fibrillation: effects of warfarin treatment. Br Heart J 1995; 73:527. 42. Asakura H, Hifumi S, Jokaji H, et al. Prothrombin fragment F1 + 2 and thrombin- antithrombin III complex are useful markers of the hypercoagulable state in atrial fibrillation. Blood Coagul Fibrinolysis 1992; 3:469. 43. Lip GY, Blann A. von Willebrand factor: a marker of endothelial dysfunction in vascular disorders? Cardiovasc Res 1997; 34:255. 44. Lip GY, Lowe GD. Fibrin D-dimer: a useful clinical marker of thrombogenesis? Clin Sci (Lond) 1995; 89:205. 45. Lip GY, Rumley A, Dunn FG, Lowe GD. Plasma fibrinogen and fibrin D-dimer in patients with atrial fibrillation: effects of cardioversion to sinus rhythm. Int J Cardiol 1995; 51:245. 46. Abe, Y, Kim, et al. Evidence for the intravascular hyperclotting state induced by atrial fibrillation itself (abstract). J Am Coll Cardiol 1996; 27(Suppl A):35A. 47. Vene N, Mavri A, Kosmelj K, Stegnar M. High D-dimer levels predict cardiovascular events in patients with chronic atrial fibrillation during oral anticoagulant therapy. Thromb Haemost 2003; 90:1163. 48. Sadanaga T, Sadanaga M, Ogawa S. Evidence that D-dimer levels predict subsequent thromboembolic and cardiovascular events in patients with atrial fibrillation during oral anticoagulant therapy. J Am Coll Cardiol 2010; 55:2225. 49. Petersen P, Kastrup J, Helweg-Larsen S, et al. Risk factors for thromboembolic complications in chronic atrial fibrillation. The Copenhagen AFASAK study. Arch Intern Med 1990; 150:819. 50. Lip GY, Lip PL, Zarifis J, et al. Fibrin D-dimer and beta-thromboglobulin as markers of thrombogenesis and platelet activation in atrial fibrillation. Effects of introducing ultra-low- dose warfarin and aspirin. Circulation 1996; 94:425. https://www.uptodate.com/contents/mechanisms-of-thrombogenesis-in-atrial-fibrillation/print 12/20 7/5/23, 9:15 AM Mechanisms of thrombogenesis in atrial fibrillation - UpToDate 51. Li-Saw-Hee FL, Blann AD, Lip GY. Effects of fixed low-dose warfarin, aspirin-warfarin combination therapy, and dose-adjusted warfarin on thrombogenesis in chronic atrial fibrillation. Stroke 2000; 31:828. 52. Goldsmith I, Kumar P, Carter P, et al. Atrial endocardial changes in mitral valve disease: a scanning electron microscopy study. Am Heart J 2000; 140:777. 53. Conway DS, Pearce LA, Chin BS, et al. Plasma von Willebrand factor and soluble p-selectin as indices of endothelial damage and platelet activation in 1321 patients with nonvalvular atrial fibrillation: relationship to stroke risk factors. Circulation 2002; 106:1962. 54. Conway DS, Pearce LA, Chin BS, et al. Prognostic value of plasma von Willebrand factor and soluble P-selectin as indices of endothelial damage and platelet activation in 994 patients with nonvalvular atrial fibrillation. Circulation 2003; 107:3141. 55. Freestone B, Lip GY, Chong AY, et al. Circulating endothelial cells in atrial fibrillation with and without acute cardiovascular disease. Thromb Haemost 2005; 94:702. 56. Lip GY. Does paroxysmal atrial fibrillation confer a paroxysmal thromboembolic risk? Lancet 1997; 349:1565. 57. Ritchie DG, Levy BA, Adams MA, Fuller GM. Regulation of fibrinogen synthesis by plasmin- derived fragments of fibrinogen and fibrin: an indirect feedback pathway. Proc Natl Acad Sci U S A 1982; 79:1530. 58. Boos CJ, Anderson RA, Lip GY. Is atrial fibrillation an inflammatory disorder? Eur Heart J 2006; 27:136. 59. Conway DS, Buggins P, Hughes E, Lip GY. Relationship of interleukin-6 and C-reactive protein to the prothrombotic state in chronic atrial fibrillation. J Am Coll Cardiol 2004; 43:2075. 60. Conway DS, Buggins P, Hughes E, Lip GY. Relation of interleukin-6, C-reactive protein, and the prothrombotic state to transesophageal echocardiographic findings in atrial fibrillation. Am J Cardiol 2004; 93:1368. 61. Conway DS, Buggins P, Hughes E, Lip GY. Prognostic significance of raised plasma levels of interleukin-6 and C-reactive protein in atrial fibrillation. Am Heart J 2004; 148:462. 62. Lip GY, Patel JV, Hughes E, Hart RG. High-sensitivity C-reactive protein and soluble CD40 ligand as indices of inflammation and platelet activation in 880 patients with nonvalvular atrial fibrillation: relationship to stroke risk factors, stroke risk stratification schema, and prognosis. Stroke 2007; 38:1229. 63. Mar n F, Rold n V, Climent V, et al. Is thrombogenesis in atrial fibrillation related to matrix metalloproteinase-1 and its inhibitor, TIMP-1? Stroke 2003; 34:1181. https://www.uptodate.com/contents/mechanisms-of-thrombogenesis-in-atrial-fibrillation/print 13/20 7/5/23, 9:15 AM Mechanisms of thrombogenesis in atrial fibrillation - UpToDate 64. Chung NA, Belgore F, Li-Saw-Hee FL, et al. Is the hypercoagulable state in atrial fibrillation mediated by vascular endothelial growth factor? Stroke 2002; 33:2187. 65. Blann AD, Belgore FM, McCollum CN, et al. Vascular endothelial growth factor and its receptor, Flt-1, in the plasma of patients with coronary or peripheral atherosclerosis, or Type II diabetes. Clin Sci (Lond) 2002; 102:187. 66. Makin AJ, Chung NA, Silverman SH, Lip GY. Vascular endothelial growth factor and tissue factor in patients with established peripheral artery disease: a link between angiogenesis and thrombogenesis? Clin Sci (Lond) 2003; 104:397. 67. Freestone B, Chong AY, Lim HS, et al. Angiogenic factors in atrial fibrillation: a possible role in thrombogenesis? Ann Med 2005; 37:365. 68. Sbarouni E, Bradshaw A, Andreotti F, et al. Relationship between hemostatic abnormalities and neuroendocrine activity in heart failure. Am Heart J 1994; 127:607. 69. Lip GY, Lowe GD, Metcalfe MJ, et al. Is diastolic dysfunction associated with thrombogenesis? A study of circulating markers of a prothrombotic state in patients with coronary artery disease. Int J Cardiol 1995; 50:31. 70. Minamino T, Kitakaze M, Sanada S, et al. Increased expression of P-selectin on platelets is a risk factor for silent cerebral infarction in patients with atrial fibrillation: role of nitric oxide. Circulation 1998; 98:1721. 71. Choudhury A, Chung I, Blann AD, Lip GY. Platelet surface CD62P and CD63, mean platelet volume, and soluble/platelet P-selectin as indexes of platelet function in atrial fibrillation: a comparison of "healthy control subjects" and "disease control subjects" in sinus rhythm. J Am Coll Cardiol 2007; 49:1957. 72. Igarashi Y, Yamaura M, Ito M, et al. Elevated serum lipoprotein(a) is a risk factor for left atrial thrombus in patients with chronic atrial fibrillation: a transesophageal echocardiographic study. Am Heart J 1998; 136:965. 73. Lip GY, Lane D, Van Walraven C, Hart RG. Additive role of plasma von Willebrand factor levels to clinical factors for risk stratification of patients with atrial fibrillation. Stroke 2006; 37:2294. 74. Rold n V, Mar n F, Mui a B, et al. Plasma von Willebrand factor levels are an independent risk factor for adverse events including mortality and major bleeding in anticoagulated atrial fibrillation patients. J Am Coll Cardiol 2011; 57:2496. 75. Hijazi Z, Siegbahn A, Andersson U, et al. High-sensitivity troponin I for risk assessment in patients with atrial fibrillation: insights from the Apixaban for Reduction in Stroke and other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial. Circulation 2014; 129:625. https://www.uptodate.com/contents/mechanisms-of-thrombogenesis-in-atrial-fibrillation/print 14/20 7/5/23, 9:15 AM Mechanisms of thrombogenesis in atrial fibrillation - UpToDate 76. Hijazi Z, Wallentin L, Siegbahn A, et al. High-sensitivity troponin T and risk stratification in patients with atrial fibrillation during treatment with apixaban or warfarin. J Am Coll Cardiol 2014; 63:52. 77. Hijazi Z, Wallentin L, Siegbahn A, et al. N-terminal pro-B-type natriuretic peptide for risk assessment in patients with atrial fibrillation: insights from the ARISTOTLE Trial (Apixaban for the Prevention of Stroke in Subjects With Atrial Fibrillation). J Am Coll Cardiol 2013; 61:2274. 78. Lip GY. Stroke and bleeding risk assessment in atrial fibrillation: when, how, and why? Eur Heart J 2013; 34:1041. 79. Esteve-Pastor MA, Rivera-Caravaca JM, Roldan V, et al. Long-term bleeding risk prediction in 'real world' patients with atrial fibrillation: Comparison of the HAS-BLED and ABC-Bleeding risk scores. The Murcia Atrial Fibrillation Project. Thromb Haemost 2017; 117:1848. 80. Rivera-Caravaca JM, Rold n V, Esteve-Pastor MA, et al. Long-Term Stroke Risk Prediction in Patients With Atrial Fibrillation: Comparison of the ABC-Stroke and CHA2DS2-VASc Scores. J Am Heart Assoc 2017; 6. 81. Rold n V, Rivera-Caravaca JM, Shantsila A, et al. Enhancing the 'real world' prediction of cardiovascular events and major bleeding with the CHA2DS2-VASc and HAS-BLED scores using multiple biomarkers. Ann Med 2018; 50:26. 82. Lip GY, Rasmussen LH, Olsson SB, et al. Oral direct thrombin inhibitor AZD0837 for the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation: a randomized dose-guiding, safety, and tolerability study of four doses of AZD0837 vs. vitamin K antagonists. Eur Heart J 2009; 30:2897. 83. Weitz JI, Connolly SJ, Patel I, et al. Randomised, parallel-group, multicentre, multinational phase 2 study comparing edoxaban, an oral factor Xa inhibitor, with warfarin for stroke prevention in patients with atrial fibrillation. Thromb Haemost 2010; 104:633. 84. Connolly SJ, Eikelboom J, Dorian P, et al. Betrixaban compared with warfarin in patients with atrial fibrillation: results of a phase 2, randomized, dose-ranging study (Explore-Xa). Eur Heart J 2013; 34:1498. 85. Ezekowitz MD, Reilly PA, Nehmiz G, et al. Dabigatran with or without concomitant aspirin compared with warfarin alone in patients with nonvalvular atrial fibrillation (PETRO Study). Am J Cardiol 2007; 100:1419. Topic 981 Version 14.0 https://www.uptodate.com/contents/mechanisms-of-thrombogenesis-in-atrial-fibrillation/print 15/20 7/5/23, 9:15 AM Mechanisms of thrombogenesis in atrial fibrillation - UpToDate GRAPHICS Clinical and echocardiographic predictors of stroke in atrial fibrillation Clinical factors History of hypertension Recent (within 3 months) HF Previous cerebrovascular event (stroke or TIA) Echocardiographic factors Global left ventricular dysfunction Dilated atrium on M-mode ( 4.7 cm or 2.4 cm/m2) Stroke risk (per year) based on clinical factors No risk factors 2.5 percent 1 risk factor 7.2 percent 1 or 2 risk factors 17.6 percent Stroke risk (per year) based on clinical and echocardiographic factors No risk factors 1.0 percent 1 risk factor 6.0 percent 2 or 3 risk factors 18.6 percent Adapted from: Stroke Prevention in Atrial Fibrillation Investigators. Ann Intern Med 1992; 116:1 and 1992; 116:6. Graphic 64291 Version 3.0 https://www.uptodate.com/contents/mechanisms-of-thrombogenesis-in-atrial-fibrillation/print 16/20 7/5/23, 9:15 AM Mechanisms of thrombogenesis in atrial fibrillation - UpToDate Indicators of thromboembolic risk on transesophageal echocardiography in patients with atrial fibrillation Left atrial appendage size and function Left atrial size and function Spontaneous echo contrast Left atrial or atrial appendage thrombus Intraatrial septal aneurysm Patent foramen ovale Aortic atherosclerosis with plaque in ascending aorta Graphic 72745 Version 1.0 https://www.uptodate.com/contents/mechanisms-of-thrombogenesis-in-atrial-fibrillation/print 17/20 7/5/23, 9:15 AM Mechanisms of thrombogenesis in atrial fibrillation - UpToDate Spontaneous echo contrast seen in the left atrium on transesophageal echocardiogram Transesophageal echocardiography showing spontaneous echo contrast (or "smoke") in an enlarged left atrium (LA). This finding is a marker for stasis and is associated with a higher risk of thrombus formation and thromboembolism. Courtesy of Warren Manning, MD. Graphic 66980 Version 5.0 https://www.uptodate.com/contents/mechanisms-of-thrombogenesis-in-atrial-fibrillation/print 18/20 7/5/23, 9:15 AM Mechanisms of thrombogenesis in atrial fibrillation - UpToDate Significant left ventricular dysfunction predicts stroke in AF In a prospective study of 1066 patients entered into three clinical trials evaluating the role of anticoagulation in nonvalvular AF (BAATAF, SPINAF, and SPAF), the incidence of a stroke was 9.3 percent per year in patients with moderate to severe left ventricular dysfunction compared with 4.4 percent per year in those with normal or mildly abnormal left ventricular function. Data from: Atrial Fibrillation Investigators, Arch Intern Med 1998; 158:1316. Graphic 70244 Version 4.0 https://www.uptodate.com/contents/mechanisms-of-thrombogenesis-in-atrial-fibrillation/print 19/20 7/5/23, 9:15 AM Mechanisms of thrombogenesis in atrial fibrillation - UpToDate Contributor Disclosures Gregory YH Lip, MD, FRCPE, FESC, FACC Consultant/Advisory Boards: BMS/Pfizer [Atrial fibrillation and thrombosis]; Boehringer Ingelheim [Atrial fibrillation and thrombosis]; Daiichi-Sankyo [Atrial fibrillation and thrombosis]. Speaker's Bureau: BMS/Pfizer [Atrial fibrillation and thrombosis]; Boehringer Ingelheim [Atrial fibrillation and thrombosis]; Daiichi-Sankyo [Atrial fibrillation and thrombosis]. All of the relevant financial relationships listed have been mitigated. Bradley P Knight, MD, FACC Grant/Research/Clinical Trial Support: Abbott [Electrophysiology]; Atricure [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Electrophysiology]; BSCI [Electrophysiology]; MDT [Electrophysiology]; Philips [Electrophysiology]. Consultant/Advisory Boards: Abbott [Electrophysiology]; Atricure [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Electrophysiology]; BSCI [Electrophysiology]; CVRx [Heart failure]; MDT [Electrophysiology]; Philips [Electrophysiology]; Sanofi [Arrhythmias]. Speaker's Bureau: Abbott [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Transeptal catheterization]; BSCI [Electrophysiology]; MDT [Electrophysiology]. All of the relevant financial relationships listed have been mitigated. Nisha Parikh, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/mechanisms-of-thrombogenesis-in-atrial-fibrillation/print 20/20