BβArg448Lys polymorphism is associated with altered fibrin clot structure and fibrinolysis in type 2 diabetes

Katie A. Greenhalgh; Mark W. Strachan; Saad Alzahrani; Paul D. Baxter; Kristina F. Standeven; Robert F. Storey; Robert A. S. Ariens; Peter J. Grant; Jackie F. Price; Ramzi A. Ajjan

doi:10.1160/TH16-07-0554

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 2017; 117(02): 295-302
DOI: 10.1160/TH16-07-0554

Coagulation and Fibrinolysis

Schattauer GmbH

BβArg448Lys polymorphism is associated with altered fibrin clot structure and fibrinolysis in type 2 diabetes

Authors

Katie A. Greenhalgh

¹Division of Cardiovascular and Diabetes Research, Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, UK
Mark W. Strachan

²Metabolic Unit, Western General Hospital, Edinburgh, UK
Saad Alzahrani

³Specialised Diabetes and Endocrine Centre, King Fahad Medical City, Riaydh, KSA
Paul D. Baxter

¹Division of Cardiovascular and Diabetes Research, Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, UK
Kristina F. Standeven

¹Division of Cardiovascular and Diabetes Research, Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, UK
Robert F. Storey

⁴Department of Infection, Immunity & Cardiovascular Disease, University of Sheffield, Sheffield, UK
Robert A. S. Ariens

¹Division of Cardiovascular and Diabetes Research, Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, UK
Peter J. Grant

¹Division of Cardiovascular and Diabetes Research, Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, UK
Jackie F. Price^*

⁵Centre for Population Health Sciences, University of Edinburgh, Edinburgh, UK
Ramzi A. Ajjan^*

¹Division of Cardiovascular and Diabetes Research, Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, UK

Abstract

Summary

Both type 2 diabetes (T2DM) and Bß448Lys variant of fibrinogen are associated with dense fibrin clots, impaired fibrinolysis and increased cardiovascular risk. It was our objective to investigate whether BßArg448Lys adds to vascular risk by modulating fibrin network structure and/or fibrinolysis in diabetes. The primary aim was to study effects of BßArg448Lys on fibrin network characteristics in T2DM. Secondary aims investigated interactions between gender and BßArg448Lys substitution in relation to fibrin clot properties and vascular disease. Genotyping for BßArg448Lys and dynamic clot studies were carried out on 822 T2DM patients enrolled in the Edinburgh Type 2 Diabetes Study. Turbidimetric assays of individual plasma samples analysed fibrin clot characteristics with additional experiments conducted on clots made from purified fibrinogen, further examined by confocal and electron microscopy. Plasma clot lysis time in Bß448Lys was longer than Bß448Arg variant (mean ± SD; 763 ± 322 and 719 ± 351 seconds [s], respectively; p<0.05). Clots made from plasma-purified fibrinogen of individuals with Arg/Arg, Arg/Lys and Lys/Lys genotypes showed differences in fibre thickness (46.75 ± 8.07, 38.40 ± 6.04 and 25 ± 4.99 nm, respectively; p<0.001) and clot lysis time (419 ± 64, 442 ± 87 and 517 ± 65 s, respectively; p=0.02), directly implicating the polymorphism in the observed changes. Women with Bß448Lys genotype had increased risk of cerebrovascular events and were younger compared with Bß448Arg variant (67.2 ± 4.0 and 68.2 ± 4.4 years, respectively; p=0.035). In conclusion, fibrinogen Bβ448Lys variant is associated with thrombotic fibrin clots in diabetes independently of traditional risk factors. Prospective studies are warranted to fully understand the role of BβArg448Lys in predisposition to vascular ischaemia in T2DM with the potential to develop individualised antithrombotic management strategies.

Keywords

Diabetes Mellitus - fibrinogen - genetic polymorphism - thrombosis - vascular diseases

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Referenzen

References
1 Puri R, Kataoka Y, Uno K. et al. The distinctive nature of atherosclerotic vascular disease in diabetes: pathophysiological and morphological insights. Curr Diab Rep 2012; 12: 280-285.
2 Ferreiro JL, Gomez-Hospital JA, Angiolillo DJ. Platelet abnormalities in diabetes mellitus. Diab Vasc Dis Res 2010; 07: 251-259.
3 Alzahrani SH, Ajjan RA. Coagulation and fibrinolysis in diabetes. Diab Vasc Dis Res 2010; 07: 260-273.
4 Mercer BN, Morais S, Cubbon RM. et al. Diabetes mellitus and the heart. Int J Clin Pract 2012; 66: 640-647.
5 Ajjan R, Grant PJ. Coagulation and atherothrombotic disease. Atherosclerosis 2006; 186: 240-259.
6 Kannel WB, D’Agostino RB, Wilson PW. et al. Diabetes, fibrinogen, and risk of cardiovascular disease: the Framingham experience. Am Heart J 1990; 120: 672-676.
7 Pieters M, van Zyl DG, Rheeder P. et al. Glycation of fibrinogen in uncontrolled diabetic patients and the effects of glycaemic control on fibrinogen glycation. Thromb Res 2007; 120: 439-446.
8 Hess K, Alzahrani SH, Mathai M. et al. A novel mechanism for hypofibrinolysis in diabetes: the role of complement C3. Diabetologia 2012; 55: 1103-1113.
9 Ajjan R, Lim BC, Standeven KF. et al. Common variation in the C-terminal region of the fibrinogen beta-chain: effects on fibrin structure, fibrinolysis and clot rigidity. Blood 2008; 111: 643-650.
10 Jorneskog G, Egberg N, Fagrell B. et al. Altered properties of the fibrin gel structure in patients with IDDM. Diabetologia 1996; 39: 1519-1523.
11 Raynaud E, Perez-Martin A, Brun J. et al. Relationships between fibrinogen and insulin resistance. Atherosclerosis 2000; 150: 365-370.
12 Diamant M, Nieuwland R, Pablo RF. et al. Elevated numbers of tissue-factor exposing microparticles correlate with components of the metabolic syndrome in uncomplicated type 2 diabetes mellitus. Circulation 2002; 106: 2442-2447.
13 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.
14 Mansfield MW, Heywood DM, Grant PJ. Circulating levels of factor VII, fibrinogen, and von Willebrand factor and features of insulin resistance in first-degree relatives of patients with NIDDM. Circulation 1996; 94: 2171-2176.
15 Ceriello A, Esposito K, Ihnat M. et al. Simultaneous control of hyperglycemia and oxidative stress normalizes enhanced thrombin generation in type 1 diabetes. J Thromb Haemost 2009; 07: 1228-1230.
16 Dunn EJ, Philippou H, Ariens RA. et al. Molecular mechanisms involved in the resistance of fibrin to clot lysis by plasmin in subjects with type 2 diabetes mellitus. Diabetologia 2006; 49: 1071-1080.
17 Watala C, Pluta J, Golanski J. et al. Increased protein glycation in diabetes mellitus is associated with decreased aspirin-mediated protein acetylation and reduced sensitivity of blood platelets to aspirin. J Mol Med 2005; 83: 148-158.
18 Alzahrani SH, Hess K, Price JF. et al. Gender-specific alterations in fibrin structure function in type 2 diabetes: associations with cardiometabolic and vascular markers. J Clin Endocrinol Metab 2012; 97: E2282-E2287.
19 French JK, Van de Water NS, Sutton TM. et al. Potential thrombophilic mutations/polymorphisms in patients with no flow-limiting stenosis after myocardial infarction. Am Heart J 2003; 145: 118-124.
20 Carter AM, Catto AJ, Bamford JM. et al. Gender-specific associations of the fibrinogen B beta 448 polymorphism, fibrinogen levels, and acute cerebrovascular disease. Arterioscler Thromb Vasc Biol 1997; 17: 589-594.
21 Behague I, Poirier O, Nicaud V. et al. Beta fibrinogen gene polymorphisms are associated with plasma fibrinogen and coronary artery disease in patients with myocardial infarction. The ECTIM Study. Etude Cas-Temoins sur l’Infarctus du Myocarde. Circulation 1996; 93: 440-449.
22 Jacquemin B, Antoniades C, Nyberg F. et al. Common genetic polymorphisms and haplotypes of fibrinogen alpha, beta, and gamma chains affect fibrinogen levels and the response to proinflammatory stimulation in myocardial infarction survivors: the AIRGENE study. J Am Coll Cardiol 2008; 52: 941-952.
23 Price JF, Reynolds RM, Mitchell RJ. et al. The Edinburgh Type 2 Diabetes Study: study protocol. BMC Endocr Disord 2008; 08: 18.
24 Marioni RE, Deary IJ, Murray GD. et al. Genetic associations between fibrinogen and cognitive performance in three Scottish cohorts. Behav Genet 2011; 41: 691-699.
25 Undas A, Kolarz M, Kopec G. et al. Altered fibrin clot properties in patients on long-term haemodialysis: relation to cardiovascular mortality. Nephrol Dial Transplant 2008; 23: 2010-2015.
26 Collet JP, Allali Y, Lesty C. et al. Altered fibrin architecture is associated with hypofibrinolysis and premature coronary atherothrombosis. Arterioscler Thromb Vasc Biol 2006; 26: 2567-2573.
27 Dunn EJ, Ariens RA, Grant PJ. The influence of type 2 diabetes on fibrin structure and function. Diabetologia 2005; 48: 1198-1206.
28 Henschen-Edman AH. Fibrinogen non-inherited heterogeneity and its relationship to function in health and disease. Ann NY Acad Sci 2001; 936: 580-593.