Prognostic impact of haemostatic derangements in chronic heart failure

Summary

Heart failure is characterised by activation of haemostasis. We sought to explore the prognostic impact of deranged haemostasis in chronic heart failure. In stable, optimally managed outpatients with chronic heart failure, baseline levels of prothrombin fragment F1+2, D-dimer, and tPA and PAI-1 antigens were determined. Clinical follow-up was obtained and the rate of events (heart failure related deaths or hospitalisations) was recorded. We included 195 patients [32.3% female, NYHA class II (66.2%) or III (33.8%), mean age 71 years]. During a median follow up of 693 (interquartile range [IQR] 574–788) days, 63 (30.9%) patients experienced an event; those with an event had higher levels of tPA antigen (median 11.8 [IQR 8.7–14.0] vs. 9.4 [7.9–12.1] µg/l; p=0.033) and D-dimer (938 [485–1269] vs. 620 [37–1076] µg/l; p=0.018). However, on Cox multivariate analysis, only tPA levels above optimal cut-off value of 10.2 µg/l (but not D-dimer) emerged as an independent predictor of prognosis (HR_adjusted 2.695, 95% confidence interval 1.233–5.363; p=0.017). Our findings suggest that elevated tPA antigen levels are an independent prognostic predictor in patients with chronic stable heart failure.

Keywords

Congestive heart failure - prognosis - haemostasis

• References

• 1 Jafri S. Hypercoagulability in heart failure. Semin Thromb Hemost 1997; 23: 543-545.
• 2 Davis C, Gurbel P, Gattis W. et al. Hemostatic abnormalities in patients with congestive heart failure: diagnostic significance and clinical challenge. Int J Cardiol 2000; 75: 15-21.
• 3 Lip GYH, Gibbs CR. Does heart failure confer a hypercoagulable sate? Virchow’s triad revisited [Editorial]. J Am Coll Cardiol 1999; 33: 1424-1426.
• 4 Lip GYH, Lowe GD, Metcalfe M. et al. Effects of warfarin therapy on plasma fibrinogen, von Willenbrand factor, and fibrin D-dimer in left ventricular dysfunction secondary to coronary artery disease with and without aneurisms. Am J Cardiol 1995; 76: 453-458.
• 5 Chin BS, Conway DS, Chung NA. et al. Interleukin-6, tissue factor and von Wilenbrand factor in acute decompensated heart failure: relationship to treatment and prognosis. Blood Coagul Fibrinolysis 2003; 14: 515-521.
• 6 Chong A-Y, Lip GYH. Viewpoint: The prothrombotic state in heart failure: A maladaptive inflammatory response?. Eur J Heart Fail 2007; 09: 124-128.
• 7 Keber I, Keber D, Stegnar M. et al. Tissue plasminogen activator release in chronic venous hypertension due to heart failure. Thromb Haemost 1992; 68: 321-324.
• 8 Riza Erbay A, Turhan H, Aksoy Y. et al. Activation of coagulation system in dilated cardiomyopathy: comparison of patients with and without left ventricular thrombus. Coron Artery Dis 2004; 15: 265-268.
• 9 Moss AJ, Goldstein RE, Marder VJ. et al. Thrombogenic factors and recurrent coronary events. Circulation 1999; 99: 2517-2522.
• 10 Li Y-H, Teng J-K, Tsai W-C. et al. Prognostic significance of elevated hemostatic markers in patients with acute myocardial infarction. J Am Coll Cardiol 1999; 33: 1543-1548.
• 11 Danesh J, Whincup P, Walker M. et al. Fibrin D-dimer and coronary heart disease : Prospective study and meta-analysis. Circulation 2001; 103: 2323-2327.
• 12 Lowe GDO, Danesh J, Lewington S. et al. Tissue plasminogen activator antigen and coronary heart disease: Prospective study and meta-analysis. Eur Heart J 2004; 25: 252-259.
• 13 Feinberg WM, Erickson LP, Bruck D. et al. Hemostatic markers in acute ischemic atroke: Association with stroke type, severity, and outcome. Stroke 1996; 27: 1296-1300.
• 14 Barber M, Langhorne P, Rumley A. et al. Hemostatic function and progressing ischemic stroke: D-dimer predicts early clinical progression. Stroke 2004; 35: 1421-1425.
• 15 Barber M, Langhorne P, Rumley A. et al. D-dimer predicts early clinical progression in ischemic stroke: Confirmation using routine clinical assays. Stroke 2006; 37: 1113-1115.
• 16 van der Bom JG, Bots ML, Haverkate F. et al. Activation products of the haemostatic system in coronary, cerebrovascular and peripheral arterial disease. Thromb Haemost 2001; 85: 234-239.
• 17 Vene N, Mavri A, Kosmelj K. et al. High D-dimer levels predict cardiovascular events in patients with chronic atrial fibrillation during oral anticoagulation therapy. Thromb Haemost 2003; 90: 1163-1172.
• 18 Sbarouni E, Bradshaw A, Andreotti F. et al. Relationship between hemostatic abnormalities and neuroendocrine activity in heart failure. Am Heart J 1994; 127: 607-612.
• 19 Alehagen U, Dahlstrom U, Lindahl TL. Elevated D-dimer level is an independent risk factor for cardiovascular death in out-patients with symptoms compatible with heart failure. Thromb Haemost 2004; 92: 1250-1258.
• 20 Butler J, Khadim G, Paul K. et al. Selection of patients for heart transplantation in the current era of heart failure therapy. J Am Coll Cardiol 2004; 43: 787-793.
• 21 Zugck C, Haunstetter A, Kruger C. et al. Impact of beta-blocker treatment on the prognostic value of currently used risk predictors in congestive heart failure. J Am Coll Cardiol 2002; 39: 1615-1622.
• 22 Paulus WJ, Tschope C, Sanderson JE. et al. How to diagnose diastolic heart failure: a consensus statement on the diagnosis of heart failure with normal left ventricular ejection fraction by the Heart Failure and Echocardiography Associations of the European Society of Cardiology. Eur Heart J 2007; 28: 2539-2550.
• 23 Dupont W, Plummer W. Power and Sample Size Calculations: A Review and Computer Program. Controlled Clinical Trials 1990; 11: 116-128.
• 24 Williams B, Mandrekar N, Mandrekar S. et al. Finding optimal cutpoints for continuous covariates with binary and time-to-event outcomes. Technical Report Series #79. Rochester, Minnesota: Department of Health Sciences Research, Mayo Clinic; 2006: 26.
• 25 Vaughan D, Lazos S, Tong K. Angiotensin II regulates the expression of plasminogen activator inhibitor-1 in cultured endothelial cells: a potential link between the renin-angiotensin system and thrombosis. J Clin Invest 1995; 95: 995-1001.
• 26 Preckel D, von Kanel R. Regulation of hemostasis by the sympathetic nervous system: any contrubution to coronary artery disease?. Heart Drug 2004; 04: 123-130.
• 27 Cugno M, Mari D, Meroni PL. et al. Hemostatic and infalmmatory biomarkers in advanced heart failure: role of oral anticoagulants and successful heart transplantation. Br J Hematol 2006; 126: 85-92.
• 28 Danenberg HD, Szalai AJ, Swaminathan RV. et al. Increased thrombosis after arterial injury in human C-reactive protein-transgenic mice. Circulation 2003; 108: 512-515.
• 29 Devaraj S, Xu DY, Jialal I. C-reactive protein increases plasminogen activator inhibitor-1 expression and activity in human aortic endothelial cells: Implications for the metabolic syndrome and atherothrombosis. Circulation 2003; 107: 398-404.
• 30 Gonway D, Buggins P, Hughes E. et al. Relationship of interleukin-6 and C-reactive protein to the prothrombotic state in atrial fibrillation. J Am Coll Cardiol 2004; 43: 2075-2082.
• 31 Sbarouni E, Bradshaw A, Andreotti F. et al. Relationship between hemostatic abnormalities and neuroendocrine activity in heart failure. Am Heart J 1994; 127: 607-612.
• 32 Gibbs CR, Blann AD, Watson RDS. et al. Abnormalities of hemorheological, endothelial, and platlet function in patients with chronic heart failure in synus rhythm: effects of angiotensin converting enzyme inhibitor and beta blocker therapy. Circulation 2002; 103: 3-4.
• 33 Kothari SA, Le MK, Ghandi PJ. Effects of angiotensin converting enzyme inhibitors on thrombotic mediators: Potential clinical implications. J Thromb Thrombolysis 2003; 15: 217-225.
• 34 Labinjoh C, Newby DE, Pellegrini MP. et al. Potentiation of bradykinin-induced tissue plasminogen activator release by angiotensin-converting enzyme inhibition. J Am Coll Cardiol 2001; 38: 1402-1408.
• 35 Agewall S, Bokemark L, Wikstrand J. et al. Insulin sensitivity and hemostatic factors in clinically healthy 58-year-old men. Thromb Haemost 2000; 84: 571-575.
• 36 Alessi M-C, Juhan-Vague I. Metabolic syndrome, haemostasis and thrombosis. Thromb Haemost 2008; 99: 995-1000.
• 37 Doehner W, Rauchhaus M, Ponikowski P. et al. Impaired insulin sensitivity as an independent risk factor for mortality in patients with stable chronic heart failure. J Am Coll Cardiol 2005; 46: 1019-1026.
• 38 Cleland JGF, Findlay I, Jafri S. et al. The Warfarin/ Aspirin Study in Heart Failure (WASH): A Randomized Trial Comparing Antithrombotic Strategies for Patients With Heart Failure. Am Heart J 2004; 148: 157-164.
• 39 Massie BM, Collins JF, Ammon SE. et al. Randomized Trial of Warfarin, Aspirin, and Clopidogrel in Patients With Chronic Heart Failure. The Warfarin and Antiplatelet Therapy in Chronic Heart Failure (WATCH) Trial. Circulation. 2009 119. Published online before print March 16, 2009, doi: 10.1161/CIRCULATIONAHA.108.801753.
• 40 Kjekshus J, Apetrei J, Barrios V. Rosuvastatin in older patients with heart failure. N Engl J Med 2007; 357: 2248-2261.
• 41 Cleland JGF, Freemantle N, Ball SG. et al. The heart failure revascularisation trial (HEART): rationale, design and methodology. Eur J Heart Fail 2003; 05: 295-303.
• 42 Alehagen U, Eriksson H, Nylander E. et al. Heart Failure in the Elderly: Characteristics of a Swedish Primary Health Care Population. Heart Drug 2002; 02: 211-220.
• 43 Loh PH, Tin L, Goode K. et al. Disturbed haemostasis predicts mortality in patients with heart failure due to left ventricular systolic dysfunction [Abstract]. Eur Heart J 2007; 28 (Suppl) 810.
• 44 Thogersen AM, Jansson J-H, Boman K. et al. High plasminogen activator inhibitor and tissue plasminogen activator levels in plasma precede a first acute myocardial infarction in both men and women: Evidence for the fibrinolytic system as an independent primary risk factor. Circulation 1998; 98: 2241-2247.
• 45 Juhan-Vague I, Pyke SDM, Alessi MC. et al. Fibrinolytic factors and the risk of myocardial infarction or sudden death in patients with angina pectoris. Circulation 1996; 94: 2057-2063.
• 46 Andreasen P. Plasminogen activator inhibitor-1 (PAI-1): A molecule at the crossroads to cell survival or cell death. Thromb Haemost 2008; 100: 965-968.
• 47 Merlini PA, Bauer KA, Oltrona L. et al. Persistent activation of coagulation mechanism in unstable angina and myocardial infarction. Circulation 1994; 90: 61-68.