Skip to main content
Original communication

Peripheral artery disease and the risk of venous thromboembolism

Published Online:https://doi.org/10.1024/0301-1526/a001029

Summary:Background: Peripheral artery disease (PAD) impacts 3–12% of patients worldwide and is characterized by endothelial dysfunction and inflammatory pathways which are also common to venous thromboembolism (VTE), but there is a paucity of evidence regarding VTE risk in PAD patients. We investigated whether PAD is an independent risk factor for VTE. Patients and methods: We reviewed medical records of patients undergoing ABI studies at Mayo Clinic from 01/1996-02/2020. We classified patients by ABI (low [<1.0], normal [1.0–1.4], or elevated [>1.4]), as well as by specific low ABI subgroup: severely reduced (ABI: 0.00–0.39), moderately reduced (0.40–0.69), mildly reduced (0.70–0.90), and borderline reduced (0.91–0.99). The primary outcome was incident VTE event (acute lower extremity deep vein thrombosis or pulmonary embolism) after ABI measurement. Multivariable Cox proportional regression was used to calculate hazard ratios (HR) with 95% confidence intervals (CI) after adjusting for age, sex, active smoking, cancer, previous VTE, thrombophilia, anticoagulation, and revascularization. Results: 39,834 unique patients (mean age 66.3±14.3 years, median follow-up 34 months) were identified. 2,305 VTE events occurred in patients without PAD (13.0%), 2,218 in low ABI patients (13.0%), and 751 in elevated ABI patients (14.8%). After risk factor adjustment, VTE risk was modestly increased for PAD overall (HR: 1.12, 95% CI [1.06, 1.18]), including low ABI (HR: 1.11, 95% CI [1.04, 1.18]) and elevated ABI groups (HR: 1.15, 95% CI [1.04, 1.26]), compared to patients without PAD. The greatest VTE risk was in severely low ABI patients (HR: 1.46, 95% CI [1.31, 1.64]). Conclusions: In a large longitudinal cohort, we present strong clinical evidence of PAD, with low and elevated ABI, as an independent VTE risk factor, with the highest risk seen in patients with severely low ABI. Continued research is required to further investigate this relationship and its intersection with functional performance status to optimize VTE risk reduction or anticoagulation strategies in the PAD population.

References

  • 1 Criqui MH, Fronek A, Barrett-Connor E, Klauber MR, Gabriel S, Goodman D. The prevalence of peripheral arterial disease in a defined population. Circulation. 1985;71:510–5. First citation in articleCrossref MedlineGoogle Scholar

  • 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;110:738–43. First citation in articleCrossref MedlineGoogle Scholar

  • 3 Creager MA, Matsushita K, Arya S, Beckman JA, Duval S, Goodney PP, et al. Reducing nontraumatic lower-extremity amputations by 20% by 2030: time to get to our feet: a policy statement from the American Heart Association. Circulation. 2021;143:875–91. First citation in articleCrossref MedlineGoogle Scholar

  • 4 Gerhard-Herman MD, Gornik HL, Barrett C, Barshes NR, Corriere MA, Drachman DE, et al. 2016 AHA/ACC Guideline on the Management of Patients With Lower Extremity Peripheral Artery Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. 2017;135:e726–79. First citation in articleCrossref MedlineGoogle Scholar

  • 5 Schröder F, Diehm N, Kareem S, Ames M, Pira A, Zwettler U, et al. A modified calculation of ankle-brachial pressure index is far more sensitive in the detection of peripheral arterial disease. J Vasc Surg. 2006;44:531–6. First citation in articleCrossref MedlineGoogle Scholar

  • 6 Leng GC, Lee AJ, Fowkers FGR, Whiteman M, Dunbar J, Housley E, et al. Incidence, natural history and cardiovascular events in symptomatic and asymptomatic peripheral arterial disease in the general population. Int J Epidemiol. 1996;25:1172–81. First citation in articleCrossref MedlineGoogle Scholar

  • 7 Firth C, Tseng AS, Abdelmalek M, Girardo M, Atwal D, Cooper L, et al. Discordant values in lower extremity physiologic studies predict increased cardiovascular risk. J Am Heart Assoc. 2020;9:e015398. First citation in articleCrossref MedlineGoogle Scholar

  • 8 Kushner A, West WP, Pillarisetty LS. Virchow triad. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2020. First citation in articleGoogle Scholar

  • 9 Klarin D, Lynch J, Aragam K, Chaffin M, Assimes TL, Huang J, et al. Genome-wide association study of peripheral artery disease in the Million Veteran Program. Nat Med. 2019;25:1274–9. First citation in articleCrossref MedlineGoogle Scholar

  • 10 Klarin D, Busenkell E, Judy R, Lynch J, Levin M, Haessler J, et al. Genome-wide association analysis of venous thromboembolism identifies new risk loci and genetic overlap with arterial vascular disease. Nat Genet. 2019;51:1574–9. First citation in articleCrossref MedlineGoogle Scholar

  • 11 Zöller B, Svensson PJ, Huang W, Jianguang J. Reactome pathway analysis of venous thromboembolism, peripheral artery disease, stroke, and coronary artery disease. Thromb Haemost. 2021;121:964–6. First citation in articleCrossref MedlineGoogle Scholar

  • 12 Prandoni P, Bilora F, Marchiori A, Bernardi E, Petrobelli F, Lensing AWA, et al. An association between atherosclerosis and venous thrombosis. N Engl J Med. 2003;348:1435–41. First citation in articleCrossref MedlineGoogle Scholar

  • 13 Gregson J, Kaptoge S, Bolton T, Pennells L, Willeit P, Burgess S, et al. Cardiovascular risk factors associated with venous thromboembolism. JAMA Cardiol. 2019;4:163–73. First citation in articleCrossref MedlineGoogle Scholar

  • 14 Diehm C, Lange S, Darius H, Pittrow D, von Stritzky B, Tepohl G, et al. Association of low ankle brachial index with high mortality in primary care. Eur Heart J. 2006;27:1743–9. First citation in articleCrossref MedlineGoogle Scholar

  • 15 Frank U, Nikol S, Belch J, Boc V, Brodmann M, Carpentier PH, et al. ESVM Guideline on peripheral arterial disease. Vasa. 2019;48:1–79. First citation in articleLinkGoogle Scholar

  • 16 Ratchford EV, Salameh MJ. Epidemiology and natural history of peripheral artery disease. In DP SlovutSM DeanMR JaffPA Schneider, eds. Comprehensive review in vascular and endovascular medicine. Minneapolis: Cardiotext; 2012. 368. First citation in articleGoogle Scholar

  • 17 White RH, Chew HK, Zhou H, Parikh-Patel A, Harris D, Harvey D, et al. Incidence of venous thromboembolism in the year before the diagnosis of cancer in 528,693 adults. Arch Intern Med. 2005;165:1782–7. First citation in articleCrossref MedlineGoogle Scholar

  • 18 Aziz F, Patel M, Ortenzi G, Reed AB. Incidence of postoperative deep venous thrombosis is higher among cardiac and vascular surgery patients as compared with general surgery patients. Ann Vasc Surg. 2015;29:661–9. First citation in articleCrossref MedlineGoogle Scholar

  • 19 Aziz F, Lehman E, Blebea J, Lurie F. Postoperative complications after lower extremity arterial bypass increase the risk of new deep venous thrombosis. Phlebology. 2018;33:558–66. First citation in articleCrossref MedlineGoogle Scholar

  • 20 Zöller B, Li X, Sundquist J, Sundquist K. A nationwide family study of venous thromboembolism and risk of arterial vascular disease. Heart. 2016;102:1315–21. First citation in articleCrossref MedlineGoogle Scholar

  • 21 Chang SL, Huang YL, Lee MC, Hu S, Hsiao YC, Chang SW, et al. Association of varicose veins with incident venous thromboembolism and peripheral artery disease. JAMA. 2018;319:807–17. First citation in articleCrossref MedlineGoogle Scholar

  • 22 Folsom AR, Lutsey PL, Astor BC, Cushman M. C-reactive protein and venous thromboembolism. A prospective investigation in the ARIC cohort. Thromb Haemost. 2009;102:615–9. First citation in articleCrossref MedlineGoogle Scholar

  • 23 Ridker PM, Danielson E, Fonseca FAH, Genest J, Gotto AM, Kastelein JJP, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008;359:2195–207. First citation in articleCrossref MedlineGoogle Scholar

  • 24 Franchini M, Mannucci PM. Association between venous and arterial thrombosis: Clinical implications. Eur J Intern Med. 2012;23:333–7. First citation in articleCrossref MedlineGoogle Scholar

  • 25 Narula N, Dannenberg AJ, Olin JW, Bhatt DL, Johnson KW, Nadkarni G, et al. Pathology of peripheral artery disease in patients with critical limb ischemia. J Am Coll Cardiol. 2018;72:2152–63. First citation in articleCrossref MedlineGoogle Scholar

  • 26 Steinberg HO, Baron AD. Vascular function, insulin resistance and fatty acids. Diabetologia. 2002;45:623–34. First citation in articleCrossref MedlineGoogle Scholar

  • 27 Stabley JN, Towler DA. Arterial calcification in diabetes mellitus: Preclinical models and translational implications. Arterioscler Thromb Vasc Biol. 2017;37:205–17. First citation in articleCrossref MedlineGoogle Scholar

  • 28 Stoberock K, Kaschwich M, Nicolay SS, Mahmoud N, Heidemann F, Rieß HC, et al. The interrelationship between diabetes mellitus and peripheral arterial disease. Vasa. 2020;50:323–30. First citation in articleLinkGoogle Scholar

  • 29 Wells PS, Anderson DR, Rodger M, Forgie M, Kearon C, Dreyer J, et al. Evaluation of D-dimer in the diagnosis of suspected deep-vein thrombosis. N Engl J Med. 2003;349:1227–35. First citation in articleCrossref MedlineGoogle Scholar

  • 30 Aboyans V, Ricco J-B, Bartelink M-LEL, Björck M, Brodmann M, Cohnert T, et al. 2017 ESC Guidelines on the Diagnosis and Treatment of Peripheral Arterial Diseases, in collaboration with the European Society for Vascular Surgery (ESVS): Document covering atherosclerotic disease of extracranial carotid and vertebral, mesenteric, renal, upper and lower extremity arteries Endorsed by: the European Stroke Organization (ESO)The Task Force for the Diagnosis and Treatment of Peripheral Arterial Diseases of the European Society of Cardiology (ESC) and of the European Society for Vascular Surgery (ESVS). Eur Heart J. 2018;39:763–816. First citation in articleCrossref MedlineGoogle Scholar

  • 31 Branch KR, Probstfield JL, Eikelboom JW, Bosch J, Maggioni AP, Cheng RK, et al. Rivaroxaban With or Without Aspirin in Patients With Heart Failure and Chronic Coronary or Peripheral Artery Disease. Circulation. 2019;140:529–37. First citation in articleCrossref MedlineGoogle Scholar

  • 32 Bonaca MP, Bauersachs RM, Anand SS, Debus ES, Nehler MR, Patel MR, et al. Rivaroxaban in peripheral artery disease after revascularization. N Engl J Med. 2020;382:1994–2004. First citation in articleCrossref MedlineGoogle Scholar