Fibrinolytic Activity in Peripheral Atherosclerosis in the Elderly

Summary

Increased concentrations of plasminogen activator inhibitor type 1 (PAI-1) and of D-dimer have jointly been found in subjects with cardiovascular disease. To understand this apparent paradox of increased inhibition of fibrinolysis (high PAI-1) combined with increased fibrinolytic activity (high D-dimer), we examined the relation between D-dimer, PAI-1 and the activator of fibrinolysis, tissue type plasminogen activator (t-PA) in subjects with varying severity of peripheral atherosclerosis. In 325 subjects selected from the Rotterdam Study, a cohort of 7983 men and women aged 55 years and over, the ankle to brachial systolic blood pressure ratio, t-PA antigen and activity, PAI-1 antigen and D-dimer were measured.

T-PA antigen and t-PA activity were, independent from each other, increased with degree of atherosclerosis; t-PA antigen increased with 3.5 ng/ml (SE 1.7, p = 0.04) and t-PA activity with 0.46 IU/ml (0.20, p = 0.02) per unit decrease in ankle to brachial pressure ratio (i.e. increase in atherosclerosis). PAI-1 antigen was not related to atherosclerosis. More marked atherosclerosis was associated with increased D-dimer, mainly in subgroups with PAI-1 antigen below 50 ng/ml, t-PA antigen below 10 ng/ml, or t-PA activity above 1.5 IU/ml. In contrast to current beliefs, we found that only a fraction of the variation of t-PA antigen was due to the variation in circulating PAI-1 antigen. A slight positive association was observed between t-PA antigen and D-dimer. PAI-1 and t-PA activity were not associated with D-dimer concentration.

In conclusion, in subjects with peripheral atherosclerosis PAI-1 antigen is not increased, but low PAI-1 levels (and possibly also low levels of t-PA antigen and high levels of t-PA activity) appear to be required to increase circulating D-dimer. This suggests that increased D-dimer levels in subjects with atherosclerosis do not reflect increased inhibition, but rather reflect increased fibrinolysis.

• References

• 1 Fuster V, Badimon L, Badimon JJ, Chesebro JH. The pathogenesis of coronary artery disease and the acute coronary syndromes (first of two parts). N Engl J Med 1992; 23: 242-50.
• 2 Ridker PM, Vaughan DE, Stampfer MJ, Manson JE, Hennekens CH. Endogenous tissue-type plasminogen activator and risk of myocardial infarction. Lancet 1993; 341: 1165-8.
• 3 Thompson SG, Kienast J, Pyke SDM, Haverkate F. van de Loo JCW for the European Concerted Action on Thrombosis and Disabilities Angina Pectoris Study Group. Hemostatic factors and risk of myocardial infarction or sudden death in patients with angina pectoris. N Engl J Med 1995; 332: 635-41.
• 4 Hamsten A, de Faire U, Walldius G, Dahlen G, Szamosi A, Landou C, Blomback M, Wiman B. Plasminogen Activator Inhibitor in plasma: risk factor for recurrent myocardial infarction. Lancet 1987; 4: 3-9.
• 5 Munkvad S, Gram J, Jespersen J. A depression of active tissue plasminogen activator in plasma characterizes patients with unstable angina pectoris who develop myocardial infarction. Eur Heart J 1990; 6: 525-8.
• 6 Gram J, Jespersen J. A selective depression of tissue plasminogen activator (t-PA) activity in euglobulin characterizes a risk group among young survivors of acute myocardial infarction. Thromb Haemost 1987; 57: 137-9.
• 7 Gram J, Jespersen J, Kluft C, Rijken DC. On the usefulness of fibrinolysis variables in the characterization of a risk group for myocardial reinfarction. Acta Med Scand 1987; 221: 149-53.
• 8 Boisclair MD, Ireland H, Lane DA. Assessment of hypercoagulable states by measurement of activation fragments and peptides. Blood Rev 1990; 4: 25-40.
• 9 Fowkes FGR, Lowe GDO, Rattray A, Rumley A, Elton RA, MacGregor IR, Dawes J. Cro-linked fibrin degradation products, progression of peripheral arterial disease, and risk of coronary heart disease. Lancet 1993; 342: 84-6.
• 10 Ridker PM, Hennekens CH, Cerskus A, Stampfer MJ. Plasma concentration of cro-linked fibrin degradation product (D-dimer) and the risk of future myocardial infarction among apparently healthy men. Circulation 1994; 90: 2236-40.
• 11 Cortellaro M, Cofrancesco E, Boschetti C, Mussoni L, Donati MB, Catalano M, Gabrieli L, Lombardi B, Specchia G, Tavazzi L, Tremoli E, Pozzoli E, Turri M. Increased fibrin turnover and high PAI-1 activity as predictors of ischemic events in atherosclerotic patients. A case control study. Arterioscler Thromb 1993; 13: 1412-7.
• 12 Salomaa V, Stinson V, Kark JD, Folsom AR, Davis CE, Wu KK. Associations of fibrinolytic parameters with early atherosclerosis. Circulation 1995; 91: 284-90.
• 13 Heinrich J, Schulte H, Sch Enfeld R, K^hler E, Assmann G. Association of variables of coagulation, fibrinolysis and acute phase with atherosclerosis in coronary and peripheral arteries and those arteries supplying the brain. Thromb Haemost 1995; 73: 374-9.
• 14 Oseroff A, Krishnamurti C, Hassett A, Tang D, Alving B. Plasminogen activator and plasminogen activator inhibitor activities in men with coronary artery disease. J Lab Clin Med 1989; 113: 88-93.
• 15 Mehta F, Mehta P, Lawson D, Saldeen T. Plasma tissue plasminogen activator inhibitor levels in coronary artery disease: correlation with age and serum triglyceride concentrations. JACC 1987; 9: 263-8.
• 16 Paramo JA, Colucci M, Collen D. Plasminogen activator inhibitor in the blood of patients with coronary artery disease. Br med J 1985; 291: 573-4.
• 17 Huber K, Resch I, Stefenelli TH, Lang I, Probst P, Kaindl F, Binder BR. Plasminogen activator inhibitor-1 levels in patients with chronic angina pectoris with or without angiographic evidence of coronary sclerosis. Thromb Haemost 1990; 63: 336-9.
• 18 ECAT angina pectoris study group. ECAT angina pectoris study: baseline associations of haemostatic factors with extent of coronary arteriosclerosis and other coronary risk factors in 3000 patients with angina pectoris undergoing coronary angiography. Eur Heart J 1993; 14: 8-17.
• 19 Blann AD, Dobrotova M, Kubisz P, McCollum CN. von Willebrand factor, soluble P-selectin, tissue plasminogen activator and plasminogen activator inhibitor in atherosclerosis. Thromb Haemost 1995; 74: 626-30.
• 20 Aznar J, Estelles A, Tormo G, Sapena P, Tormo V, Blanch S, Espana F. Plasminogen activator activity and other fibrinolytic variables in patients with coronary artery disease. Br Heart J 1988; 59: 535-41.
• 21 Lee AJ, Fowkes GR, Lowe GDO, Rumley A. Determinants of fibrin D-Dimer in the Edinburgh Artery Study. Arterioscler Thromb Vasc Biol 1995; 15: 1094-7.
• 22 Juhan-Vague I, Roul C, Alessi MC, Ardissone JP, Heim M, Vague P. Increased plasminogen activator inhibitor activity in non insulin dependent diabetic patients. Relationship with plasma insulin. Thromb Haemost 1989; 61: 370-3.
• 23 Smith FB, Lowe GDO, Fowkes FGR, Rumley A, Rumley AG, Donnan PT, Housley E. Smoking, hemostatic function and lipid peroxides in a population case control study of peripheral arterial disease. Atherosclerosis 1993; 102: 155-62.
• 24 Smith FB, Lee AJ, Rumley A, Fowkes FGR, Lowe GDO. Tissue-plasminogen activator, plasminogen activator inhibitor and risk of peripheral arterial disease. Atherosclerosis 1995; 115: 35-43.
• 25 Hofman A, Grobbee DE, de Jong PTVM, van den Ouweland FA. Determinants of disease and disability in the elderly: the Rotterdam Elderly Study. Eur J Epidemiol 1991; 7: 403-22.
• 26 Bemmel JH van, Kors JA, Herpen van G. Methodology of the Modular ECG Analysis System MEANS. Meth Inform Med 1990; 29: 346-53.
• 27 Willems JL, Abreu-Lima C, Arnaud P, van Bemmel JH, Brohet C, Degani R. et al The diagnostic performance of computer programs for the interpretation of electrocardiograms. N Engl J Med 1991; 325: 1767-73.
• 28 Vogt MT, Wolfson SK, Kuller LH. Lower extremity arterial disease and the aging process: A review. J Clin Epidemiol 1992; 45: 529-42.
• 29 van der Bom JG, Bots ML, Slagboom PE, Haverkate F, Hofman A, Meijer P, Kluft C, Grobbee DE. Smoking modifies the risk of myocardial infarction associated with the 4G5G polymorphism at the PAI-1 locus. (submitted).
• 30 van der Bom JG, de Knijff P, Haverkate F, Bots ML, Meijer P, de Jong PTVM, Hofman A, Kluft C, Grobbee DE. Tissue type plasminogen activator and risk of myocardial infarction. The Rotterdam Study. Circulation 1997; 95: 2623-7.
• 31 Rose GA, Blackburn H, Gillum RF. Cardiovascular survey methods. World Heath Organization; Geneva, Switzerland: 1982
• 32 Bots ML, van Swieten JC, Breteler MM, de Jong PTVM, van Gijn J, Hof-man A, Grobbee DE. Cerebral white matter lesions and atherosclerosis in the Rotterdam Study. Lancet 1993; 341: 1232-37.
• 33 van der Bom JG, Bots ML, de Bruijn AM, Hofman A, Grobbee DE. Measurement of flthromboglobulin in the elderly. Findings from the Rotterdam Study. Fibrinolysis 1994; 8 (Suppl. 02) Suppl 157-9.
• 34 Al-Zahrani H, Lowe GDO, Douglas JT, Cushieri R, Pollock JG, Smith WCS. Increased fibrin turnover in patients with peripheral artery disease: comparison with a population study. Clin Hemorheol 1992; 12: 867-72.
• 35 Panchenko E, Dobrovolsky A, Davletov K, Titaeva E, Kravets A, Podinovskaya J, Karpov Y. D-Dimer and fibrinolysis in patients with various degrees of atherosclerosis. Eur Heart J 1995; 16: 38-42.
• 36 Vaughan DE, DeClerck PJ, Van Houtte E, De Mol M, Collen D. Reactivated recombinant plasminogen activator inhibitor 1 (rPAI-1) effectively prevents thrombolysis in vivo. Thromb Haemost 1992; 68: 60-3.
• 37 Biemond BJ, Levi M, Coronel R, Janse MJ, ten Cate JW, Pannekoek H. Thrombolysis and reocclusion in experimental jugular vein and coronary artery thrombosis. Effect of a plasminogen activator inhibitor type 1 neutralizing monoclonal antibody. Circulation 1995; 91: 1175-81.
• 38 Smith EB, Keen Anne Grant A, Strik C. Fate of fibrinogen in human arterial intima. Arteriosclerosis 1990; 10: 263-75.
• 39 Kluft C. Constitutive synthesis of tissue type plasminogen activator and plasminogen activator inhibitor type 1: conditions and therapeutic targets. Fibrinolysis 1994; 8 (Suppl. 02) Suppl 1-7.
• 40 Alessi MC, Juhan-Vague I, Declerck PJ, Anfosso F, Guenoun E, Collen D. Correlations between t-PA and PAI-1 antigen and activity and t-PA/PAI-1 complexes in plasma of control subjects and of patients with increased t-PA or PAI-1 levels. Thromb Res 1990; 60: 509-16.
• 41 Potter van Loon BJ, Kluft C, Radder JK, Blankenstein MA, Meinders AE. The cardiovascular risk factor plasminogen activator inhibitor type 1 is related to insulin resistance. Metabolism 1993; 42: 945-9.
• 42 Juhan-Vague I, Thompson SG, Jespersen J. Involvement of the hemostatic system in the insulin resistance syndrome. A study of 1500 patients with angina pectoris. Arterioscler Thromb 1993; 13: 1865-73.