Dietary omega-3 alpha-linolenic acid does not prevent venous thrombosis in mice

Martin F. Reiner; Kimberly Martinod; Simona Stivala; Gianluigi Savarese; Giovanni G. Camici; Thomas F. Lüscher; Denisa D. Wagner; Jürg H. Beer

doi:10.1160/TH14-03-0200

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2015; 113(01): 177-184
DOI: 10.1160/TH14-03-0200

Stroke, Systemic or Venous Thromboembolism

Schattauer GmbH

Dietary omega-3 alpha-linolenic acid does not prevent venous thrombosis in mice

Martin F. Reiner^*

¹Laboratory for Platelet Research, Center for Molecular Cardiology, University of Zurich, Schlieren, Switzerland

²Department of Internal Medicine, Cantonal Hospital of Baden, Switzerland

,

Kimberly Martinod^*

³Program in Cellular and Molecular Medicine, Children’s Hospital, Harvard Medical School, Boston, Massachusetts, USA

,

Simona Stivala

¹Laboratory for Platelet Research, Center for Molecular Cardiology, University of Zurich, Schlieren, Switzerland

²Department of Internal Medicine, Cantonal Hospital of Baden, Switzerland

,

Gianluigi Savarese

¹Laboratory for Platelet Research, Center for Molecular Cardiology, University of Zurich, Schlieren, Switzerland

,

Giovanni G. Camici

¹Laboratory for Platelet Research, Center for Molecular Cardiology, University of Zurich, Schlieren, Switzerland

,

Thomas F. Lüscher

¹Laboratory for Platelet Research, Center for Molecular Cardiology, University of Zurich, Schlieren, Switzerland

⁵Department of Cardiology, University Heart Center, University Hospital Zurich, Switzerland

,

Denisa D. Wagner

³Program in Cellular and Molecular Medicine, Children’s Hospital, Harvard Medical School, Boston, Massachusetts, USA

⁴Division of Hematology/Oncology, Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA

,

Jürg H. Beer

¹Laboratory for Platelet Research, Center for Molecular Cardiology, University of Zurich, Schlieren, Switzerland

²Department of Internal Medicine, Cantonal Hospital of Baden, Switzerland

› Author Affiliations

Abstract

Summary

Venous thromboembolism (VTE) is a leading cause of cardiovascular death. Omega-3 fatty acids (n-3 FA) exhibit protective effects against cardiovascular disease. Others and our group have reported that the plant-derived n-3 FA alpha-linolenic acid (ALA) displays antiinflammatory, anticoagulant and antiplatelet effects, thereby reducing atherosclerosis and arterial thrombosis in mice fed a high ALA diet. Since procoagulant factors such as tissue factor and fibrin as well as platelets and leukocytes are crucially involved in the development of VTE, we investigated possible protective effects of dietary ALA on venous thrombus formation in a mouse model of stenosis- and furthermore, in a mouse model of endothelial injury-induced venous thrombosis. Four week old C57BL/6 mice underwent four weeks of high (7.3g%) or low ALA (0.03g%) treatment before being exposed to inferior vena cava (IVC) stenosis for 48 hours or laser injury of the endothelium of the internal jugular vein (IJV). Thrombus generation frequency, thrombus size and composition (IVC stenosis group) and time to thrombus formation (endothelial injury group) were assessed. In addition, plasma glycocalicin, a marker of platelet activation, platelet P-selectin and activated integrin expression as well as plasma thrombin generation was determined, but did not reveal any significant differences between he groups. Despite its protective properties against arterial thrombus formation, dietary ALA did not protect against venous thrombosis neither in the IVC stenosis nor the endothelial injury model, further indicating that the biological processes involved in arterial and venous thrombosis are different.

Keywords

Alpha-linolenic acid - cardiovascular disease - eep vein thrombosis - omega-3 fatty acids - venous thromboembolism

Full Text

References

References
1 Go AS, Mozaffarian D, Roger VL. et al. Heart disease and stroke statistics—2013 update: a report from the American Heart Association. Circulation 2013; 127: e6-e245.
2 Cohen AT, Agnelli G, Anderson FA. et al. Venous thromboembolism (VTE) in Europe. The number of VTE events and associated morbidity and mortality. Thromb Haemost 2007; 98: 756-764.
3 von Bruhl ML, Stark K, Steinhart A. et al. Monocytes, neutrophils, and platelets cooperate to initiate and propagate venous thrombosis in mice in vivo. J Exp Med 2012; 209: 819-835.
4 Esmon CT. Basic mechanisms and pathogenesis of venous thrombosis. Blood Rev 2009; 23: 225-229.
5 Pan A, Chen M, Chowdhury R. et al. alpha-Linolenic acid and risk of cardiovascular disease: a systematic review and meta-analysis. Am J Clin Nutr 2012; 96: 1262-1273.
6 Larsson SC, Orsini N, Wolk A. Long-chain omega-3 polyunsaturated fatty acids and risk of stroke: a meta-analysis. Eur J Epidemiol 2012; 27: 895-901.
7 Chowdhury R, Stevens S, Gorman D. et al. Association between fish consumption, long chain omega 3 fatty acids, and risk of cerebrovascular disease: systematic review and meta-analysis. Br Med J 2012; 345: e6698.
8 Tavazzi L, Maggioni AP, Marchioli R. et al. 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: 1223-1230.
9 Stebbins CL, Stice JP, Hart CM, Mbai FN, Knowlton AA. Effects of dietary deco-sahexaenoic acid (DHA) on eNOS in human coronary artery endothelial cells. J Cardiovasc Pharmacol Ther 2008; 13: 261-268.
10 De Caterina R, Cybulsky MI, Clinton SK. et al. The omega-3 fatty acid docosa-hexaenoate reduces cytokine-induced expression of proatherogenic and proin-flammatory proteins in human endothelial cells. Arterioscler Thromb 1994; 14: 1829-1836.
11 Abeywardena MY, Head RJ. Longchain n-3 polyunsaturated fatty acids and blood vessel function. Cardiovasc Res 2001; 52: 361-371.
12 Winnik S, Lohmann C, Richter EK. et al. Dietary alpha-linolenic acid diminishes experimental atherogenesis and restricts T cell-driven inflammation. Eur Heart J 2011; 32: 2573-2584.
13 Holy EW, Forestier M, Richter EK. et al. Dietary alpha-linolenic acid inhibits arterial thrombus formation, tissue factor expression, and platelet activation. Ar-terioscler Thromb Vasc Biol 2011; 31: 1772-1780.
14 Stivala S, Reiner MF, Lohmann C. et al. Dietary alpha-linolenic acid increases the platelet count in ApoE-/- mice by reducing clearance. Blood. 2013 Epub ahead of print.
15 Owens 3rd AP, Mackman N. Tissue factor and thrombosis: The clot starts here. Thromb Haemost 2010; 104: 432-439.
16 Mackman N. Triggers, targets and treatments for thrombosis. Nature 2008; 451: 914-918.
17 Smeeth L, Cook C, Thomas S. et al. Risk of deep vein thrombosis and pulmonary embolism after acute infection in a community setting. Lancet 2006; 367: 1075-1079.
18 Eppihimer MJ, Schaub RG. P-Selectin-dependent inhibition of thrombosis during venous stasis. Arterioscler Thromb Vasc Biol 2000; 20: 2483-2488.
19 Brill A, Fuchs TA, Savchenko AS. et al. Neutrophil extracellular traps promote deep vein thrombosis in mice. J Thromb Haemost 2012; 10: 136-144.
20 Fuchs TA, Brill A, Duerschmied D. et al. Extracellular DNA traps promote thrombosis. Proc Natl Acad Sci USA 2010; 107: 15880-15885.
21 Martinod K, Demers M, Fuchs TA. et al. Neutrophil histone modification by peptidylarginine deiminase 4 is critical for deep vein thrombosis in mice. Proc Natl Acad Sci USA 2013; 110: 8674-8679.
22 Brill A, Fuchs TA, Chauhan AK. et al. von Willebrand factor-mediated platelet adhesion is critical for deep vein thrombosis in mouse models. Blood 2011; 117: 1400-1407.
23 Tchaikovski SN, Van Vlijmen BJ, Rosing J, Tans G. Development of a calibrated automated thrombography based thrombin generation test in mouse plasma. J Thromb Haemost 2007; 05: 2079-2086.
24 Thevenaz P, Unser M. User-friendly semiautomated assembly of accurate image mosaics in microscopy. Microsc Res Tech 2007; 70: 135-146.
25 Beer JH, Buchi L, Steiner B. Glycocalicin: a new assay—the normal plasma levels and its potential usefulness in selected diseases. Blood 1994; 83: 691-702.
26 Becattini C, Agnelli G, Schenone A. et al. Aspirin for preventing the recurrence of venous thromboembolism. N Engl J Med 2012; 366: 1959-1967.
27 Breitenstein A, Tanner FC, Luscher TF. Tissue factor and cardiovascular disease: quo vadis?. Circ J 2010; 74: 3-12.
28 Zheng J, Huang T, Yu Y. et al. Fish consumption and CHD mortality: an updated meta-analysis of seventeen cohort studies. Public Health Nutr 2012; 15: 725-737.