Please wait a minute...
Reviews in Cardiovascular Medicine  2019, Vol. 20 Issue (4): 245-254     DOI: 10.31083/j.rcm.2019.04.56
Review Previous articles | Next articles
Factors IX, XI, and XII: Potential Therapeutic Targets for Anticoagulant Therapy in Atherothrombosis
Vikrant Rai1, Marcus W. Balters2, Devendra K. Agrawal3, *()
1 Department of Biomedical Sciences, Creighton University School of Medicine, Omaha, NE, 68178, USA
2 Department of Surgery, Creighton University School of Medicine, Omaha, NE, 68178, USA
3 Department of Translational Research, Western University of Health Sciences, Pomona, CA, 91766, USA
Download:  PDF(2437KB)  ( 1029 ) Full text   ( 82 )
Export:  BibTeX | EndNote (RIS)      
Abstract:

Atherosclerosis is a leading cause of cardiovascular and neurological ischemic events. Plaque rupture leads to the exposure of highly thrombogenic material with blood and results in the activation of the coagulation cascade, thrombus formation, and embolic events. Although antiplatelets and anticoagulants are used to prevent thromboembolic episodes, bleeding episodes remain the major adverse effect. Decreased ischemic events have been reported while comparing oral rivaroxaban and apixaban with aspirin to improve the therapeutic outcome in several clinical trials, including Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects with Acute Coronary Syndrome-Thrombolysis in Myocardial Infarction 51, Apixaban for Prevention of Acute Ischemic and Safety Events, and GEMINI-ACS-1 phase II clinical trials. However, there were bleeding episodes. Thus, there is an unmet need for better therapeutic strategies. Therefore, the current focus is to target Factors IX, XI, and XII to develop safer and efficient strategies. In this article, we critically reviewed and discussed the limitations of current therapies and the potential of targeting Factors IX, XI, and XII for anticoagulant therapy in atherothrombosis.

Key words:  Atherothrombosis      atherosclerotic plaque      plaque rupture      blood coagulation      factor IX, XI, and XII inhibition     
Submitted:  28 May 2019      Accepted:  17 December 2019      Published:  30 December 2019     
Fund: 
  • R01HL144125/National Heart, Lung and Blood Institute, National Institutes of Health, USA
  • R01HL128063/National Heart, Lung and Blood Institute, National Institutes of Health, USA
  • R01HL147662/National Heart, Lung and Blood Institute, National Institutes of Health, USA
*Corresponding Author(s):  Devendra K. Agrawal     E-mail:  dagrawal@westernu.edu

Cite this article: 

Vikrant Rai, Marcus W. Balters, Devendra K. Agrawal. Factors IX, XI, and XII: Potential Therapeutic Targets for Anticoagulant Therapy in Atherothrombosis. Reviews in Cardiovascular Medicine, 2019, 20(4): 245-254.

URL: 

https://rcm.imrpress.com/EN/10.31083/j.rcm.2019.04.56     OR     https://rcm.imrpress.com/EN/Y2019/V20/I4/245

Figure 1.  Schematic model for Atherothrombosis after plaque rupture. The plaque rupture brings in the thrombogenic material in contact with blood leading to the secretion of tissue factor (TF). This leads to the activation of factor (F) VII and FX followed by formation of thrombin, fibrin and platelet rich fibrin clot called as thrombus (extrinsic coagulation pathway). The activated platelets also secrete inorganic polymer polyphosphate (polyP) which activates FXII to FXIIa followed by activation of FXI, FIX, and FX leading to formation of thrombin, fibrin and thrombus (intrinsic coagulation pathway). TF secreted from circulating monocyte and plaque macrophages and neutrophil extracellular traps (NETs) from activated neutrophils also activate FXII.

Figure 2.  Potential targets in atherothrombosis. Factor IX, XI, and XII are the novel targets in atherothrombosis. NETs-neutrophil extracellular traps; polyP-inorganic polymer polyphosphate; TF-tissue factor; TFPI-tissue factor pathway inhibitors.

Table 1.  Clinical Trials for anticoagulation.
Trials Therapy Subjects Outcome
Dabigatran vs. placebo Randomized double-blind, phase II trial (Oldgren et al., 2011) Dabigatran 50 mg (n = 369), 75 mg (n = 368), 110 mg (n = 406), 150 mg (n = 347), or placebo (n = 371). 1861 Dabigatran was associated with a dose-dependent increase in bleeding events
Significantly reduced coagulation activity in patients with a recent myocardial infarction.
ATLAS ACS 2-TIMI 46
phase II trial (Mega et al., 2009)
Aspirin only (n = 761) or aspirin + thienopyridine (n = 2730) and placebo or rivaroxaban (5-20 mg) given once daily to both groups. 3491 Increases bleeding in a dose-dependent manner.
Might reduce the deaths from cardiovascular cause or stroke.
ATLAS ACS 2-TIMI 51
Phase III (Cavender et al., 2015)
2.5 mg or 5 mg of rivaroxaban or placebo twice daily 15,526 Rivaroxaban reduced the risk of death from cardiovascular causes, myocardial infarction, or stroke. Rivaroxaban increased the risk of major bleeding and intracranial hemorrhage but not the risk of fatal bleeding.
GEMINI-ACS-1 phase II (Ohman et al., 2017; Povsic et al., 2016) Rivaroxaban [2.5 mg twice daily] + P2Y12 inhibitor with dual pathway antithrombotic therapy (aspirin (100 mg) + P2Y12 inhibitor) 3037 Low-dose rivaroxaban with a P2Y12 inhibitor had similar risk of clinically significant bleeding as aspirin and a P2Y12 inhibitor.
APPRAISE phase II trial (Alexander et al., 2009) Placebo (n = 611) or 1 of 4 doses of apixaban: 2.5 mg twice daily (n = 317), 10 mg once daily (n = 318), 10 mg twice daily (n = 248), or 20 mg once daily (n = 221) 1715 A dose-related increase in bleeding Reduction in ischemic events with the addition of apixaban to antiplatelet therapy
Table 2.  Ongoing clinical trials related to atherothrothrombosis.
Clinical trial Aim Status
CONTACT
NCT02785718
To investigate the influence of the proteins of the contact activation system on thrombus formation in human blood in a flow and static model Recruiting patients
Thrombus Formation Under Different Flow-conditions
NCT01114074
To study the effects of the proteins of the contact activation system on platelet mediated thrombus formation, embolization and degradation on collagen in a perfusion flow model. Recruiting patients
ATIS-NVAF
NCT03062319
To evaluate the efficacy and safety of mono-drug therapy with oral anticoagulant compared to combination therapy with antiplatelet drug, in ischemic stroke patients with non-valvular atrial fibrillation and atherothrombosis. Not yet open for participant recruitment.
CHARISMA trial
NCT00050817
To assess the efficacy and safety of clopidogrel 75 mg once-daily by comparison with a placebo in preventing cardiovascular morbidity/mortality. This study has been completed but results have not been posted https://clinicaltrials.gov
Triple versus dual antiplatelet therapy
NCT00404716
To evaluat the safety and efficacy of triple antiplatelet regimen of aspirin, clopidogrel and cilostazol compared with dual antiplatelet regimen of aspirin and clopidogrel in patients with acute coronary syndrome undergoing successful coronary artery stenting. This study has been completed but results have not been posted https://clinicaltrials.gov
Trial for efficacy and safety of rivaroxaban prophylaxis compared with placebo in ambulatory cancer patients at high risk for venous thrombo-embolism; phase III
NCT02555878
To demonstrate that rivaroxaban is superior to placebo for reducing the risk of the primary composite outcome Currently recruiting participants
[1] Alexander, J. H., Becker, R. C., Bhatt, D. L., Cools, F., Crea, F., Dellborg, M., Fox K, A., Goodman, S. G., Harrington, R. A., Huber, K., Husted, S., Lewis, B. S., Lopez-Sendon, J., Mohan, P., Montalescot, G., Ruda, M., Ruzyllo, W., Verheugt, F., Wallentin, L. and APPRAISE Steering Committee and Investigators. (2009) Apixaban, an oral, direct, selective factor Xa inhibitor, in combination with antiplatelet therapy after acute coronary syndrome: results of the Apixaban for Prevention of Acute Ischemic and Safety Events (APPRAISE) trial. Circulation 119, 2877-2885.
doi: 10.1161/CIRCULATIONAHA.108.832139 pmid: 19470889
[2] Alexander, J. H., Lopes, R. D., James, S., Kilaru, R., He, Y., He, Y., Mohan, P., Bhatt, D. L., Goodman, S., Verheugt, F. W., Flather, M., Huber, K., Liaw, D., Husted, S. E., Lopez-Sendon, J., De Caterina, R., Jansky, P., Darius, H., Vinereanu, D., Cornel, J. H., Cools, F., Atar, D., Leiva-Pons, J. L., Keltai, M., Ogawa, H., Pais, P., Parkhomenko, A., Ruzyllo, W., Diaz, R., White, H., Ruda, M., Geraldes, M., Lawrence, J., Harrington, R. A., Wallentin, L. and APPRAISE-2 Investigators. (2011) Apixaban with antiplatelet therapy after acute coronary syndrome. New England Journal of Medicine 365, 699-708.
doi: 10.1056/NEJMoa1105819 pmid: 21780946
[3] Badimon, L. and Vilahur, G. (2015) Neutrophil extracellular traps: a new source of tissue factor in atherothrombosis. European Heart Journal 36, 1364-1366.
doi: 10.1093/eurheartj/ehv105 pmid: 25845929
[4] Bhatt, D. L., Steg, P. G., Ohman, E. M., Hirsch, A. T., Ikeda, Y., Mas, J. L., Goto, S., Liau, C. S., Richard, A. J., Rother, J., Wilson, P. W. and REACH Registry Investigators. (2006) International prevalence, recognition, and treatment of cardiovascular risk factors in outpatients with atherothrombosis. JAMA Network 295, 180-189.
doi: 10.1001/jama.295.2.180 pmid: 17591377
[5] Buller, H. R., Bethune, C., Bhanot, S., Gailani, D., Monia, B. P., Raskob, G. E., Segers, A., Verhamme, P., Weitz, J. I. and FXI-ASO TKA Investigators. (2015) Factor XI antisense oligonucleotide for prevention of venous thrombosis. The New England Journal of Medicine 372, 232-240.
doi: 10.1056/NEJMoa1405760 pmid: 25482425
[6] Baeriswyl, V., Calzavarini, S., Chen, S., Zorzi, A., Bologna, L., Angelillo-Scherrer, A. and Heinis, C. (2015) A Synthetic Factor XIIa Inhibitor Blocks Selectively Intrinsic Coagulation Initiation. ACS Chemical Biology 10, 1861-1870.
doi: 10.1021/acschembio.5b00103 pmid: 25989088
[7] Cavender, M. A., Gibson, C. M., Braunwald, E., Wiviott, S. D., Murphy, S. A., Toda Kato, E., Plotnikov, A. N., Amuchástegui, M., Oude Ophuis, T., van Hessen, M. and Mega, J. L. (2015) The effect of rivaroxaban on myocardial infarction in the ATLAS ACS 2 - TIMI 51 trial. European Heart Journal Acute Cardiovasc Care 4, 468-474.
doi: 10.1177/1740774515626411 pmid: 26908543
[8] Cheng, Q., Tucker, E. I., Pine, M. S., Sisler, I., Matafonov, A., Sun, M. F., White-Adams, T. C., Smith, S. A., Hanson, S. R., McCarty, O. J., Renné, T., Gruber, A. and Gailani, D. (2010) A role for factor XIIa-mediated factor XI activation in thrombus formation in vivo. Blood 116, 3981-3989.
doi: 10.1182/blood-2010-02-270918 pmid: 20634381
[9] Cohen, M. and Iyer, D. (2014) The "dual-pathway" strategy after acute coronary syndrome: rivaroxaban and antiplatelet agents in the ATLAS ACS 2-TIMI 51 trial. Cardiovascular Therapeutics 32, 224-232.
doi: 10.1111/1755-5922.12083
[10] Crosby, J. R., Marzec, U., Revenko, A. S., Zhao, C., Gao, D., Matafonov, A., Gailani, D., MacLeod, A. R., Tucker, E. I., Gruber, A., Hanson, S. R. and Monia, B. P. (2013) Antithrombotic effect of antisense factor XI oligonucleotide treatment in primates. Arteriosclerosis Thrombosis and Vascular Biology 33, 1670-1678.
doi: 10.1161/ATVBAHA.113.301282
[11] Crowther, M. A. and Cuker, A. (2017) Reduced-Intensity Rivaroxaban for the Prevention of Recurrent Venous Thromboembolism. The New England Journal of Medicine 376, 1279-1280.
doi: 10.1056/NEJMe1701628 pmid: 28316277
[12] Cuker, A. (2015) Factor XI Antisense: A Challenge to Common Sense. The Hematologist 12, 1.
[13] de Jong, H. K., van der Poll T. and Wiersinga, W. J. (2010) The systemic pro-inflammatory response in sepsis. Journal of Innate Immunity 2, 422-430.
doi: 10.1159/000316286 pmid: 20530955
[14] Eikelboom, J. W., Zelenkofske, S. L. and Rusconi, C. P. (2010) Coagulation factor IXa as a target for treatment and prophylaxis of venous thromboembolism. Arteriosclerosis Thrombosis and Vascular Biology 30, 382-387.
doi: 10.1161/ATVBAHA.117.310588 pmid: 29419409
[15] Gailani, D., Geng, Y., Verhamme, I., Sun, M. F., Bajaj, S. P., Messer, A. and Emsley, J. (2014) The mechanism underlying activation of factor IX by factor XIa. Thrombosis Research 133, S48-S51.
doi: 10.1016/j.thromres.2014.03.020
[16] Gupta, G. K., Agrawal, T., Rai, V., Del Core, M. G., Hunter, W. J. 3rd. and Agrawal., D. K. (2016) Vitamin D Supplementation Reduces Intimal Hyperplasia and Restenosis following Coronary Intervention in Atherosclerotic Swine. PLoS One 11, e0156857.
doi: 10.1371/journal.pone.0156857 pmid: 27271180
[17] Gurbel, P. A. and Tantry, U. S. (2017) GEMINI-ACS-1: toward unearthing the antithrombotic therapy cornerstone for acute coronary syndromes. Lancet 389, 1773-1775.
doi: 10.1016/S0140-6736(17)30760-2 pmid: 28325639
[18] Gruber, A. and Hanson, S. R. (2003) Factor XI-dependence of surface- and tissue factor-initiated thrombus propagation in primates. Blood 102, 953-955.
doi: 10.1182/blood-2003-01-0324 pmid: 12689935
[19] Heestermans, M. and van Vlijmen B. J. M. (2017) Oligonucleotides targeting coagulation factor mRNAs: use in thrombosis and hemophilia research and therapy. Thrombosis Journal 15, 7.
doi: 10.1186/s12959-017-0130-8 pmid: 28286423
[20] Hopp, S., Albert-Weissenberger, C., Mencl, S., Bieber, M., Schuhmann, M. K., Stetter, C., Nieswandt, B., Schmidt, P. M., Monoranu, C. M., Alafuzoff, I., Marklund, N., Nolte, M. W., Sirén, A. L. and Kleinschnitz, C. (2016) Targeting coagulation factor XII as a novel therapeutic option in brain trauma. Annals of Neurology 79, 970-982.
doi: 10.1002/ana.24655 pmid: 27043916
[21] Howard, E. L., Becker, K. C., Rusconi, C. P. and Becker, R. C. (2007) Factor IXa inhibitors as novel anticoagulants. Arteriosclerosis Thrombosis and Vascular Biology 27, 722-727.
doi: 10.1161/01.ATV.0000259363.91070.f1 pmid: 17272750
[22] Huynh, K. (2017) Acute coronary syndromes: Similar bleeding risks with low-dose rivaroxaban versus aspirin. Nature Reviews Cardiology 14, 252-253.
doi: 10.1038/nrcardio.2017.42 pmid: 28397847
[23] Kenne, E., Nickel, K. F., Long, A. T., Fuchs, T. A., Stavrou, E. X., Stahl, F. R. and Renné, T. (2015) Factor XII: a novel target for safe prevention of thrombosis and inflammation. Journal of Internal Medicine 278, 571-585.
doi: 10.1111/joim.12430 pmid: 26373901
[24] Kenne, E. and Renne, T. (2014) Factor XII: a drug target for safe interference with thrombosis and inflammation. Drug Discovery Today 19, 1459-1464.
doi: 10.1016/j.drudis.2014.06.024
[25] Key, N. S. (2014) Epidemiologic and clinical data linking factors XI and XII to thrombosis. Hematology. American Society of Hematology. Education Program 2014, 66-70.
doi: 10.1182/asheducation-2017.1.66 pmid: 29222238
[26] Kleinschnitz, C., Stoll, G., Bendszus, M., Schuh, K., Pauer, H. U., Burfeind, P., Renné, C., Gailani, D., Nieswandt, B. and Renné, T. (2006) Targeting coagulation factor XII provides protection from pathological thrombosis in cerebral ischemia without interfering with hemostasis. Journal of Experimental Medicine 203, 513-518.
doi: 10.1084/jem.20052458 pmid: 16533887
[27] Krantz, M. J. and Kaul, S. (2013) The ATLAS ACS 2-TIMI 51 trial and the burden of missing data: (Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects With Acute Coronary Syndrome ACS 2-Thrombolysis In Myocardial Infarction 51). Journal of the American College of Cardiology 62, 777-781.
doi: 10.1016/j.jacc.2013.05.024
[28] Kuijpers, M. J., van der Meijden, P. E., Feijge, M. A., Mattheij, N. J., May, F., May, F., Govers-Riemslag, J., Meijers, J. C., Heemskerk, J. W., Renné, T. and Cosemans, J. M. (2014) Factor XII regulates the pathological process of thrombus formation on ruptured plaques. Arteriosclerosis Thrombosis and Vascular Biology 34, 1674-1680.
doi: 10.1161/ATVBAHA.114.303315
[29] Labberton, L., Kenne, E., Long, A. T., Nickel, K. F., Di Gennaro, A., Rigg, R. A., Hernandez, J. S., Butler, L., Maas, C., Stavrou, E. X. and Renné, T. (2016) Neutralizing blood-borne polyphosphate in vivo provides safe thromboprotection. Nature Communication 7, 12616.
doi: 10.1038/ncomms12616 pmid: 27596064
[30] Larsson, M., Rayzman, V., Nolte, M. W., Nickel, K. F., Bjorkqvist, J., Jämsä, A., Hardy, M. P., Fries, M., Schmidbauer, S., Hedenqvist, P., Broomé, M., Pragst, I., Dickneite, G., Wilson, M. J., Nash, A. D., Panousis, C. and Renné, T. (2014) A factor XIIa inhibitory antibody provides thromboprotection in extracorporeal circulation without increasing bleeding risk. Science and Translational Medicine 6, 222ra217.
doi: 10.1126/scitranslmed.3006804 pmid: 24500405
[31] Lawson, J. H. and Mann, K. G. (1991) Cooperative activation of human factor IX by the human extrinsic pathway of blood coagulation. Journal of Biological Chemistry 266, 11317-11327.
pmid: 2040636
[32] Lowenberg, E. C., Meijers, J. C., Monia, B. P. and Levi, M. (2010) Coagulation factor XI as a novel target for antithrombotic treatment. Journal of Thrombosis and Haemostasis 8, 2349-2357.
doi: 10.1111/j.1538-7836.2010.04031.x pmid: 20727068
[33] Morrissey, J. H. (2013) Targeting factor XI to prevent thrombosis. Arteriosclerosis Thrombosis and Vascular Biology 33, 1454-1455.
doi: 10.1161/ATVBAHA.113.301598 pmid: 29727017
[34] Muller, F., Gailani, D. and Renne, T. (2011) Factor XI and XII as antithrombotic targets. Current Opinion in Hematology 18, 349-355.
doi: 10.1097/MOH.0b013e3283497e61
[35] Mackman, N. (2014) New targets for atherothrombosis. Arteriosclerosis Thrombosis and Vascular Biology 34, 1607-1608.
doi: 10.1161/ATVBAHA.114.304005 pmid: 25031326
[36] Mega, J. L., Braunwald, E., Mohanavelu, S., Burton, P., Poulter, R., Misselwitz, F., Hricak, V., Barnathan, E. S., Bordes, P., Witkowski, A., Markov, V., Oppenheimer, L., Gibson, C. M and ATLAS ACS-TIMI 46 study group. (2009) Rivaroxaban versus placebo in patients with acute coronary syndromes (ATLAS ACS-TIMI 46): a randomised, double-blind, phase II trial. Lancet 374, 29-38.
doi: 10.1016/S0140-6736(09)60738-8 pmid: 19539361
[37] Mega, J. L., Braunwald, E., Wiviott, S. D., Bassand, J. P., Bhatt, D. L., Bode, C., Burton, P., Cohen, M., Cook-Bruns, N., Fox, K. A., Goto, S., Murphy, S. A., Plotnikov, A. N., Schneider, D., Sun, X., Verheugt, F. W., Gibson, C. M. and ATLAS ACS 2-TIMI 51 Investigators. (2012) Rivaroxaban in patients with a recent acute coronary syndrome. New England Journal of Medicine 366, 9-19.
doi: 10.1056/NEJMoa1112277
[38] Nickel, K. F., Long, A. T., Fuchs, T. A., Butler, L. M. and Renne, T. (2017) Factor XII as a Therapeutic Target in Thromboembolic and Inflammatory Diseases. Arteriosclerosis Thrombosis and Vascular Biology 37, 13-20.
doi: 10.1161/ATVBAHA.116.308595 pmid: 27834692
[39] Oldgren, J., Budaj, A., Granger, C. B., Khder, Y., Roberts, J., Siegbahn, A., Tijssen, J. G., Van de Werf, F., Wallentin, L. and RE-DEEM Investigators. (2011) Dabigatran vs. placebo in patients with acute coronary syndromes on dual antiplatelet therapy: a randomized, double-blind, phase II trial. European Heart Journal 32, 2781-2789.
doi: 10.1093/eurheartj/ehr113
[40] Ohman, E. M., Roe, M. T., Steg, P. G., James, S. K., Povsic, T. J., White, J., Rockhold, F., Plotnikov, A., Mundl, H., Strony, J., Sun, X., Husted, S., Tendera, M., Montalescot, G., Bahit, M. C., Ardissino, D., Bueno, H., Claeys, M. J., Nicolau, J. C., Cornel, J. H., Goto, S., Kiss, R. G., Güray, Ü., Park, D. W., Bode, C., Welsh, R. C. and Gibson, C. M. (2017) Clinically significant bleeding with low-dose rivaroxaban versus aspirin, in addition to P2Y12 inhibition, in acute coronary syndromes (GEMINI-ACS-1): a double-blind, multicentre, randomised trial. Lancet 389, 1799-1808.
doi: 10.1016/S0140-6736(17)30751-1 pmid: 28325638
[41] Pedicord, D. L., Seiffert, D. and Blat, Y. (2007) Feedback activation of factor XI by thrombin does not occur in plasma. Proceedings of the National Academy of Sciences of the United States of America 104, 12855-12860.
doi: 10.1073/pnas.0705566104 pmid: 17652512
[42] Povsic, T. J., Roe, M. T., Ohman, E. M., Steg, P. G., James, S., Plotnikov., A., Mundl, H., Welsh, R., Bode, C. and Gibson, C. M. (2016) A randomized trial to compare the safety of rivaroxaban vs aspirin in addition to either clopidogrel or ticagrelor in acute coronary syndrome: The design of the GEMINI-ACS-1 phase II study. American Heart Journal 174, 120-128.
doi: 10.1016/j.ahj.2016.01.004 pmid: 26995378
[43] Puy, C., Tucker, E. I., Matafonov, A., Cheng, Q., Zientek, K. D., Gailani, D., Gruber, A. and McCarty, O. J. (2015) Activated factor XI increases the procoagulant activity of the extrinsic pathway by inactivating tissue factor pathway inhibitor. Blood 125, 1488-1496.
doi: 10.1182/blood-2014-10-604587 pmid: 25587039
[44] Rai, V., Rao, V. H., Shao, Z. and Agrawal, D. K. (2016) Dendritic Cells Expressing Triggering Receptor Expressed on Myeloid Cells-1 Correlate with Plaque Stability in Symptomatic and Asymptomatic Patients with Carotid Stenosis. PLoS One 11, e0154802.
doi: 10.1371/journal.pone.0154802 pmid: 27148736
[45] Rao, V. H., Rai, V., Stoupa, S., Subramanian, S. and Agrawal, D. K. (2016) Tumor necrosis factor-alpha regulates triggering receptor expressed on myeloid cells-1-dependent matrix metalloproteinases in the carotid plaques of symptomatic patients with carotid stenosis. Atherosclerosis 248, 160-169.
doi: 10.1016/j.atherosclerosis.2016.03.021 pmid: 27017522
[46] Reininger, A. J., Bernlochner, I., Penz, S. M., Ravanat, C., Smethurst, P., Farndale, R. W., Gachet, C., Brandl, R. and Siess, W. (2010) A 2-step mechanism of arterial thrombus formation induced by human atherosclerotic plaques. Journal of the American College of Cardiology 55, 1147-1158.
doi: 10.1016/j.jacc.2009.11.023 pmid: 20223370
[47] Schmaier, A. H. (2014) Extracorporeal circulation without bleeding. Science Translational Medicine 6, 222fs227.
doi: 10.1126/scitranslmed.aax7533 pmid: 31894106
[48] Smith, S. A., Baker, C. J., Gajsiewicz, J. M., and Morrissey, J. H. (2017) Silica particles contribute to the procoagulant activity of DNA and polyphosphate isolated using commercial kits. Blood 130, 88-91.
doi: 10.1182/blood-2017-03-772848 pmid: 28533308
[49] Smith, S. A., Baker, C. J., Gajsiewicz, J. M. and Morrissey, J. H. (2017) Silica particles contribute to the procoagulant activity of DNA and polyphosphate isolated using commercial kits. Blood 130, 88-91.
doi: 10.1182/blood-2017-03-772848 pmid: 28533308
[50] Sorensen, R. and Gislason, G. (2014) Triple antithrombotic therapy: risky but sometimes necessary. Revista Española de Cardiología (Engl Ed) 67, 171-175.
doi: 10.1016/j.rec.2013.08.010 pmid: 24774390
[51] Sullenger, B., Woodruff, R. and Monroe, D. M. (2012) Potent anticoagulant aptamer directed against factor IXa blocks macromolecular substrate interaction. Journal of Biological Chemistry 287, 12779-12786.
doi: 10.1074/jbc.M111.300772
[52] Takahashi, M., Yamashita, A., Moriguchi-Goto, S., Sugita, C., Matsumoto, T., Matsuda, S., Sato, Y., Kitazawa, T., Hattori, K., Shima, M. and Asada, Y. (2010) Inhibition of factor XI reduces thrombus formation in rabbit jugular vein under endothelial denudation and/or blood stasis. Thrombosis Research 125, 464-470.
doi: 10.1016/j.thromres.2009.12.013 pmid: 20089298
[53] Tatsumi, K. and Mackman, N. (2015) Tissue Factor and Atherothrombosis. Journal of Atherosclerosis and Thrombosis 22, 543-549.
doi: 10.5551/jat.30940 pmid: 26016513
[54] van Montfoort, M. L., Knaup, V. L., Marquart, J. A., Bakhtiari, K., Castellino, F. J., Hack, C. E. and Meijers, J. C. (2013) Two novel inhibitory anti-human factor XI antibodies prevent cessation of blood flow in a murine venous thrombosis model. Thrombosis and Haemostasis 110, 1065-1073.
doi: 10.1160/TH13-05-0429 pmid: 23925504
[55] van Montfoort, M. L., Kuijpers, M. J., Knaup, V. L., Bhanot, S., Monia, B. P., Roelofs, J. J., Heemskerk, J. W. and Meijers, J. C. (2014) Factor XI regulates pathological thrombus formation on acutely ruptured atherosclerotic plaques. Arterioscler Thrombosis and Vascular Biology 34, 1668-1673.
doi: 10.1161/ATVBAHA.114.303209 pmid: 24947525
[56] Viles-Gonzalez, J. F., Anand, S. X., Zafar, M. U., Fuster, V. and Badimon, J. J. (2004) Tissue factor coagulation pathway: a new therapeutic target in atherothrombosis. Journal of Cardiovascular Pharmacology 43, 669-676.
doi: 10.1097/00005344-200405000-00009 pmid: 15071354
[57] Viles-Gonzalez, J. F. and Badimon, J. J. (2004) Atherothrombosis: the role of tissue factor. The International Journal of Biochemistry & Cell Biology 36, 25-30.
doi: 10.1016/j.biocel.2015.01.003 pmid: 25595463
[58] Walsh, P. (2003) Roles of factor XI, platelets and tissue factor‐initiated blood coagulation. Journal of Thrombosis and Haemostsis 1, 2081-2086.
doi: 10.1046/j.1538-7836.2003.00460.x pmid: 14521588
[59] Weitz, J. I. and Fredenburgh, J. C. (2017) Factors XI and XII as Targets for New Anticoagulants. Frontiers in Medicine (Lausanne) 4, 19.
doi: 10.3389/fmed.2017.00019 pmid: 28286749
[60] Wielders, S. J., Beguin, S., Hemker, H. C. and Lindhout, T. (2004) Factor XI-dependent reciprocal thrombin generation consolidates blood coagulation when tissue factor is not available. Arteriosclerosis Thrombosis and Vascular Biology 24, 1138-1142.
doi: 10.1161/01.ATV.0000128125.80559.9c pmid: 15072993
[61] Worm, M., Kohler, E. C., Panda, R., Long, A., Butler, L. M., Stavrou, E. X., Nickel, K. F., Fuchs, T. A. and Renné, T. (2015) The factor XIIa blocking antibody 3F7: a safe anticoagulant with anti-inflammatory activities. Annala of Translational Medicine 3, 247.
doi: 10.3978/j.issn.2305-5839.2015.09.07 pmid: 26605293
[62] Zhang, H., Lowenberg, E. C., Crosby, J. R., MacLeod, A. R., Zhao, C., Gao, D., Black, C., Revenko, A. S., Meijers, J. C., Stroes, E. S., Levi, M. and Monia, B. P. (2010) Inhibition of the intrinsic coagulation pathway factor XI by antisense oligonucleotides: a novel antithrombotic strategy with lowered bleeding risk. Blood 116, 4684-4692.
doi: 10.1182/blood-2010-04-277798 pmid: 20807891
[1] Arthur E. Weyman. Future Directions in Echocardiography[J]. Reviews in Cardiovascular Medicine, 2009, 10(1): 4-13.
[2] John J. Young, Jill Jesurum, Mark Reisman, William A. Gray. News from the SIS 2006 Emerging Technologies Symposium[J]. Reviews in Cardiovascular Medicine, 2007, 8(1): 21-24.
[3] Prediman K. Shah. Thrombogenic Risk Factors for Atherothrombosis[J]. Reviews in Cardiovascular Medicine, 2006, 7(1): 10-16.
[4] David P. Faxon. Use of Antiplatelet Agents and Anticoagulants for Cardiovascular Disease: Current Standards and Best Practices[J]. Reviews in Cardiovascular Medicine, 2005, 6(S4): 3-14.
[5] Campbell D.K. Rogers. Drug-Eluting Stents: Role of Stent Design, Delivery Vehicle, and Drug Selection[J]. Reviews in Cardiovascular Medicine, 2002, 3(S5): 10-15.
No Suggested Reading articles found!