Increased thrombin generation in persons with echogenic carotid plaques

Ann-Trude With Notø; Ellisiv Bøgeberg Mathiesen; Bjarne Østerud; Jean Amiral; Anne Marie Vissac; John-Bjarne Hansen

doi:10.1160/TH07-08-0493

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2008; 99(03): 602-608
DOI: 10.1160/TH07-08-0493

Cardiovascular Biology and Cell Signalling

Schattauer GmbH

Increased thrombin generation in persons with echogenic carotid plaques

Ann-Trude With Notø

¹Center for Atherothrombotic Research in Tromsø (CART)

,

Ellisiv Bøgeberg Mathiesen

²Department of Neurology, Institute of Clinical Medicine

,

Bjarne Østerud

³Institute of Community Medicine, and Institute of Medical Biology, University of Tromsø, Tromsø, Norway

,

Jean Amiral

⁴HYPHEN BioMed, Neuville sur Oise, France

,

Anne Marie Vissac

⁴HYPHEN BioMed, Neuville sur Oise, France

,

John-Bjarne Hansen

¹Center for Atherothrombotic Research in Tromsø (CART)

› Author Affiliations

Abstract

Summary

Echolucent carotid plaques are associated with higher risk for future ischemic cerebrovascular events (CVE) than echogenic plaques independent of the degree of stenosis.Elevated markers of thrombin generation are associated with atherosclerotic plaques and are increased in the acute and chronic phases of CVE. The present study was conducted to investigate the influence of plaque morphology on thrombin generation in persons with carotid stenosis. One hundred twenty-eight persons with carotid stenosis (≥35% lumen diameter reduction) and 136 matched controls without stenosis were recruited from the health survey of the Tromsø Study. Blood samples were collected and plaque morphology determined by ultrasonography. Thrombin generation was assessed by thrombin-antithrombin complexes (TAT) and by prothrombin fragment 1+2 (F1+2).Persons with echogenic plaques (n=63) had significantly higher levels of TAT (5.24 μg/l, 4.33–6.14) (mean, 95%CI) than persons with echolucent plaques (n=65) (3.44 μg/l, 2.91–3.96, p<0.001) and controls (n=136) (3.33 μg/l, 3.06–3.60, p<0.001).They also had significantly higher levels of F1+2 (2.14 nM, 1.83–2.45) than persons with echolucent plaques (1.54 nM, 1.38–1.71, p<0.001) and controls (1.49 nM, 1.40–1.58, p<0.001). TAT and F1+2 increased linearly with plaque echogenicity (p=0.002 and p=0.001, respectively) independent of the degree of stenosis. Increased thrombin generation was associated with a significant increase in plasma factorV levels among persons with echogenic plaques compared to echolucent plaques (p=0.049) and controls (p=0.025). The present findings indicate that increasing plaque echogenicity, rather than plaque echolucency and the degree of stenosis, is associated with thrombin generation in persons with carotid stenosis.

Keywords

Carotid stenosis - plaque morphology - thrombin generation - TAT - F1+2

Full Text

References

References
1 Rapaport SI, Rao LV. The tissue factor pathway: how it has become a “prima ballerina”. Thromb Haemost 1995; 74: 7-17.
2 Wilcox JN, Smith KM, Schwartz SM. et al. Localization of tissue factor in normal vessel and in the atherosclerotic plaque. Proc Natl Acad Sci USA 1989; 86: 2839-2843.
3 Toschi V, Gallo R, Lettino M. et al. Tissue factor modulates the thrombogenicity of human atherosclerotic plaques. Circulation 1997; 95: 594-599.
4 Broze GJ, Jr. Warren LA, Novotny WF. et al. The lipoprotein- associated coagulation inhibitor that inhibits the factor VII-tissue factor complex also inhibits factor Xa: insight into its possible mechanism of action. Blood 1988; 71: 335-343.
5 Badimon JJ, Lettino M, Toschi V. et al. Local inhibition of tissue factor reduces the thrombogenicity of disrupted human atherosclerotic plaques: effects of tissue factor pathway inhibitor on plaque thrombogenicity under flow conditions. Circulation 1999; 99: 1780-1787.
6 Smith EB. Fibrinogen, fibrin and fibrin degradation products in relation to atherosclerosis. Clin Haematol 1986; 15: 355-370.
7 Niewiarowski S, Rao AK. Contribution of thrombogenic factors to the pathogenesis of atherosclerosis. Prog Cardiovasc Dis 1983; 26: 197-222.
8 Kienast J, Thompson SG, Raskino C. et al. Prothrombin activation fragment 1 + 2 and thrombin antithrombin III complexes in patients with angina pectoris: relation to the presence and severity of coronary atherosclerosis. Thromb Haemost 1993; 70: 550-553.
9 Paramo JA, Orbe J, Beloqui O. et al. Prothrombin fragment 1+2 is associated with carotid intima-media thickness in subjects free of clinical cardiovascular disease. Stroke 2004; 35: 1085-1089.
10 Migdalski A, Jawien A, Kotschy M. et al. Selected haemostatic factors in carotid bifurcation plaques of patients undergoing carotid endarterectomy. Eur J Vasc Endovasc Surg 2004; 27: 172-179.
11 Merlini PA, Bauer KA, Oltrona L. et al. Persistent activation of coagulation mechanism in unstable angina and myocardial infarction. Circulation 1994; 90: 61-68.
12 Soncini M, Gasparini P, Lorena M. et al. Prognostic significance of markers of thrombin generation in the acute and chronic phases of non cardioembolic ischemic stroke. Minerva Cardioangiol 2000; 48: 349-356.
13 Ardissino D, Merlini PA, Bauer KA. et al. Coagulation activation and long-term outcome in acute coronary syndromes. Blood 2003; 102: 2731-2735.
14 Gronholdt ML. Ultrasound and lipoproteins as predictors of lipid-rich, rupture-prone plaques in the carotid artery. Arterioscler Thromb Vasc Biol 1999; 19: 2-13.
15 Mathiesen EB, Bonaa KH, Joakimsen O. Echolucent plaques are associated with high risk of ischemic cerebrovascular events in carotid stenosis: The Tromso Study. Circulation 2001; 103: 2171-2175.
16 Gronholdt ML, Nordestgaard BG, Schroeder TV. et al. Ultrasonic echolucent carotid plaques predict future strokes. Circulation 2001; 104: 68-73.
17 With Notø AT, Mathiesen EB, Amiral J. et al. Endothelial dysfunction and systemic inflammation in persons with echolucent carotid plaques. Thromb Haemost 2006; 96: 53-59.
18 Mathiesen EB, Joakimsen O, Bonaa KH. Prevalence of and risk factors associated with carotid artery stenosis: the Tromso Study. Cerebrovasc Dis 2001; 12: 44-51.
19 Mathiesen EB, Joakimsen O, Bonaa KH. Intersonographer reproducibility and intermethod variability of ultrasound measurements of carotid artery stenosis: The Tromso Study. Cerebrovasc Dis 2000; 10: 207-213.
20 Gray-Weale AC, Graham JC, Burnett JR. et al. Carotid artery atheroma: comparison of preoperative B-mode ultrasound appearance with carotid endarterectomy specimen pathology. J Cardiovasc Surg 1988; 29: 676-681.
21 Joakimsen O, Bonaa KH, Stensland-Bugge E. Reproducibility of ultrasound assessment of carotid plaque occurrence, thickness, and morphology. The Tromso Study. Stroke 1997; 28: 2201-2207.
22 Hansen JB, Huseby NE, Sandset PM. et al. Tissuefactor pathway inhibitor and lipoproteins. Evidence for association with and regulation by LDL in human plasma. Arterioscler Thromb 1994; 14: 223-229.
23 Morrissey JH, Macik BG, Neuenschwander PF. et al. Quantitation of activated factor VII levels in plasma using a tissue factor mutant selectively deficient in promoting factor VII activation. Blood 1993; 81: 734-744.
24 Cote R, Wolfson C, Solymoss S. et al. Hemostatic markers in patients at risk of cerebral ischemia. Stroke 2000; 31: 1856-1862.
25 Agewall S, Wikstrand J, Suurkula M. et al. Carotid artery wall morphology, haemostatic factors and cardiovascular disease. An ultrasound study in men at high and low risk for atherosclerotic disease. Blood Coagul Fibrinolysis 1994; 5: 895-904.
26 Carr S, Farb A, Pearce WH. et al. Atherosclerotic plaque rupture in symptomatic carotid artery stenosis. J Vasc Surg 1996; 23: 755-765.
27 Virmani R, Burke AP, Kolodgie FD. et al. Vulnerable plaque: the pathology of unstable coronary lesions. J Interv Cardiol 2002; 15: 439-446.
28 Woodward M, Lowe GD, Rumley A. et al. Epidemiology of coagulation factors, inhibitors and activation markers: The Third Glasgow MONICA Survey. II. Relationships to cardiovascular risk factors and prevalent cardiovascular disease. Br J Haematol 1997; 97: 785-797.
29 Bar-Shavit R, Benezra M, Sabbah V. et al. Thrombin as a multifunctional protein: induction of cell adhesion and proliferation. Am J Respir Cell Mol Biol 1992; 6: 123-130.
30 Rickles FR, Edwards RL. Activation of blood coagulation in cancer: Trousseau’s syndrome revisited. Blood 1983; 62: 14-31.
31 Edwards RL, Levine JB, Green R. et al. Activation of blood coagulation in Crohn’s disease. Increased plasma fibrinopeptide A levels and enhanced generation of monocyte tissue factor activity. Gastroenterology 1987; 92: 329-337.
32 Asakura H, Wada H, Okamoto K. et al. Evaluation of haemostatic molecular markers for diagnosis of disseminated intravascular coagulation in patients with infections. Thromb Haemost 2006; 95: 282-287.
33 Mann KG, Nesheim ME, Church WR. et al. Surface- dependent reactions of the vitamin K-dependent enzyme complexes. Blood 1990; 76: 1-16.
34 Nesheim ME, Taswell JB, Mann KG. The contribution of bovine Factor V and Factor Va to the activity of prothrombinase. J Biol Chem 1979; 254: 10952-10962.
35 Redondo M, Watzke HH, Stucki B. et al. Coagulation factors II, V, VII, and X, prothrombin gene 20210G–>A transition, and factor V Leiden in coronary artery disease: high factor V clotting activity is an independent risk factor for myocardial infarction. Arterioscler Thromb Vasc Biol 1999; 19: 1020-1025.
36 Demarmels BF, Berger D, Mattle HP. et al. Hemostatic risk factors in ischemic stroke. Thromb Haemost 2003; 90: 1094-1099.
37 Merlini PA, Ardissino D, Oltrona L. et al. Heightened thrombin formation but normal plasma levels of activated factor VII in patients with acute coronary syndromes. Arterioscler Thromb Vasc Biol 1995; 15: 1675-1679.
38 Al-Obaidi MK, Philippou H, Stubbs PJ. et al. Relationships between homocysteine, factor VIIa, and thrombin generation in acute coronary syndromes. Circulation 2000; 101: 372-377.
39 Hansen JB, Huseby KR, Huseby NE. et al. Tissue factor pathway inhibitor in complex with low density lipoprotein isolated from human plasma does not possess anticoagulant function in tissue factor-induced coagulation in vitro. Thromb Res 1997; 85: 413-425.
40 Brodin E, Borvik T, Sandset PM. et al. Coagulation activation in young survivors of myocardial infarction (MI) – a population-based case-control study. Thromb Haemost 2004; 92: 178-184.