General mechanisms of coagulation and targets of anticoagulants (Section I)

Raffaele De Caterina; Steen Husted; Lars Wallentin; Felicita Andreotti; Harald Arnesen; Fedor Bachmann; Colin Baigent; Kurt Huber; Jørgen Jespersen; Steen Dalby Kristensen; Gregory Y. H. Lip; João Morais; Lars Hvilsted Rasmussen; Agneta Siegbahn; Freek W. A. Verheugt; Jeffrey I. Weitz

doi:10.1160/TH12-10-0772

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2013; 109(04): 569-579
DOI: 10.1160/TH12-10-0772

Position Paper

Schattauer GmbH

General mechanisms of coagulation and targets of anticoagulants (Section I)

Position Paper of the ESC Working Group on Thrombosis – Task Force on Anticoagulants in Heart Disease

Authors

Raffaele De Caterina^*

¹Cardiovascular Division, Ospedale SS. Annunziata, G. d’Annunzio University, Chieti, Italy
Steen Husted^*

²Medical-Cardiological Department, Aarhus Sygehus, Aarhus, Denmark
Lars Wallentin^*

³Cardiology, Uppsala Clinical Research Centre and Department of Medical Sciences, Uppsala University, Uppsala, Sweden
Felicita Andreotti^**

⁴Institute of Cardiology, Catholic University, Rome, Italy
Harald Arnesen^**

⁵Medical Department, Oslo University Hospital, Ulleval, Norway
Fedor Bachmann^**

⁶Department of Medicine, University of Lausanne, Lausanne, Switzerland
Colin Baigent^**

⁷Cardiovascular Science, Oxford University, Oxford, UK
Kurt Huber^**

⁸3rd Department of Medicine, Wilhelminenspital, Vienna, Austria
Jørgen Jespersen^**

⁹Unit for Thrombosis Research, University of Southern Denmark, Esbjerg, Denmark
Steen Dalby Kristensen^**

¹⁰Department of Cardiology, Aarhus University Hospital, Skejby, Aarhus, Denmark
Gregory Y. H. Lip^**

¹¹Haemostasis Thrombosis & Vascular Biology Unit, Centre for Cardiovascular Sciences, City Hospital, Birmingham, UK
João Morais^**

¹²Cardiology, Leiria Hospital, Leiria, Portugal
Lars Hvilsted Rasmussen^**

¹³Department of Cardiology, Thrombosis Center Aalborg, Aarhus University Hospital, Aalborg, Denmark
Agneta Siegbahn^**

¹⁴Coagulation and Inflammation Science, Department of Medical Sciences, Uppsala University, Uppsala, Sweden
Freek W. A. Verheugt^**

¹⁵Cardiology, Medical Centre, Radboud University Nijmegen, Nijmegen, Netherlands
Jeffrey I. Weitz^**

¹⁶Thrombosis & Atherosclerosis Research Institute, Hamilton General Hospital, Hamilton, Ontario, Canada

Abstract

Summary

Contrary to previous models based on plasma, coagulation processes are currently believed to be mostly cell surface-based, including three overlapping phases: initiation, when tissue factor-expressing cells and microparticles are exposed to plasma; amplification, whereby small amounts of thrombin induce platelet activation and aggregation, and promote activation of factors (F)V, FVIII and FXI on platelet surfaces; and propagation, in which the Xase (tenase) and prothrombinase complexes are formed, producing a burst of thrombin and the cleavage of fibrinogen to fibrin. Thrombin exerts a number of additional biological actions, including platelet activation, amplification and self-inhibition of coagulation, clot stabilisation and anti-fibrinolysis, in processes occurring in the proximity of vessel injury, tightly regulated by a series of inhibitory mechanisms. ″Classical″ anticoagulants, including heparin and vitamin K antagonists, typically target multiple coagulation steps. A number of new anticoagulants, already developed or under development, target specific steps in the process, inhibiting a single coagulation factor or mimicking natural coagulation inhibitors.

Keywords

Anticoagulants - coagulation - tissue factor - heart disease - coronary heart disease - heart failure - atrial fibrillation

Full Text

References

References
1 Patrono C, Andreotti F, Arnesen H. et al. Antiplatelet agents for the treatment and prevention of atherothrombosis. Expert position paper on the use of anti-platelet agents by the Task Force of the European Society of Cardiology on the use of antiplatelet agents for the treatment and prevention of atherothrombosis. Eur Heart J 2011; 32: 2922-2932.
2 De Caterina R, Husted S, Wallentin L. et al. Anticoagulants in heart disease: current status and perspectives. Eur Heart J 2007; 28: 880-913.
3 De Caterina R, Husted S, Wallentin L. et al. New oral anticoagulants in atrial fibrillation and acute coronary syndromes: ESC Working Group on Thrombosis-Task force on Anticoagulants in Heart Disease Position Paper. J Am Coll Cardiol 2012; 59: 1413-1425.
4 Astrup T. The haemostatic balance. Thromb Diath Haemorrh 1958; 02: 347-357.
5 Davie EW, Fujikawa K, Kisiel W. The coagulation cascade: initiation, maintenance, and regulation. Biochemistry 1991; 30: 10363-10370.
6 Owens 3rd AP, Mackman N. Tissue factor and thrombosis: The clot starts here. Thromb Haemost 2010; 104: 432-439.
7 Pawlinski R, Mackman N. Cellular sources of tissue factor in endotoxemia and sepsis. Thromb Res 2010; 125 (Suppl. 01) S70-73.
8 Day SM, Reeve JL, Pedersen B. et al. Macrovascular thrombosis is driven by tissue factor derived primarily from the blood vessel wall. Blood 2005; 105: 192-198.
9 Wang L, Miller C, Swarthout RF. et al. Vascular smooth muscle-derived tissue factor is critical for arterial thrombosis after ferric chloride-induced injury. Blood 2009; 113: 705-713.
10 Roque M, Reis ED, Fuster V. et al. Inhibition of tissue factor reduces thrombus formation and intimal hyperplasia after porcine coronary angioplasty. J Am Coll Cardiol 2000; 36: 2303-2310.
11 Pawashe AB, Golino P, Ambrosio G. et al. A monoclonal antibody against rabbit tissue factor inhibits thrombus formation in stenotic injured rabbit carotid arteries. Circ Res 1994; 74: 56-63.
12 Lee AY, Vlasuk GP. Recombinant nematode anticoagulant protein c2 and other inhibitors targeting blood coagulation factor VIIa/tissue factor. J Intern Med 2003; 254: 313-321.
13 Giugliano RP, Wiviott SD, Stone PH. et al. Recombinant nematode anticoagulant protein c2 in patients with non-ST-segment elevation acute coronary syndrome: the ANTHEM-TIMI-32 trial. J Am Coll Cardiol 2007; 49: 2398-2407.
14 Belting M, Dorrell MI, Sandgren S. et al. Regulation of angiogenesis by tissue factor cytoplasmic domain signalling. Nat Med 2004; 10: 502-509.
15 Rao LVM, Pendurthi UR. Tissue factor-factor VIIa signalling. Arterioscler Thromb Vasc Biol 2005; 25: 47-56.
16 Siegbahn A, Johnell M, Sorensen BB. et al. Regulation of chaemotaxis by the cy-toplasmic domain of tissue factor. Thromb Haemost 2005; 93: 27-34.
17 Siegbahn A, Johnell M, Nordin A. et al. TF/FVIIa transactivate PDGFRβ to regulate PDGF-BB-induced chaemotaxis in different cell types: involvement of Src and PLC. Arterioscler Thromb Vasc Biol 2008; 28: 135-141.
18 Owens 3rd AP, Mackman N. Sources of tissue factor that contribute to thrombosis after rupture of an atherosclerotic plaque. Thromb Res 2012; 129 (Suppl. 02) S30-33.
19 Morel O, Jesel L, Freyssinet JM. et al. Cellular mechanisms underlying the formation of circulating microparticles. Arterioscler Thromb Vasc Biol 2011; 31: 15-26.
20 Rautou PE, Vion AC, Amabile N. et al. Microparticles, vascular function, and atherothrombosis. Circ Res 2011; 109: 593-606.
21 Lacroix R, Dignat-George F. Microparticles as a circulating source of procoagulant and fibrinolytic activities in the circulation. Thromb Res 2012; 129 (Suppl. 02) S27-29.
22 Choudhury A, Chung I, Blann AD. et al. Elevated platelet microparticle levels in nonvalvular atrial fibrillation: relationship to P-selectin and antithrombotic therapy. Chest 2007; 131: 809-815.
23 Østerud B. Tissue factor/TFPI and blood cells. Thromb Res 2012; 129: 274-278.
24 Holy EW, Tanner FC. Tissue factor in cardiovascular disease: pathophysiology and pharmacological intervention. Adv Pharmacol 2010; 59: 259-292.
25 Boing AN, Hau CM, Sturk A. et al. Human alternatively spliced tissue factor is not secreted and does not trigger coagulation. J Thromb Haemost 2009; 07: 1423-1426.
26 Crawley JTB, Lane DA. The haemostatic role of tissue factor pathway inhibitor. Arterioscler Thromb Vasc Biol 2008; 28: 233-242.
27 Lwaleed BA, Bass PS. Tissue factor pathway inhibitor: structure, biology and involvement in disease. J Pathol 2006; 208: 327-339.
28 Bajaj MS, Kuppuswamy MN, Saito H. et al. Cultured normal human hepato-cytes do not synthesize lipoprotein-associated coagulation inhibitor: evidence that endothelium is the principal site of its synthesis. Proc Natl Acad Sci USA 1990; 87: 8869-8873.
29 Sandset PM, Abildgaard U, Larsen ML. Heparin induces release of extrinsic coagulation pathway inhibitor (EPI). Thromb Res 1988; 50: 803-813.
30 Hackeng TM, Rosing J. Protein S as cofactor for TFPI. Arterioscler Thromb Vasc Biol 2009; 29: 2015-2020.
31 Hackeng TM, Sére KM, Tans G. et al. Protein S stimulates inhibition of the tissue factor pathway by tissue factor pathway inhibitor. Proc Natl Acad Sci USA 2006; 103: 3106-3111.
32 Abraham E, Reinhart K, Opal S. et al. Efficacy and safety of tifacogin (recombinant tissue factor pathway inhibitor) in severe sepsis: a randomized controlled trial. J Am Med Assoc 2003; 290: 238-247.
33 Dahlback B. Blood coagulation. Lancet 2000; 355: 1627-1632.
34 Hoffman M, Monroe 3rd DM. A cell-based model of haemostasis. Thromb Haemost 2001; 85: 958-965.
35 Monroe DM, Hoffman M, Roberts HR. Platelets and thrombin generation. Ar-terioscler Thromb Vasc Biol 2002; 22: 1381-1389.
36 Mann KG. Thrombin formation. Chest 2003; 124: 4S-10S.
37 Monroe DM, Hoffman M. What does it take to make the perfect clot?. Arterioscler Thromb Vasc Biol 2006; 26: 41-48.
38 Roberts HR, Hoffman M, Monroe DM. A cell-based model of thrombin generation. Semin Thromb Haemost 2006; 32 (Suppl. 01) 32-38.
39 Mann KG, Brummel K, Butenas S. What is all that thrombin for?. J Thromb Haemost 2003; 01: 1504-1514.
40 Müller F, Gailani D, Renné T. Factor XI and XII as antithrombotic targets. Curr Opin Hematol 2011; 18: 349-355.
41 Jalbert LR, Rosen ED, Moons L. et al. Inactivation of the gene for anticoagulant protein C causes lethal perinatal consumptive coagulopathy in mice. J Clin Invest 1998; 102: 1481-1488.
42 Rosenberg RD. Thrombomodulin gene disruption and mutation in mice. Thromb Haemost 1997; 78: 705-79.
43 Bouma BN, Meijers JC. Thrombin-activatable fibrinolysis inhibitor (TAFI, plasma procarboxypeptidase B, procarboxypeptidase R, procarboxypeptidase U). J Thromb Haemost 2003; 01: 1566-1574.
44 Meltzer ME, Doggen CJ, de Groot PG. et al. The impact of the fibrinolytic system on the risk of venous and arterial thrombosis. Semin Thromb Haemost 2009; 35: 468-477.
45 Levi M, van der Poll T. Two-way interactions between inflammation and coagulation. Trends Cardiovasc Med 2005; 15: 254-259.
46 Petäjä J. Inflammation and coagulation. An overview. Thromb Res 2011; 127 (Suppl. 02) S34-37.
47 Symmons DP, Gabriel SE. Epidemiology of CVD in rheumatic disease, with a focus on RA and SLE. Nat Rev Rheumatol 2011; 07: 399-408.
48 Esmon CT. Crosstalk between inflammation and thrombosis. Maturitas 2004; 47: 305-314.
49 Coughlin SR. Protease-activated receptors in haemostasis, thrombosis and vascular biology. J Thromb Haemost 2005; 03: 1800-1814.
50 Riewald M, Petrovan RJ, Donner A. et al. Activation of endothelial cell protease activated receptor 1 by the protein C pathway. Science 2002; 296: 1880-1882.
51 Ruf W, Dorfleutner A, Riewald M. Specificity of coagulation factor signalling. J Thromb Haemost 2003; 01: 1495-1503.
52 Morrow DA, Braunwald E, Bonaca MP. et al. Vorapaxar in the secondary prevention of atherothrombotic events. N Engl J Med 2012; 366: 1404-1413.
53 Tricoci P, Huang Z, Held C. et al. Thrombin-receptor antagonist vorapaxar in acute coronary syndromes. N Engl J Med 2012; 366: 20-33.
54 Collin N, Assumpção TC, Mizurini DM. et al. Lufaxin, a Novel Factor Xa Inhibitor From the Salivary Gland of the Sand Fly Lutzomyia longipalpis Blocks Protease-Activated Receptor 2 Activation and Inhibits Inflammation and Thrombosis In Vivo. Arterioscler Thromb Vasc Biol 2012; 32: 2185-2198.
55 Jerjes-Sanchez C. Venous and arterial thrombosis: a continuous spectrum of the same disease?. Eur Heart J 2005; 26: 3-4.
56 Fuster V, Moreno PR, Fayad ZA. et al. Atherothrombosis and high-risk plaque: part I: evolving concepts. J Am Coll Cardiol 2005; 46: 937-954.
57 Hansson GK. Inflammation, atherosclerosis, and coronary artery disease. N Eng J Med 2005; 352: 1685-1695.
58 Lippi G, Franchini M, Targher G. Arterial thrombus formation in cardiovascular disease. Nat Rev Cardiol 2011; 08: 502-512.
59 Arbustini E, Dal Bello B, Morbini P. et al. Plaque erosion is a major substrate for coronary thrombosis in acute myocardial infarction. Heart 1999; 82: 269-272.
60 Becker RC. Thrombogenesis in atrial fibrillation contributing mechanisms and natural history. J Thromb Haemost 2009; 27: 119-121.
61 Watson T, Shantsila E, Lip GY. Mechanisms of thrombogenesis in atrial fibrillation: Virchow’s triad revisited. Lancet 2009; 373: 155-166.
62 de Peuter OR, Kok WE, Torp-Pedersen C. et al. Systolic heart failure: a pro-thrombotic state. Semin Thromb Haemost 2009; 35: 497-504.
63 Bettari L, Fiuzat M, Becker R. et al. Thromboembolism and antithrombotic therapy in patients with heart failure in sinus rhythm: current status and future directions. Circ Heart Fail 2011; 04: 361-368.
64 Lopez-Cuenca A, Marin F, Roldan V. et al. Genetic polymorphisms and atrial fibrillation: Insights into the prothrombotic state and thromboembolic risk. Ann Med 2010; 42: 562-575.
65 Olesen JB, Lip GY, Hansen ML. et al. Validation of risk stratification schemes for predicting stroke and thromboembolism in patients with atrial fibrillation: nationwide cohort study. Br Med J 2011; 342: d124.
66 Connolly S, Pogue J, Hart R. et al. Clopidogrel plus aspirin versus oral antico-agulation for atrial fibrillation in the Atrial fibrillation Clopidogrel Trial with Ir-besartan for prevention of Vascular Events (ACTIVE W): a randomised controlled trial. Lancet 2006; 367: 1903-1912.
67 Connolly SJ, Eikelboom J, Joyner C. et al. Apixaban in patients with atrial fibrillation. N Engl J Med 2011; 364: 806-817.
68 Hirsh J, Raschke R. Heparin and low-molecular-weight heparin: the Seventh American College of Chest Physicians Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004; 126: 188S-203S.
69 Garcia DA, Baglin TP, Weitz JI. et al. Parenteral anticoagulants: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141: e24S-43S.
70 Tollefsen DM, Majerus DW, Blank MK. Heparin cofactor II. Purification and properties of a heparin-dependent inhibitor of thrombin in human plasma. J Biol Chem 1982; 257: 2162-2169.
71 Ageno W, Gallus AS, Wittkowsky A. et al. Oral anticoagulant therapy: Anti-thrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141: e44S-88S.
72 Weitz JI. Factor Xa and thrombin as targets for new oral anticoagulants. Thromb Res 2011; 127 (Suppl. 02) S5-S12.
73 Fox KAA, Cokkinos DV, Deckers J. et al. The ENACT study: a pan-European survey of acute coronary syndromes. European Network for Acute Coronary Treatment. Eur Heart J 2000; 21: 1440-1449.
74 Fox KAA, Goodman SG, Klein W. et al. Management of acute coronary syndromes. Variations in practice and outcome; findings from the Global Registry of Acute Coronary Events (GRACE). Eur Heart J 2002; 23: 1177-1189.
75 Hasdai D, Behar S, Wallentin L. et al. A prospective survey of the characteristics, treatments and outcomes of patients with acute coronary syndromes in Europe and the Mediterranean basin; the Euro Heart Survey of Acute Coronary Syndromes (Euro Heart Survey ACS). Eur Heart J 2002; 23: 1190-1201.
76 Bauer T, Gitt AK, Jünger C. et al. Guideline-recommended secondary prevention drug therapy after acute myocardial infarction: predictors and outcomes of nonadherence. Eur J Cardiovasc Prev Rehab 2010; 17: 576-581.
77 Bauer T, Gitt A, Zahn R. et al. Impact of chronic antithrombotic therapy on hospital course of patients with acute myocardial infarction. The Acute COronary Syndromes Registry (ACOS) Investigators. Clin Cardiol 2009; 32: 718-723.
78 Wood DA. for the EUROASPIRE II Study Group. Lifestyle and risk factor management and use of drug therapies in coronary patients from 15 countries; Principal results from EUROASPIRE II. Euro Heart Survey Programme. Eur Heart J 2001; 22: 554-572.
79 Ogilvie IM, Welner SA, Cowell W. et al. Ischaemic stroke and bleeding rates in ‘real-world’ atrial fibrillation patients. Thromb Haemost 2011; 106: 34-44.
80 Ogilvie IM, Newton N, Welner SA. et al. Underuse of oral anticoagulants in atrial fibrillation: a systematic review. Am J Med 2010; 123: 638-645.
81 Ogilvie IM, Welner SA, Cowell W. et al. Characterisation of the proportion of untreated and antiplatelet therapy treated patients with atrial fibrillation. Am J Cardiol 2011; 108: 151-161.
82 Gallagher AM, Setakis E, Plumb JM. et al. Risks of stroke and mortality associated with suboptimal anticoagulation in atrial fibrillation patients. Thromb Haemost 2011; 106: 968-977.
83 Nieuwlaat R, Capucci A, Camm AJ. et al. Atrial fibrillation management: a prospective survey in ESC member countries: The Euro Heart Survey on Atrial Fibrillation. Eur Heart J 2005; 26: 2422-2434.
84 Garcia DA, Lopes RD, Hylek EM. New-onset atrial fibrillation and warfarin initiation: High risk periods and implications for new antithrombotic drugs. Thromb Haemost 2010; 104: 1099-1105.
85 Lip GY, Andreotti F, Fauchier L. et al. Bleeding risk assessment and management in atrial fibrillation patients: a position document from the European Heart Rhythm Association, endorsed by the European Society of Cardiology Working Group on Thrombosis. Europace 2011; 13: 723-746.
86 Camm AJ, Lip GY, De Caterina R. et al. 2012 focused update of the ESC Guidelines for the management of atrial fibrillation: An update of the 2010 ESC Guidelines for the management of atrial fibrillation * Developed with the special contribution of the European Heart Rhythm Association. Eur Heart J.. 2012 doi:10.1093/eurheartj/ehs253.
87 Whitlock RP, Sun JC, Fremes SE. et al. Antithrombotic and thrombolytic therapy for valvular disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141: e576S-600S.
88 Akhtar RP, Abid AR, Zafar H. et al. Aniticoagulation in patients following prosthetic heart valve replacement. Ann Thorac Cardiovasc Surg 2009; 15: 10-17.
89 Vahanian A, Alfieri O, Andreotti F. et al. Guidelines on the management of valvular heart disease (version 2012): The Joint Task Force on the Management of Valvular Heart Disease of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J 2012; 33: 2451-2496.
90 Bonow RO, Carabello BA, Chatterjee K. et al. 2008 Focused update incorporated into the ACC/AHA 2006 guidelines for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 1998 Guidelines for the Management of Patients With Valvular Heart Disease): endorsed by the Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. Circulation 2008; 118: e523-661.
91 Butchart EG, De Caterina R. Antithrombotic management in patients with prosthetic valves. Therapeutic Advances in Thrombosis.. 2013. Wiley-Blackwell; Hoboken, NJ, USA: 246-271.
92 Freudenberger RS, Schumaecker MM, Homma S. What is the appropriate approach to prevention of thromboembolism in heart failure?. Thromb Haemost 2010; 103: 489-495.
93 Lip GH, Gibbs CR. Anticoagulation for heart failure in sinus rhythm. Cochrane Database Syst Rev 2011; 03: CD003336.
94 Homma S, Thompson JL, Pullicino PM. et al. Warfarin and aspirin in patients with heart failure and sinus rhythm. N Engl J Med 2012; 366: 1859-1869.
95 Mujib M, Rahman AAZ, Desai RV. et al. Warfarin use and outcomes in patients with advanced chronic systolic heart failure without atrial fibrillation, prior thromboembolic events, or prosthetic valves. Am J Cardiol 2011; 107: 552-557.