Anticoagulation beyond direct thrombin and factor Xa inhibitors: indications for targeting the intrinsic pathway?

Maurits L. van Montfoort; Joost C. M. Meijers

doi:10.1160/TH12-11-0803

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 2013; 110(02): 223-232
DOI: 10.1160/TH12-11-0803

Review Article

Schattauer GmbH

Anticoagulation beyond direct thrombin and factor Xa inhibitors: indications for targeting the intrinsic pathway?

Maurits L. van Montfoort

¹Department of Experimental Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

,

Joost C. M. Meijers

¹Department of Experimental Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

› Institutsangaben

Abstract

Summary

Antithrombotic drugs like vitamin K antagonists and heparin have been the gold standard for the treatment and prevention of thromboembolic disease for many years. Unfortunately, there are several disadvantages of these antithrombotic drugs: they are accompanied by serious bleeding problems, it is necessary to monitor the therapeutic window, and there are various interactions with food and other drugs. This has led to the development of new oral anticoagulants, specifically inhibiting either thrombin or factor Xa. In terms of effectiveness, these drugs are comparable to the currently available anticoagulants; however, they are still associated with issues such as bleeding, reversal of the drug and complicated laboratory monitoring. Vitamin K antagonists, heparin, direct thrombin and factor Xa inhibitors have in common that they target key proteins of the haemostatic system. In an attempt to overcome these difficulties we investigated whether the intrinsic coagulation factors (VIII, IX, XI, XII, prekallikrein and high-molecular-weight kininogen) are superior targets for anticoagulation. We analysed epidemiological data concerning thrombosis and bleeding in patients deficient in one of the intrinsic pathway proteins. Furthermore, we discuss several thrombotic models in intrinsic coagulation factor-deficient animals. The combined results suggest that intrinsic coagulation factors could be suitable targets for anticoagulant drugs.

Keywords

Venous thrombosis - coagulation factors - arterial thrombosis - drug design

Volltext

Referenzen

References
1 Guyatt GH, Akl EA, Crowther M. et al. Executive summary: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141: 7S-47S.
2 Mannucci PM, Levi M. Prevention and treatment of major blood loss. N Engl J Med 2007; 356: 2301-2311.
3 Schulman S, Beyth RJ, Kearon C. et al. Haemorrhagic complications of anticoagulant and thrombolytic treatment: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. 8th Edition. Chest. 2008. 133 257S-98S.
4 Van Es J, Eerenberg ES, Kamphuisen PW. et al. How to prevent, treat, and overcome current clinical challenges of VTE. J Thromb Haemost 2011; 09 (Suppl. 01) 265-274.
5 Connolly SJ, Ezekowitz MD, Yusuf S. et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009; 361: 1139-1151.
6 Patel MR, Mahaffey KW, Garg J. et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011; 365: 883-891.
7 Bauersachs R, Berkowitz SD, Brenner B. et al. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 2010; 363: 2499-2510.
8 Buller HR, Prins MH, Lensin AW. et al. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med 2012; 366: 1287-1297.
9 Granger CB, Alexander JH, McMurray JJ. et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011; 365: 981-992.
10 Miller CS, Grandi SM, Shimony A. et al. Meta-Analysis of Efficacy and Safety of New Oral Anticoagulants (Dabigatran, Rivaroxaban, Apixaban) Versus Warfarin in Patients With Atrial Fibrillation. Am J Cardiol. 2012 Epub ahead of print..
11 Hillarp A, Baghaei F, Fagerberg B. et al. Effects of the oral, direct factor Xa inhibitor rivaroxaban on commonly used coagulation assays. J Thromb Haemost 2011; 09: 133-139.
12 van Ryn J, Stangier J, Haertter S. et al. Dabigatran etexilate--a novel, reversible, oral direct thrombin inhibitor: interpretation of coagulation assays and reversal of anticoagulant activity. Thromb Haemost 2010; 103: 1116-1127.
13 Eerenberg ES, Kamphuisen PW, Sijpkens MK. et al. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled, crossover study in healthy subjects. Circulation 2011; 124: 1573-1579.
14 Hirsh J, O’Donnell M, Weitz JI. New anticoagulants. Blood 2005; 105: 453-463.
15 Bi L, Lawler AM, Antonarakis SE. et al. Targeted disruption of the mouse factor VIII gene produces a model of haemophilia A. Nat Genet 1995; 10: 119-121.
16 Singh I, Smith A, Vanzieleghem B. et al. Antithrombotic effects of controlled inhibition of factor VIII with a partially inhibitory human monoclonal antibody in a murine vena cava thrombosis model. Blood 2002; 99: 3235-3240.
17 Jacquemin M, Stassen JM, Saint-Remy JM. et al. A human monoclonal antibody inhibiting partially factor VIII activity reduces thrombus growth in baboons. J Thromb Haemost 2009; 07: 429-437.
18 Verhamme P, Tangelder M, Verhaeghe R. et al. Single intravenous administration of TB-402 for the prophylaxis of venous thromboembolism after total knee replacement: a dose-escalating, randomized, controlled trial. J Thromb Haemost 2011; 09: 664-671.
19 Verhamme P, Pakola S, Jensen TJ. et al. Tolerability and pharmacokinetics of TB-402 in healthy male volunteers. Clin Ther 2010; 32: 1205-1220.
20 Tangelder M, Long C, Emmerechts J. et al. Antidote strategies to reverse anticoagulation with TB-402, a long-acting partial inhibitor of factor VIII. J Thromb Haemost 2012; 10: 1371-1378.
21 Spiegel PC, Kaiser SM, Simon JA. et al. Disruption of protein-membrane binding and identification of small-molecule inhibitors of coagulation factor VIII. Chem Biol 2004; 11: 1413-1422.
22 Wang L, Zoppe M, Hackeng TM. et al. A factor IX-deficient mouse model for haemophilia B gene therapy. Proc Natl Acad Sci USA 1997; 94: 11563-11566.
23 de Araujo RM, Vaz AF, Santos ME. et al. A new exogen anticoagulant with high selectivity to intrinsic pathway of coagulation. Thromb Res 2011; 128: 395-397.
24 Ogawa T, Chijiwa T, Oda-Ueda N. et al. Molecular diversity and accelerated evolution of C-type lectin-like proteins from snake venom. Toxicon 2005; 45: 1-14.
25 Roser-Jones C, Chan M, Howard EL. et al. Factor IXa as a target for pharmacologic inhibition in acute coronary syndrome. Cardiovasc Ther 2011; 29: e22-e35.
26 Mizurini DM, Francischetti IM, Andersen JF. et al. Nitrophorin 2, a factor IX (a)-directed anticoagulant, inhibits arterial thrombosis without impairing haemostasis. Thromb Haemost 2010; 104: 1116-1123.
27 Eriksson BI, Dahl OE, Lassen MR. et al. Partial factor IXa inhibition with TTP889 for prevention of venous thromboembolism: an exploratory study. J Thromb Haemost 2008; 06: 457-463.
28 Povsic TJ, Wargin WA, Alexander JH. et al. Pegnivacogin results in near complete FIX inhibition in acute coronary syndrome patients: RADAR pharmacokinetic and pharmacodynamic substudy. Eur Heart J 2011; 32: 2412-2419.
29 Domm JA, Hudson MG, Janco RL. Complications of central venous access devices in paediatric haemophilia patients. Haemophilia 2003; 09: 50-56.
30 Vidler V, Richards M, Vora A. Central venous catheter-associated thrombosis in severe haemophilia. Br J Haematol 1999; 104: 461-464.
31 Hermans C, Hammer F, Lobet S. et al. Subclinical deep venous thrombosis observed in 10% of haemophilic patients undergoing major orthopedic surgery. J Thromb Haemost 2010; 08: 1138-1140.
32 Girolami A, Scandellari R, Zanon E. et al. Non-catheter associated venous thrombosis in haemophilia A and B A critical review of all reported cases. J Thromb Thrombolysis 2006; 21: 279-284.
33 Girolami A, Ruzzon E, Fabris F. et al. Myocardial infarction and other arterial occlusions in haemophilia a patients A cardiological evaluation of all 42 cases reported in the literature. Acta Haematol 2006; 116: 120-125.
34 Girolami A, Randi ML, Ruzzon E. et al. Myocardial infarction, other arterial thrombosis and invasive coronary procedures, in hemaophilia B: a critical evaluation of reported cases. J Thromb Thrombolysis 2005; 20: 43-46.
35 Foley CJ, Nichols L, Jeong K. et al. Coronary atherosclerosis and cardiovascular mortality in haemophilia. J Thromb Haemost 2010; 08: 208-211.
36 Zwiers M, Lefrandt JD, Mulder DJ. et al. Coronary artery calcification score and carotid intima-media thickness in patients with haemophilia. J Thromb Haemost 2012; 10: 23-29.
37 Jenkins PV, Rawley O, Smith OP. et al. Elevated factor VIII levels and risk of venous thrombosis. Br J Haematol 2012; 157: 653-663.
38 Plug I, Mauser-Bunschoten EP, Brocker-Vriends AH. et al. Bleeding in carriers of haemophilia. Blood 2006; 108: 52-56.
39 Sramek A, Kriek M, Rosendaal FR. Decreased mortality of ischaemic heart disease among carriers of haemophilia. Lancet 2003; 362: 351-354.
40 Tuinenburg A, Mauser-Bunschoten EP, Verhaar MC. et al. Cardiovascular disease in patients with haemophilia. J Thromb Haemost 2009; 07: 247-254.
41 Gailani D, Lasky NM, Broze Jr GJ. A murine model of factor XI deficiency. Blood Coagul Fibrinolysis 1997; 08: 134-144.
42 Lowenberg EC, Meijers JC, Monia BP. et al. Coagulation factor XI as a novel target for antithrombotic treatment. J Thromb Haemost 2010; 08: 2349-2357.
43 Muller F, Gailani D, Renne T. Factor XI and XII as antithrombotic targets. Curr Opin Hematol 2011; 18: 349-355.
44 Schumacher WA, Luettgen JM, Quan ML. et al. Inhibition of factor XIa as a new approach to anticoagulation. Arterioscler Thromb Vasc Biol 2010; 30: 388-392.
45 Rosen ED, Gailani D, Castellino FJ. FXI is essential for thrombus formation following FeCl3-induced injury of the carotid artery in the mouse. Thromb Haemost 2002; 87: 774-776.
46 Tucker EI, Marzec UM, White TC. et al. Prevention of vascular graft occlusion and thrombus-associated thrombin generation by inhibition of factor XI. Blood 2009; 113: 936-944.
47 Younis HS, Crosby J, Huh JI. et al. Antisense inhibition of coagulation factor XI prolongs APTT without increased bleeding risk in cynomolgus monkeys. Blood 2012; 119: 2401-2408.
48 Zhang H, Lowenberg EC, Crosby JR. et al. Inhibition of the intrinsic coagulation pathway factor XI by antisense oligonucleotides: a novel antithrombotic strategy with lowered bleeding risk. Blood 2010; 116: 4684-4692.
49 Salomon O, Steinberg DM, Koren-Morag N. et al. Reduced incidence of ischemic stroke in patients with severe factor XI deficiency. Blood 2008; 111: 4113-4117.
50 Salomon O, Steinberg DM, Dardik R. et al. Inherited factor XI deficiency confers no protection against acute myocardial infarction. J Thromb Haemost 2003; 01: 658-661.
51 Salomon O, Steinberg DM, Zucker M. et al. Patients with severe factor XI deficiency have a reduced incidence of deep-vein thrombosis. Thromb Haemost 2011; 105: 269-273.
52 Asakai R, Chung DW, Davie EW. et al. Factor XI deficiency in Ashkenazi Jews in Israel. N Engl J Med 1991; 325: 153-158.
53 Bolton-Maggs PH, Young Wan-Yin B, McCraw AH. et al. Inheritance and bleeding in factor XI deficiency. Br J Haematol 1988; 69: 521-528.
54 Bolton-Maggs PH, Patterson DA, Wensley RT. et al. Definition of the bleeding tendency in factor XI-deficient kindreds--a clinical and laboratory study. Thromb Haemost 1995; 73: 194-202.
55 Bolton-Maggs PH. Factor XI deficiency--resolving the enigma?. Hematology Am Soc Hematol Educ Program 2009; 97-105.
56 Seligsohn U. Factor XI deficiency in humans. J Thromb Haemost 2009; 07 (Suppl. 01) 84-87.
57 Peyvandi F, Bolton-Maggs PH, Batorova A. et al. Rare bleeding disorders. Haemophilia 2012; 18 (Suppl. 04) 148-153.
58 Gomez K, Bolton-Maggs P. Factor XI deficiency. Haemophilia 2008; 14: 1183-1189.
59 Girolami A, Candeo N, De Marinis GB. et al. Comparative incidence of thrombosis in reported cases of deficiencies of factors of the contact phase of blood coagulation. J Thromb Thrombolysis 2011; 31: 57-63.
60 Kleinschnitz C, Stoll G, Bendszus M. et al. Targeting coagulation factor XII provides protection from pathological thrombosis in cerebral ischemia without interfering with haemostasis. J Exp Med 2006; 203: 513-518.
61 Cheng Q, Tucker EI, Pine MS. et al. A role for factor XIIa-mediated factor XI activation in thrombus formation in vivo. Blood 2010; 116: 3981-3989.
62 Revenko AS, Gao D, Crosby JR. et al. Selective depletion of plasma prekallikrein or coagulation factor XII inhibits thrombosis in mice without increased risk of bleeding. Blood 2011; 118: 5302-5311.
63 Renne T, Pozgajova M, Gruner S. et al. Defective thrombus formation in mice lacking coagulation factor XII. J Exp Med 2005; 202: 271-281.
64 Pauer HU, Renne T, Hemmerlein B. et al. Targeted deletion of murine coagulation factor XII gene-a model for contact phase activation in vivo. Thromb Haemost 2004; 92: 503-508.
65 Bird JE, Smith PL, Wang X. et al. Effects of plasma kallikrein deficiency on haemostasis and thrombosis in mice: Murine Ortholog of the Fletcher Trait. Thromb Haemost 2012; 107: 1141-1150.
66 Adams GN, LaRusch GA, Stavrou E. et al. Murine prolylcarboxypeptidase depletion induces vascular dysfunction with hypertension and faster arterial thrombosis. Blood 2011; 117: 3929-3937.
67 Merkulov S, Zhang WM, Komar AA. et al. Deletion of murine kininogen gene 1 (mKng1) causes loss of plasma kininogen and delays thrombosis. Blood 2008; 111: 1274-1281.
68 Langhauser F, Gob E, Kraft P. et al. Kininogen deficiency protects from ischemic neurodegeneration in mice by reducing thrombosis, blood-brain-barrier damage and inflammation. Blood. 2012 Epub ahead of print..
69 Gailani D, Renne T. The intrinsic pathway of coagulation: a target for treating thromboembolic disease?. J Thromb Haemost 2007; 05: 1106-1112.
70 Girolami A, Scarparo P, Vettore S. The association of a mild FXII deficiency with myocardial infarction and venous thrombosis is completely unjustified. J Thromb Thrombolysis 2009; 27: 454-455.
71 Lessiani G, Falco A, Nicolucci E. et al. Deep venous thrombosis and previous myocardial infarction in mild factor XII deficiency: a risk factor for both venous and arterial thrombosis. J Thromb Thrombolysis 2009; 27: 348-351.
72 Lessiani G, Falco A, Nicolucci E. et al. Relationship between factor XII deficiency and thrombosis: the debate is still open?. J Thromb Thrombolysis 2009; 27: 456-457.
73 Cushman M, O’Meara ES, Folsom AR. et al. Coagulation factors IX through XIII and the risk of future venous thrombosis: the Longitudinal Investigation of Thromboembolism Etiology. Blood 2009; 114: 2878-2883.
74 Johnson CY, Tuite A, Morange PE. et al. The factor XII -4C> T variant and risk of common thrombotic disorders: A HuGE review and meta-analysis of evidence from observational studies. Am J Epidemiol 2011; 173: 136-144.
75 Doggen CJ, Rosendaal FR, Meijers JC. Levels of intrinsic coagulation factors and the risk of myocardial infarction among men: Opposite and synergistic effects of factors XI and XII. Blood 2006; 108: 4045-4051.
76 Govers-Riemslag JW, Smid M, Cooper JA. et al. The plasma kallikrein-kinin system and risk of cardiovascular disease in men. J Thromb Haemost 2007; 05: 1896-1903.
77 Siegerink B, Govers-Riemslag JW, Rosendaal FR. et al. Intrinsic coagulation activation and the risk of arterial thrombosis in young women: results from the Risk of Arterial Thrombosis in relation to Oral contraceptives (RATIO) casecontrol study. Circulation 2010; 122: 1854-1861.
78 Endler G, Marsik C, Jilma B. et al. Evidence of a U-shaped association between factor XII activity and overall survival. J Thromb Haemost 2007; 05: 1143-1148.
79 Renne T, Schmaier AH, Nickel KF. et al. In vivo roles of factor XII. Blood. 2012 Epub ahead of print..
80 von Bruhl ML, Stark K, Steinhart A. et al. Monocytes, neutrophils, and platelets cooperate to initiate and propagate venous thrombosis in mice in vivo. J Exp Med 2012; 209: 819-835.
81 Wakefield TW, Strieter RM, Wilke CA. et al. Venous thrombosis-associated inflammation and attenuation with neutralising antibodies to cytokines and adhesion molecules. Arterioscler Thromb Vasc Biol 1995; 15: 258-268.
82 Johnson K, Choi Y, DeGroot E. et al. Potential mechanisms for a proinflammatory vascular cytokine response to coagulation activation. J Immunol 1998; 160: 5130-5135.
83 Brinkmann V, Reichard U, Goosmann C. et al. Neutrophil extracellular traps kill bacteria. Science 2004; 303: 1532-1535.
84 Fuchs TA, Brill A, Wagner DD. Neutrophil Extracellular Trap (NET) Impact on Deep Vein Thrombosis. Arterioscler Thromb Vasc Biol 2012; 32: 1777-1783.
85 Wachtfogel YT, Pixley RA, Kucich U. et al. Purified plasma factor XIIa aggregates human neutrophils and causes degranulation. Blood 1986; 67: 1731-1737.
86 Wachtfogel YT, Kucich U, James HL. et al. Human plasma kallikrein releases neutrophil elastase during blood coagulation. J Clin Invest 1983; 72: 1672-1677.
87 Henderson LM, Figueroa CD, Muller-Esterl W. et al. Assembly of contact-phase factors on the surface of the human neutrophil membrane. Blood 1994; 84: 474-482.
88 Muller F, Renne T. Novel roles for factor XII-driven plasma contact activation system. Curr Opin Hematol 2008; 15: 516-521.
89 Renne T. The procoagulant and proinflammatory plasma contact system. Semin Immunopathol 2012; 34: 31-41.
90 Morrissey JH, Choi SH, Smith SA. Polyphosphate: an ancient molecule that links platelets, coagulation, and inflammation. Blood 2012; 119: 5972-5979.
91 Morrissey JH. Polyphosphate: a link between platelets, coagulation and inflammation. Int J Hematol 2012; 95: 346-352.
92 Eikelboom JW, Zelenkofske SL, Rusconi CP. Coagulation factor IXa as a target for treatment and prophylaxis of venous thromboembolism. Arterioscler Thromb Vasc Biol 2010; 30: 382-387.