Endothelial Dysfunction and Altered Coagulation As Mediators of Thromboembolism in Behçet Disease

Abstract

Behçet disease (BD) is a rare multisystem, inflammatory disease of unknown etiology with vascular involvement and associated thrombogenicity. This review aims to describe the involvement of various mediators in endothelial cell damage and in the hypercoagulable state of BD. The scenario of the chronic inflammation present in BD shows an increased oxidative condition that contributes to endothelial cell damage and induces platelet, leukocyte, and endothelial cell activation through the release of proinflammatory cytokines and chemokines. These factors, together with the increased levels of homocysteine observed in BD patients, induce the endothelial cell expression of adhesion molecules (VCAM-1 and ICAM-1) and tissue factor; the release of cytokines, soluble CD40L (sCD40L), matrix metalloproteinase-9, and blood coagulation factor V; the inhibition of fibrinolysis; the disruption of nitric oxide metabolism; and the increase in platelet reactivity and lipid peroxidation. Endothelial cell dysfunction leads to a prothrombotic and antifibrinolytic phenotype in BD patients. Increased levels of homocysteine, fibrinogen, and plasminogen activator inhibitor type 1 seem to be involved in the procoagulant condition of this pathology that has been verified by end-point tests as well as by global coagulation tests.

Keywords

Behçet disease - endothelial cell dysfunction - procoagulant condition

• References

• 1 Ambrose NL, Haskard DO. Differential diagnosis and management of Behçet syndrome. Nat Rev Rheumatol 2013; 9 (2) 79-89
• 2 Altenburg A, Mahr A, Maldini C , et al. Epidemiology and clinical aspects of Adamantiades-Behçet disease in Germany. Current data [in German]. Ophthalmologe 2012; 109 (6) 531-541
• 3 Davatchi F, Assaad-Khalil S, Calamia KT , et al; International Team for the Revision of the International Criteria for Behçet's Disease (ITR-ICBD). The International Criteria for Behçet's Disease (ICBD): a collaborative study of 27 countries on the sensitivity and specificity of the new criteria. J Eur Acad Dermatol Venereol 2014; 28 (3) 338-347
• 4 Wakefield TW, Myers DD, Henke PK. Mechanisms of venous thrombosis and resolution. Arterioscler Thromb Vasc Biol 2008; 28 (3) 387-391
• 5 Camerer E, Huang W, Coughlin SR. Tissue factor- and factor X-dependent activation of protease-activated receptor 2 by factor VIIa. Proc Natl Acad Sci U S A 2000; 97 (10) 5255-5260
• 6 Rao LV, Pendurthi UR. Tissue factor-factor VIIa signaling. Arterioscler Thromb Vasc Biol 2005; 25 (1) 47-56
• 7 Kaplanski G, Fabrigoule M, Boulay V , et al. Thrombin induces endothelial type II activation in vitro: IL-1 and TNF-alpha-independent IL-8 secretion and E-selectin expression. J Immunol 1997; 158 (11) 5435-5441
• 8 Chi L, Li Y, Stehno-Bittel L , et al. Interleukin-6 production by endothelial cells via stimulation of protease-activated receptors is amplified by endotoxin and tumor necrosis factor-alpha. J Interferon Cytokine Res 2001; 21 (4) 231-240
• 9 Raza SL, Nehring LC, Shapiro SD, Cornelius LA. Proteinase-activated receptor-1 regulation of macrophage elastase (MMP-12) secretion by serine proteinases. J Biol Chem 2000; 275 (52) 41243-41250
• 10 McLean K, Schirm S, Johns A, Morser J, Light DR. FXa-induced responses in vascular wall cells are PAR-mediated and inhibited by ZK-807834. Thromb Res 2001; 103 (4) 281-297
• 11 Ozyazgan S, Andican G, Erman H , et al. Relation of protein oxidation parameters and disease activity in patients with Behçet's disease. Clin Lab 2013; 59 (7-8) 819-825
• 12 Mungan AG, Can M, Açikgöz S, Eştürk E, Altinyazar C. Lipid peroxidation and homocysteine levels in Behçet's disease. Clin Chem Lab Med 2006; 44 (9) 1115-1118
• 13 Orem A, Yandi YE, Vanizor B, Cimşit G, Uydu HA, Malkoç M. The evaluation of autoantibodies against oxidatively modified low-density lipoprotein (LDL), susceptibility of LDL to oxidation, serum lipids and lipid hydroperoxide levels, total antioxidant status, antioxidant enzyme activities, and endothelial dysfunction in patients with Behçet's disease. Clin Biochem 2002; 35 (3) 217-224
• 14 Margutti P, Matarrese P, Conti F , et al. Autoantibodies to the C-terminal subunit of RLIP76 induce oxidative stress and endothelial cell apoptosis in immune-mediated vascular diseases and atherosclerosis. Blood 2008; 111 (9) 4559-4570
• 15 Bassyouni IH, Gamal S, Talaat RM, Siam I. Autoantibodies against complement C1q in patients with Behcet's disease: association with vascular involvement. Mod Rheumatol 2014; 24 (2) 316-320
• 16 Stichtenoth DO, Frölich JC. Nitric oxide and inflammatory joint diseases. Br J Rheumatol 1998; 37 (3) 246-257
• 17 Beckman JS, Koppenol WH. Nitric oxide, superoxide, and peroxynitrite: the good, the bad, and ugly. Am J Physiol 1996; 271 (5, Pt 1) C1424-C1437
• 18 MacAllister RJ, Fickling SA, Whitley GS, Vallance P. Metabolism of methylarginines by human vasculature; implications for the regulation of nitric oxide synthesis. Br J Pharmacol 1994; 112 (1) 43-48
• 19 Antoniades C, Shirodaria C, Leeson P , et al. Association of plasma asymmetrical dimethylarginine (ADMA) with elevated vascular superoxide production and endothelial nitric oxide synthase uncoupling: implications for endothelial function in human atherosclerosis. Eur Heart J 2009; 30 (9) 1142-1150
• 20 Böger RH, Maas R, Schulze F, Schwedhelm E. Elevated levels of asymmetric dimethylarginine (ADMA) as a marker of cardiovascular disease and mortality. Clin Chem Lab Med 2005; 43 (10) 1124-1129
• 21 Sahin M, Arslan C, Naziroglu M , et al. Asymmetric dimethylarginine and nitric oxide levels as signs of endothelial dysfunction in Behcet's disease. Ann Clin Lab Sci 2006; 36 (4) 449-454
• 22 Ozuguz P, Karabulut AA, Tulmac M, Kisa U, Kocak M, Gunduz O. Markers of endothelial dysfunction and evaluation of vascular reactivity tests in Behcet disease. Angiology 2014; 65 (10) 937-943
• 23 Ulusoy RE, Karabudak O, Kilicaslan F, Kirilmaz A, Us MH, Cebeci BS. Noninvasive assessment of impaired endothelial dysfunction in mucocutaneous Behçet's disease. Rheumatol Int 2008; 28 (7) 617-621
• 24 Orem A, Vanizor B, Cimşit G, Kiran E, Değer O, Malkoç M. Decreased nitric oxide production in patients with Behçet's disease. Dermatology 1999; 198 (1) 33-36
• 25 Buldanlioglu S, Turkmen S, Ayabakan HB , et al. Nitric oxide, lipid peroxidation and antioxidant defence system in patients with active or inactive Behçet's disease. Br J Dermatol 2005; 153 (3) 526-530
• 26 Harzallah O, Kerkeni A, Baati T, Mahjoub S. Oxidative stress: correlation with Behçet's disease duration, activity and severity. Eur J Intern Med 2008; 19 (7) 541-547
• 27 Kiraz S, Ertenli I, Calgüneri M , et al. Interactions of nitric oxide and superoxide dismutase in Behçet's disease. Clin Exp Rheumatol 2001; 19 (5, Suppl 24): S25-S29
• 28 Undas A, Brozek J, Szczeklik A. Homocysteine and thrombosis: from basic science to clinical evidence. Thromb Haemost 2005; 94 (5) 907-915
• 29 Kartal Durmazlar SP, Akgul A, Eskioglu F. Homocysteine may involve in the pathogenesis of Behcet's disease by inducing inflammation. Mediators Inflamm 2008; 2008: 407972
• 30 Taysi S, Sari RA, Dursun H , et al. Evaluation of nitric oxide synthase activity, nitric oxide, and homocysteine levels in patients with active Behcet's disease. Clin Rheumatol 2008; 27 (12) 1529-1534
• 31 Er H, Evereklioglu C, Cumurcu T , et al. Serum homocysteine level is increased and correlated with endothelin-1 and nitric oxide in Behçet's disease. Br J Ophthalmol 2002; 86 (6) 653-657
• 32 Ateş A, Aydintuğ O, Olmez U, Düzgün N, Duman M. Serum homocysteine level is higher in Behçet's disease with vascular involvement. Rheumatol Int 2005; 25 (1) 42-44
• 33 Kayikçioğlu M, Aksu K, Hasdemir C , et al. Endothelial functions in Behçet's disease. Rheumatol Int 2006; 26 (4) 304-308
• 34 Sarican T, Ayabakan H, Turkmen S, Kalaslioglu V, Baran F, Yenice N. Homocysteine: an activity marker in Behçet's disease?. J Dermatol Sci 2007; 45 (2) 121-126
• 35 Gönül M, Gül U, Kilinç C, Cakmak SK, Soylu S, Kiliç A. Homocysteine levels in patients with Behçet's disease and patients with recurrent aphthous stomatitis. Clin Rheumatol 2009; 28 (10) 1153-1156
• 36 Messedi M, Frigui M, Chaabouni Kh , et al. Methylenetetrahydrofolate reductase C677T and A1298C polymorphisms and variations of homocysteine concentrations in patients with Behcet's disease. Gene 2013; 527 (1) 306-310
• 37 Lievens D, Zernecke A, Seijkens T , et al. Platelet CD40L mediates thrombotic and inflammatory processes in atherosclerosis. Blood 2010; 116 (20) 4317-4327
• 38 Hamzaoui K, Hamzaoui A, Guemira F, Bessioud M, Hamza M, Ayed K. Cytokine profile in Behçet's disease patients. Relationship with disease activity. Scand J Rheumatol 2002; 31 (4) 205-210
• 39 Fernández Bello I, Álvarez MT, López-Longo FJ , et al. Platelet soluble CD40L and matrix metalloproteinase 9 activity are proinflammatory mediators in Behçet disease patients. Thromb Haemost 2012; 107 (1) 88-98
• 40 Pay S, Abbasov T, Erdem H , et al. Serum MMP-2 and MMP-9 in patients with Behçet's disease: do their higher levels correlate to vasculo-Behçet's disease associated with aneurysm formation?. Clin Exp Rheumatol 2007; 25 (4, Suppl 45): S70-S75
• 41 Navarro S, Ricart JM, Medina P , et al. Activated protein C levels in Behçet's disease and risk of venous thrombosis. Br J Haematol 2004; 126 (4) 550-556
• 42 Fernández-Bello I, López-Longo FJ, Arias-Salgado EG, Jiménez-Yuste V, Butta NV. Behçet's disease: new insight into the relationship between procoagulant state, endothelial activation/damage and disease activity. Orphanet J Rare Dis 2013; 8: 81
• 43 Cekmen M, Evereklioglu C, Er H , et al. Vascular endothelial growth factor levels are increased and associated with disease activity in patients with Behçet's syndrome. Int J Dermatol 2003; 42 (11) 870-875
• 44 Balta I, Balta S, Koryurek OM , et al. Serum endocan levels as a marker of disease activity in patients with Behçet disease. J Am Acad Dermatol 2014; 70 (2) 291-296
• 45 Chamorro AJ, Marcos M, Hernández-García I , et al. Association of allelic variants of factor V Leiden, prothrombin and methylenetetrahydrofolate reductase with thrombosis or ocular involvement in Behçet's disease: a systematic review and meta-analysis. Autoimmun Rev 2013; 12 (5) 607-616
• 46 Lenk N, Ozet G, Alli N, Coban O, Erbaşi S. Protein C and protein S activities in Behçet's disease as risk factors of thrombosis. Int J Dermatol 1998; 37 (2) 124-125
• 47 Nalçaci M, Pekçelen Y. Antithrombin III, protein C and protein S plasma levels in patients with Behçet's disease. J Int Med Res 1998; 26 (4) 206-208
• 48 Akar S, Ozcan MA, Ateş H , et al. Circulated activated platelets and increased platelet reactivity in patients with Behçet's disease. Clin Appl Thromb Hemost 2006; 12 (4) 451-457
• 49 Martínez M, Ricart JM, Ruiz-Aja S , et al. Platelet activation and red blood cell phosphatidylserine exposure evaluated by flow cytometry in patients with Behçet's disease: are they related to thrombotic events?. Pathophysiol Haemost Thromb 2007; 36 (1) 18-22
• 50 Espinosa G, Font J, Tàssies D , et al. Vascular involvement in Behçet's disease: relation with thrombophilic factors, coagulation activation, and thrombomodulin. Am J Med 2002; 112 (1) 37-43
• 51 Brogren H, Karlsson L, Andersson M, Wang L, Erlinge D, Jern S. Platelets synthesize large amounts of active plasminogen activator inhibitor 1. Blood 2004; 104 (13) 3943-3948
• 52 Nylander M, Osman A, Ramström S, Aklint E, Larsson A, Lindahl TL. The role of thrombin receptors PAR1 and PAR4 for PAI-1 storage, synthesis and secretion by human platelets. Thromb Res 2012; 129 (4) e51-e58
• 53 Pihusch V, Pihusch M, Penovici M, Kolb HJ, Hiller E, Pihusch R. Transforming growth factor beta-1 released from platelets contributes to hypercoagulability in veno-occlusive disease following hematopoetic stem cell transplantation. Thromb Res 2005; 116 (3) 233-240
• 54 Ozoran K, Dügün N, Gürler A, Tutkak H, Tokgöz G. Plasma von Willebrand factor, tissue plasminogen activator, plasminogen activator inhibitor, and antithrombin III levels in Behçet's disease. Scand J Rheumatol 1995; 24 (6) 376-382
• 55 Haznedaroğlu IC, Celik I, Büyükaşik Y, Koşar A, Kirazli S, Dündar SV. Haemostasis, thrombosis, and endothelium in Behçet's disease. Acta Haematol 1998; 99 (4) 236-237
• 56 Yaşar Bilge NS, Akay OM, Kaşifoğlu T, Kuş G, Korkmaz C. The role of hemostatic mechanisms in the development of thrombosis in Behcet's disease: an analysis by modified rotation thromboelastogram (ROTEM). Clin Rheumatol 2013; 32 (12) 1815-1818
• 57 Kupesiz A, Rajpurkar M, Warrier I , et al. Tissue plasminogen activator induced fibrinolysis: standardization of method using thromboelastography. Blood Coagul Fibrinolysis 2010; 21 (4) 320-324
• 58 Hemker HC, Al Dieri R, De Smedt E, Béguin S. Thrombin generation, a function test of the haemostatic-thrombotic system. Thromb Haemost 2006; 96 (5) 553-561
• 59 Weitz JI, Hudoba M, Massel D, Maraganore J, Hirsh J. Clot-bound thrombin is protected from inhibition by heparin-antithrombin III but is susceptible to inactivation by antithrombin III-independent inhibitors. J Clin Invest 1990; 86 (2) 385-391