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Reviews in Cardiovascular Medicine  2019, Vol. 20 Issue (4): 245-254     DOI: 10.31083/j.rcm.2019.04.56
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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
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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     
  • 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:

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.

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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.
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.
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
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
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
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.
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
Triple versus dual antiplatelet therapy
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
Trial for efficacy and safety of rivaroxaban prophylaxis compared with placebo in ambulatory cancer patients at high risk for venous thrombo-embolism; phase III
To demonstrate that rivaroxaban is superior to placebo for reducing the risk of the primary composite outcome Currently recruiting participants
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