Prothrombotic activity is associated with the anatomical as well as the functional severity of peripheral arterial occlusive diseaseFinancial support: The study was supported with unrestricted grants from Pfizer AS, Norway.
09 January 2006
Accepted after revision 03 March 2006
30 November 2017 (online)
The importance of prothrombotic activity in cardiovascular disease has been well established. However, limited data exist on the relationship between prothrombotic activity and the severity of peripheral arterial occlusive disease (PAD).The objective of the present study was to investigate the relationship between markers of haemostasis and the diagnostic measures of PAD: ankle-brachial-index (ABI), maximum treadmill walking distance and angiographic score. In a cross-sectional study of 127 patients (mean age 66 years; 64% males) with angiographically verified PAD, fasting blood samples were drawn, and citrated plasma was obtained for determination of selected haemostatic variables: von Willebrand factor (vWF), thrombomodulin (sTM), thrombin-antithrombin complex (TAT), soluble tissue factor (sTF), tPA antigen (tPAag) and D-dimer were all significantly correlated with the angiographic score (p<0.05 for all). D-dimer, tPAag and fibrinogen were inversely correlated with the maximum treadmill walking distance, (p<0.0001, p<0.04 and p<0.05, respectively), whereas fibrinogen was the only variable correlating to ABI (r = –0.223, p<0.05). After adjustment for relevant covariates, D-dimer and TAT remained statistically significantly associated with the angiographic score (p<0.001), and fibrinogen was, independent of other risk factors, inversely related with both the maximum treadmill walking distance and the ABI (p<0.01 for both).This rather large study in patients with PAD showed that plasma levels of D-dimer, TAT and fibrinogen significantly predicted the extent of atherosclerosis, evaluated by angiographic score, maximum treadmill walking distance and ABI, respectively. These findings demonstrate a prothrombotic state in PAD patients, which might be of importance in future diagnosis and treatment of the disease.
- 1 Fowkes FGR, Housley E, Cawood EHH. et al. Edinburgh Artery Study: Prevalence of asymptomatic and symptomatic peripheral arterial disease in the general population. IntJ Epidemiology 1991; 20: 383-92.
- 2 Dormandy JA, Murray GD, Mahir M. et al. The fate of the claudicant –a prospective study of 1969 claudicants. Eur J Vasc Surg 1991; 05: 131-3.
- 3 Selvin E, Erlinger TP. Prevalence of and risk factors for peripheral arterial disease in the United States. Circulation 2004; 110: 738-43.
- 4 Libby P, Ridker PM, Maseri A. Inflammation and atherosclerosis. Circulation 2002; 105: 1135-43.
- 5 Ross R. Atherosclerosis – an inflammatory disease. N Engl J Med 1999; 340: 115-26.
- 6 Blann A, Seigneur M. Endothelial cell markers in peripheral arterial disease and vascular surgery. Crit Ischaemia 1996; 06: 87-95.
- 7 Mannucchi PM. von Willebrand Factor: A marker of endothelial damage?. Ateroscler Thromb Vasc Biol 1998; 18: 1359-62.
- 8 Folsom AR, Wu KK, Rosamond WD. et al. Prospective study of hemostatic factors and incidence of coronary heart disease. The ARIC Study. Circulation 1997; 96: 1102-8.
- 9 Thompson SG, Kienast J, Pyke SDM. et al. Hemostatic factors and the risk of myocardial infarction of sudden death in patients with angina pectoris. N Engl J Med 1995; 332: 635-41.
- 10 Jansson JH, Nilsson TK, Johnson O. von Willebrand factor in plasma: a novel risk factor for recurrent myocardial infarction and death. Br Heart J 1991; 66: 351-5.
- 11 Smith FB, Rumley A, Lee AJ. et al. Haemostatic factors and prediction of ischaemic heart disease and stroke in claudicants. Br J Haematol 1998; 100: 758-63.
- 12 Van der Born JG, Bots ML, Haverkate F. et al. Activation products of the haemostatic system in coronary, cerebrovascular, and peripheral disease. Thromb Haemost 2001; 85: 234-9.
- 13 Ridker PM, Hennekens CH, Cerskus A. et al. Plasma concentration of cross-linked fibrin degradation product (D-dimer) and the risk of future myocardial infarction among apparently healthy men. Circulation 1994; 90: 2236-40.
- 14 Fowkes FGR, Lowe GDO, Housley E. et al. Crosslinked fibrin degradation products, progression of peripheral arterial disease, and risk of coronary heart disease. Lancet 1993; 342: 84-6.
- 15 Lee AJ, Fowkes FGR, Lowe GD. et al. Fibrin D-dimer, haemostatic factors and peripheral arterial disease. Thromb Haemost 1995; 74: 828-32.
- 16 Seljeflot I, Hurlen M, Hole T, Arnesen H. Soluble tissue factor as predictor of secondary events in patients with acute myocardial infarction. Thromb Res 2003; 369-72.
- 17 McDermott MM, Liu K, Guralnik JM. The ankle brachial index independently predicts walking velocity and walking endurance in peripheral arterial disease. J Am Geriatr Soc 1998; 46: 1355-62.
- 18 McDermott MM, Greenland P, Liu K. et al. The ankle brachial index is associated with leg function and physical activity: The walking and leg circulation study. Ann Intern Med 2002; 136: 873-83.
- 19 Fowkes FGR. The measurement of atherosclerotic peripheral arterial disease in epidemiological surveys. Int J Epid 1988; 17: 248-54.
- 20 McDermott M, Greenland P, Liu K. et al. Asymptomatic arterial disease is independently associated with impaired lower extremity functioning: the women´s health and ageing study. Circulation 2000; 101: 1007-12.
- 21 Knox WG, Finby N. Limitations of arteriography in determining operability for femoropopliteal occlusive disease. Ann Surg 1965; 161: 509-15.
- 22 Carter S. Clinical measurement of systolic pressures in limbs with arterial occlusive disease. JAMA 1969; 297: 1869-74.
- 23 Meaney JFM. Stepping-table gladolinium-enhanced digital subtraction MR angiography of the aorta and lower extremity arteries: Preliminary experience. Radiology 1999; 211: 59-67.
- 24 Clauss A. Gerinnungsphysiologische Schnellmetode zur Bestimmung des Fibrinogens. Acta Haematol 1957; 17: 237-46.
- 25 Nylænde M, Kroese A, Seljeflot I. et al. Markers of vascular inflammation are associated with the extent of atherosclerosis assessed as angiographic score and treadmill walking distances in patients with peripheral arterial occlusive disease. Vasc Med. 2006 in press.
- 26 Woodburn KR, Lowe GD, Rumley A. et al. Relation of haemostatic, fibrinolytic, and rheological variables to the angiographic extent of peripheral arterial occlusive disease. Int Angiol 1995; 14: 219-25.
- 27 Smith FB, Lee AJ, Fowkes FG. et al. Smoking, haemostatic factors and the severity of aorto-iliac and femoropopliteal disease. Thromb Haemost 1996; 75: 19-24.
- 28 Koksch M, Zeiger F, Wittig K. et al. Haemostatic derangement in advanced peripheral occlusive arterial disease. Int Angiol 1999; 18: 256-62.
- 29 McDermott MM, Greenland P, Green D. et al. D-dimer, inflammatory markers, and lower extremity functioning in patients with and without peripheral arterial disease. Circulation 2003; 107: 3191-8.
- 30 McDermott MM, Greenland P, Guralnik JM. et al. Inflammatory markers, D-dimer, prothrombotic factors, and physical activity levels in patients with peripheral arterial disease. Vasc Med 2004; 09: 107-15.
- 31 Philipp CS, Cisar LA, Kim HC. et al. Association of hemostatic factors with peripheral vascular disease. Am HeartJ 1997; 134: 978-84.
- 32 McDermott MM, Green D, Greenland P. et al. Relation of levels of hemostatic factors and inflammatory markers to the ankle brachial index. Am J Cardiol 2003; 92: 194-9.
- 33 Blann AD, Farrell A, Picton A. et al. Relationship between endothelial cell markers and arterial stenosis in peripheral and carotid artery disease. Thromb Res 2000; 97: 209-16.
- 34 Cassar K, Bachoo P, Ford I. et al. Markers of coagulation activation, endothelial stimulation and inflammation in patients with peripheral arterial disease. Eur J Vasc Endovasc Surg 2005; 29: 171-6.
- 35 Østerud B. Tissue factor expression by monocytes: regulation and pathophysiological roles. Blood Coagul Fibrinolysis 1998; (Suppl. 01) S9-14.
- 36 Lassila R, Peltonen S, Lepantalo M. et al. Severity of peripheral atherosclerosis is associated with fibrinogen and degradation of cross-linked fibrin. Arterioscler Thromb 1993; 13: 1738-42.
- 37 De Buyzere M, Philippe J, Duprez D. et al. Coagulation system activation and increase of D-dimer levels in peripheral arterial occlusive disease. Am J Hematol 1993; 43: 91-4.
- 38 Pelzer H, Schwarz A, Heimberger N. Determination of human prothrombin activation fragment III complex in plasma with an enzyme-linked immunosorbent assay. Thromb Haemos 1988; 59: 101-6.
- 39 Koenig W. Haemostatic risk factors for cardiovascular diseases. Eur Heart J 1998; 19 (Suppl C): C39-C43.
- 40 Ernst E, Koenig W. Fibrinogen and cardiovascular risk. Vasc Med 1997; 02: 115-25.
- 41 Bollinger A, Breddin K, Hess H. et al. Semiquantitative assessment of lower limb atherosclerosis from routine angiographic images. Atherosclerosis 1981; 38: 339-46.
- 42 Scott DJ, Hunt G, Beard JD. et al. Arteriogram scoring systems and pulse generated run-off in the assessment of patients with critical ischaemia for femorodistal bypass. BrJ Surg 1989; 76: 1202-6.
- 43 Peter K, Nawroth P, Conradt C. et al. Circulating vascular cell adhesion molecule-1 correlates with the estent of human atherosclerosis in contrast to circulating intercellular adhesion molecule-1, E-selectin, P-selectin, and thrombomodulin. Ateroscler Thromb Vasc Biol 1997; 17: 505-12.
- 44 Gardner AW, Skinner JS, Cantwell BW. et al. Progressive vs. single-stage treadmill tests for evaluation of claudication. Med Sci Sports Medicine 1990; 23: 402-8.