Correspondence

Hemostatic Factors and the Risk of Myocardial Infarction

N Engl J Med 1995; 333:389-390August 10, 1995

Article

To the Editor:

On the basis of a two-year follow-up, Thompson et al. (March 9 issue)1 conducted a prospective study to evaluate the influence of hemostatic factors on cardiovascular risk. The authors report that patients with high cholesterol levels but low fibrinogen levels had a low risk of coronary events. They conclude that the fibrinogen level can be used to identify patients with hypercholesterolemia who are at particularly high risk for coronary events.

We think that an important factor has not been considered in this conclusion. The concentration of high-density lipoprotein (HDL) cholesterol is known to be inversely correlated with fibrinogen level.2 Since patients with high HDL levels have been shown to have a lower cardiovascular risk than those with low HDL levels,3 the reported effect may have been due to an elevated level of HDL cholesterol (which was not measured in the study by Thompson et al.).

Carsten Otto, M.D.
Werner O. Richter, M.D.
University of Munich, D-81366 Munich, Germany

3 References

1. 1

   Thompson SG, Kienast J, Pyke SDM, Haverkate F, van de Loo JCW. Hemostatic factors and the risk of myocardial infarction or sudden death in patients with angina pectoris. N Engl J Med 1995;332:635-641
   Full Text | Web of Science | Medline

2. 2

   Koenig W, Sund M, Ernst E, Mraz W, Hombach V, Keil U. Association between rheology and components of lipoproteins in human blood: results from the MONICA project. Circulation 1992;85:2197-2204
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   Abbott RD, Wilson PW, Kannel WB, Castelli WP. High density lipoprotein cholesterol, total cholesterol screening, and myocardial infarction: the Framingham Study. Arteriosclerosis 1988;8:207-211
   CrossRef | Medline

To the Editor:

Thompson and colleagues provide important data on the use of tissue plasminogen activator (t-PA) as a marker for the risk of thrombotic events, confirming prior observations in healthy persons1,2 and in patients with angina pectoris.3 In interpreting these data, however, Thompson et al. and Hamsten, in an accompanying editorial,4 suggest that increases in the t-PA antigen level are the result of circulating t-PA–plasminogen-activator inhibitor type 1 (PAI-1) complexes, implying that PAi-1 levels are the fundamental determinant of t-PA antigen levels in plasma. Although the hypothesis presented is tenable and worthy of consideration, it is important to note that neither the PAI-1 antigen level nor PAI-1 activity was predictive of cardiac events in the data presented by Thompson et al. or in the earlier studies.1-3 Furthermore, it is unclear how a high PAI-1 level stimulates endothelial cells to produce or secrete more t-PA at the cellular or molecular level. Thus, we believe the simplest interpretation of the accumulated data is that t-PA antigen levels are a potent indicator of thrombotic risk but that PAI-1 antigen levels and PAI-1 activity are not. The question of whether t-PA antigen levels are the result of prevalent endothelial dysfunction, represent a net activation of endogenous fibrinolysis in response to underlying atherosclerosis, or represent a net inhibition of fibrinolysis due to an unknown mechanism is unlikely to be resolved in an epidemiologic setting and will require direct experimental testing.

Paul M. Ridker, M.D.
Brigham and Women's Hospital, Boston, MA 02115

Douglas E. Vaughan, M.D.
Vanderbilt University Medical Center, Nashville, TN 37232

4 References

1. 1

   Ridker PM, Vaughan DE, Stampfer MJ, Manson JE, Hennekens CH. Endogenous tissue-type plasminogen activator and risk of myocardial infarction. Lancet 1993;341:1165-1168
   CrossRef | Web of Science | Medline

2. 2

   Ridker PM, Hennekens CH, Stampfer MJ, Manson JE, Vaughan DE. Prospective study of endogenous tissue plasminogen activator and risk of stroke. Lancet 1994;343:940-943
   CrossRef | Web of Science | Medline

3. 3

   Jansson JH, Olofsson BO, Nilsson TK. Predictive value of tissue plasminogen activator mass concentration on long-term mortality in patients with coronary artery disease: a 7-year follow-up. Circulation 1993;88:2030-2034
   Web of Science | Medline

4. 4

   Hamsten A. Hemostatic function and coronary artery disease. N Engl J Med 1995;332:677-678
   Full Text | Web of Science | Medline

Author/Editor Response

The authors reply:

To the Editor: Drs. Otto and Richter propose an increase in the HDL cholesterol level as an explanation for the low coronary risk among patients with low fibrinogen levels and increased total cholesterol levels. In our study, HDL cholesterol and other lipoprotein fractions were measured in stored samples. A cross-sectional analysis showed only a slight inverse correlation between HDL cholesterol and fibrinogen levels (r = -0.13). The prospective data, however, have not yet been fully evaluated and will be the subject of a future report.

Ridker and Vaughan doubt that the risk associated with an increased t-PA antigen level could be due to an increase in the t-PA–PAI-1 complex circulating in plasma. First, we note that the PAi-1 antigen level and activity — in spite of their high variability among persons1 — were positively associated with coronary risk when adjustments were made only for center, age, and sex. The mean PAI-1 antigen level in the patients who had coronary events was 20.4 ng per milliliter, as compared with 17.6 ng per milliliter in the event-free group (P = 0.007); the corresponding results for PAI-1 activity were 15.8 and 13.9 U per milliliter (P = 0.08). When we adjusted the analysis for all other coronary risk factors, however, these relations were no longer statistically significant (P = 0.48 and P = 0.86, respectively). In terms of understanding the cause of coronary disease, such associations should not be dismissed.2 Second, there is a strong positive correlation between the t-PA antigen level and the PAI-1 antigen level and activity,3 which suggests the presence of t-PA–PAI-1 complexes in the circulation. Third, PAI-1 regulates plasmin formation in patients with ischemic heart disease.4 Taken together, these observations suggest that PAI-1 plays a central part in the pathophysiology of cardiovascular disease.

Jürgen C.W. van de Loo, M.D.
University of Münster, D-48129 Münster, Germany

Frits Haverkate, Ph.D.
Gaubius Laboratory, 2300 AD Leiden, the Netherlands

Simon G. Thompson, M.A.
London School of Hygiene and Tropical Medicine, London WC1E 7HT, United Kingdom

4 References

1. 1

   Jansson JH, Norberg B, Nilsson TK. Impact of acute phase on concentrations of tissue plasminogen activator and plasminogen activator inhibitor in plasma after deep-vein thrombosis or open-heart surgery. Clin Chem 1989;35:1544-1545
   Web of Science | Medline

2. 2

   Phillips AN, Smith GD. How independent are “independent“ effects? Relative risk estimation when correlated exposures are measured imprecisely. J Clin Epidemiol 1991;44:1223-1231
   CrossRef | Web of Science | Medline

3. 3

   Haverkate F, Thompson SG, Duckert F. Haemostasis factors in angina pectoris: relation to gender, age and acute-phase reaction. Thromb Haemost 1995;73:561-567
   Web of Science | Medline

4. 4

   Pedersen OD, Gram J, Jespersen J. Plasminogen activator inhibitor type-1 determines plasmin formation in patients with ischaemic heart disease. Thromb Haemost 1995;73:835-840
   Web of Science | Medline

Citing Articles (1)

Citing Articles

1. 1

   G. Hornstra, C. A. Barth, C. Galli, R. P. Mensink, M. Mutanen, R. A. Riemersma, M. Roberfroid, K. Salminen, G. Vansant, P. M. Verschuren. (1998) Functional food science and the cardiovascular system. British Journal of Nutrition 80:S1, S113
   CrossRef