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Current Vascular Pharmacology


ISSN (Print): 1570-1611
ISSN (Online): 1875-6212

Review Article

Novel Direct Anticoagulants and Atherosclerosis

Author(s): Andrej Fabjan* and Fajko F. Bajrović

Volume 17, Issue 1, 2019

Page: [29 - 34] Pages: 6

DOI: 10.2174/1570161116666180206111217

Price: $65


Coagulation factors can affect cellular processes that include inflammatory signaling by acting on endothelial protease activated receptors, vascular smooth muscle and inflammatory cells beyond the coagulation cascade. This is important in the pathogenesis of atherosclerosis. Accordingly, experimental data points to beneficial effects of coagulation protease inhibitors on the attenuation of atherosclerosis progression in animal models. However, available clinical data do not support the use of anticoagulants as an add-on treatment of atherosclerosis. New clinical studies are needed with a better selection of patients to clarify the role of novel direct anticoagulants in the management of atherosclerosis.

Keywords: Atherosclerosis, coagulation factors, thrombin, activated factor X, direct anticoagulants, SMC.

Graphical Abstract
Weber C, Zernecke A, Libby P. The multifaceted contributions of leukocyte subsets to atherosclerosis: Lessons from mouse models. Nat Rev Immunol 2008; 8: 802-15.
Ross R. Atherosclerosis-an inflammatory disease. N Engl J Med 1999; 340: 115-26.
Libby P, Ridker PM, Hansson GK. Progress and challenges in translating the biology of atherosclerosis. Nature 2011; 473: 317-25.
Foley JH, Conway EM. Cross talk pathways between coagulation and inflammation. Circ Res 2016; 118: 1392-408.
Levi M, ten Cate H, van der Poll T. Endothelium: Interface between coagulation and inflammation. Crit Care Med 2002; 30(5)(Suppl.): 220-4.
Coughlin SR. Protease-activated receptors in hemostasis, thrombosis and vascular biology. J Thromb Haemost 2005; 3: 1800-14.
Kalz J, ten Cate H, Spronk HM. Thrombin generation and atherosclerosis. J Thromb Thrombolysis 2014; 37: 45-55.
Borissoff JI, Heeneman S, Kilinc E, et al. Early atherosclerosis exhibits an enhanced procoagulant state. Circulation 2010; 122: 821-30.
Bea F, Kreuzer J, Preusch M, et al. Melagatran reduces advanced atherosclerotic lesion size and may promote plaque stability in apolipoprotein E-deficient mice. Arterioscler Thromb Vasc Biol 2006; 26: 2787-92.
Borissoff JI, Spronk HM, Heeneman S, ten Cate H. Is thrombin a key player in the ‘coagulation-atherogenesis’ maze? Cardiovasc Res 2009; 82: 392-403.
Preusch MR, Ieronimakis N, Wijelath ES, et al. Dabigatran etexilate retards the initiation and progression of atherosclerotic lesions and inhibits the expression of oncostatin M in apolipoprotein E-deficient mice. Drug Des Devel Ther 2015; 9: 5203-11.
Smith SA, Travers RJ, Morrissey JH. How it all starts: Initiation of the clotting cascade. Crit Rev Biochem Mol Biol 2015; 50: 326-36.
Madhusudhan T, Kerlin BA, Isermann B. The emerging role of coagulation proteases in kidney disease. Nat Rev Nephrol 2016; 12: 94-109.
Vu TK, Hung DT, Wheaton VI, Coughlin SR. Molecular cloning of a functional thrombin receptor reveals a novel proteolytic mechanism of receptor activation. Cell 1991; 64: 1057-68.
Ishihara H, Connolly AJ, Zeng D, et al. Protease-activated receptor 3 is a second thrombin receptor in humans. Nature 1997; 386: 502-6.
Nystedt S, Emilsson K, Wahlestedt C, Sundelin J. Molecular cloning of a potential proteinase activated receptor. PN AS 1994; 91: 9208-12.
Xu WF, Andersen H, Whitmore TE, et al. Cloning and characterization of human protease-activated receptor 4. PN AS 1998; 95: 6642-6.
Zhao P, Metcalf M, Bunnett NW. Biased signaling of protease-activated receptors. Front Endocrinol 2014; 5: 67.
Dery O, Corvera CU, Steinhoff M, Bunnett NW. Proteinase-activated receptors: Novel mechanisms of signaling by serine proteases. Am J Physiol 1998; 274(6 Pt 1): 1429-52.
Sun WY, Witte DP, Degen JL, et al. Prothrombin deficiency results in embryonic and neonatal lethality in mice. PN AS 1998; 95: 7597-602.
Frenette PS, Mayadas TN, Rayburn H, Hynes RO, Wagner DD. Susceptibility to infection and altered hematopoiesis in mice deficient in both P- and E-selectins. Cell 1996; 84: 563-74.
Hattori R, Hamilton KK, Fugate RD, McEver RP, Sims PJ. Stimulated secretion of endothelial von Willebrand factor is accompanied by rapid redistribution to the cell surface of the intracellular granule membrane protein GMP-140. J Biol Chem 1989; 264: 7768-71.
Malik AB, Fenton JW 2nd. Thrombin-mediated increase in vascular endothelial permeability. Semin Thromb Hemost 1992; 18: 193-9.
Alberelli MA, De Candia E. Functional role of protease activated receptors in vascular biology. Vascul Pharmacol 2014; 62: 72-81.
Hamilton JR, Moffatt JD, Frauman AG, Cocks TM. Protease-activated receptor (PAR) 1 but not PAR2 or PAR4 mediates endothelium-dependent relaxation to thrombin and trypsin in human pulmonary arteries. J Cardiovasc Pharmacol 2001; 38: 108-19.
Ku DD, Zaleski JK. Receptor mechanism of thrombin-induced endothelium-dependent and endothelium-independent coronary vascular effects in dogs. J Cardiovasc Pharmacol 1993; 22: 609-16.
Wilcox JN, Noguchi S, Casanova JR, Rasmussen ME. Extrahepatic synthesis of FVII in human atheroma and smooth muscle cells in vitro. Ann N Y Acad Sci 2001; 947: 433-8.
Bini A, Fenoglio JJ Jr, Mesa-Tejada R, Kudryk B, Kaplan KL. Identification and distribution of fibrinogen, fibrin, and fibrin(ogen) degradation products in atherosclerosis. Use of monoclonal antibodies. Arteriosclerosis 1989; 9: 109-21.
Maas C, Govers-Riemslag JW, Bouma B, et al. Misfolded proteins activate factor XII in humans, leading to kallikrein formation without initiating coagulation. J Clin Invest 2008; 118: 3208-18.
Garcia JG, Painter RG, Fenton JW 2nd, English D, Callahan KS. Thrombin-induced prostacyclin biosynthesis in human endothelium: Role of guanine nucleotide regulatory proteins in stimulus/coupling responses. J Cell Physiol 1990; 142: 186-93.
Stern DM, Bank I, Nawroth PP, et al. Self-regulation of procoagulant events on the endothelial cell surface. J Exp Med 1985; 162: 1223-35.
Goldfarb RH, Liotta LA. Thrombin cleavage of extracellular matrix proteins. Ann N Y Acad Sci 1986; 485: 288-92.
Nelken NA, Coughlin SR, Gordon D, Wilcox JN. Monocyte chemoattractant protein-1 in human atheromatous plaques. J Clin Invest 1991; 88: 1121-7.
Colotta F, Sciacca FL, Sironi M, Luini W, Rabiet MJ, Mantovani A. Expression of monocyte chemotactic protein-1 by monocytes and endothelial cells exposed to thrombin. Am J Pathol 1994; 144: 975-85.
Boring L, Gosling J, Cleary M, Charo IF. Decreased lesion formation in CCR2-/- mice reveals a role for chemokines in the initiation of atherosclerosis. Nature 1998; 394: 894-7.
Minami T, Sugiyama A, Wu SQ, Abid R, Kodama T, Aird WC. Thrombin and phenotypic modulation of the endothelium. Arterioscler Thromb Vasc Biol 2004; 24: 41-53.
Chung SW, Park JW, Lee SA, Eo SK, Kim K. Thrombin promotes proinflammatory phenotype in human vascular smooth muscle cell. Biochem Biophys Res Commun 2010; 396: 748-54.
Kranzhofer R, Clinton SK, Ishii K, Coughlin SR, Fenton JW 2nd, Libby P. Thrombin potently stimulates cytokine production in human vascular smooth muscle cells but not in mononuclear phagocytes. Circ Res 1996; 79: 286-94.
Sarembock IJ, Gertz SD, Gimple LW, Owen RM, Powers ER, Roberts WC. Effectiveness of recombinant desulphatohirudin in reducing restenosis after balloon angioplasty of atherosclerotic femoral arteries in rabbits. Circulation 1991; 84: 232-43.
McNamara CA, Sarembock IJ, Gimple LW, Fenton JW 2nd, Coughlin SR, Owens GK. Thrombin stimulates proliferation of cultured rat aortic smooth muscle cells by a proteolytically activated receptor. J Clin Invest 1993; 91: 94-8.
Noda-Heiny H, Sobel BE. Vascular smooth muscle cell migration mediated by thrombin and urokinase receptor. Am J Physiol 1995; 268(5 Pt 1): 1195-201.
Flynn PD, Byrne CD, Baglin TP, Weissberg PL, Bennett MR. Thrombin generation by apoptotic vascular smooth muscle cells. Blood 1997; 89: 4378-84.
Harker LA, Hanson SR, Runge MS. Thrombin hypothesis of thrombus generation and vascular lesion formation. Am J Cardiol 1995; 75: 12-7.
Hatton MW, Moar SL, Richardson M. Deendothelialization in vivo initiates a thrombogenic reaction at the rabbit aorta surface. Correlation of uptake of fibrinogen and antithrombin III with thrombin generation by the exposed subendothelium. Am J Pathol 1989; 135: 499-508.
Smith EB, Crosbie L, Carey S. Prothrombin-related antigens in human aortic intima. Semin Thromb Hemost 1996; 22: 347-50.
Wilcox JN, Rodriguez J, Subramanian R, et al. Characterization of thrombin receptor expression during vascular lesion formation. Circ Res 1994; 75: 1029-38.
Borissoff JI, Otten JJ, Heeneman S, et al. Genetic and pharmacological modifications of thrombin formation in apolipoprotein e-deficient mice determine atherosclerosis severity and atherothrombosis onset in a neutrophil-dependent manner. PLoS One 2013; 8: e55784.
Kadoglou NP, Moustardas P, Katsimpoulas M, et al. The beneficial effects of a direct thrombin inhibitor, dabigatran etexilate, on the development and stability of atherosclerotic lesions in apolipoprotein E-deficient mice: Dabigatran etexilate and atherosclerosis. Cardiovasc Drugs Ther 2012; 26: 367-74.
Lee IO, Kratz MT, Schirmer SH, Baumhakel M, Bohm M. The effects of direct thrombin inhibition with dabigatran on plaque formation and endothelial function in apolipoprotein E-deficient mice. J Pharmacol Exp Ther 2012; 343: 253-7.
Pingel S, Tiyerili V, Mueller J, Werner N, Nickenig G, Mueller C. Thrombin inhibition by dabigatran attenuates atherosclerosis in ApoE deficient mice. Arch Med Sci 2014; 10: 154-60.
Mahley RW, Apolipoprotein E. Cholesterol transport protein with expanding role in cell biology. Science 1988; 240: 622-30.
Pendse AA, Arbones-Mainar JM, Johnson LA, Altenburg MK, Maeda N. Apolipoprotein E knock-out and knock-in mice: Atherosclerosis, metabolic syndrome, and beyond. J Lipid Res 2009; 50(Suppl.): 178-82.
Fuster JJ, Castillo AI, Zaragoza C, Ibanez B, Andres V. Animal models of atherosclerosis. Prog Mol Biol Transl Sci 2012; 105: 1-23.
Clarke M, Bennett M. The emerging role of vascular smooth muscle cell apoptosis in atherosclerosis and plaque stability. Am J Nephrol 2006; 26: 531-5.
Borissoff JI, Spronk HM, ten Cate H. The hemostatic system as a modulator of atherosclerosis. N Engl J Med 2011; 364: 1746-60.
Spronk HM, de Jong AM, Crijns HJ, Schotten U, Van Gelder IC, Ten Cate H. Pleiotropic effects of factor Xa and thrombin: What to expect from novel anticoagulants. Cardiovasc Res 2014; 101: 344-51.
Ragosta M, Gimple LW, Gertz SD, et al. Specific factor Xa inhibition reduces restenosis after balloon angioplasty of atherosclerotic femoral arteries in rabbits. Circulation 1994; 89: 1262-71.
Zhou Q, Bea F, Preusch M, et al. Evaluation of plaque stability of advanced atherosclerotic lesions in apo E-deficient mice after treatment with the oral factor Xa inhibitor rivaroxaban. Mediators Inflamm 2011; 2011: 432080.
Zuo P, Zhou Q, Zuo Z, Wang X, Chen L, Ma G. Effects of the factor Xa inhibitor, fondaparinux, on the stability of atherosclerotic lesions in apolipoprotein E-deficient mice. Circ J 2015; 79: 2499-508.
Hara T, Fukuda D, Tanaka K, et al. Rivaroxaban, a novel oral anticoagulant, attenuates atherosclerotic plaque progression and destabilization in ApoE-deficient mice. Atherosclerosis 2015; 242: 639-46.
Gibson CM, Mega JL, Burton P, et al. Rationale and design of the Anti-Xa therapy to lower cardiovascular events in addition to standard therapy in subjects with acute coronary syndrome-thrombolysis in myocardial infarction 51 (ATLAS-ACS 2 TIMI 51) trial: A randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of rivaroxaban in subjects with acute coronary syndrome. Am Heart J 2011; 161: 815-21.
Mega JL, Braunwald E, Mohanavelu S, et al. Rivaroxaban versus placebo in patients with acute coronary syndromes (ATLAS ACS-TIMI 46): A randomised, double-blind, phase II trial. Lancet 2009; 374: 29-38.
Bernhard H, Wipfler P, Leschnik B, et al. Relationship between thrombin generation and carotid intima-media thickness. Hamostaseologie 2010; 30(Suppl. 1): 168-71.
Paramo JA, Orbe J, Beloqui O, et al. Prothrombin fragment 1+2 is associated with carotid intima-media thickness in subjects free of clinical cardiovascular disease. Stroke 2004; 35: 1085-9.
Borissoff JI, Joosen IA, Versteylen MO, Spronk HM, ten Cate H, Hofstra L. Accelerated in vivo thrombin formation independently predicts the presence and severity of CT angiographic coronary atherosclerosis. JACC Cardiovasc Imaging 2012; 5: 1201-10.
Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009; 361: 1139-51.
Connolly SJ, Ezekowitz MD, Yusuf S, Reilly PA, Wallentin L. Randomized evaluation of long-term anticoagulation therapy I. Newly identified events in the RELY trial. N Engl J Med 2010; 363: 1875-6.
Hohnloser SH, Oldgren J, Yang S, et al. Myocardial ischemic events in patients with atrial fibrillation treated with dabigatran or warfarin in the RELY (Randomized Evaluation of Long-Term Anticoagulation Therapy) trial. Circulation 2012; 125: 669-76.
Uchino K, Hernandez AV. Dabigatran association with higher risk of acute coronary events: Meta-analysis of noninferiority randomized controlled trials. Arch Intern Med 2012; 172: 397-402.
Connolly SJ, Eikelboom J, Joyner C, et al. Apixaban in patients with atrial fibrillation. N Engl J Med 2011; 364: 806-17.
Mega JL, Braunwald E, Wiviott SD, et al. Comparison of the efficacy and safety of two rivaroxaban doses in acute coronary syndrome (from ATLAS ACS 2-TIMI 51). Am J Cardiol 2013; 112: 472-8.
Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011; 365: 883-91.
Eikelboom JW, Connolly SJ, Bosch J, et al. Rivaroxaban with or without aspirin in stable cardiovascular disease. N Engl J Med 2017; 377: 1319-30.
Chatrou ML, Winckers K, Hackeng TM, Reutelingsperger CP, Schurgers LJ. Vascular calcification: The price to pay for anticoagulation therapy with vitamin K-antagonists. Blood Rev 2012; 26: 155-66.

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