Abstract
Purpose
Dyslipidemia is common in type 2 diabetes (T2D) and contributes to cardiovascular disease (CVD) by exacerbating atherosclerosis and hypercoagulability. Statins can stabilize atherosclerotic plaque and reduce prothrombotic status. In the present study we aimed to evaluate the coagulation activity and the effect of statins on procoagulant state of T2D patients using a novel activated protein C (APC)-dependent thrombin-generation assay.
Methods
Procoagulant status (by HemosIL ThromboPath (ThP) assay) and in vivo platelet activation (by plasma soluble (s)CD40L levels) were analyzed in a retrospective, cross-sectional study of 198 patients with long-standing T2D and 198 controls.
Results
Procoagulant status of T2D patients was enhanced when compared to control subjects (p < 0.0001). Similarly, sCD40L levels were increased in T2D (p < 0.0001). When testing ThP as the dependent variable in a multivariate regression model, sCD40L (p < 0.0001) and statin treatment (p = 0.019) were independent predictors of the procoagulant state of T2D patients. Subgroup analysis showed a significant improvement of coagulability in T2D patients on statins (p = 0.012).
Conclusions
The use of a standardized, easy-to-run, and commercially available APC-dependent thrombin-generation assay detected the presence of a procoagulant status in a large series of patients with long-standing T2D and demonstrated a significant impact of statins in the coagulation status of patients with T2D.
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References
Krentz AJ. Lipoprotein abnormalities and their consequences for patients with type 2 diabetes. Diabetes Obes Metab. 2003;5:S19–27.
Mottillo S, Filion KB, Genest J, Joseph L, Pilote L, Poirier P, et al. The metabolic syndrome and cardiovascular risk a systematic review and meta-analysis. J Am Coll Cardiol. 2010;56:1113–32.
Ferroni P, Basili S, Falco A, Davi G. Platelet activation in type 2 diabetes mellitus. J Thromb Haemost. 2004;2:1282–91.
Beckman JA, Creager MA, Libby P. Diabetes and atherosclerosis: epidemiology, pathophysiology, and management. JAMA. 2002;287:2570–81.
Tripodi A, Branchi A, Chantarangkul V, Clerici M, Merati G, Artoni A, et al. Hypercoagulability in patients with type 2 diabetes mellitus detected by a thrombin generation assay. J Thromb Thrombolysis. 2011;31:165–72.
Palomo I, Alarcon M, Moore-Carrasco R, Argiles JM. Hemostasis alterations in metabolic syndrome (review). Int J Mol Med. 2006;18:969–74.
Rubba P. Effects of atorvastatin on the different phases of atherogenesis. Drugs. 2007;67:17–27.
Ludwig S, Shen GX. Statins for diabetic cardiovascular complications. Curr Vasc Pharmacol. 2006;4:245–51.
Guadagni F, Albertini G, Barbanti P, Volterrani M, Palma E, Lancia A, et al. Foundation and Organization of a high-throughput technology-based Multidisciplinary and InterInstitutional Biobank at the IRCCS San Raffaele Pisana. Biopreserv Biobanking. 2010;7:201–2.
Guadagni F, Spila A, Nanni U, Somma P, Perrone V, De Angelis F, et al. Automated processing of biological samples. The experience of the InterInstitutional Multidisciplinary Biobank (BioBIM). Biopreserv Biobanking. 2010;7:230–1.
Wlodarczyk J, Sullivan D, Smith M. Comparison of benefits and risks of rosuvastatin versus atorvastatin from a meta-analysis of head-to-head randomized controlled trials. Am J Cardiol. 2008;102:1654–62.
Nicholls SJ, Brandrup-Wognsen G, Palmer M, Barter PJ. Meta-analysis of comparative efficacy of increasing dose of Atorvastatin versus Rosuvastatin versus Simvastatin on lowering levels of atherogenic lipids (from VOYAGER). Am J Cardiol. 2010;105:69–76.
Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation. 2002; 106:3143–421.
Riondino S, Martini F, La Farina F, Spila A, Guadagni F, Ferroni P. Increased plasma levels of soluble CD40 ligand correlate with platelet activation markers and underline the need for standardized pre-analytical conditions. Clin Biochem. 2010;43:666–70.
Toulon P, Smirnov M, Triscott M, Safa O, Biguzzi E, Bouziane K, et al. A new chromogenic assay (HemosIL ThromboPath) is sensitive to major prothrombotic risk factors affecting the protein C pathway. Results of a multicenter study. Thromb Res. 2009;124:137–43.
Adeghate E, Schattner P, Dunn E. An update on the etiology and epidemiology of diabetes mellitus. Ann NY Acad Sci. 2006;1084:1–29.
Ferroni P, La Farina F, Palmirotta R, Martini F, Raparelli V, Nigro C, et al. Predictive value of thrombopath determination in women with pregnancy complications. Clin Chim Acta. 2010;411:37–42.
Tripodi A, Legnani C, Lemma L, Cosmi B, Palareti G, Chantarangkul V, et al. Abnormal Protac-induced coagulation inhibition chromogenic assay results are associated with an increased risk of recurrent venous thromboembolism. J Thromb Thrombolysis. 2010;30:215–9.
De Stefano V, Finazzi G, Mannucci PM. Inherited thrombophilia: pathogenesis, clinical syndromes, and management. Blood. 1996;87:3531–44.
Krentz A. Type 2 diabetes and atherosclerotic cardiovascular disease: do they share common antecedents? Br J Diabetes Vasc Dis. 2002;2:370–8.
Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998; 352:837–53.
Gerstein HC, Miller ME, Byington RP, Goff Jr DC, Bigger JT, Buse JB, et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008;358:2545–59.
Patel A, MacMahon S, Chalmers J, Neal B, Billot L, Woodward M, et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008;358:2560–72.
Duckworth W, Abraira C, Moritz T, Reda D, Emanuele N, Reaven PD, et al. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med. 2009;360:129–39.
Colhoun HM, Thomason MJ, Mackness MI, Maton SM, Betteridge DJ, Durrington PN, et al. Design of the Collaborative AtoRvastatin Diabetes Study (CARDS) in patients with type 2 diabetes. Diabet Med. 2002;19:201–11.
Vasudevan MM, Ballantyne CM. Advances in lipid testing and management in patients with diabetes mellitus. Endocr Pract. 2009;15:641–52.
Ceriello A, Quatraro A, Marchi E, Barbanti M, Dello Russo P, Lefebvre P, et al. The role of hyperglycaemia-induced alterations of antithrombin III and factor X activation in the thrombin hyperactivity of diabetes mellitus. Diabet Med. 1990;7:343–8.
Sauls DL, Banini AE, Boyd LC, Hoffman M. Elevated prothrombin level and shortened clotting times in subjects with type 2 diabetes. J Thromb Haemost. 2007;5:638–9.
Santilli F, Davi G, Consoli A, Cipollone F, Mezzetti A, Falco A, et al. Thromboxane-dependent CD40 ligand release in type 2 diabetes mellitus. J Am Coll Cardiol. 2006;47:391–7.
Lim HS, Blann AD, Lip GY. Soluble CD40 ligand, soluble P-selectin, interleukin-6, and tissue factor in diabetes mellitus: relationships to cardiovascular disease and risk factor intervention. Circulation. 2004;109:2524–8.
Varo N, Libby P, Nuzzo R, Italiano J, Doria A, Schönbeck U. Elevated release of sCD40L from platelets of diabetic patients by thrombin, glucose and advanced glycation end products. Diab Vasc Dis Res. 2005;2:81–7.
Neubauer H, Setiadi P, Günesdogan B, Pinto A, Börgel J, Mügge A. Influence of glycaemic control on platelet bound CD40-CD40L system, P-selectin and soluble CD40 ligand in Type 2 diabetes. Diabet Med. 2010;27:384–90.
Bláha V, Andrýs C, Smahelová A, Knízek J, Hyspler R, Solichová D, et al. Effect of atorvastatin on soluble CD14, CD40 Ligand, sE- and sP-selectins and MCP-1 in patients with type 2 diabetes mellitus: relationship to cholesterol turnover. Pharmacol Res. 2006;54:421–8.
Varo N, Vicent D, Libby P, Nuzzo R, Calle-Pascual AL, Bernal MR, et al. Elevated plasma levels of the atherogenic mediator soluble CD40 ligand in diabetic patients: a novel target of thiazolidinediones. Circulation. 2003;107:2664–9.
Santini E, Madec S, Corretti V, Ferrannini E, Solini A. Effect of statins on soluble CD40 ligand in hypercholesterolemic Type 2 diabetic patients. J Endocrinol Invest. 2008;31:660–5.
Kinlay S, Schwartz GG, Olsson AG, Rifai N, Sasiela WJ, Szarek M, et al. Effect of atorvastatin on risk of recurrent cardiovascular events after an acute coronary syndrome associated with high soluble CD40 ligand in the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) Study. Circulation. 2004;110:386–91.
Jaumdally RJ, Lip GY, Varma C, Blann AD. Impact of high-dose atorvastatin on endothelial, platelet, and angiogenic indices: effect of ethnicity, cardiovascular disease, and diabetes. Angiology. 2011;62:571–8.
Kannel WB. Overview of atherosclerosis. Clin Ther. 1998;20:B2–B17.
Undas A, Brummel-Ziedins KE, Mann KG. Statins and blood coagulation. Arterioscler Thromb Vasc Biol. 2005;25:287–94.
Arnaboldi L, Corsini A. Do structural differences in statins correlate with clinical efficacy? Curr Opin Lipidol. 2010;21:298–304.
Kearney PM, Blackwell L, Collins R, Keech A, Simes J, Peto R, et al. Efficacy of cholesterol-lowering therapy in 18,686 people with diabetes in 14 randomised trials of statins: a meta-analysis. Lancet. 2008;371:117–25.
Avogaro A, Guida P, Giorda C, Mannucci E, Medea G, Comaschi M, et al. The under-use of statin in type 2 diabetic patients attending diabetic clinics in Italy. Nutr Metab Cardiovasc Dis. 2007;17:32–40.
Kumar A, Singh V. Atherogenic dyslipidemia and diabetes mellitus: what’s new in the management arena? Vasc Health. Risk Manag. 2010;6:665–9.
Acknowledgments
This work was partially supported by the Italian Ministry of Health Grant ACC-WP 3/1b and MERIT RBNE08NKH7. The authors wish to thank Francesco De Angelis and Vincenzino Perrone (InterInstitutional Multidisciplinary BioBank, Department of Laboratory Medicine and Advanced Biotechnologies, IRCCS San Raffaele, Rome, Italy), for their excellent technical assistance.
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The authors declare that they have no conflict of interest.
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Ferroni, P., Della-Morte, D., Pileggi, A. et al. Impact of Statins on the Coagulation Status of Type 2 Diabetes Patients Evaluated by a Novel Thrombin-Generation Assay. Cardiovasc Drugs Ther 26, 301–309 (2012). https://doi.org/10.1007/s10557-012-6388-y
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DOI: https://doi.org/10.1007/s10557-012-6388-y