(Circulation. 1996;93:1970-1975.)
© 1996 American Heart Association, Inc.
Articles |
Relation of Hormone-Replacement Therapy to Measures of Plasma Fibrinolytic Activity
Presented in part at the 34th American Heart Association Annual Conference on Cardiovascular Disease Epidemiology and Prevention, Tampa, Fla, March 16-19, 1994.
From the Division of Epidemiology (E.S., A.R.F., P.G.M.), School of Public Health, University of Minnesota (Minneapolis); Department of Epidemiology and Health Promotion (V.V.S.), National Public Health Institute, Helsinki, Finland; Division of Hematology-Oncology (V.L.S., K.K.W.), University of Texas Medical School (Houston); Division of Epidemiology and Clinical Applications (T.S.), National Heart, Lung, and Blood Institute, Bethesda, Md; and Collaborative Studies Coordinating Center (L.E.C.), University of North Carolina (Chapel Hill).
Correspondence to Eyal Shahar, MD, Division of Epidemiology, School of Public Health, University of Minnesota, 1300 South Second St, Suite 300, Minneapolis, MN 55454-1015.
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
Background The mechanisms by which replacement hormones may reduce the risk of coronary heart disease are not fully understood. Of specific interest is a potential effect of replacement hormones on plasma fibrinolytic activity, a putative determinant of thrombotic events.
Methods and Results We investigated the relation of current use of replacement hormones to three measures of plasma fibrinolytic activity: tissue-type plasminogen activator (TPA) antigen, plasminogen activator inhibitor–1 (PAI-1) antigen, and D-dimer. The sample was composed of 288 women, free of clinical cardiovascular disease, who were selected for a case-control study of atherosclerosis: 142 women with ultrasonographic evidence of carotid intimal-medial thickening (cases) and 146 control subjects. Twenty percent (59 women) reported current use of replacement hormones. TPA antigen and PAI-1 antigen were highly correlated with each other (r=.67), whereas D-dimer correlated only weakly with TPA or PAI-1. Compared with nonusers, current users of replacement hormones had lower mean levels of TPA and PAI-1 antigens, suggesting enhanced fibrinolytic potential. In the entire sample, the multivariate-adjusted geometric mean values of TPA antigen were 6.3 and 7.3 ng/mL among current users and nonusers, respectively (P=.01); the corresponding values for PAI-1 antigen were 6.1 and 7.5 ng/mL (P=.13). These results were generally consistent for both atherosclerosis cases and their control subjects. D-dimer levels were lower in current hormone users than in nonusers, but the difference was not statistically significant (P>.15) in any of the analyses.
Conclusions The use of replacement hormones appears to be associated with enhancement of endogenous fibrinolytic potential. Enhanced plasma fibrinolytic activity among hormone users may explain, in part, the inverse association between hormone replacement therapy and coronary heart disease.
Key Words: atherosclerosis • hormones • fibrinolysis
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Treatment with replacement hormones to alleviate menopausal symptoms has been associated with reduced risk of coronary heart disease,1 most likely due to a favorable effect on the disease risk profile.2 Current use of replacement hormones in the postmenopausal period is associated with improved plasma levels of HDL and LDL cholesterol, apolipoprotein B, lipoprotein(a), fibrinogen, fasting insulin, and glucose.3 4 Although most studies have evaluated the effects of treatment with estrogen alone, an estrogen-progestin combination appears to be equally beneficial.3
Recent evidence suggests that reduced plasma fibrinolytic activity is a marker of increased cardiovascular disease risk. In the Northwick Park Heart Study, ischemic heart disease incidence among men 40 to 54 years old was inversely related to baseline fibrinolytic activity, with measurement based on dilute blood clot lysis time.5 Markers of endogenous fibrinolytic potential, such as levels of PAI-1 or TPA, have been associated with various manifestations of cardiovascular disease, including early asymptomatic carotid atherosclerosis,6 symptomatic coronary stenosis,7 myocardial infarction8 and reinfarction,9 thrombotic events,10 stroke,11 and long-term mortality.12
Little is known about a potential effect on the endogenous fibrinolytic activity of replacement hormones taken at the postmenopausal period. We studied, in a cross-sectional manner, the relation of current hormone use to three parameters of plasma fibrinolytic activity (PAI-1 antigen, TPA antigen, and D-dimer) among 288 female participants in the ARIC study.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
The sample population for this study was drawn from the ARIC Study cohort, which comprised population-based samples from four US communities: Forsyth County, NC; Jackson, Miss; suburban Minneapolis, Minn; and Washington County, Md. The complete design of ARIC has been published previously.13 In brief, 15 800 men and women ages 45 to 64 were recruited from 1987 through 1989 through the use of probability sampling techniques. At 3-year intervals, participants have undergone comprehensive examinations in field center clinics that included measurements of demographic, lifestyle, and physiological characteristics. This report is based on data from the baseline examination of the cohort (1987 through 1989).
One design feature of ARIC involved B-mode ultrasound examination of the extracranial carotid arteries and measurements of the intimal-medial thickness,14 a surrogate measure of early atherosclerosis.15 16 A subset of 984 participants in the baseline examination (606 men and 378 women) was identified for a series of case-control studies of risk factors for asymptomatic atherosclerotic disease, including markers of plasma fibrinolytic activity. Atherosclerosis cases (n=492) were defined by intimal-medial thickening (>90th percentile of the distribution) in the absence of clinical cardiovascular disease. Control subjects, with intimal-medial thickness below the 75th percentile of the entire ARIC cohort, were individually matched to cases on the bases of age, sex, race, field center, and date of clinic examination. Three markers of the plasma fibrinolytic activity (PAI-1 antigen, TPA antigen, and D-dimer) were measured in cases and control subjects,6 providing an opportunity to study correlates of these factors.
Methods for blood collection and processing in ARIC have been described in detail previously.17 18 Participants were requested to fast for 12 hours before the clinic visit. Trained technicians drew blood from antecubital veins of sitting participants and recorded the filling time of the first tube as a quality indicator of the venipuncture procedure. Specimens for measurement of plasma fibrinolytic activity were collected into vacuum tubes containing 3.8% sodium citrate. After centrifugation at the field center at 3000g for 10 minutes at 4°C, supernatant aliquots were stored at -70°C and shipped to the ARIC Central Hemostasis Laboratory at the University of Texas at Houston for assay. The laboratory personnel were blinded to the case-control status and other participant characteristics.
TPA antigen and D-dimer were measured with the use of EIA19 with kits obtained from American Bioproducts Co. A 96-well plate was precoated with monoclonal antibody to TPA or D-dimer. Plasma samples were added, and another monoclonal antibody conjugated to peroxidase was added. Peroxidase activity was measured spectrophotometrically with 2,2'azino-di(3-ethyl-benzthiazoline sulfonate) as the substrate for the enzyme. In each assay, a calibration curve was established, and the concentration of an unknown sample was determined by relating its optic density to the calibration curve. PAI-1 was also measured with the use of EIA with a kit obtained from American Diagnostica, Inc. The assay detects active and latent inactive forms of PAI-1, with a detection level below 1 ng/mL in the undiluted sample. Quality control material for each assay included lyophilized pooled plasma (Universal Coagulation Reference Plasma) obtained from Pacific Hemostasis. To assess the laboratory component of reliability, 33 blood samples were each divided, at the field centers, into two tubes and sent to the laboratory for analysis in a blinded fashion. Reliability coefficients were .97, .83, and .80 for TPA antigen, PAI-1 antigen, and D-dimer, respectively.
Trained interviewers obtained information on current and former use of replacement hormones and menopausal status. Participants were classified as current users (of estrogen alone or of estrogen plus progestin), former users, or never users. Menopausal status was defined as postmenopausal, perimenopausal, premenopausal, or primary amenorrhea. Postmenopausal women had not menstruated during the 2 years before the examination. Perimenopausal women were those reporting reaching menopause (or who did not know their status) but had menstruated in the past 2 years. Premenopausal women reported not reaching menopause and had menstruated in the past 2 years.
Education level, smoking status, pack-years of smoking, and alcohol consumption were assessed by interviews. Body mass index (kg/m2) was computed from weight measured to the nearest pound and height measured to the nearest centimeter. Sitting blood pressure was measured three times; the average of the last two readings was used. Triglyceride20 and total cholesterol21 levels were measured with the use of enzymatic methods. Insulin was measured with a radioimmunoassay (125Insulin Kit; Cambridge Medical Diagnostics).
Statistical Analysis
Measurements of fibrinolytic factors were available for a total
of 334 women. Forty-six women, classified as premenopausal, were
excluded from analyses involving replacement hormones. Use of
replacement hormones was defined as the current use of estrogen alone
or estrogen plus progestin. Past or never users were grouped and
labeled nonusers.
The distributions of all three fibrinolytic factors were skewed but improved to approximately normal after logarithmic transformation. Consequently, all analyses were carried out for log10-transformed fibrinolytic variables. Geometric mean values and 95% CIs were calculated by exponentiating the estimates obtained for transformed variables. In the case of univariate analyses, the geometric mean values were essentially identical to the median values of nontransformed variables. Geometric mean levels of current users and nonusers were compared with the use of unpaired t tests. Mean values were multivariately adjusted and compared with the use of ANCOVA. The multivariate models included age; race; body mass index; SBP; pack-years of smoking; alcohol consumption; levels of cholesterol, triglycerides, and insulin; and time of blood draw. The addition of education level to these models did not materially affect the estimates.
Because the analysis sample was composed of atherosclerosis cases and control subjects, we initially performed, and report here, analyses for cases and control subjects separately. Because tests for an interaction between case-control status and hormone use in relation to fibrinolytic factors were not statistically significant (P>.1), combined analyses of cases and control subjects were also performed. In combined analyses, control subjects, who were selected from below the 75th percentile of the carotid wall thickness distribution at each of six sites, were weighted to cases (selected from the upper decile) at a ratio of 7.5:1 by means of weighted regressions. In addition, a variable indicating case or control status was added to the models. SAS22 was used for computations.
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Of 288 women, 59 (20%) reported current use of replacement hormones (estrogen alone or an estrogen-progestin combination), similar to the percentage in the entire ARIC cohort.3 The majority of them (41 women) reported using estrogen alone.
Univariate associations between hormone use and several
characteristics are shown in Table 1
. The differences
between current users and nonusers were generally
consistent with previously reported findings from the entire
ARIC cohort.3 Current users of replacement hormones were
somewhat younger than nonusers, but the two groups were similar
with respect to race and SBP. Current users tended to have a lower body
mass, lower levels of cholesterol and insulin, and higher
levels of triglycerides than did nonusers. Eighty
percent of current users had at least a high school education compared
with 69% of nonusers. There were no important differences
between the two groups in the prevalence of smoking or in the number of
pack-years of smoking, but hormone users were more likely to drink
alcohol. Atherosclerosis cases were equally
represented in the two groups.
|
TPA antigen and PAI-1 antigen were highly correlated in this sample
(rSpearman=.67), but D-dimer
correlated only weakly with the others
(rSpearman
.10). With one exception, the
geometric mean values of PAI-1 antigen and TPA antigen were
significantly (P<.05) lower in current users of replacement
hormones than in nonusers, among the
atherosclerosis cases, among their control subjects,
and in the entire sample (Fig 1). There was no
statistical evidence of differences between cases and control subjects
in any of the observed associations. In the entire sample, the mean
values of TPA antigen and PAI-1 antigen were 18% and 28% lower,
respectively, among current users than among nonusers. D-dimer
level was lower among current users than among nonusers, but
the difference was not statistically significant in either cases or
control subjects or in the entire sample (P>.15).
|
The association of current hormone use with lower TPA antigen and PAI-1
antigen remained consistent after multivariate
adjustment, although the differences did not always reach the
conventional level of statistical significance (Table 2). In the entire sample, the
multivariate-adjusted geometric mean values of TPA
antigen were 6.3 and 7.3 ng/mL among current users and
nonusers, respectively (P=.01); the corresponding
values for PAI-1 antigen were 6.1 and 7.5 ng/mL (P=.13).
These results were consistent in direction for both
atherosclerosis cases and control subjects but for
PAI-1 antigen reached statistical significance among the cases only.
D-dimer level, although lower among current users than
among nonusers, failed to reach or even approach statistical
significance (P>.15) in any of the groups.
|
Tests for two-way interactions between hormone use and the
covariates were not statistically significant except for an interaction
with fasting insulin in relation to TPA antigen that was evident among
the atherosclerosis cases (P=.04), their
matched control subjects (P=.06), and the entire sample
(P=.004). Stratified analysis according to tertiles
of insulin revealed gradual attenuation of the association between
hormone use and TPA antigen at higher insulin concentrations (Fig 2).
|
The relation of menopausal status to fibrinolytic factors was assessed
among premenopausal and postmenopausal women who did not use
replacement hormones (Table 3). There were 38
premenopausal women (16 atherosclerosis cases and 22
control subjects) and 219 postmenopausal women (107 cases and 112
control subjects). When considered in univariate
analysis, postmenopausal women had higher geometric mean levels
of TPA antigen (P<.001) and PAI-1 antigen
(P=.01) than did premenopausal women. After
multivariate adjustment, the difference was no longer
statistically significant (P>.10) for either factor. Age
(entered as a continuous variable) accounted for some, but not all,
of the confounding. D-dimer was not associated
(P>.25) with the menopausal status either
univariately or after multivariate
adjustment.
|
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Although direct measurements of plasma fibrinolytic activity were not available in this study, plasma levels of both PAI-1 antigen and TPA antigen likely reflect the fibrinolytic potential. PAI-1 antigen is highly and positively correlated with the inhibitory activity of the enzyme,23 and a high level has been associated with myocardial infarction.24 TPA is the key enzyme in fibrinolysis activation, but, surprisingly, a high level of TPA antigen, not a low level, has been associated with increased risk of coronary artery disease7 and myocardial infarction.8 The explanation is probably related to the TPA antigen assay that may be detecting circulating complexes of inactive TPA and PAI-1.25 Regardless, lower levels of both antigens with current use of replacement hormones, as reported here, suggest enhanced endogenous fibrinolytic activity and potential cardiovascular benefit.
Given the high correlation between TPA antigen and PAI-1 antigen (r=.67), it is possible that the two factors are surrogates of a single physiological characteristic. The varying statistical significance in their observed associations with hormone use is most likely attributable to measurement variability. In general, TPA antigen, which appeared to have been measured with very high laboratory reliability, was more consistently associated with the use of replacement hormones than was PAI-1 antigen. The associations of hormone use with D-dimer, a fibrin breakdown product, did not approach the conventional level of statistical significance, although the pattern was consistent with lower levels among hormone users than among nonusers. D-dimer correlated only weakly with either TPA antigen or PAI-1 antigen and was measured least reliably.
Only a few previous studies have examined the association of hormone-replacement therapy with endogenous fibrinolytic activity. ARIC data are in agreement with the results of four observational studies reporting higher levels of plasminogen26 or lower levels of PAI-1 and/or TPA antigens,27 28 29 both indicators of enhanced fibrinolysis, in current users of replacement hormones as compared with nonusers. In most of these studies, the associations of hormone use with plasminogen,26 PAI-1,27 29 and TPA29 remained statistically significant after multivariate adjustment. Experimental data are likewise scarce. Two small trials found that treatment with replacement hormones increased plasminogen antigen and plasmin activity30 or transiently decreased PAI-1 activity.31 Another small trial, however, did not detect any effect of conjugated estrogens, supplemented cyclically with medroxyprogesterone, on TPA activity.32
The mechanisms by which replacement hormones may affect the concentrations or activity of fibrinolytic factors toward enhanced fibrinolysis remain speculative. Endogenous fibrinolytic activity is strongly and inversely correlated with body mass, body fat distribution, triglycerides, and insulin,33 34 35 36 which are themselves highly intercorrelated. It is uncertain which of these factors, if any, are causally related to the fibrinolytic potential of the plasma, although most evidence points to the importance of insulin. Hyperinsulinemia or insulin resistance states have been associated with attenuated fibrinolysis,37 38 and, at least in vitro, insulin39 or insulin precursors40 augment PAI-1 synthesis. Lowering of insulin concentration3 41 and reduction in insulin resistance are possible mechanisms by which the use of replacement hormones could enhance the fibrinolytic potential.
In ARIC data, multivariate adjustment for numerous
variables, including fasting insulin, only modestly affected the
differences in TPA and PAI-1 antigens between hormone users and
nonusers. Assuming that insulin is on the mediating pathway,
one might have expected that adjustment for fasting insulin and related
characteristics, such as body mass, would have explained much of the
association between hormone use and the fibrinolytic factors. The role
of insulin, however, appeared to be more complicated. Although current
use of hormones was associated with a lower level of fasting insulin,
insulin also emerged as an effect modifier of the association between
hormone use and plasma fibrinolytic factors. At least for TPA antigen,
the most reliably measured fibrinolytic factor, the difference between
hormone users and nonusers gradually diminished at higher
levels of insulin (Fig 2
). This finding warrants replication.
Similar to other studies,42 43 44 ARIC data indicated attenuation of the endogenous fibrinolytic activity at menopause. When considered in univariate analysis, postmenopausal women had higher levels of both TPA antigen and PAI-1 antigen than did premenopausal women. Additional covariates accounted for much of the difference in TPA antigen and all of the difference in PAI-1 antigen, but the interpretation of multivariate models is not entirely clear. For example, factors such as cholesterol and triglyceride levels, which rise at menopause,45 46 47 may affect fibrinolytic factors. Estrogen therapy has also been associated with higher HDL cholesterol,3 which, in turn, has been inversely associated with TPA antigen.48 Of note, little is known about the effect of menopause on insulin concentrations.
A few limitations of this analysis should be considered. First, the study sample, although originating in a population-based cohort, consisted of women with some evidence of early atherosclerosis and their matched control subjects. None of the women, however, had clinical cardiovascular disease, nor was there statistical evidence that any of the observed associations differed between cases and control subjects. The sample size was modest but not appreciably different from that of other published studies. It is worth noting that despite sample size constraints, the results were internally consistent and reached or approached the conventional level of statistical significance. Unfortunately, we had insufficient statistical power to test for differences in fibrinolytic factors between users of estrogen alone and users of estrogen plus progestin.
In summary, ARIC data provide nonexperimental evidence for enhanced endogenous fibrinolytic activity among current users of replacement hormones, which may explain, in part, the favorable association of hormone-replacement therapy with coronary heart disease risk. Conclusive evidence of cause and effect awaits a large-scale experimental study.
|
Selected Abbreviations and Acronyms |
|---|
|
|
Acknowledgments |
|---|
This study was supported by National Heart, Lung, and Blood Institute contracts NO1-HC-55015, NO1-HC-55016, NO1-HC-55018, NO1-HC-55019, NO1-HC-55020, NO1-HC-55021, and NO1-HC-55022. We thank Ami Claxton and Lori Vitelli for programming assistance and Sherrie Weller for assistance with manuscript preparation.
|
Footnotes |
|---|
Guest editor for this article was Désiré Collen, MD, University of Leuven (Belgium).
Received September 14, 1995; revision received December 4, 1995; accepted December 6, 1995.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
-
Stampfer MJ, Colditz GA. Estrogen
replacement therapy and coronary heart disease: a quantitative
assessment of the epidemiologic evidence. Prev Med. 1991;20:47-63. [Medline]
[Order article via Infotrieve]
-
Belchetz PE. Hormonal treatment of
postmenopausal women. N Engl J Med. 1994;330:1062-1071.
[Free Full Text]
-
Nabulsi AA, Folsom AR, White A, Patsch W, Heiss G, Wu
KK, Szklo M. Association of hormone-replacement therapy with
various cardiovascular risk factors in postmenopausal
women. N Engl J Med. 1993;328:1069-1075.
[Abstract/Free Full Text]
-
Manolio TA, Furberg CD, Shemanski L, Psaty BM,
O'Leary DH, Tracy RP, Bush TL. Associations of postmenopausal
estrogen use with cardiovascular disease and its risk
factors in older women. Circulation.
1993;88(pt 1):2163-2171.
-
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;342:1076-1079. [Medline]
[Order article via Infotrieve]
-
Salomaa V, Stinson V, Kark JD, Folsom, AR, Davis CE,
Wu KK. Association of fibrinolytic parameters with
early atherosclerosis: the ARIC Study.
Circulation. 1995;91:284-290.
[Abstract/Free Full Text]
-
Olofsson BO, Dahlen G, Nilsson TK. Evidence for
increased levels of plasminogen inhibitor and
tissue plasminogen activator in plasma of
patients with angiographically verified coronary artery
disease. Eur Heart J. 1989;10:77-82.
[Abstract/Free Full Text]
-
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. [Medline]
[Order article via Infotrieve]
-
Hamsten A, Walldius G, Szamosi A, Blombäck M,
Faire U, Dahlen G, Landou C, Wiman B. Plasminogen
activator inhibitor in plasma: risk factor for
recurrent myocardial infarction. Lancet. 1987;2:3-9. [Medline]
[Order article via Infotrieve]
-
Cortellaro M, Cofrancesco E, Boschetti C, Mussoni L,
Donati MB, Cardillo M, Catalano L, Gabrielli L, Lombardi B, Specchia G,
Tavazzi L, Tremoli E, Pozzoli E, Turri M, for the PLAT Group. Increased
fibrin turnover and high PAI-1 activity as predictors of
ischemic events in atherosclerotic patients: a case-control
study. Arterioscler Thromb. 1993;13:1412-1417.
[Abstract/Free Full Text]
-
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. [Medline]
[Order article via Infotrieve]
-
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(pt 1):2030-2034.
-
The ARIC Investigators. The
Atherosclerosis Risk in Communities (ARIC) Study:
design and objectives. Am J Epidemiol. 1989;129:687-702.
[Abstract/Free Full Text]
-
Riley WA, Barnes RW, Bond MG, Evans G, Chambless LE,
Heiss G, for the ARIC Study Group. High resolution B-mode ultrasound
reading methods in the Atherosclerosis Risk in
Communities (ARIC) cohort. J Neuroimaging. 1991;1:168-172. [Medline]
[Order article via Infotrieve]
-
Pignoli P, Tremoli E, Poli A, Oreste P, Paoletti
R. Intimal plus medial thickness of arterial wall: a
direct measurement with ultrasound imaging.
Circulation. 1986;74:1399-1406.
[Abstract/Free Full Text]
-
Heiss G, Sharrett AR, Barnes R, Chambless LE, Szklo M,
Alzola C, and the ARIC Investigators. Carotid
atherosclerosis measured by B-mode ultrasound in
populations: associations with cardiovascular risk
factors in the ARIC Study. Am J Epidemiol. 1991;134:250-256.
[Abstract/Free Full Text]
-
Papp AC, Hatzakis H, Bracey A, Wu KK. ARIC
Hemostasis Study, I: development of a blood collection and processing
system suitable for multicenter hemostatic studies.
Thromb Haemost. 1989;61:15-19. [Medline]
[Order article via Infotrieve]
-
Wu KK, Papp AC, Patsch W, Rock R, Eckfeldt J, Sharrett
R. ARIC Hemostasis Study, II: organizational plan and
feasibility study. Thromb Haemost. 1990;64:521-525. [Medline]
[Order article via Infotrieve]
-
Atherosclerosis Risk in
Communities Manual 9: Hemostasis Determinations. Chapel Hill, NC:
National Heart, Lung, and Blood Institute of the National Institute of
Health, Collaborative Studies Coordinating Center, University of North
Carolina; April 28, 1987.
-
Nägele U, Hägele EO, Sauer G, Wiedemann E,
Lehmann P, Walefeld AW. Reagent for the enzymatic determination
of serum total triglycerides with improved lipolytic
efficiency. J Clin Chem Clin Biochem. 1984;22:165-174. [Medline]
[Order article via Infotrieve]
-
Siedel J, Hagele EO, Ziegenhorn J, Wahlefeld AW.
Reagent for the enzymatic determination of serum total
cholesterol with improved lipolytic efficiency.
Clin Chem. 1983;29:1075-1080.
[Abstract/Free Full Text]
-
SAS/STAT User's Guide: Version 6. 4th ed.
Cary, NC: SAS Institute; 1990.
-
Andreotti F, deBart ACW, Regan T, Maseri A, Kluft
C. Factors affecting the relation between
plasminogen activator inhibitor
(PAI) activity and PAI-1 antigen levels in normals and in patients with
arterial disease.
Fibrinolysis. 1990;4(suppl 2):134-135.
-
Hamsten A, Winman B, deFaire U, Blomback M.
Increased plasma levels of a rapid inhibitor of tissue
plasminogen activator in young survivors of
acute myocardial infarction. N Engl J Med. 1985;313:1557-1563. [Abstract]
-
Juhan-Vague I, Rijken DC, de Cock F, Mendez C, Collen
D. Extrinsic plasminogen activator
levels in clinical plasma samples. Prog Fibrinol. 1983;6:65-69.
-
Meilahn EN, Kuller LH, Matthews KA, Kiss JE.
Hemostatic factors according to menopausal status and use of hormone
replacement therapy. Ann Epidemiol. 1992;2:445-455. [Medline]
[Order article via Infotrieve]
-
Scarabin PY, Plu-Bureau G, Bara L, Bonithon-Kopp C,
Guize L, Samama MM. Haemostatic variables and menopausal
status: influence of hormone replacement therapy. Thromb
Haemost. 1993;70:584-587. [Medline]
[Order article via Infotrieve]
-
Meilahn EN, Cauley JA, Tracy RP, Macy EM, Gutai JP,
Kuller LH. Variation in plasma fibrinogen and PAI-1 by sex
hormones and adiposity among older women.
Circulation. 1993;87(suppl I):I-15. Abstract.
-
Gebara OCE, Mittleman MA, Sutherland P, Lipinska I,
Matheney T, Xu P, Welty FK, Wilson PWF, Levy D, Muller JE, Tofler
GH. Association between increased estrogen status and
increased fibrinolytic potential in the Framingham offspring
study. Circulation. 1995;91:1952-1958.
[Abstract/Free Full Text]
-
Notelovitz M, Kitchens CS, Ware MD. Coagulation
and fibrinolysis in estrogen-treated surgically
menopausal women. Obstet Gynecol. 1984;63:621-625.
[Abstract/Free Full Text]
-
Sporrong T, Mattsson LA, Samsioe G, Stigendal L,
Hellgren M. Haemostatic changes during continuous
oestradiol-progestogen treatment of postmenopausal women.
Br J Obstet Gynaecol. 1990;97:939-944. [Medline]
[Order article via Infotrieve]
-
Boschetti C, Cortellaro M, Nencioni T, Bertolli V,
Della Volpe A, Zanussi C. Short- and long-term effects of
hormone replacement therapy (transdermal estradiol vs oral conjugated
equine estrogens, combined with medroxyprogesterone
acetate) on blood coagulation factors in postmenopausal women.
Thromb Res. 1991;62:1-8. [Medline]
[Order article via Infotrieve]
-
Vague P, Juhan-Vague I, Aillaud MR, Badier C, Viard R,
Alessi MC, Collen D. Correlation between blood fibrinolytic
activity, plasminogen activator
inhibitor level, plasma insulin level, and relative body
weight in normal and obese subjects.
Metabolism. 1986;35:250-253. [Medline]
[Order article via Infotrieve]
-
Vague P, Juhan-Vague I, Chabert V, Alessi MC, Atlan
C. Fat distribution and plasminogen
activator inhibitor activity in nondiabetic
obese women. Metabolism. 1989;38:913-915. [Medline]
[Order article via Infotrieve]
-
Juhan-Vague I, Alessi MC, Vague P. Increased
plasma plasminogen activator
inhibitor 1 levels: a possible link between insulin
resistance and atherothrombosis. Diabetologia. 1991;34:457-462. [Medline]
[Order article via Infotrieve]
-
Folsom AR, Qamhieh HT, Wing RR, Jeffery RW, Stinson VL,
Kuller LH, Wu KK. Impact of weight loss on
plasminogen activator inhibitor
(PAI-1), factor VII, and other hemostatic factors in moderately
overweight adults. Arterioscler Thromb. 1993;13:162-169.
[Abstract/Free Full Text]
-
Juhan-Vague I, Vague P. Interrelations between
carbohydrates, lipids, and the hemostatic system in relation to the
risk of thrombotic and cardiovascular disease.
Am J Obstet Gynecol. 1990;163:313-315. [Medline]
[Order article via Infotrieve]
-
Williams B. Insulin resistance: the shape of
things to come. Lancet. 1994;1:521-524.
-
Schneider DJ, Sobel BE. Augmentation of
synthesis of plasminogen activator
inhibitor type 1 by insulin and insulin-like growth
factor type I: implications for vascular disease in
hyperinsulinemic states. Proc Natl Acad
Sci U S A. 1991;88:9959-9963.
[Abstract/Free Full Text]
-
Nordt TK, Schneider DJ, Sobel BE. Augmentation
of the synthesis of plasminogen activator
inhibitor type-1 by precursors of insulin: a potential risk
factor for vascular disease. Circulation. 1994;89:321-330.
[Abstract/Free Full Text]
-
Barrett-Connor E, Laakso M. Ischemic
heart disease risk in postmenopausal women: effects of estrogen use on
glucose and insulin levels.
Arteriosclerosis. 1990;10:531-534.
[Abstract/Free Full Text]
-
Heinrich J, Dirkes-Kersting A, Schulte H, Assmann
G. Effects of age, menopause and human growth hormone on
variables of fibrinolysis.
Fibrinolysis. 1992;6(suppl 3):33-35.
-
Lindoff C, Petersson F, Lecander I, Martinsson G,
Åstedt B. Passage of the menopause is followed by haemostatic
changes. Maturitas. 1993;17:17-22. [Medline]
[Order article via Infotrieve]
-
Winkler UH. Menopause, hormone replacement
therapy and cardiovascular disease: a review of
haemostaseological findings.
Fibrinolysis. 1992;6(suppl 3):5-10.
-
Hjortland MC, McNamara PM, Kannel WB. Some
atherogenic concomitants of menopause: the Framingham Study.
Am J Epidemiol. 1976;103:304-311.
[Abstract/Free Full Text]
-
Matthews KA, Meilahn E, Kuller LH, Kelsey SF, Caggiula
AW, Wing RR. Menopause and risk factors for coronary
heart disease. N Engl J Med. 1989;321:641-646. [Abstract]
-
Bonithon-Kopp C, Scarabin PY, Darne B, Malmejac A,
Guize L. Menopause-related changes in lipoproteins and some
other cardiovascular risk factors. Int J
Epidemiol. 1990;19:42-48.
[Abstract/Free Full Text]
-
Ridker PM, Vaughan DE, Stampfer MJ, Sacks FM, Hennekens
CH. A cross-sectional study of endogenous tissue
plasminogen activator, total
cholesterol, HDL cholesterol, and
apolipoprotein A-I, A-II, and B-100.
Arterioscler Thromb. 1993;13:1587-1592.
[Abstract/Free Full Text]
This article has been cited by other articles:
 |
|
 |
|
  S. I. Savitz, G. Schlaug, L. Caplan, and M. Selim Arterial Occlusive Lesions Recanalize More Frequently in Women Than in Men After Intravenous Tissue Plasminogen Activator Administration for Acute Stroke Stroke, July 1, 2005; 36(7): 1447 - 1451. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E.-G. V. Giardina, H. J. Chen, R. R. Sciacca, and L. E. Rabbani Dynamic Variability of Hemostatic and Fibrinolytic Factors in Young Women J. Clin. Endocrinol. Metab., December 1, 2004; 89(12): 6179 - 6184. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. D. Pradhan, A. Z. LaCroix, R. D. Langer, M. Trevisan, C. E. Lewis, J. A. Hsia, A. Oberman, J. M. Kotchen, and P. M Ridker Tissue Plasminogen Activator Antigen and D-Dimer as Markers for Atherothrombotic Risk Among Healthy Postmenopausal Women Circulation, July 20, 2004; 110(3): 292 - 300. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. E. Rabbani, N. A. Seminario, R. R. Sciacca, H. J. Chen, and E.-G. V. Giardina Oral conjugated equine estrogen increases plasma von Willebrand factor in postmenopausal women J. Am. Coll. Cardiol., December 4, 2002; 40(11): 1991 - 1999. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. S. Hayward, R. P. Kelly, and P. Collins The roles of gender, the menopause and hormone replacement on cardiovascular function Cardiovasc Res, April 1, 2000; 46(1): 28 - 49. [Full Text] [PDF]
|
|
|
|
 |
|
 M. Lansink, M. Jong, M. Bijsterbosch, M. Bekkers, K. Toet, L. Havekes, J. Emeis, and T. Kooistra Increased Clearance Explains Lower Plasma Levels of Tissue-Type Plasminogen Activator by Estradiol: Evidence for Potently Enhanced Mannose Receptor Expression in Mice Blood, August 15, 1999; 94(4): 1330 - 1336. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Jousilahti, E. Vartiainen, J. Tuomilehto, and P. Puska Sex, Age, Cardiovascular Risk Factors, and Coronary Heart Disease : A Prospective Follow-Up Study of 14 786 Middle-Aged Men and Women in Finland Circulation, March 9, 1999; 99(9): 1165 - 1172. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Pahor, M. B. Elam, R. J. Garrison, S. B. Kritchevsky, and W. B. Applegate Emerging Noninvasive Biochemical Measures to Predict Cardiovascular Risk Arch Intern Med, February 8, 1999; 159(3): 237 - 245. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 O C E Gebara, M A Mittleman, B W Walsh, I Lipinska, F K Welty, G Bellotti, J E Muller, F K Sacks, and G H Tofler Fibrinolytic potential is significantly increased by oestrogen treatment in postmenopausal women with mild dyslipidaemia Heart, September 1, 1998; 80(3): 235 - 239. [Abstract] [Full Text]
|
|
|
|
 |
|
 C. A. DeSouza, P. P. Jones, and D. R. Seals Physical Activity Status and Adverse Age-Related Differences in Coagulation and Fibrinolytic Factors in Women Arterioscler. Thromb. Vasc. Biol., March 1, 1998; 18(3): 362 - 368. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P.-Y. Scarabin, M. Alhenc-Gelas, G. Plu-Bureau, P. Taisne, R. Agher, and M. Aiach Effects of Oral and Transdermal Estrogen/Progesterone Regimens on Blood Coagulation and Fibrinolysis in Postmenopausal Women : A Randomized Controlled Trial Arterioscler. Thromb. Vasc. Biol., November 1, 1997; 17(11): 3071 - 3078. [Abstract] [Full Text]
|
|
|
|
 |
|
 K. K. Koh, R. Mincemoyer, M. N. Bui, G. Csako, F. Pucino, V. Guetta, M. Waclawiw, and R. O. Cannon Effects of Hormone-Replacement Therapy on Fibrinolysis in Postmenopausal Women N. Engl. J. Med., March 6, 1997; 336(10): 683 - 691. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 HRT May Enhance Plasma Fibrinolytic Activity Journal Watch Women's Health, July 1, 1996; 1996(701): 11 - 11. [Full Text]
|
|
|
|
 |
|
 HORMONE REPLACEMENT THERAPY IMPROVES FIBRINOLYTIC ACTIVITY Journal Watch (General), June 18, 1996; 1996(618): 4 - 4. [Full Text]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||