Abstract
The prevalence of type 2 diabetes mellitus (T2DM) has quadrupled within three decades since 1980, affecting 422 million adults in 2016. It remains one of the most common noncommunicable chronic diseases and the underlying risk factor for cardiovascular diseases worldwide. There are different underlying mechanisms that play a role in the development of pathologies associated with the disease such as hyperglycaemia, oxidative stress, obesity, inflammation and hypercoagulation; each of which are interlinked. Hyperglycaemia, oxidative stress and obesity play a huge role in the activation of inflammation and coagulation. Activation of inflammatory pathways increases the production of thrombin which predisposes the development of thrombotic related diseases. One of the factors that contribute to the increase of thrombin is the impairment of the fibrinolysis process due to decreased expression of tissue-plasminogen activator (tPA) by increased levels of plasminogen activator inhibitor-1 (PAI-1). Coagulation factor XIII (FXIII), a transglutaminase that is composed of subunits A and B (FXIII-A2B2), is essential for the last step of fibrin clot formation in the coagulation pathway. Genetic variation of FXIII-A in the form of single nucleotide polymorphisms (SNPs) alters the activity of FXIII, altering clot properties which influence disease outcomes. This review discusses the link between underlying mechanisms of T2DM, well known FXIII-A variants and coagulation.
Keywords: Type 2 diabetes mellitus, coagulation, factor XIII, single nucleotide polymorphisms, pathological, mechanisms.
[3]
Soma P, Pretorius E. Interplay between ultrastructural findings and atherothrombotic complications in type 2 diabetes mellitus. Cardiovasc Diabetol 2015; 14: 96.
[4]
Pretorius E. Precision medicine and a patient-orientated approach: Is this the future for tracking cardiovascular disorders? Curr Pharm Des 2017; 23(6): 889-93.
[5]
Pretorius E, Bester J, Vermeulen N, et al. Poorly controlled type 2 diabetes is accompanied by significant morphological and ultrastructural changes in both erythrocytes and in thrombin-generated fibrin: Implications for diagnostics. Cardiovasc Diabetol 2015; 14: 30.
[6]
Soma P, Swanepoel AC, du Plooy JN, Mqoco T, Pretorius E. Flow cytometric analysis of platelets type 2 diabetes mellitus reveals ‘angry’ platelets. Cardiovasc Diabetol 2016; 15(1): 52.
[7]
Pretorius E. Mechanisms of hypercoagulation and aberrant clot
lyses in type 2 diabetes. In: Kartha CRS, Pillai R, Eds. Mechanisms of Vascular Defects in Diabetes Mellitus: Springer, Cham. 2017.
[8]
Dooley J, Tian L, Schonefelt S, et al. Genetic predisposition for beta cell fragility under type 1 and type 2 diabetes. Nat Genet 2016; 48(5): 519-27.
[9]
Bonnefond A, Froguel P. Rare and common genetic events in type 2 diabetes: What should biologiest know? Cell Metab 2015; 21: 357-68.
[10]
Bonnefond A, Clement N, Fawcett K, et al. Meta-Analysis of Glucose and Insulin-Related Traits Consortium (MAGIC). Rare MNTR1B variants imparing melatonin receptor 1B function contributes to type 2 diabetes. Nat Genet 2012; 44: 297-301.
[11]
Barroso I, Luan J, Middelberg RPS, et al. Candidate gene association study in type 2 diabetes indicates a role for genes involved in beta-cell function as well as insulin action. PLoS Biol 2003; 1: 41-55.
[12]
Stumvoll M. Control of glycaemia: Form molecules of men. Minkowski Lecture 2003. Diabetologia 2004; 47: 770-81.
[13]
Du M, Prescott J, Cornelis MC, et al. Genetic predisposition to high body mass index or type 2 diabetes and leukocytes telomere length in the nurses' health study. PLoS One 2013 ; 8 (2) e52240.
[http://dx.doi.org/10. 1371/journal.pone.0052240.]
[http://dx.doi.org/10. 1371/journal.pone.0052240.]
[14]
Njajou OTCR, Blackburn EH, Harris TB, et al. Shorter telomeres are associated with obesity and weight gain in the elderly. IJO 2011; 36(9): 1176.
[15]
Xia C, Rao X, Zhong J. Role of T lymphocytes in type 2 diabetes and diabetes-associated inflammation. J Diabetes Res 2017; 2017: 1-7.
[http://dx.doi.org/10.1155/2017/6494795]
[http://dx.doi.org/10.1155/2017/6494795]
[16]
Esser NL-PS, Piette J, Scheen AJ, Paquot N. Inflammation as a link between obesity, metabolic syndrome and type 2 diabetes. Diabetes Res Clin Pract 2014; 105(2): 141-50.
[17]
Abouzeid S, Sherif N. Role of alteration in Treg/Th17 cells balance in nephropathic patients with Type 2 diabetes mellitus. Electron Phys 2015; 7(8): 1613-8.
[18]
Guzm’an-Flores JM, Portales-P’erez DP. Mechanisms of suppression by regulatory T cells (Treg). Gac Med Mex 2013; 149(6): 630-8.
[19]
Jagannathan-Bogdan M, McDonnell ME, Shine H, et al. Elevated proinflammatory cytokine production by a skewed T cell compartment requires monocytes and promotes inflammation in type 2 diabetes. J Immunol 2011; 186(2): 1162-72.
[20]
Zeng L, Lu H, Deng H, Mu P, Li X, Wang M. Noninferiority effects on glycemic control and B-cell functionn improvement in newly diagnosed type 2 diabetes patients: Basal insulin monotherapy versus continous subcutaneous insulin infusion treatment. Diabetes Technol Ther 2012; 14(1): 35-42.
[21]
Jenne CN, Urrutia R, Kubes P. Platelets: bridging hemostais, inflammation, and immuity. Lab Hematol 2013; 35: 254-61.
[22]
Pieter M, Covie N, Loots du T, et al. The effect of glycaemic control on fibrin network structure of type 2 diabetes subjects. Thromb Haemost 2006; 96: 623-39.
[23]
Lim BC, Ariens RA, Carter AM, Weisel JW, Grant PJ. Genetic regulation of fibrin structure and function: Complex gene-environment interactions may modulate vascular risk. Lancet 2003; 361(9367): 1424-31.
[24]
Schoelson SV, Lee S, Goldfine AB. Inflammation and insulin resistance. J Clin Invest 2006; 116(7): 1793-801.
[25]
Aguirre V, Uchida T, Yenush LDR, White MF. The c-June N-terminal kinase promotes insulin resistance during association with insulin receptor substrate-1 and phosphorylation of ser(307). J Biol Chem 2000; 275: 9047-54.
[27]
Ozcan U. Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science 2004; 306: 457-61.
[28]
Aguirre V. Phosphorylation of Ser307 in insulin receptor substrate-1 blocks interactions with the insulin receptor and inhibits insulin action. J Biol Chem 2002; 277: 1531-7.
[29]
Werner ED, Lee J, Hansen L, Yuan M, Shoelson SE. Insulin resistance due to phosphyralation of insulin receptor substrate-1 at serin 302. J Biol Chem 2004; 279: 35298-305.
[30]
Goldberg RG. Cytokines and cytokine-like inflammation markers, endothelial dysfunction and imbalanced coagulation development of diabetes and its complication. J Clin Endocrinol Metab 2009; 94(9): 3171-82.
[31]
Mazzon T, Chait A, Plutzky J. Addressing cardiovascular disease risk in diabetes: Insights from mechanistic studies. Lancet 2008; 371(9626): 1800-9.
[32]
Tangvarasittichai S. Oxidative stress, insulin resistance, dyslipidemia and type 2 diabetes mellitus. World J Diabetes 2015; 6(3): 456-80.
[33]
Domingueti CP, Dusse LMSA. das Gracas Carvalho M, de Sousa LP, Gomes LB, Fernandes AP. Diabetes Mellitus: The linkage between oxidative stress, inflammation, hypercoagulability and vascular complications. J Diabetes Complications 2016; 30: 738-45.
[34]
Lemkes BA, Hermanides J, DeVries JH, Holleman F, Meijers JC, Hoekstra JB. Hyperglycemia: A prothrombotic factor? J Thromb Haemost 2010; 8: 1663-9.
[35]
Vink H, Constantinescu AA, Spaan JA. Oxidized lipoproteins degrade the endothelial surface layer: Implications for platelet-endothelial cell adhesion. Circulation 2000; 101: 1500-2.
[36]
Paneni F, Beckman JA, Creager MA, Cosentino F. Diabetes and vascular disease: pathophysiology, clinical consequences, and medical therapy: part 1. Eur Heart J 2013; 34: 2436-46.
[37]
Behl T, Velpandian T, Kotwani A. Role of altered coagulation-fibrinolytic system in the pathophysiology of diabetic retinopathy. Vascul Pharmacol 2017; 92: 1-5.
[38]
Verkleij CJ, Gerdes VE, de Bruijn R, Meijers JC, Marx PF. The hemostatic system in pateints with and without cardiovascular disease. J Thromb Haemost 2009; 7(Suppl. 2).WE-336
[39]
Grant PJ. Diabetes mellitus as a prothrombotic condition. (Review). J Intern Med 2007; 262: 157-72.
[40]
Reusch JEB. Current concepts in insulin resistance, type 2 diabetes mellitus, and the metabolic syndrome. Am J Cardiol 2002; 90(Suppl.): 19G-26G.
[41]
Kearney KT. D; Smith, K; Ajjan, R. Hypofibrinolysis in diabetes: A therapeutic target for the reduction of cardiovascular risk. Cardiovasc Diabetol 2017; 16(1): 34.
[42]
Meltzer MELT, de Groot PG, Meijers JC, le Cessie S, Doggen CJ, Rosendaal FR. Venous thrombosis risk associated with plasma hypofibrinolysis is explained by elevated plasma levels of TAFI and PAI-1. Blood 2010; 116(1): 113-21.
[43]
Brouwers GJ, Leebeek FW, Tanck MW, Wouter JJ, Kluft C, de Maat MP. Association between thrombin-activatable fibrinolysis inhibitor (TAFI) and clinical outcome in patients with unstable angina pectoris. Thromb Haemost 2003; 90(1): 92-100.
[44]
Montaner J, Ribó M, Monasterio J, Molina CA, Alvarez-Sabín J. Thrombin- activable fibrinolysis inhibitor levels in the acute phase of ischemic stroke. Stroke 2003; 34(4): 1038-40.
[45]
van Tilburg NH, Rosendaal FR, Bertina RM. Thrombin activatable fibrinolysis inhibitor and the risk for deep vein thrombosis. Blood 2000; 95(9): 2855-9.
[46]
Leenaerts D, Bosmans JM, van der Veken P, Sim Y, Lambeir AM, Hendriks D. Plasma levels of carboxypeptidase U (CPU, CPB2 or TAFIa) are elevated in patients with acute myocardial infarction. J Thromb Haemost 2015; 13(12): 2227-32.
[47]
Martín-Timón I, Sevillano-Collantes C, Marín-Peñalver JJ, del Cañizo-Gómez FJ. Management of cardiovascular risk factors in type 2 diabetes mellitus patients. EMJ 2016; 1(4): 89-97.
[48]
Zheng NS, Chen X, Lv XW. Associations between inflammatory markers, hemostatic markers, and microvascular complications in 182 chinese patients with type 2 diabetes mellitus. Lab Med Summer 2015; 46(3): 214-20.
[49]
Alzahrani SH, Ajjan RA. Coagulation and fibrinolysis in diabetes. Diab Vasc Dis Res 2010; 7(4): 260-73.
[50]
Erem C, Hacihasanoğlu A, Celik S. Coagulation and fibrinolysis parameters in type 2 diabetic patients with and without diabetic vascular complications. Med Princ Pract 2005; 14(1): 22-30.
[51]
Ceriello AGD, Quatraro A. Induced hyperglycaemia alters antithrombin III activity but not its plasma concentration in healthy normal subjects. Diabetes 1987; 36: 320-3.
[52]
Caccamo N, Dieli F. Inflammation and the coagulation system in tuberculosis: Tissue Factor leads the dance. Eur J Immunol 2016; 46(2): 303-6.
[53]
King GJ, Grant PJ. Diabetes and cardiovascular diseasee: pathophysiology of a life-threatening epidemic. Herz 2016; 41(3): 184-92.
[54]
Gaiz A, Mosawy S, Colson N, Singh I. Thrombotic and cardiovascular risk in type two diabetes; Role of platelets hyperactivity. Biomed Pharmacother 2017; 94: 679-86.
[55]
Santhakumar AB, Bulmer AC, Singh A. A review of the mechanisms and effectiveness of diatery polyphenols in reducing oxidative stress and thrombotic risk. J Hum Nutr Diet 2014; 27(1): 1-21.
[56]
Gawaz M, Ott I, Reininger A, Neumann F. Effects of magnesium of platelets aggregation and adhesion. Magnesium modulates surface expression of glycoproteins on platelets in vitro and ex vivo. Thromb Haemost 1994; 72(6): 912-6.
[57]
Weidmann N, Heikaus L, Long AT, Naudin C, Schluter H, Renne T. The plasma contact system, a protease cascade at the nexus of inflammation, coagultion and immunity. BBA-Mol Cell Res 2017; 1864: 2118-27.
[58]
Jerrey IW. Factor XI and Factor XII as targets for new anticoagulants. Thromb Res 2016; 1415s2: s40-5..
[59]
Antoniak S, Mackman N. Editorial commentary: Tissue factor expression by the endothelium: Coagulation or inflammation. Trends Cardiovasc Med 2016; 29: 304-5.
[60]
Kim KH, Kim JE, Parks SH, Kim YI, Nam-Goong IS, Kim ES. High coagulation factors levels and low protein C levels contributes to enhanced thrombin generation in pateints with diabetes who do not have macrovascular complications. J Diabet Complications 2014; 28: 365-9.
[61]
Kool RO, Kohler HP, Coutiinho JM. meijers CM, Schroedor V. Coagulation factor XIII-A subunit and activation peptide levels in individuals with estabilished symptomatic acute deep vein thrombosis. Thromb Res 2017; 159: 96-9.
[62]
Pitkanen HH, Jouppila A, Lemponen M, Ilmakunnas M, Ahonen J, Lassila R. Factor XIII deficiency enhances thrombin generation due to impaired fibrin polymerization-An effect corrected by Factor XIII replacement. Thromb Res 2017; 149: 56-61.
[63]
Frazer KA, Murray SS, Schork NJ, Topol EJ. Human genetic variation and its contribution to complex traits. Nat Rev Genet 2009; 10(4): 241-51.
[65]
Paul DS, Soranzo N, Beck S. Functional interpretation of non-coding sequence variation: concepts and challenges. BioEssays 2014; 36(2): 191-9.
[66]
Tinholt M, Sandset PM, Inversen N. Polymorphisms of the coagulation system and risk of cancer. Thromb Res 2016; 140s1: s49-s54..
[67]
Uitte de Willige S, de Visser MC, Houwing-Duistermaat JJ, Rosendaal FR, Vos HL, Bertina RM. Genetic variaton in the fibrionoen gamma gene increases the risk for deep venous thrombosis by reducing plasma fibrinogen gamma’ levels. Blood 2005; 106: 4176-83.
[68]
Van Hylckma Vlieg A, Komanasin N, Ariens RA, et al. Factor XIII Val34Leu polymorphism, factor XIII antigen levels and activity and the risk of deep venous thrombosis. Br J Haematol 2002; 119: 169-75.
[69]
Mezei ZA, Katona E, Kallai J, et al. Factor XIII levels and factor XIII B subunits polymorphisms in patients with venous thromboembolism. Thromb Res 2017; 158: 93-7.
[70]
Wartiovaara U, Mikkola H, Szoke G, et al. Effect of Val34Leu polymorphism on the activation of the coagulation factor XIII-A. Thromb Haemost 2000; 84(4): 595-600.
[71]
Komanasin N, Catto AJ, Futers TS, et al. A novel polymorphism in the factor XIII B-subunit (His95Arg): Relationship to subunit dissociation and venous thrombosis. J Thromb Haemost 2005; 3(11): 2487-96.
[72]
Iwata H, Kitano T, Umetsu K, et al. Distinct C-terminus of the B subunit of factor XIII in a population associated major phenoty: the first case of complete allele-specific alternative spliing products in the coagulation and fibrinolytic systems. J Throm Haemost 2009; 7(7): 1084-91.
[73]
Consortium GP, Auton A, Brooks LD, et al. A global reference for human genetic variation. Nature 2015; 526(7571): 68-74.
[74]
Reiner APHS, Vos HL, Ariëns RA, et al. Genetic variants of coagultion factors XIII, postmenopausal estrogen therapy and the riskof nonfatal myocardial infarction. Blood 2003; 102(1): 25-30.
[75]
Jung JH, Kim J, Song GG, Choi SJ. Association of F13A Val34Leu polymorphism and recurrent pregnancy loss: A meta-analysis. Eur J Obstet Gynecol Reprod Biol 2017; 215: 234-40.
[76]
Weger W, Renner W, Stanger O, et al. Role of factor XIII Val34Leu polymorphism in retinal artery occlusion. Stroke 2001; 32(12): 2759-61.
[77]
Catto AJ, Kohler HP, Coore J, Mansfield MW, Stickland MH, Grant PJ. Association of a common polymorphism in the factor XIII gene with venous thrombosis. Blood 1999; 93: 906-8.
[78]
Fransco RF, Reitsma PH, Lourenco D, et al. Factor XIII Val43Leu is a genetic factor involved in the aeitology of venous thrombosis. Thromb Haemost 1999; 81(5): 676-9.
[79]
Elbaz A, Poirier O, Canaple S, Chedru F, Amarenco P. The association between the Val34Leu polymorphism in the factor XIII gene and brain infarction. Blood 2000; 95(2): 586-91.
[80]
Corral J, Gonzalez-Conejero R, Iniesta JA, Rivera J, Martinez C, Vicente V. The FXIII Val34Leu polymorphism in venous and arterial thromboembolism. Haematologia 2000; 85(3): 293-7.
[81]
Franco RF, Pazin-Filho A, Tavella MH, Simoes MV, Martin-Neto JA, Zago MA. Factor XIII Val43Leu and the risk of myocardial infarction. Haematologia 2000; 85(1): 67-71.
[82]
Sajjadi SM, Khoravi A, Pakravesh J, et al. Factor XIII Val34Leu polymorphism and risk of recurrent pregnancy loss in Iranian population:a case control study. Front Biol 2016; 11(6): 471-5.
[83]
Kreutz RP, Bitar A, Owens J, et al. Factor XIII Val34Leu polymorphism and recurrent myocardial infarction in patients with coronary artery disease. J Thromb Thrombolysis 2014; 38(3): 380-7.
[84]
Ye X, Ye B. Association between the Val34Leu polymorphism blood coagulation factor XIII-A and intracerebral hemorrhage: a meta-analysis. Genet Mol Res 2016; 15(3)15038327
[85]
Ma J, Li H, You C, Liu Y, Ma L, et al. Blood coagulation factor XIII-A subunit Val34Leu polymorphisms and intracerebral hemorrhage risk: A meta-analysis. Br J Neurosurg 2015; 29(5): 672-7.
[86]
Naderi M, Dorgalaleh A, Tabibian S, Eshgh P, Bamed T, Alizadeh S. Association Between Val34Leu polymorphism and risk of umbilical cord bleeding in severe congenital coagultion factor xiii deficiency in southeast of Iran. Gene Cell Tissue 2014; 1(1)e18360
[87]
Gemmati D, Serino ML, Ongaro A, et al. A common mutation in the gene for coagulation factor XIII-A (Val34Leu): A risk factor for primary intracerebral hemorrage is protective against atherombotic diseases. Am J Hematol 2001; 67: 183-8.
[88]
de Lange M, Andrew T, Snieder H, et al. Joint linkage and association of six single-nucleotide polymorphisms in the factor xiii-a subunit gene point to V34L as the main functional locus. Aterioscler Thromb Vasc Biol 2006; 26: 1914-9.
[89]
Hancer VS, Diz-Kuckkaya R, Bilge AK, et al. The association between factor XIII Val34Leu polymorphism and early myocardial infarction. Circ J 2006; 70: 239-42.
[90]
Ariens RAA, Philippou H, Nagaswami C, Weisel JW, Lane DA, Grant PJ. The factor XIII V34L polymorphism accelerates thrombin activation of factor XIII and affects cross-linked fibrin structure. Blood 2000; 96(3): 988-95.
[91]
Naderi M, Tabibian S, Alizadeh S, Abtahi ZS, Dorgalaleh A. Coagulation factor XIII-A A614T gene variation is suggestive of founder effect in iranian patients with sever congenital factor XIII deficiency. JCMA 2016; 1(1): 19-22.
[92]
Reiner AP, Schwarts SM, Frank MB, et al. Polymorphisms of coagulation factor XIII subunit a and risk of nonfatal hemorrhagic stroke in young white women. Stroke 2001; 32: 2580-7.
Article Metrics
40
2
1
1