Semin Thromb Hemost 2015; 41(03): 315-322
DOI: 10.1055/s-0034-1395352
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

The Effect of Omega-3 Polyunsaturated Fatty Acids on Fibrin and Thrombin Generation in Healthy Subjects and Subjects with Cardiovascular Disease

Bradley J. McEwen
1   Northern Blood Research Centre, Kolling Institute of Medical Research, University of Sydney, Sydney, New South Wales, Australia
2   Department of Haematology and Transfusion Medicine, Royal North Shore Hospital, St Leonards, New South Wales, Australia
Marie-Christine Morel-Kopp
1   Northern Blood Research Centre, Kolling Institute of Medical Research, University of Sydney, Sydney, New South Wales, Australia
2   Department of Haematology and Transfusion Medicine, Royal North Shore Hospital, St Leonards, New South Wales, Australia
Geoffrey H. Tofler
3   Department of Cardiology, Royal North Shore Hospital, St Leonards, New South Wales, Australia
Christopher M. Ward
1   Northern Blood Research Centre, Kolling Institute of Medical Research, University of Sydney, Sydney, New South Wales, Australia
2   Department of Haematology and Transfusion Medicine, Royal North Shore Hospital, St Leonards, New South Wales, Australia
› Author Affiliations
Further Information

Publication History

Publication Date:
19 February 2015 (online)


Hypercoagulability plays a key role in the progression of cardiovascular disease (CVD). Although omega-3 polyunsaturated fatty acid (PUFA) intake has been inversely related to the risk of cardiovascular events, the mechanisms are not fully understood. The aim of this study was to investigate the effects of omega-3 on novel markers of global coagulation. The generation of fibrin and thrombin, measured via overall hemostasis potential (OHP) assay and calibrated automated thrombography, respectively, was determined in 40 healthy subjects and 16 patients with CVD at baseline and after 4 weeks of 640 mg/day omega-3 PUFA. In healthy subjects, fibrin generation was significantly reduced, as measured by overall coagulation potential (p = 0.013), OHP (p < 0.001), velocity of fibrin polymerization (p = 0.002), and significant increase in delay to fibrin generation (p = 0.002). The peak of generated thrombin was significantly reduced (p = 0.043). In subjects with CVD, omega-3 PUFA significantly reduced OHP and significantly increased the lag time to thrombin generation (both p < 0.001). Treatment with omega-3 PUFA had no effect on other fibrin and thrombin generation parameters in CVD patients. Four-week omega-3 PUFA supplementation reduced thrombotic potential in healthy subjects, as shown by reduced fibrin generation and peak thrombin. There was a greater effect on fibrin generation in healthy subjects compared with those with CVD.

  • References

  • 1 Go AS, Mozaffarian D, Roger VL , et al; American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics—2014 update: a report from the American Heart Association. Circulation 2014; 129 (3) e28-e292
  • 2 Dyerberg J, Bang HO, Hjorne N. Fatty acid composition of the plasma lipids in Greenland Eskimos. Am J Clin Nutr 1975; 28 (9) 958-966
  • 3 Bang HO, Dyerberg J. Plasma lipids and lipoproteins in Greenlandic west coast Eskimos. Acta Med Scand 1972; 192 (1-2) 85-94
  • 4 Albert CM, Hennekens CH, O'Donnell CJ , et al. Fish consumption and risk of sudden cardiac death. JAMA 1998; 279 (1) 23-28
  • 5 Kromhout D, Bosschieter EB, de Lezenne Coulander C. The inverse relation between fish consumption and 20-year mortality from coronary heart disease. N Engl J Med 1985; 312 (19) 1205-1209
  • 6 Benatti P, Peluso G, Nicolai R, Calvani M. Polyunsaturated fatty acids: biochemical, nutritional and epigenetic properties. J Am Coll Nutr 2004; 23 (4) 281-302
  • 7 Harris WS, Kris-Etherton PM, Harris KA. Intakes of long-chain omega-3 fatty acid associated with reduced risk for death from coronary heart disease in healthy adults. Curr Atheroscler Rep 2008; 10 (6) 503-509
  • 8 Din JN, Newby DE, Flapan AD. Omega 3 fatty acids and cardiovascular disease—fishing for a natural treatment. BMJ 2004; 328 (7430) 30-35
  • 9 Surette ME. The science behind dietary omega-3 fatty acids. CMAJ 2008; 178 (2) 177-180
  • 10 Kris-Etherton PM, Harris WS, Appel LJ ; Nutrition Committee. Fish consumption, fish oil, omega-3 fatty acids, and cardiovascular disease. Arterioscler Thromb Vasc Biol 2003; 23 (2) e20-e30
  • 11 Meade TW, Ruddock V, Stirling Y, Chakrabarti R, Miller GJ. Fibrinolytic activity, clotting factors, and long-term incidence of ischaemic heart disease in the Northwick Park Heart Study. Lancet 1993; 342 (8879) 1076-1079
  • 12 Stec JJ, Silbershatz H, Tofler GH , et al. Association of fibrinogen with cardiovascular risk factors and cardiovascular disease in the Framingham Offspring Population. Circulation 2000; 102 (14) 1634-1638
  • 13 Koenig W. Haemostatic risk factors for cardiovascular diseases. Eur Heart J 1998; 19 (Suppl C): C39-C43
  • 14 Kannel WB, Wolf PA, Castelli WP, D'Agostino RB. Fibrinogen and risk of cardiovascular disease. The Framingham Study. JAMA 1987; 258 (9) 1183-1186
  • 15 Kamphuisen PW, Eikenboom JC, Bertina RM. Elevated factor VIII levels and the risk of thrombosis. Arterioscler Thromb Vasc Biol 2001; 21 (5) 731-738
  • 16 Kyrle PA, Minar E, Hirschl M , et al. High plasma levels of factor VIII and the risk of recurrent venous thromboembolism. N Engl J Med 2000; 343 (7) 457-462
  • 17 Spiel AO, Gilbert JC, Jilma B. von Willebrand factor in cardiovascular disease: focus on acute coronary syndromes. Circulation 2008; 117 (11) 1449-1459
  • 18 Al Dieri R, de Laat B, Hemker HC. Thrombin generation: what have we learned?. Blood Rev 2012; 26 (5) 197-203
  • 19 Goodnight Jr SH, Harris WS, Connor WE, Illingworth DR. Polyunsaturated fatty acids, hyperlipidemia, and thrombosis. Arteriosclerosis 1982; 2 (2) 87-113
  • 20 Nomura S, Kanazawa S, Fukuhara S. Effects of eicosapentaenoic acid on platelet activation markers and cell adhesion molecules in hyperlipidemic patients with Type 2 diabetes mellitus. J Diabetes Complications 2003; 17 (3) 153-159
  • 21 Dyerberg J, Bang HO. Haemostatic function and platelet polyunsaturated fatty acids in Eskimos. Lancet 1979; 2 (8140) 433-435
  • 22 Annuzzi G, Rivellese A, Capaldo B , et al. A controlled study on the effects of n-3 fatty acids on lipid and glucose metabolism in non-insulin-dependent diabetic patients. Atherosclerosis 1991; 87 (1) 65-73
  • 23 Connor WE, Prince MJ, Ullmann D , et al. The hypotriglyceridemic effect of fish oil in adult-onset diabetes without adverse glucose control. Ann N Y Acad Sci 1993; 683: 337-340
  • 24 Marchioli R, Barzi F, Bomba E , et al; GISSI-Prevenzione Investigators. Early protection against sudden death by n-3 polyunsaturated fatty acids after myocardial infarction: time-course analysis of the results of the Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico (GISSI)-Prevenzione. Circulation 2002; 105 (16) 1897-1903
  • 25 Tavazzi L, Maggioni AP, Marchioli R , et al; Gissi-HF Investigators. Effect of n-3 polyunsaturated fatty acids in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial. Lancet 2008; 372 (9645) 1223-1230
  • 26 Shahar E, Folsom AR, Wu KK , et al. Associations of fish intake and dietary n-3 polyunsaturated fatty acids with a hypocoagulable profile. The Atherosclerosis Risk in Communities (ARIC) Study. Arterioscler Thromb 1993; 13 (8) 1205-1212
  • 27 Curnow JL, Morel-Kopp MC, Roddie C, Aboud M, Ward CM. Reduced fibrinolysis and increased fibrin generation can be detected in hypercoagulable patients using the overall hemostatic potential assay. J Thromb Haemost 2007; 5 (3) 528-534
  • 28 He S, Antovic A, Blombäck M. A simple and rapid laboratory method for determination of haemostasis potential in plasma. II. Modifications for use in routine laboratories and research work. Thromb Res 2001; 103 (5) 355-361
  • 29 Antovic A. Screening haemostasis—looking for global assays: the Overall Haemostasis Potential (OHP) method—a possible tool for laboratory investigation of global haemostasis in both hypo- and hypercoagulable conditions. Curr Vasc Pharmacol 2008; 6 (3) 173-185
  • 30 Antovic A. The overall hemostasis potential: a laboratory tool for the investigation of global hemostasis. Semin Thromb Hemost 2010; 36 (7) 772-779
  • 31 McEwen BJ, Phillips CL, Morel-Kopp MC , et al. Diurnal changes and levels of fibrin generation are not altered by continuous positive airway pressure (CPAP) in obstructive sleep apnoea (OSA). A randomised, placebo-controlled crossover study. Thromb Haemost 2012; 108 (4) 701-709
  • 32 Baglin T. The measurement and application of thrombin generation. Br J Haematol 2005; 130 (5) 653-661
  • 33 Hemker HC, Giesen P, Al Dieri R , et al. Calibrated automated thrombin generation measurement in clotting plasma. Pathophysiol Haemost Thromb 2003; 33 (1) 4-15
  • 34 Adams M. Assessment of thrombin generation: useful or hype?. Semin Thromb Hemost 2009; 35 (1) 104-110
  • 35 Lee KW, Lip GY. Effects of lifestyle on hemostasis, fibrinolysis, and platelet reactivity: a systematic review. Arch Intern Med 2003; 163 (19) 2368-2392
  • 36 McEwen BJ, Morel-Kopp MC, Chen W, Tofler GH, Ward CM. Effects of omega-3 polyunsaturated fatty acids on platelet function in healthy subjects and subjects with cardiovascular disease. Semin Thromb Hemost 2013; 39 (1) 25-32
  • 37 Cohen MG, Rossi JS, Garbarino J , et al. Insights into the inhibition of platelet activation by omega-3 polyunsaturated fatty acids: beyond aspirin and clopidogrel. Thromb Res 2011; 128 (4) 335-340
  • 38 Singer P, Wirth M. Can n-3 PUFA reduce cardiac arrhythmias? Results of a clinical trial. Prostaglandins Leukot Essent Fatty Acids 2004; 71 (3) 153-159
  • 39 He S, Bremme K, Blombäck M. A laboratory method for determination of overall haemostatic potential in plasma. I. Method design and preliminary results. Thromb Res 1999; 96 (2) 145-156
  • 40 Hemker HC, Giesen P, AlDieri R , et al. The calibrated automated thrombogram (CAT): a universal routine test for hyper- and hypocoagulability. Pathophysiol Haemost Thromb 2002; 32 (5-6) 249-253
  • 41 Larson MK, Tormoen GW, Weaver LJ , et al. Exogenous modification of platelet membranes with the omega-3 fatty acids EPA and DHA reduces platelet procoagulant activity and thrombus formation. Am J Physiol Cell Physiol 2013; 304 (3) C273-C279
  • 42 Gajos G, Zalewski J, Rostoff P, Nessler J, Piwowarska W, Undas A. Reduced thrombin formation and altered fibrin clot properties induced by polyunsaturated omega-3 fatty acids on top of dual antiplatelet therapy in patients undergoing percutaneous coronary intervention (OMEGA-PCI clot). Arterioscler Thromb Vasc Biol 2011; 31 (7) 1696-1702
  • 43 Vanschoonbeek K, Feijge MA, Paquay M , et al. Variable hypocoagulant effect of fish oil intake in humans: modulation of fibrinogen level and thrombin generation. Arterioscler Thromb Vasc Biol 2004; 24 (9) 1734-1740
  • 44 Monroe DM, Hoffman M, Roberts HR. Platelets and thrombin generation. Arterioscler Thromb Vasc Biol 2002; 22 (9) 1381-1389
  • 45 Gebauer SK, Psota TL, Harris WS, Kris-Etherton PM. n-3 fatty acid dietary recommendations and food sources to achieve essentiality and cardiovascular benefits. Am J Clin Nutr 2006; 83 (6, Suppl) 1526S-1535S
  • 46 National Heart Foundation of Australia. Position statement: Fish, fish oils, n-3 polyunsaturated fatty acids and cardiovascular health. In: National Heart Foundation of Australia; 2008
  • 47 Blonk MC, Bilo HJ, Nauta JJ, Popp-Snijders C, Mulder C, Donker AJ. Dose-response effects of fish-oil supplementation in healthy volunteers. Am J Clin Nutr 1990; 52 (1) 120-127
  • 48 Schmidt EB, Varming K, Ernst E, Madsen P, Dyerberg J. Dose-response studies on the effect of n-3 polyunsaturated fatty acids on lipids and haemostasis. Thromb Haemost 1990; 63 (1) 1-5
  • 49 Hjerkinn EM, Seljeflot I, Ellingsen I , et al. Influence of long-term intervention with dietary counseling, long-chain n-3 fatty acid supplements, or both on circulating markers of endothelial activation in men with long-standing hyperlipidemia. Am J Clin Nutr 2005; 81 (3) 583-589
  • 50 Lee KW, Blann AD, Lip GY. Effects of omega-3 polyunsaturated fatty acids on plasma indices of thrombogenesis and inflammation in patients post-myocardial infarction. Thromb Res 2006; 118 (3) 305-312
  • 51 Mackay I, Ford I, Thies F, Fielding S, Bachoo P, Brittenden J. Effect of Omega-3 fatty acid supplementation on markers of platelet and endothelial function in patients with peripheral arterial disease. Atherosclerosis 2012; 221 (2) 514-520
  • 52 Toft I, Bønaa KH, Ingebretsen OC, Nordøy A, Jenssen T. Fibrinolytic function after dietary supplementation with omega3 polyunsaturated fatty acids. Arterioscler Thromb Vasc Biol 1997; 17 (5) 814-819