Thromb Haemost 2010; 104(01): 71-77
DOI: 10.1160/TH09-11-0772
Blood Coagulation, Fibrinolysis and Cellular Haemostasis
Schattauer GmbH

Thrombophilic risk factors and peripheral arterial disease severity

Michelangelo Sartori
1   Angiology and Haemostasis Unit “Marino Golinelli”, University Hospital S. Orsola-Malpighi, Bologna, Italy
,
Elisabetta Favaretto
1   Angiology and Haemostasis Unit “Marino Golinelli”, University Hospital S. Orsola-Malpighi, Bologna, Italy
,
Cristina Legnani
1   Angiology and Haemostasis Unit “Marino Golinelli”, University Hospital S. Orsola-Malpighi, Bologna, Italy
,
Michela Cini
1   Angiology and Haemostasis Unit “Marino Golinelli”, University Hospital S. Orsola-Malpighi, Bologna, Italy
,
Eleonora Conti
1   Angiology and Haemostasis Unit “Marino Golinelli”, University Hospital S. Orsola-Malpighi, Bologna, Italy
,
Alfio Amato
1   Angiology and Haemostasis Unit “Marino Golinelli”, University Hospital S. Orsola-Malpighi, Bologna, Italy
,
Gualtiero Palareti
1   Angiology and Haemostasis Unit “Marino Golinelli”, University Hospital S. Orsola-Malpighi, Bologna, Italy
› Author Affiliations
Further Information

Publication History

Received: 14 November 2009

Accepted after major revision: 12 February 2010

Publication Date:
23 November 2017 (online)

Summary

Few data are available on thrombophilic risk factors and progression of atherosclerotic peripheral arterial disease (PAD). Thrombophilic alterations can be an aggravating factor when arterial stenoses are present. In a cross-sectional study, we evaluated the presence of the thrombophilic factors fibrinogen, homocysteine, factor (F)VIII, lupus anticoagulant (LAC), FII G20210A, and FV R506Q mutations in 181 patients with PAD at Fontaine’s stage II (claudication), in 110 patients with critical limb ischaemia (CLI), and in 210 controls. Fibrinogen was higher in patients with CLI vs. those with claudication and controls (427.9 ± 10.5 vs. 373.1 ± 5.2 vs. 348.9 ± 7.0 p=0.001, respectively). Homocysteine and FVIII were higher in patients with PAD than in controls, but were similar in patients with CLI and claudication. The prevalence of LAC increased in patients with CLI vs. those with claudication and controls (21.4% vs. 7.8% vs. 5.2% p<0.001, respectively). The prevalence of FII 20210A allele was higher in patients with CLI vs. those with claudication and controls. Using a logistic model, FII G20210A mutation (odds ratio [OR] 19.8, confidence interval [CI] 4.5–87.1, p=0.001), LAC (OR 2.7, CI1.1–6.5, p=0.032), and fibrinogen (OR 1.01, CI 1.00–1.01, p=0.001) were associated with CLI, whereas homocysteine, FVIII, and FV R506Q mutation were not. CLI risk increased according to the number of thrombophilic alterations. In conclusion, altered levels of some important thrombophilic risk factors are independently associated with PAD severity. These data suggest that the presence of two or more thrombophilic risk factors raise the likelihood of PAD being more severe, justifying the need for larger longitudinal studies.

 
  • References

  • 1 Andreozzi GM, Arosio E, Martini R. et al Consensus document on intermittent claudication from the Central European Vascular Forum 1st edition. Int Angiol 2008; 27: 93-113.
  • 2 Selvin E, Erlinger TP. Prevalence of and risk factors for peripheral arterial disease in the United States: results from the National Health and Nutrition Examination Survey, 1999–2000. Circulation 2004; 110: 738-743.
  • 3 Aboyans V, Criqui MH, Denenberg JO. et al Risk factors for progression of peripheral arterial disease in large and small vessels. Circulation 2006; 113: 2623-2629.
  • 4 Cohn DM, Roshani S, Middeldorp S. Thrombophilia and venous thromboembolism: Implications for testing. Sem Thromb Haemost 2007; 33: 573-581.
  • 5 Bennett PC, Silverman SH, Gill PS, Lip GY. Peripheral arterial disease and Virchow's triad. Thromb Haemost 2009; 101: 1032-1040.
  • 6 Hurks R, Peeters W, Derksen WJ. et al Biobanks and the search for predictive biomarkers of local and systemic outcome in atherosclerotic disease. Thromb Haemost 2009; 101: 48-54.
  • 7 Tzoulaki I, Murray GD, Lee AJ. et al Inflammatory, haemostatic, and rheological markers for incident peripheral arterial disease: Edinburgh Artery Study. Eur Heart J 2007; 28: 354-362.
  • 8 Lee AJ, Fowkes FGR, Lowe GDO. et al Fibrin d-dimer, haemostatic factors and peripheral arterial disease. Thromb Haemost 1995; 74: 828-832.
  • 9 ACC/AHA 2005. Practice Guidelines for the management of patients with peripheral arterial disease (lower extremity, renal, mesenteric, and abdominal aortic): a collaborative report from the American Association for Vascular Surgery/Society for Vascular Surgery, Society for Cardiovascular Angiography and Interventions, Society for Vascular Medicine and Biology, Society of Interventional Radiology, and the ACC/AHA Task Force on Practice Guidelines (Writing Committee to Develop Guidelines for the Management of Patients With Peripheral Arterial Disease): endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation; National Heart, Lung, and Blood Institute; Society for Vascular Nursing; TransAtlantic Inter-Society Consensus; and Vascular Disease Foundation. Circulation 2006. 113 e463-654.
  • 10 Greenland P, Abrams J, Aurigemma GP. et al Prevention Conference V: Beyond Secondary Prevention: identifying the high-risk patient for primary prevention: non-invasive tests of atherosclerosis burden. Writing Group III. Circulation 2000; 101: 16-22.
  • 11 Cifkova R, Erdine S, Fagard R. et al Practice guidelines for primary care physicians: 2003 ESH/ESC hypertension guidelines. J Hypertens 2003; 21: 1779-1786.
  • 12 Third Report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation and treatment of high blood cholesterol in adult (Adult Treatment Panel III). Final Report. Circulation 2002. 106 3143-3421.
  • 13 Favaretto E, Pili C, Amato A. et al Analysis of agreement between Duplex ultra-sound scanning and arteriography in patients with lower limb artery disease. J Cardiovasc Med 2007; 08: 337-341.
  • 14 Clauss A. Gerinnungsphysiologische Schnellmethode zur Bestimmung des Fibrinogens. Acta Haematol 1975; 17: 237-246.
  • 15 Legnani C, Cosmi B, Cini M. et al High plasma levels of factor VIII and risk of recurrence of venous thromboembolism. Br J Haematol 2004; 124: 504-510.
  • 16 Legnani C, Palareti G, Guazzaloca G. et al Venous thromboembolism in young women; role of thrombophilic mutations and oral contraceptive use. Eur Heart J 2002; 23: 984-990.
  • 17 Studies Collaboration. Collaborative meta-analysis of prospective studies of plasma fibrinogen and cardiovascular disease. Eur J Cardiovasc Prev Rehabil 2004. 11 9-17.
  • 18 Smith FB, Lee AJ, Hau CM. et al Plasma fibrinogen, haemostatic factors and prediction of peripheral arterial disease in the Edinburgh Artery Study. Blood Coagul Fibrinolysis 2000; 11: 43-50.
  • 19 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: 194-199.
  • 20 Nylaende M, Kroese A, Stranden E. et al Prothrombotic activity is associated with the anatomical as well as the functional severity of peripheral arterial occlusive disease. Thromb Haemost 2006; 95: 702-707.
  • 21 Tzoulaki I, Murray GD, Price JF. et al Hemostatic Factors, Inflammatory Markers, and Progressive Peripheral Atherosclerosis. Am J Epidemiol 2006; 163: 334-341.
  • 22 Taylor Jr LM, DeFrang RD, Harris EJ. et al The association of elevated plasma homocyst(e)ine with progression of symptomatic peripheral arterial disease. J Vasc Surg 1991; 13: 128-136.
  • 23 Taylor Jr LM, Moneta GL, Sexton GJ. et al Prospective blinded study of the relationship between plasma homocysteine and progression of symptomatic peripheral arterial disease. J Vasc Surg 1999; 29: 8-19.
  • 24 Sofi F, Lari B, Rogolino A. et al Thrombophilic risk factors for symptomatic peripheral arterial disease. J Vasc Surg 2005; 41: 255-260.
  • 25 Lijfering WM, Veeger NJ, Brouwer JL. et al The risk of venous and arterial thrombosis in hyperhomocysteinemic subjects may be a result of elevated factor VIII levels. Haematologica 2007; 92: 1703-1706.
  • 26 Kamphuisen PW, Eikenboom JC, Bertina RM. Elevated factor VIII levels and the risk of thrombosis. Arterioscler Thromb Vasc Biol 2001; 21: 731-738.
  • 27 Reich LM, Heiss G, Boland LL. et al Ankle-brachial index and hemostatic markers in the Atherosclerosis Risk in Communities (ARIC) study cohort. Vasc Med 2007; 12: 267-273.
  • 28 Lim W, Crowther MA, Eikelboom JW. Management of antiphospholipid anti-body syndrome: a systematic review. J Am Med Assoc 2006; 295: 1050-1057.
  • 29 Long BR, Leya F. The role of antiphospholipid syndrome in cardiovascular disease. Hematol Oncol Clin North Am 2008; 22: 79-94.
  • 30 Taylor Jr LM, Chitwood RW, Dalman RL. et al Antiphospholipid antibodies in vascular surgery patients. A cross-sectional study. Ann Surg 1994; 220: 544-550.
  • 31 Fligelstone LJ, Cachia PG, Ralis H. et al Lupus anticoagulant in patients with peripheral vascular disease: a prospective study. Eur J Vasc Endovasc Surg 1995; 09: 277-283.
  • 32 Puisieux F, de Groote P, Masy E. et al Association between anticardiolipin anti-bodies and mortality in patients with peripheral arterial disease. Am J Med 2000; 109: 635-641.
  • 33 Neville C, Rauch J, Kassis J. et al Antiphospholipid antibodies predict imminent vascular events independently from other risk factors in a prospective cohort. Thromb Haemost 2009; 101: 100-107.
  • 34 Lam EY, Taylor Jr LM, Landry GJ. et al Relationship between antiphospholipid antibodies and progression of lower extremity arterial occlusive disease after lower extremity bypass operations. J Vasc Surg 2001; 33: 976-982.
  • 35 Galli M, Luciani D, Bertolini G. et al Lupus anticoagulants are stronger risk factors for thrombosis than anticardiolipin antibodies in the antiphospholipid syndrome: a systematic review of the literature. Blood 2003; 10: 1827-1832.
  • 36 Anand S, Yusuf S, Xie C. et al Oral anticoagulant and antiplatelet therapy and peripheral arterial disease. N Engl J Med 2007; 357: 217-227.
  • 37 Sartori M, Favaretto E, Legnani C. et al G20210A prothrombin mutation and critical limb ischaemia in patients with peripheral arterial disease. Eur J Vasc Endovasc Surg 2009; 38: 113-117.
  • 38 Gerdes VE, ten Cate H, de Groot E. et al Arterial wall thickness and the risk of recurrent ischemic events in carriers of the prothrombin G20210A mutation with clinical manifestations of atherosclerosis. Atherosclerosis 2002; 163: 135-140.
  • 39 Reny JL, Alhenc-Gelas M, Fontana P. et al The factor II G20210A gene polymorphism, but not factor V Arg506Gln, is associated with peripheral arterial disease: results of a case-control study. J Thromb Haemost 2004; 02: 1334-1340.
  • 40 Renner W, Köppel H, Brodmann M. et al Factor II G20210A and factor V G1691A gene mutations and peripheral arterial occlusive disease. Thromb Haemost 2000; 83: 20-22.
  • 41 Mueller T, Marschon R, Dieplinger B. et al Factor V Leiden, prothrombin G20210A, and methylenetetrahydrofolate reductase C677T mutations are not associated with chronic limb ischemia: the Linz Peripheral Arterial Disease (LIPAD) study. J Vasc Surg 2005; 41: 808-815.
  • 42 Feinbloom D, Bauer KA. Assessment of hemostatic risk factors in predicting arterial thrombotic events. Arterioscler Thromb Vasc Biol 2005; 25: 2043-2053.
  • 43 Weck M, Rietzsch H, Lawall H. et al Intermittent intravenous urokinase for critical limb ischemia in diabetic foot ulceration. Thromb Haemost 2008; 100: 475-482.