Targeting factor Xa and thrombin: impact on coagulation and beyond

Charles T. Esmon

doi:10.1160/TH13-09-0730

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 2014; 111(04): 625-633
DOI: 10.1160/TH13-09-0730

Review Article

Schattauer GmbH

Targeting factor Xa and thrombin: impact on coagulation and beyond

Charles T. Esmon

¹Howard Hughes Medical Institute, Coagulation Biology Laboratory, Oklahoma Medical Research Foundation, and Departments of Pathology and Biochemistry & Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA

› Institutsangaben

Abstract

Summary

Great advances have been made in recent years in understanding the haemostatic system and the molecular and cellular basis of thrombus formation. Although directly targeting factor Xa or thrombin (factor IIa) for effective anticoagulation is now well established, evidence has emerged suggesting that factor Xa and thrombin are involved in other physiological and pathophysiological cellular processes, including inflammation. These non-haemostatic activities of factor Xa and thrombin are predominantly mediated via the activation of proteinaseactivated receptors. Studies have indicated a potential role of coagulation proteins (including factor Xa and thrombin) in the progression of disease conditions such as atherothrombosis. Preclinical studies have provided evidence for the effects of direct factor Xa or direct thrombin inhibition beyond anticoagulation, including anti-inflammatory activities and atherosclerotic plaque stabilisation. In this article, the non-haemostatic activities of factor Xa and thrombin and the effects of direct inhibition of these coagulation factors on these activities are summarised. In addition, the potential roles of factor Xa and thrombin in atherosclerosis and atherothrombosis are explored and the cardiovascular profiles of rivaroxaban, apixaban and dabigatran etexilate observed in phase III clinical studies are discussed.

Keywords

Atherothrombosis - coagulation factors - proteinase-activated receptors (PAR) - thrombin

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Referenzen

References
1 Esmon CT. Crosstalk between inflammation and thrombosis.. Maturitas 2008; 61: 122-131.
2 Sarangi PP, Lee HW, Kim M. Activated protein C action in inflammation.. Br J Haematol 2010; 148: 817-833.
3 Eriksson BI, Quinlan DJ, Eikelboom JW. Novel oral Factor Xa and thrombin inhibitors in the management of thromboembolism.. Annu Rev Med 2011; 62: 41-57.
4 Borissoff JI, Spronk HM, ten Cate H. The hemostatic system as a modulator of atherosclerosis.. N Engl J Med 2011; 364: 1746-1760.
5 Borensztajn K, Peppelenbosch MP, Spek CA. Factor Xa: at the crossroads between coagulation and signaling in physiology and disease.. Trends Mol Med 2008; 14: 429-440.
6 Licari LG, Kovacic JP. Thrombin physiology and pathophysiology.. J Vet Emerg Crit Care 2009; 19: 11-22.
7 Ellinghaus P, Laux V, Perzborn E. Effect of rivaroxaban on thrombin-induced pro-inflammatory gene expression in human umbilical vein endothelial cells.. J Thromb Haemost 2011; 9: 491 Abstract P-TU-577.
8 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.
9 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.
10 Mann KG, Butenas S, Brummel K. The dynamics of thrombin formation.. Arte-rioscler Thromb Vasc Biol 2003; 23: 17-25.
11 Chou J, Mackman N, Merrill-Skoloff G. et al. Hematopoietic cell-derived micro-particle tissue factor contributes to fibrin formation during thrombus propagation.. Blood 2004; 104: 3190-3197.
12 Furie B, Furie BC. Mechanisms of thrombus formation.. N Engl J Med 2008; 359: 938-949.
13 Levi M, van der Poll T. Inflammation and coagulation.. Crit Care Med 2010; 38: S26-S34.
14 Stearns-Kurosawa DJ, Kurosawa S, Mollica JS. et al. The endothelial cell protein C receptor augments protein C activation by the thrombin-thrombomodulin complex.. Proc Natl Acad Sci USA 1996; 93: 10212-10216.
15 Mosnier LO, Zlokovic BV, Griffin JH. The cytoprotective protein C pathway.. Blood 2007; 109: 3161-3172.
16 Joyce DE, Gelbert L, Ciaccia A. et al. Gene expression profile of antithrombotic protein C defines new mechanisms modulating inflammation and apoptosis.. J Biol Chem 2001; 276: 11199-11203.
17 Vetrano S, Ploplis VA, Sala E. et al. Unexpected role of anticoagulant protein C in controlling epithelial barrier integrity and intestinal inflammation.. Proc Natl Acad Sci USA 2011; 108: 19830-19835.
18 Taylor Jr. FB, Stearns-Kurosawa DJ, Kurosawa S. et al. The endothelial cell protein C receptor aids in host defense against Escherichia coli sepsis.. Blood 2000; 95: 1680-1686.
19 Taylor Jr. FB, Chang A, Esmon CT. et al. Protein C prevents the coagulopathic and lethal effects of Escherichia coli infusion in the baboon.. J Clin Invest 1987; 79: 918-925.
20 Loubele ST, Spek CA, Leenders P. et al. Activated protein C protects against myocardial ischemia/reperfusion injury via inhibition of apoptosis and inflammation.. Arterioscler Thromb Vasc Biol 2009; 29: 1087-1092.
21 Bock F, Shahzad K, Wang H. et al. Activated protein C ameliorates diabetic nephropathy by epigenetically inhibiting the redox enzyme p66Shc.. Proc Natl Acad Sci USA 2013; 110: 648-653.
22 Cheng T, Liu D, Griffin JH. et al. Activated protein C blocks p53-mediated apoptosis in ischemic human brain endothelium and is neuroprotective.. Nat Med 2003; 9: 338-342.
23 Kalil AC, LaRosa SP. Effectiveness and safety of drotrecogin alfa (activated) for severe sepsis: a meta-analysis and metaregression.. Lancet Infect Dis 2012; 12: 678-686.
24 Wei HJ, Li YH, Shi GY. et al. Thrombomodulin domains attenuate atherosclerosis by inhibiting thrombin-induced endothelial cell activation.. Cardiovasc Res 2011; 92: 317-327.
25 Borensztajn K, Spek CA. Blood coagulation Factor Xa as an emerging drug target.. Expert Opin Ther Targets 2011; 15: 341-349.
26 Coughlin SR. Thrombin signalling and protease-activated receptors.. Nature 2000; 407: 258-264.
27 Sevigny LM, Austin KM, Zhang P. et al. Protease-activated receptor-2 modulates protease-activated receptor-1-driven neointimal hyperplasia.. Arterioscler Thromb Vasc Biol 2011; 31: e100-e106.
28 Busch G, Seitz I, Steppich B. et al. Coagulation Factor Xa stimulates interleu-kin-8 release in endothelial cells and mononuclear leukocytes: implications in acute myocardial infarction.. Arterioscler Thromb Vasc Biol 2005; 25: 461-466.
29 Shimizu T, Nishihira J, Watanabe H. et al. Macrophage migration inhibitory factor is induced by thrombin and Factor Xa in endothelial cells.. J Biol Chem 2004; 279: 13729-13737.
30 Riewald M, Ruf W. Mechanistic coupling of protease signaling and initiation of coagulation by tissue factor.. Proc Natl Acad Sci USA 2001; 98: 7742-7747.
31 Feistritzer C, Lenta R, Riewald M. Protease-activated receptors-1 and -2 can mediate endothelial barrier protection: role in factor Xa signaling.. J Thromb Haemost 2005; 3: 2798-2805.
32 Okamoto T, Tanigami H, Suzuki K. et al. Thrombomodulin: a bifunctional modulator of inflammation and coagulation in sepsis.. Crit Care Res Pract 2012; 2012: 614545.
33 Libby P. Coronary artery injury and the biology of atherosclerosis: inflammation, thrombosis, and stabilization.. Am J Cardiol 2000; 86: 3J-8J.
34 Packard RR, Libby P. Inflammation in atherosclerosis: from vascular biology to biomarker discovery and risk prediction.. Clin Chem 2008; 54: 24-38.
35 Ballantyne CM, Hoogeveen RC, Bang H. et al. Lipoprotein-associated phosp-holipase A2, high-sensitivity C-reactive protein, and risk for incident coronary heart disease in middle-aged men and women in the Atherosclerosis Risk in Communities (ARIC) study.. Circulation 2004; 109: 837-842.
36 ten Cate H. Tissue factor-driven thrombin generation and inflammation in atherosclerosis.. Thromb Res 2012; 129 (Suppl. 02) S38-S40.
37 Borissoff JI, Heeneman S, Kilinc E. et al. Early atherosclerosis exhibits an enhanced procoagulant state.. Circulation 2010; 122: 821-830.
38 Joo SS, Won TJ, Kim JS. et al. Inhibition of coagulation activation and inflammation by a novel Factor Xa inhibitor synthesized from the earthworm Eisenia andrei.. Biol Pharm Bull 2009; 32: 253-258.
39 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: 1262-1271.
40 Laurent M, Varin R, Joimel U. et al. A novel mechanism of action of riva-roxaban: inhibition of monocyte and macrophage procoagulant activity and consequence on inflammatory process.. Blood (ASH Annual Meeting Abstracts). 2009 114. Abstract 3124.
41 Chan MY, Lin M, Lucas J. et al. Plasma proteomics of patients with non-valvular atrial fibrillation on chronic anti-coagulation with warfarin or a direct Factor Xa inhibitor.. Thromb Haemost 2012; 108: 1180-1191.
42 Conway EM, Van de WM, Pollefeyt S. et al. The lectin-like domain of thrombo-modulin confers protection from neutrophil-mediated tissue damage by suppressing adhesion molecule expression via nuclear factor kappaB and mitogen-activated protein kinase pathways.. J Exp Med 2002; 196: 565-577.
43 Laszik ZG, Zhou XJ, Ferrell GL. et al. Down-regulation of endothelial expression of endothelial cell protein C receptor and thrombomodulin in coronary atherosclerosis.. Am J Pathol 2001; 159: 797-802.
44 Kim AY, Walinsky PL, Kolodgie FD. et al. Early loss of thrombomodulin expression impairs vein graft thromboresistance: implications for vein graft failure.. Circ Res 2002; 90: 205-212.
45 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: 2787-2792.
46 Lee IO, Kratz MT, Schirmer SH. et al. 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: 253-257.
47 Patel MR, Mahaffey KW, Garg J. et al. Rivaroxaban versus warfarin in nonvalvu-lar atrial fibrillation.. N Engl J Med 2011; 365: 883-891.
48 Connolly SJ, Ezekowitz MD, Yusuf S. et al. Dabigatran versus warfarin in patients with atrial fibrillation.. N Engl J Med 2009; 361: 1139-1151.
49 Connolly SJ, Ezekowitz MD, Yusuf S. et al. Newly identified events in the RE-LY trial.. N Engl J Med 2010; 363: 1875-1876.
50 Schulman S, Eriksson H, Goldhaber SZ. et al. Dabigatran or warfarin for extended maintenance therapy of venous thromboembolism.. J Thromb Haemost 2011; 9 (Suppl. 02) 731 Abstract O-TH-033.
51 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.
52 Hohnloser SH, Oldgren J, Yang S. et al. Myocardial ischemic events in patients with atrial fibrillation treated with dabigatran or warfarin in the RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy) trial.. Circulation 2012; 125: 669-676.
53 Larsen TB, Rasmussen LH, Skjoth F. et al. Efficacy and safety of dabigatran etex-ilate and warfarin in “real-world” patients with atrial fibrillation: a prospective nationwide cohort study.. J Am Coll Cardiol 2013; 61: 2264-2273.
54 Zhao HJ, Zheng ZT, Wang ZH. et al. “Triple therapy” rather than “triple threat”: a meta-analysis of the two antithrombotic regimens after stent implantation in patients receiving long-term oral anticoagulant treatment.. Chest 2011; 139: 260-270.
55 Mega JL, Braunwald E, Wiviott SD. et al. Rivaroxaban in patients with a recent acute coronary syndrome.. N Engl J Med 2012; 366: 9-19.
56 Alexander JH, Lopes RD, James S. et al. Apixaban with antiplatelet therapy after acute coronary syndrome.. N Engl J Med 2011; 365: 699-708.
57 Oldgren J, Budaj A, Granger CB. et al. Dabigatran vs. placebo in patients with acute coronary syndromes on dual antiplatelet therapy: a randomized, doubleblind, phase II trial.. Eur Heart J 2011; 32: 2781-2789.
58 Perzborn E, Harwardt M. Direct thrombin inhibitors, but not Factor Xa inhibitors, enhance thrombin formation in human plasma by interfering with the thrombin-thrombomodulin-protein C system.. Blood (ASH Annual Meeting Abstracts) 2008; 112: 198-199 Abstract 528.
59 Furugohri T, Sugiyama N, Morishima Y. et al. Antithrombin-independent thrombin inhibitors, but not direct Factor Xa inhibitors, enhance thrombin generation in plasma through inhibition of thrombin-thrombomodulin-protein C system.. Thromb Haemost 2011; 106: 1076-1083.
60 The EINSTEIN Investigators.. Oral rivaroxaban for symptomatic venous throm-boembolism.. N Engl J Med 2010; 363: 2499-2510.
61 The EINSTEIN-PE Investigators.. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism.. N Engl J Med 2012; 366: 1287-1297.
62 Connolly SJ, Ezekowitz MD, Yusuf S. et al. Dabigatran versus warfarin in patients with atrial fibrillation.. N Engl J Med 2009; 361: 1139-1151.
63 Schulman S, Kearon C, Kakkar AK. et al. Dabigatran versus warfarin in the treatment of acute venous thromboembolism.. N Engl J Med 2009; 361: 2342-2352.
64 Schulman S, Kearon C, Kakkar AK. et al. Extended use of dabigatran, warfarin, or placebo in venous thromboembolism.. N Engl J Med 2013; 368: 709-718.
65 Granger CB, Alexander JH, McMurray JJ. et al. Apixaban versus warfarin in patients with atrial fibrillation.. N Engl J Med 2011; 365: 981-992.