Upstream versus downstream thrombin inhibition

References

• Turpie AG, Gallus AS, Hoek JA. A synthetic pentasaccharide for the prevention of deep-vein thrombosis after total hip replacement. N Engl J Med. 2001;344(9):619–625.
   PubMed Web of Science ®Google Scholar
• Ageno W, Gallus AS, Wittkowsky A, et al. Oral anticoagulant therapy: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012;141(2 Suppl):e44S–88S.
   PubMed Web of Science ®Google Scholar
• Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361(12):1139–1151.
   PubMed Web of Science ®Google Scholar
• Giugliano RP, Ruff CT, Braunwald E, et al. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2013;369(22):2093–2104.
   PubMed Web of Science ®Google Scholar
• Granger CB, Alexander JH, McMurray JJV, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365(11):981–992.
   PubMed Web of Science ®Google Scholar
• Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365(10):883–891.
   PubMed Web of Science ®Google Scholar
• Agnelli G, Buller HR, Cohen A, et al. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med. 2013;369(9):799–808.
   PubMed Web of Science ®Google Scholar
• Buller HR, Büller HR, Décousus H, et al. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med. 2013;369(15):1406–1415.
   PubMed Web of Science ®Google Scholar
• Investigators E, Bauersachs R, Berkowitz SD, et al. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med. 2010;363(26):2499–2510.
   PubMed Web of Science ®Google Scholar
• Investigators E-P, Büller HR, Prins MH, et al. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med. 2012;366(14):1287–1297.
   PubMed Web of Science ®Google Scholar
• Schulman S, Kearon C, Kakkar AK, et al. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med. 2009;361(24):2342–2352.
   PubMed Web of Science ®Google Scholar
• Büller HR, Bethune C, Bhanot S, et al. Factor XI antisense oligonucleotide for prevention of venous thrombosis. N Engl J Med. 2015;372(3):232–240.
   PubMed Web of Science ®Google Scholar
• Kenne E, Nickel KF, Long AT, et al. Factor XII: a novel target for safe prevention of thrombosis and inflammation. J Intern Med. 2015;278(6):571–585.
   PubMed Web of Science ®Google Scholar
• Worm, M., Köhler EC, Panda R, et al. The factor XIIa blocking antibody 3F7: a safe anticoagulant with anti-inflammatory activities. Ann Transl Med. 2015;3(17):247.
   PubMed Web of Science ®Google Scholar
• Weiss P, Soff GA, Halkin H, et al. Decline of proteins C and S and factors II, VII, IX and X during the initiation of warfarin therapy. Thromb Res. 1987;45(6):783–790.
   PubMed Web of Science ®Google Scholar
• Chan YC, Valenti D, Mansfield AO, et al. Warfarin induced skin necrosis. Br J Surg. 2000;87(3):266–272.
   PubMed Web of Science ®Google Scholar
• Witt DM, Delate T, Hylek EM, et al. Effect of warfarin on intracranial hemorrhage incidence and fatal outcomes. Thromb Res. 2013;132(6):770–775.
   PubMed Web of Science ®Google Scholar
• Pisters R, Lane DA, Nieuwlaat R, et al. A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation: the Euro Heart Survey. Chest. 2010;138(5):1093–1100.
   PubMed Web of Science ®Google Scholar
• Van Rein N, Le Cessie S, Van Vliet IP, et al. Increased risk of major bleeding after a minor bleed during treatment with vitamin K antagonists is determined by fixed common risk factors. J Thromb Haemost. 2016;14(5):948–952.
   PubMed Web of Science ®Google Scholar
• Van Der Meijden PEJ, Bouman AC, Feijge MAH, et al. Platelet dysfunction in thrombosis patients treated with vitamin K antagonists and recurrent bleeding. PLoS One. 2013;8(5):e64112.
   Google Scholar
• Lee SH, Ryu WS, Roh JK. Cerebral microbleeds are a risk factor for warfarin-related intracerebral hemorrhage. Neurology. 2009;72(2):171–176.
   PubMed Web of Science ®Google Scholar
• Abbott NJ, Rönnbäck L, Hansson E. Astrocyte-endothelial interactions at the blood-brain barrier. Nat Rev Neurosci. 2006;7(1):41–53.
   PubMed Web of Science ®Google Scholar
• Han KH, O’Neill WC. Increased peripheral arterial calcification in patients receiving warfarin. J Am Heart Assoc. 2016;5(1):e002665.
   Web of Science ®Google Scholar
• Derksen WJM, Peeters W, Tersteeg C, et al. Age and coumarin-type anticoagulation are associated with the occurrence of intraplaque hemorrhage, while statins are associated less with intraplaque hemorrhage: a large histopathological study in carotid and femoral plaques. Atherosclerosis. 2011;214(1):139–143.
   PubMed Web of Science ®Google Scholar
• Van Ryn J, Goss A, Hauel N, et al. The discovery of dabigatran etexilate. Front Pharmacol. 2013;4:12.
   PubMed Web of Science ®Google Scholar
• Hankey GJ, Eikelboom JW. Dabigatran etexilate: a new oral thrombin inhibitor. Circulation. 2011;123(13):1436–1450.
   PubMed Web of Science ®Google Scholar
• Stangier J, Stähle H, Rathgen K, et al. Pharmacokinetics and pharmacodynamics of the direct oral thrombin inhibitor dabigatran in healthy elderly subjects. Clin Pharmacokinet. 2008;47(1):47–59.
   PubMed Web of Science ®Google Scholar
• Reilly PA, Lehr T, Haertter S, et al. The effect of dabigatran plasma concentrations and patient characteristics on the frequency of ischemic stroke and major bleeding in atrial fibrillation patients: the RE-LY Trial (Randomized Evaluation of Long-Term Anticoagulation Therapy). J Am Coll Cardiol. 2014;63(4):321–328.
   PubMed Web of Science ®Google Scholar
• Dale B, Eikelboom JW, Weitz JI, et al. Dabigatran attenuates thrombin generation to a lesser extent than warfarin: could this explain their differential effects on intracranial hemorrhage and myocardial infarction? J Thromb Thrombolysis. 2013;35(2):295–301.
   PubMed Web of Science ®Google Scholar
• Chan NC, Coppens M, Hirsh J, et al. Real-world variability in dabigatran levels in patients with atrial fibrillation. J Thromb Haemost. 2015;13(3):353–359.
   PubMed Web of Science ®Google Scholar
• Perzborn E, Strassburger J, Wilmen A, et al. In vitro and in vivo studies of the novel antithrombotic agent BAY 59-7939 – an oral, direct factor Xa inhibitor. J Thromb Haemost. 2005;3(3):514–521.
   PubMed Web of Science ®Google Scholar
• Kubitza D, Becka M, Wensing G, et al. Safety, pharmacodynamics, and pharmacokinetics of BAY 59-7939–an oral, direct factor Xa inhibitor–after multiple dosing in healthy male subjects. Eur J Clin Pharmacol. 2005;61(12):873–880.
   PubMed Web of Science ®Google Scholar
• Kubitza D, Becka M, Voith B, et al. Safety, pharmacodynamics, and pharmacokinetics of single doses of BAY 59-7939, an oral, direct factor Xa inhibitor. Clin Pharmacol Ther. 2005;78(4):412–421.
   PubMed Web of Science ®Google Scholar
• Lang D, Freudenberger C, Weinz C. In vitro metabolism of rivaroxaban, an oral, direct factor Xa inhibitor, in liver microsomes and hepatocytes of rats, dogs, and humans. Drug Metab Dispos. 2009;37(5):1046–1055.
   PubMed Web of Science ®Google Scholar
• He K, Luettgen JM, Zhang D, et al. Preclinical pharmacokinetics and pharmacodynamics of apixaban, a potent and selective factor Xa inhibitor. Eur J Drug Metab Pharmacokinet. 2011;36(3):129–139.
   PubMed Web of Science ®Google Scholar
• Carreiro J, Ansell J. Apixaban, an oral direct factor Xa inhibitor: awaiting the verdict. Expert Opin Investig Drugs. 2008;17(12):1937–1945.
   PubMed Web of Science ®Google Scholar
• Pfizer BMS. Apixaban, summary of the product characteristics; 2011 [2016 Apr 26]. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002148/WC500107728.pdf
   Google Scholar
• Raghavan N, Frost CE, Yu Z, et al. Apixaban metabolism and pharmacokinetics after oral administration to humans. Drug Metab Dispos. 2009;37(1):74–81.
   PubMed Web of Science ®Google Scholar
• Furugohri T, Isobe K, Honda Y, et al. DU-176b, a potent and orally active factor Xa inhibitor: in vitro and in vivo pharmacological profiles. J Thromb Haemost. 2008;6(9):1542–1549.
   PubMed Web of Science ®Google Scholar
• Bathala MS, Masumoto H, Oguma T, et al. Pharmacokinetics, biotransformation, and mass balance of edoxaban, a selective, direct factor Xa inhibitor, in humans. Drug Metab Dispos. 2012;40(12):2250–2255.
   PubMed Web of Science ®Google Scholar
• Ogata K, Mendell-Harary J, Tachibana M, et al. Clinical safety, tolerability, pharmacokinetics, and pharmacodynamics of the novel factor Xa inhibitor edoxaban in healthy volunteers. J Clin Pharmacol. 2010;50(7):743–753.
   PubMed Web of Science ®Google Scholar
• Lip GYH, Agnelli G. Edoxaban: a focused review of its clinical pharmacology. Eur Heart J. 2014;35(28):1844–1855.
   PubMed Web of Science ®Google Scholar
• Savaysa. Prescribing information. Parsippany (NJ): Daiichi Sankyo, Inc; 2015.
   Google Scholar
• Morimoto T, Crawford B, Wada K, et al. Comparative efficacy and safety of novel oral anticoagulants in patients with atrial fibrillation: a network meta-analysis with the adjustment for the possible bias from open label studies. J Cardiol. 2015;66(6):466–474.
   PubMed Web of Science ®Google Scholar
• Tereshchenko LG, Henrikson CA, Cigarroa J, et al. comparative effectiveness of interventions for stroke prevention in atrial fibrillation: a network meta-analysis. J Am Heart Assoc. 2016;5(5):e003206.
   PubMed Web of Science ®Google Scholar
• Sjögren V, Grzymala-Lubanski B, Renlund H, et al. Safety and efficacy of well managed warfarin. A report from the Swedish quality register Auricula. Thromb Haemost. 2015;113(6):1370–1377.
   PubMed Web of Science ®Google Scholar
• Borissoff JI, Otten JJT, 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(2):e55784.
   PubMed Web of Science ®Google Scholar
• Kadoglou NPE, 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(5):367–374.
   PubMed Web of Science ®Google Scholar
• Lee I-O, 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(2):253–257.
   PubMed Web of Science ®Google Scholar
• Borissoff JI, Spronk HMH, Ten Cate H. The hemostatic system as a modulator of atherosclerosis. N Engl J Med. 2011;364(18):1746–1760.
   PubMed Web of Science ®Google Scholar
• Bentzon JF, Falk E. Atherosclerotic lesions in mouse and man: is it the same disease? Curr Opin Lipidol. 2010;21(5):434–440.
   PubMed Web of Science ®Google Scholar
• Joseph P, Pare G, Wallentin L, et al. Dabigatran etexilate and reduction in serum apolipoprotein B. Heart. 2016;102(1):57–62.
   PubMed Web of Science ®Google Scholar
• Schurgers LJ, Spronk HMH. Differential cellular effects of old and new oral anticoagulants: consequences to the genesis and progression of atherosclerosis. Thromb Haemost. 2014;112(5):909–917.
   PubMed Web of Science ®Google Scholar
• Spronk HMH, De Jong AM, Crijns HJ, et al. Pleiotropic effects of factor Xa and thrombin: what to expect from novel anticoagulants. Cardiovasc Res. 2014;101(3):344–351.
   PubMed Web of Science ®Google Scholar
• Gailani D, Bane CE, Gruber A. Factor XI and contact activation as targets for antithrombotic therapy. J Thromb Haemost. 2015;13(8):1383–1395.
   PubMed Web of Science ®Google Scholar
• Wheeler AP, Gailani D. Why factor XI deficiency is a clinical concern. Expert Rev Hematol. 2016;9(7):629–637.
   PubMed Web of Science ®Google Scholar
• Gailani D, Broze GJ. Factor XI activation in a revised model of blood coagulation. Science. 1991;253(5022):909–912.
   PubMed Web of Science ®Google Scholar
• Kamphuisen PW, Ten Cate H. Cardiovascular risk in patients with hemophilia. Blood. 2014;123(9):1297–1301.
   PubMed Web of Science ®Google Scholar
• Bouma BN, Meijers JC. Role of blood coagulation factor XI in downregulation of fibrinolysis. Curr Opin Hematol. 2000;7(5):266–272.
   PubMed Web of Science ®Google Scholar
• Colucci M, Incampo F, Cannavò A, et al. Reduced fibrinolytic resistance in patients with factor XI deficiency. Evidence of a thrombin-independent impairment of the thrombin-activatable fibrinolysis inhibitor pathway. J Thromb Haemost. 2016;14(8):1603–1614.
   PubMed Web of Science ®Google Scholar
• Dai L, Mitchell M, Savidge G, et al. The profibrinolytic effect of plasma thrombomodulin in factor XI deficiency and its implications in hemostasis. J Thromb Haemost. 2004;2(12):2200–2204.
   PubMed Web of Science ®Google Scholar
• May F, Krupka J, Fries M, et al. FXIIa inhibitor rHA-Infestin-4: safe thromboprotection in experimental venous, arterial and foreign surface-induced thrombosis. Br J Haematol. 2016;173(5):769–778.
   PubMed Web of Science ®Google Scholar
• Renné T, Pozgajová M, Grüner S, et al. Defective thrombus formation in mice lacking coagulation factor XII. J Exp Med. 2005;202(2):271–281.
   PubMed Web of Science ®Google Scholar
• Key NS. Epidemiologic and clinical data linking factors XI and XII to thrombosis. Hematol Am Soc Hematol Educ Program. 2014;2014(1):66–70.
   PubMedGoogle Scholar
• Björkqvist J, Nickel KF, Stavrou E, et al. In vivo activation and functions of the protease factor XII. Thromb Haemost. 2014;112(5):868–875.
   PubMed Web of Science ®Google Scholar
• De Maat S, Van Dooremalen S, De Groot PG, et al. A nanobody-based method for tracking factor XII activation in plasma. Thromb Haemost. 2013;110(3):458–468.
   PubMed Web of Science ®Google Scholar
• De Maat S, De Groot PG, Maas C. Contact system activation on endothelial cells. Semin Thromb Hemost. 2014;40(8):887–894.
   PubMed Web of Science ®Google Scholar
• Konings J, Cugno M, Suffritti C, et al. Ongoing contact activation in patients with hereditary angioedema. PLoS One. 2013;8(8):e74043.
   Google Scholar
• Larsson M, Rayzman V, Nolte MW, et al. A factor XIIa inhibitory antibody provides thromboprotection in extracorporeal circulation without increasing bleeding risk. Sci Transl Med. 2014;6(222):222ra17.
   PubMed Web of Science ®Google Scholar
• Yau JW, Liao P, Fredenburgh JC, et al. Selective depletion of factor XI or factor XII with antisense oligonucleotides attenuates catheter thrombosis in rabbits. Blood. 2014;123(13):2102–2107.
   PubMed Web of Science ®Google Scholar
• Baglin TP, Langdown J, Frasson R, et al. Discovery and characterization of an antibody directed against exosite I of thrombin. J Thromb Haemost. 2016;14(1):137–142.
   PubMed Web of Science ®Google Scholar
• Eikelboom JW, Connolly SJ, Brueckmann M, et al. Dabigatran versus warfarin in patients with mechanical heart valves. N Engl J Med. 2013;369(13):1206–1214.
   PubMed Web of Science ®Google Scholar
• Jaffer IH, Stafford AR, Fredenburgh JC, et al. Dabigatran is less effective than warfarin at attenuating mechanical heart valve-induced thrombin generation. J Am Heart Assoc. 2015;4(8):e002322.
   PubMed Web of Science ®Google Scholar
• Mega JL, Braunwald E, Wiviott SD, et al. Rivaroxaban in patients with a recent acute coronary syndrome. N Engl J Med. 2012;366(1):9–19.
   PubMed Web of Science ®Google Scholar
• Alexander JH, Lopes RD, James S, et al. Apixaban with antiplatelet therapy after acute coronary syndrome. N Engl J Med. 2011;365(8):699–708.
   PubMed Web of Science ®Google Scholar
• Oldgren J, Budaj A, Granger CB, et al. Dabigatran vs. placebo in patients with acute coronary syndromes on dual antiplatelet therapy: a randomized, double-blind, phase II trial. Eur Heart J. 2011;32(22):2781–2789.
   PubMed Web of Science ®Google Scholar
• Fischer MA, Stedman MR, Lii J, et al. Primary medication non-adherence: analysis of 195,930 electronic prescriptions. J Gen Intern Med. 2010;25(4):284–290.
   PubMed Web of Science ®Google Scholar
• Shiga T, Naganuma M, Nagao T, et al. Persistence of non-vitamin K antagonist oral anticoagulant use in Japanese patients with atrial fibrillation: a single-center observational study. J Arrhythm. 2015;31(6):339–344.
   PubMed Web of Science ®Google Scholar
• Beyer-Westendorf J, Ehlken B, Evers T. Real-world persistence and adherence to oral anticoagulation for stroke risk reduction in patients with atrial fibrillation. Europace. 2016;18:1150–1157.
   PubMed Web of Science ®Google Scholar