Sex Differences in the Determinants of Fibrinolytic Activity

P. K. MacCallum; J. A. Cooper; D. J. Howarth; T. W. Meade; G. J. Miller

doi:10.1055/s-0037-1614950

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 1998; 79(03): 587-590
DOI: 10.1055/s-0037-1614950

Review Articles

Schattauer GmbH

Sex Differences in the Determinants of Fibrinolytic Activity

P. K. MacCallum

¹From the MRC Epidemiology and Medical Care Unit, Wolfson Institute of Preventive Medicine, St. Bartholomew’s and the Royal London School of Medicine and Dentistry, Queen Mary and Westfield College, Charterhouse Square, London, UK

,

J. A. Cooper

¹From the MRC Epidemiology and Medical Care Unit, Wolfson Institute of Preventive Medicine, St. Bartholomew’s and the Royal London School of Medicine and Dentistry, Queen Mary and Westfield College, Charterhouse Square, London, UK

,

D. J. Howarth

¹From the MRC Epidemiology and Medical Care Unit, Wolfson Institute of Preventive Medicine, St. Bartholomew’s and the Royal London School of Medicine and Dentistry, Queen Mary and Westfield College, Charterhouse Square, London, UK

,

T. W. Meade

¹From the MRC Epidemiology and Medical Care Unit, Wolfson Institute of Preventive Medicine, St. Bartholomew’s and the Royal London School of Medicine and Dentistry, Queen Mary and Westfield College, Charterhouse Square, London, UK

,

G. J. Miller

¹From the MRC Epidemiology and Medical Care Unit, Wolfson Institute of Preventive Medicine, St. Bartholomew’s and the Royal London School of Medicine and Dentistry, Queen Mary and Westfield College, Charterhouse Square, London, UK

› Author Affiliations

Abstract

Summary

Impaired whole blood fibrinolytic activity (FA), measured by the dilute clot lysis time (DCLT), is associated with first episodes of ischaemic heart disease (IHD) in the Northwick Park Heart Study in men, especially under 55 years, and in women. In a community-based study to investigate possible determinants of the DCLT, and therefore to assess which fibrinolytic components might be predictors of first IHD events, we measured fibrinolytic variables in a sub-sample of 150 healthy adults (73 males, 77 females) randomly selected from a single general practice.

Most of the variance in DCLT (68% in men, 63% in women) was explained by tissue-type plasminogen activator (t-PA) and plasminogen activator inhibitor type-1 (PAI-1) activities. In multiple regression analysis there was a significant difference in the strength of the association of t-PA activity with DCLT in men compared to women (test for interaction p = 0.05), the association of t-PA activity with DCLT being significant in males but not in females. Plasma PAI-1 activity was strongly associated with DCLT in both sexes. There was no independent association of DCLT with plasma fibrinogen, t-PA antigen, other fibrinolytic inhibitors, body mass index, serum lipids or C-reactive protein.

Plasma PAI-1 activity in females and both t-PA and PAI-1 activities in males are the main determinants of whole blood FA measured by DCLT. It is therefore likely that these modulators of the plasma fibrinolytic system are associated with the onset of first clinical episodes of IHD. Elevated levels of t-PA antigen were positively associated with DCLT after adjustment for age and sex and therefore indicate impaired rather than enhanced FA. Further studies of the association of FA with risk of IHD should include not only “global” measures but also assessment of t-PA and PAI-1 activities, particularly as our results suggest that their associations with IHD may differ in men and women.

Full Text

References

References
1 Ernst E, Resch KL. Fibrinogen as a cardiovascular risk factor: a meta-analysis and review of the literature. Ann Intern Med 1993; 118: 956-63.
2 Meade TW, Ruddock V, Stirling Y, Chakrabarti R, Miller GJ. Fibrinolytic activity, clotting factors, and long-term incidence of ischaemic heart disease in the Northwick Park Heart Study. Lancet 1993; 342: 1076-9.
3 Meade TW, Cooper JA, Chakrabarti R, Miller GJ, Stirling Y, Howarth DJ. Fibrinolytic activity and clotting factors in ischaemic heart disease in women. Br Med J 1996; 312: 1581.
4 Fearnley GR, Balmforth G, Fearnley E. Evidence of a diurnal fibrinolytic rhythm; with a simple method of measuring natural fibrinolysis. Clin Sci 1957; 16: 645-50.
5 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.
6 Ridker PM, Hennekens CH, Stampfer MJ, Manson JE, Vaughan DE. Prospective study of endogenous tissue plasminogen activator and risk of stroke. Lancet 1994; 343: 940-3.
7 Hamsten A, de Faire U, Walldius G, Dahlen G, Szamosi A, Landou C, Blombäck M, Wiman B. Plasminogen activator inhibitor in plasma: risk factor for recurrent myocardial infarction. Lancet 1987; 2: 3-9.
8 Thompson SG, Kienast J, Pyke SD, Haverkate F, van de Loo JC. for the ECAT Angina Pectoris Study Group. Hemostatic factors and the risk of myocardial infarction or sudden death in patients with angina pectoris. European Concerted Action on Thrombosis and Disabilities Angina Pectoris Study Group. N Engl J Med 1995; 332: 635-41.
9 van de Loo JCW, Haverkate F, Thompson SG. Hemostatic factors and the risk of myocardial infarction. N Engl J Med 1995; 333: 389-90.
10 Rånby M, Sundell IB, Nilsson TK. Blood collection in strong acidic citrate anticoagulant used in a study of dietary influence on basal tPA activity. Thromb Haemost 1989; 62: 917-22.
11 Cash JD, Leask E. Multichannel system for the automatic recording of clot lysis. J Clin Pathol 1967; 20: 209-11.
12 von Clauss A. Gerinnungsphysiologische Schnellmethode zur Bestimmung des Fibrinogens. Acta Haematol 1957; 17: 237-46.
13 Lee AJ, Smith WCS, Lowe GDO, Tunstall-Pedoe H. Plasma fibrinogen and coronary risk factors: the Scottish Heart Health Study. J Clin Epidemiol 1990; 43: 913-9.
14 Brozovic M, Stirling Y, Harricks C, North WRS, Meade TW. Factor VII in an industrial population. Br J Haematol 1974; 28: 381-91.
15 Meade TW, Mellows S, Brozovic M, Miller GJ, Chakrabarti RR, North WRS, Haines AP, Stirling Y, Imeson JD, Thompson SG. Haemostatic function and ischaemic heart disease: principal results of the Northwick Park Heart Study. Lancet 1986; 2: 533-7.
16 Mykkänen L, Rönnemaa T, Marniemi J, Haffner SM, Bergman R, Laakso M. Insulin sensitivity is not an independent determinant of plasma plasminogen activator inhibitor-1 activity. Arterioscler Thromb 1994; 14: 1264-71.
17 Hadjez JM, Combe S, Horellou MH, Conard J, Nguyen G, Van Dreden P, Samama M. Heterogeneous mechanisms responsible for reduced fibrinolytic capacity in patients with a history of venous thrombosis. Fibrinolysis 1994; 8: 87-95.
18 Eliasson M, Evrin P-E, Lundblad D, Asplund K, Rånby M. Influence of gender, age and sampling time on plasma fibrinolytic variables and fibrinogen. Fibrinolysis 1993; 7: 316-23.
19 Haverkate F, Thompson SG, Duckert F. Haemostasis factors in angina pectoris; relation to gender, age and acute-phase reaction. Results of the ECAT Angina Pectoris Study Group. Thromb Haemost 1995; 73: 561-7.
20 Juhan-Vague I, Pyke SDM, Alessi MC, Jespersen J, Haverkate F, Thompson SG. on behalf of the ECAT Study Group. Fibrinolytic factors and the risk of myocardial infarction or sudden death in patients with angina pectoris. Circulation 1996; 94: 2057-63.
21 Sakata Y, Aoki N. Significance of cross-linking of α₂-plasmin inhibitor to fibrin in inhibition of fibrinolysis and in hemostasis. J Clin Invest 1982; 69: 536-42.