicine.

[32]  J. Loscalzo,et al.  A perspective on the potential problems with aspirin as an antithrombotic agent: a comparison of studies in an animal model with clinical trials. , 1999, Journal of the American College of Cardiology.

[33]  A. Orlacchio,et al.  Platelets Release their Lysosomal Content In Vivo in Humans upon Activation , 2000, Thrombosis and Haemostasis.

[34]  Classification and diagnosis of diabetes mellitus and other categories of glucose intolerance. National Diabetes Data Group. , 1979, Diabetes.

[35]  E. Feskens,et al.  Glucose tolerance and mortality: comparison of WHO and American Diabetic Association diagnostic criteria , 1999, The Lancet.

[36]  V. Fuster,et al.  The pathogenesis of coronary artery disease and the acute coronary syndromes (2). , 1992, The New England journal of medicine.

[37]  P. Brunetti,et al.  Effects of Recent, Short-Term Hyperglycemia on Responses to Hypoglycemia in Humans: Relevance to the Pathogenesis of Hypoglycemia Unawareness and Hyperglycemia-Induced Insulin Resistance , 1995, Diabetes.

[38]  G. FitzGerald,et al.  Radioimmunoassay of 11-dehydrothromboxane B2 in human plasma and urine. , 1987, Biochimica et biophysica acta.

[39]  K. Kario,et al.  Hyperinsulinemia and hemostatic abnormalities are associated with silent lacunar cerebral infarcts in elderly hypertensive subjects. , 2001, Journal of the American College of Cardiology.

[40]  Joseph Loscalzo,et al.  Thrombosis and Hemorrhage , 2002 .

[41]  G. Davı̀,et al.  Diabetes mellitus, hypercholesterolemia, and hypertension but not vascular disease per se are associated with persistent platelet activation in vivo. Evidence derived from the study of peripheral arterial disease. , 1997, Circulation.

[42]  P. Winocour.  Platelet Abnormalities in Diabetes Mellitus , 1992, Diabetes.

[43]  W. Kannel,et al.  Diabetes and cardiovascular disease. The Framingham study. , 1979, JAMA.