help button home button Endocrine Society JCEM JCEM Call for Nominations for EIC
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Submit a related Letter to the Editor
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Giardina, E.-G. V.
Right arrow Articles by Rabbani, L. E.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Giardina, E.-G. V.
Right arrow Articles by Rabbani, L. E.
The Journal of Clinical Endocrinology & Metabolism Vol. 89, No. 12 6179-6184
Copyright © 2004 by The Endocrine Society

Dynamic Variability of Hemostatic and Fibrinolytic Factors in Young Women

Elsa-Grace V. Giardina, Hong Jun Chen, Robert R. Sciacca and LeRoy E. Rabbani

Center for Women’s Health, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, New York 10032

Address all correspondence and requests for reprints to: Elsa-Grace V. Giardina, M.D., Center for Women’s Health, Columbia University Medical Center, 630 West 168th Street, PH 3–346, New York, New York 10032. E-mail: evg1{at}columbia.edu.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
This prospective study was designed to characterize the time course and variability of hemostatic and fibrinolytic risk factors over the course of a menstrual cycle in normal premenopausal women.

Plasminogen activator inhibitor (PAI-1), tissue plasminogen activator, von Willebrand factor, fibrinogen, and fibrin D-dimer predict risk of coronary heart disease. Yet there is limited information describing the status of endogenous hormone concentrations and hemostatic and coagulation factors in premenopausal women.

Twenty premenopausal women, mean age 34 ± 7 yr, underwent testing over a cycle to measure endogenous hormones and hemostatic factors: estradiol and progesterone, FSH, LH; PAI-1, tissue plasminogen activator, von Willebrand factor, fibrin D-dimer, and fibrinogen as well as lipids: total cholesterol, high-density lipoprotein-cholesterol, low-density lipoprotein-cholesterol, and triglycerides.

There was cyclical variability in estradiol (P < 0.01) and progesterone (P < 0.001) during the follicular and luteal phases. Moreover, there was intra- and interindividual cyclical variation in hemostatic risk factors. Measures of PAI-1 (P < 0.01) and D-dimer (P < 0.05) differed during the follicular and luteal phases. As estradiol concentration increased, PAI-I decreased. There was a significant correlation between total cholesterol and PAI-1 (r = 0.56, P < 0.05), low-density lipoprotein-cholesterol and PAI-1 (r = 0.50, P < 0.05) as well as between total cholesterol and fibrinogen (r = 0.61, P < 0.05).

There is significant cyclical variability in estradiol, FSH, and progesterone as well as the hemostatic factors, PAI-1 and fibrin D-dimer. Characterization of emerging hemostatic risk factors enhances understanding of normal physiology, provides insight into the relation between estrogen and hemostatic factors, and raises the potential for predicting coronary heart disease even in relatively young women.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
THE BREAKTHROUGH EVIDENCE that hormone replacement therapy (HRT) in postmenopausal women is associated with undesirable cardiovascular events described in the Heart and Estrogen/Progestin Study (1, 2) as well as the Women’s Health Initiative (3) challenges the previously held concept that HRT is cardioprotective. Increased adverse outcomes due to coronary artery disease (CHD) were reported in both the Heart and Estrogen/Progestin Study and Women’s Health Initiative after conjugated equine estrogen and medroxyprogesterone acetate (Prempro). One potential mechanism to account for the adverse findings is that a heightened inflammatory state is associated with HRT as inferred from a rise in the proinflammatory marker, C-reactive protein (4, 5). Another possible explanation is that von Willebrand factor (vWF), a marker of endothelial dysfunction, increases after oral conjugated equine estrogen replacement therapy (ERT), highlighting the association of vWF with ERT (6). Other hemostatic and fibrinolytic variables such as plasminogen activator inhibitor (PAI)-1, tissue plasminogen activator (t-PA)/PAI-1 complex, and fibrinogen that are linked to HRT are associated with coronary syndromes (7), CHD (8, 9), first and recurrent myocardial infarction (10, 11, 12), and stroke (13, 14). HRT studies in which oral conjugated equine estrogen or 17-ß estradiol were administered to postmenopausal women, however, reveal that PAI-1, t-PA/PAI-1 complex, and fibrinogen are lower after HRT (15, 16, 17).

Despite evidence for an association between atherothrombotic factors in postmenopausal women treated with ERT and HRT, there is limited information describing endogenous hemostatic and coagulation factors in premenopausal women. We considered that the known cyclical variability of estrogen and progesterone in premenopausal women might be associated with variability in coagulation and fibrinolytic factors, parallel to the effect seen after HRT in postmenopausal women. Accordingly, this study was designed to characterize the time course and expression of PAI-1, t-PA, vWF, fibrin D-dimer, and fibrinogen in premenopausal women. Characterization of hemostatic risk factors in the premenopausal woman could enhance our understanding of normal physiology, provide insight into the relation between estrogen and hemostatic factors, and raise the potential for predicting CHD.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
The investigation was conducted in accordance with the guidelines in the Declaration of Helsinki, and the Institutional Review Board of the Columbia-Presbyterian Medical Center approved the protocol and the consent form. Subjects received written and verbal information on the purpose and procedures of the study, and written informed consent was obtained from each subject in accordance with institutional guidelines. Participants responded to an advertisement to take part in a research protocol to evaluate the time course of hormones and hemostatic and fibrinolytic factors, lipids, and blood pressure. Exclusion criteria included history of smoking, hypertension, diabetes, abnormal metabolic-renal profile, previous myocardial infarction or stroke, coronary artery disease, use of oral contraceptives, history of thrombophlebitis or thromboembolic disease, or infectious illness within 3 wk. Subjects had not participated in a regular aerobic exercise program for at least 6 months before the start of the study. A questionnaire designed to detect recent infection/inflammation (<3 wk) was administered. Subjects with a history or recent infection/inflammation did not participate to avoid confounding effects with associated hemostatic changes. No subject was taking medication(s), and each was requested to identify new medication(s) initiated during the protocol. Subjects who required medication for newly acquired illness were discontinued from the protocol.

At enrollment and at the conclusion of the protocol, each subject underwent a history and physical examination as well as complete blood count, electrolytes, hepatic and renal function, total cholesterol, low-density lipoprotein (LDL)-cholesterol, high-density lipoprotein (HDL)-cholesterol, triglycerides, thyroid function, estradiol, FSH, progesterone, and LH. Urine for analysis was also collected. All subjects described normal menstrual cycles for more than 6 months before study entry. The cycles were divided into weekly phases based on history of the last menstrual cycle, duration of uterine bleeding, and morning body temperatures. Each week, samples were collected on 2 separate days for estradiol, FSH, progesterone, LH, PAI-1 antigen, t-PA antigen, vWF antigen, fibrin D-dimer, and fibrinogen. The twice-weekly measures respectively were averaged. The weeks corresponded to: wk 1 (d 7), early follicular phase, range 5–9 d; wk 2 (d 14), late follicular phase, range 12–16 d; wk 3 (d 21), early luteal phase, range 19–23 d; wk 4 (d 28), late luteal phase, range 26–30 d.

Hemostatic variables

Blood samples were collected in the morning between 0800 and 0900 h after a 12-h fast to avoid the diurnal variation in coagulation and fibrinolytic variables. Blood samples were drawn at rest from a large antecubital vein into 0.1 M trisodium citrate tubes for analysis. The first 2–3 ml of blood was discarded, and samples were analyzed only if venous return was prompt throughout. Tubes were immediately centrifuged, and spun at 3000 x g for 20 min at 4 C, and centrifugation was performed within 1 h. Plasma was removed into aliquots and stored in –80 C for up to 4 months before analysis. Assays for PAI-1, t-PA, vWF, and human C-reactive protein (C-RP) were determined using the respective ELISA kits purchased from American Diagnostics Inc. (Greenwich, CT). PAI-1 antigen ELISA measured the total quantity of PAI-1 present (free or complexed with t-PA; in active or inactive form) (18). The t-PA antigen ELISA measured the total amount of t-PA present (free and complexed t-PA, single- and double-chain t-PA) (18). The detection limit for C-RP was 0.35 ng/ml; intra- and interassay coefficients of variation (CVs) were between 3 and 4.5% and 3 and 7%, respectively. Fibrin D-dimer was analyzed using the Asserachrom D-Di ELISA from Diagnostica Stago (Asnieres-Sur-Seine, France). Estradiol, progesterone, FSH, and LH concentrations were determined by their specific immunoassays from Diagnostic Products Corp. (Los Angeles, CA) according to the manufacturer’s instructions. Interassay CVs for estradiol at high, middle, and low control are 3.5, 4.6, and 9.6%, respectively; intraassay CVs ranged from 3 to 10%. Total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides, and fibrinogen concentrations were determined enzymatically.

Statistical analysis

Data are expressed as mean ± 1 SD. The significance of changes in measured variables between the follicular and luteal phases was determined by the nonparametric Wilcoxon paired sample test. Weekly changes were analyzed using Friedman’s test, the nonparametric analog of the repeated-measures ANOVA. Dunn’s multiple comparison test was used to test post hoc differences among weekly data. Spearman’s rank correlation was used to determine the relation between variables at specific time points during the menstrual cycle as well as averaged across the menstrual cycle. P < 0.05 was considered significant for all analyses.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Study population

Twenty-three premenopausal women enrolled; three did not complete the protocol because complete data points over a cycle were not collected due to noncompliance with strict timing of phlebotomies (2) or concurrent infection (1). Twenty subjects, free of overt disease as assessed by medical history, physical exam, and baseline laboratory data participated (Table 1Go). The mean age of the subjects was 34 ± 7 yr (range 23–44); weight was 150 ± 36 lb (range 108–248); and body mass index (BMI) was 25 ± 6 (range 20–40). The average duration of the menstrual cycle was 29 ± 5 d (range 24–30).


View this table:
[in this window]
[in a new window]
  		TABLE 1. Clinical characteristics of subjects (n = 20)

 
The mean total cholesterol was 167 ± 25 mg/dl (range 132–219); LDL-cholesterol was 95 ± 30 mg/dl (range 57–160); HDL-cholesterol was 53 ± 16 mg/dl (range 24–91); and the triglyceride concentration was 94 ± 34 mg/dl (range 43–179).

Hormone concentrations

For estradiol there were differences between the follicular and luteal phases and mean change ({Delta}) = 30 ± 53 pg/ml (P < 0.01) (Table 2Go) as well as wk 1 and 2, {Delta} = 39 ± 48 pg/ml (P < 0.05); wk 1 and 3, {Delta} = 51 ± 43 pg/ml (P < 0.01); and wk 1 and 4, {Delta} = 65 ± 65 pg/ml (P < 0.001) (Fig. 1Go). For progesterone there were also differences between the follicular and luteal phases, {Delta} = 6.3 ± 3.2 ng/ml (P < 0.001) as well as wk 1 and 4, {Delta} = 7.7 ± 6.1 ng/ml (P < 0.001), and wk 2 and 4, {Delta} = 8.3 ± 6.0 ng/ml (P < 0.001). For FSH there were also significant differences between the follicular and luteal phases, {Delta} = 2.3 ± 6.7 mIU/ml (P < 0.05) as well as wk 1 and 4, {Delta}= 4.2 ± 10.4 mIU/ml (P < 0.01), and wk 2 and 4, {Delta} = 3.4 ± 6.2 mIU/ml (P < 0.001). The differences between follicular and luteal phases for LH did not reach significance.


View this table:
[in this window]
[in a new window]
  		TABLE 2. Hormones and hemostatic factors during follicular and luteal phases (n = 20)1

 


View larger version (21K):
[in this window]
[in a new window]
  		FIG. 1. There is intra- and interindividual variability in estradiol over 4 wk (n = 20). The weeks corresponded to: wk 1, early follicular phase; wk 2, late follicular phase; wk 3, early luteal phase; and wk 4, late luteal phase. For estradiol there were differences between the follicular and luteal phases, {Delta} = 30 ± 53 pg/ml (P < 0.01) as well as wk 1 and 2, {Delta} = 39 ± 48 pg/ml (P < 0.05), wk 1 and 3, {Delta} = 51 ± 43 pg/ml (P < 0.01), and wk 1 and 4, {Delta} = 65 ± 65 pg/ml (P < 0.001).

 
Hemostatic concentrations

There was intra- and interindividual variability over the cycle for each of the hemostatic variables (Table 2Go). The difference between the follicular and luteal phases was significant for PAI-1 ({Delta} = 10 ± 14 ng/ml, P < 0.01 (Fig. 2Go), and for D-dimer ({Delta} = 57 ± 93 ng/ml, P < 0.05); the changes for t-PA, vWF, and fibrinogen did not reach significance. There was an inverse relation between the concentration of estradiol and PAI-1 (Fig. 3Go). There was no difference between measures of C-RP during the follicular (0.41 ± 0.18 mg/l) or luteal (0.38 ± 0.10 mg/l) phases.



View larger version (17K):
[in this window]
[in a new window]
  		FIG. 2. The difference between the follicular and luteal phases was significant for PAI-1 ({Delta} = 10 ± 14 ng/ml, P < 0.01). PAI-1 concentration for four subjects was substantially higher than others.

 


View larger version (15K):
[in this window]
[in a new window]
  		FIG. 3. The average estradiol and PAI-1 concentrations over 4 wk are inversely related. The difference in the follicular and luteal phases for estradiol (P < 0.01) and PAI-1 (P < 0.01) are significant.

 
Relation between lipids and hemostatic factors

There was a significant relation between the total cholesterol and PAI-1 (r = 0.56, P < 0.05) (Fig. 4Go) and total cholesterol and fibrinogen (r = 0.61, P < 0.05). There was also a significant relation between LDL-cholesterol and PAI-1 (r = 0.50, P < 0.05). There was no significant relationship between PAI-1 and triglycerides.



View larger version (10K):
[in this window]
[in a new window]
  		FIG. 4. The linear relation between total cholesterol and PAI-1 is significant (r = 0.56, P < 0.05).

 
BMI

There was no significant relation between BMI and hormones (estradiol, progesterone, FSH, LH) during the follicular and luteal phases. There was a significant correlation between BMI and t-PA during the follicular (r = 0.51, P < 0.05) and luteal phases (r = 0.64, P < 0.01). No change in BMI, body weight, blood pressure, or lipids occurred over the study.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Fibrinolysis and menopausal status

Despite substantial data in older subjects (8, 9, 10, 11, 12), information describing coagulation and fibrinolysis in premenopausal women is limited. The current study increased our understanding of the dynamic physiology of hemostatic factors by describing their variability during the menstrual cycle. In the current study, the time course of PAI-1, t-PA, vWF, fibrin D-dimer, and fibrinogen is described as well as intra- and interindividual variability. We report that in normal premenopausal women, cyclical changes in endogenous estradiol (P < 0.01), progesterone (P < 0.001), FSH (P < 0.05), PAI-1 (P < 0.01), and fibrin D-dimer (P < 0.05) were observed. Furthermore, an inverse relation between estradiol and PAI-1 was observed, such that as estradiol increased, PAI-1 decreased paralleling reports of ERT or HRT on PAI-1 in postmenopausal women (15, 16, 17) (Fig. 3Go).

PAI-1 is the major regulator of the fibrinolytic system, and disturbances in the plasma fibrinolytic system have been implicated in the pathogenesis of CHD. Increased levels of PAI-1 result in less plasmin degradation of fibrin and, thus, would be expected to be prothrombotic. Both clinical and epidemiological data suggest that reduced endogenous fibrinolytic activity, characterized by increased PAI-1 antigen, t-PA antigen, and PAI-1 activity and reduced t-PA activity, is a major factor in both the development and severity of atherosclerosis and thrombosis (19, 20, 21, 22, 23). The finding that hemostatic factors, PAI-1, t-PA, and fibrinogen, are relatively lower in premenopausal women has been used to explain the protection against CHD experienced by younger women (15, 24). In the Framingham Offspring Study (24), subjects with high estrogen status (premenopausal women or postmenopausal women receiving HRT) had lower PAI-1 than subjects with low estrogen status (men or postmenopausal women without HRT). In postmenopausal women, the reduction in PAI-1, t-PA, and fibrinogen from hormones (15, 16, 23, 25) has been used to infer increased fibrinolytic potential; however, this finding as an underlying principle for cardiac protection, is open to question (25, 26, 27, 28).

Cyclical variation

The model estradiol curve expects a peak in phase II with a smaller peak in phase III. To accommodate outpatient subjects, weekly hormone and/or hemostatic factors were measured. Other time points, however, such as 36-h peak estradiol levels, compared with early follicular levels, and urinary LH surge time values in relation to the LH peak might have resulted in classical estradiol curves. Atypical cycling, intra- and interindividual variability, inadequate historical information, and the timing of collections in this outpatient study could account for the fact that the estradiol determinations did not reflect the idealized nadir and peaks of the follicular and luteal phases (Fig. 1Go). Nonetheless, the finding of significant cyclical variability in PAI-1 and D-dimer reported here supplements the known diurnal variation in hemostatic and coagulation factors. The present findings highlight that an appreciation of endogenous cyclical timing and biologic variability is important for interpreting the nature of hemostatic and fibrinolytic factors in the mechanism of disease and for the design of studies. Future studies to determine whether the changes have biological significance are indicated. A fundamental question raised by the observed cyclical variation is whether the cardiac protection afforded to younger women results from diminished prolonged exposure to potentially prothrombotic variables like PAI-1.

Other variables also have dynamic characteristics during the menstrual cycle. Studies of blood flow and endothelial function report appreciable changes in brachial artery reactivity during the menstrual cycle (29, 30, 31, 32, 33), and cyclical low estradiol levels have been invoked to explain variant angina (34). Other examples of cyclical changes including higher HDL-cholesterol levels during the follicular phase (35) and variations in vascular endothelial growth factor associated with cyclical ovarian and uterine blood flow (36) have also been described.

PAI-1 and genetic polymorphism

We found interindividual variability in PAI-1 and plasma levels were substantially higher in four subjects (Fig. 2Go). The observation is of potential clinical utility because an easily measurable concentration of PAI-1 function might be useful for selection and dosing of patients treated with anticoagulant and fibrinolytic factors as well as for predicting risk, particularly to prothrombotic agents such as ERT or HRT. Understanding the genetics of PAI-1 as well as the environmental factors that influence its concentration is potentially attractive for screening and treatment of vascular disease.

Whereas it is acknowledged that PAI-1 levels are regulated by genetic and environmental factors, the precise determinants of PAI-1 expression are not fully explained. Basic investigations have explored a specific insertion/deletion polymorphism in the promoter region of the PAI-1 gene whereby one allele sequence has four guanosines (4G) and the other has five (5G) (37). There is in vitro evidence reporting that the 4G allele has higher activity than the 5G allele, and subjects homozygous for the 4G allele have higher plasma PAI-1 concentrations (38, 39, 40). In a small study of young men with infarction, younger than 45 yr of age, the 4G/4G genotype, was found in 43% (38). Clinical studies have explored the influence of age and gender and the relation between PAI-1 polymorphism and outcome. An increase in the mutation has been correlated with postmenopausal women with coronary artery disease (41). Another study of middle-aged men, mean age 63 yr (42), found that the 4G/5G polymorphism in the promoter of the PAI-1 gene was not a major pathogenetic risk factor. Another found that the risk of myocardial infarction was decreased among women (<45 yr) carrying the 4G allele of the PAI-1 4G/5G polymorphism (43).

Limitations

First, the hormone levels and hemostatic factors associated with the phases of the menstrual cycle could have been over- or underestimated due to timing, unpredictable cycling, intra- or interindividual variability, or inadequate historical information. That the hormone and hemostatic determinations did not match the exact nadir and peak of the follicular and luteal phases, resulting in over- or underestimation of levels in some patients, is likely. In this outpatient setting, we collected and determined weekly hormone and hemostatic factors; however, other ways to collect the hormone data, such as 36-h peak estradiol levels or LH surge times might have resulted in model estradiol curves. Second, the study was designed to characterize the time course of prothrombotic factors and their relation to hormones and due to its size and short-term nature could not determine the clinical significance of these in relation to future clinical events.

Conclusions

Among premenopausal subjects there is significant variability over the menstrual cycle for estradiol, FSH, progesterone, PAI-1, and fibrin D-dimer. Cyclical variability, like diurnal variability, should be considered in studies of hemostatic and fibrinolytic factors in premenopausal subjects and those who may be at risk for CHD. These observations are of potential clinical utility because an easily measurable concentration of PAI-1 function might be useful for selection and dosing of patients as well as for predicting risk, particularly to prothrombotic agents such as ERT or HRT. Understanding normal variability of atherothrombotic factors is potentially attractive for screening and treatment of many forms of vascular disease. Future studies to determine whether the changes have biological significance are indicated.


   Acknowledgments
 
We gratefully acknowledge the laboratory of John F. O’Connor (Irving Center for Clinical Research, Columbia University Medical Center, New York, NY).


   Footnotes
 
This work was supported in part by Grant HL-07406 from the Department of Health and Human Services, Grant RR-00645 from the Research Resources Administration (Bethesda, MD), and a grant from Linda and Peter Nisselson.

Abbreviations: BMI, Body mass index; CHD, coronary heart disease; C-RP, C-reactive protein; CV, coefficients of variation; ERT, estrogen replacement therapy; HDL, high-density lipoprotein cholesterol; HRT, hormone replacement therapy; LDL, low-density lipoprotein cholesterol; PAI, plasminogen activator inhibitor; t-PA, tissue plasminogen activator; vWF, von Willebrand factor.

Received March 29, 2004.

Accepted September 7, 2004.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

  1. Hulley S, Grady D, Bush T, Furberg C, Herrington D, Riggs B, Vittinghoff E, for the HERS Research Group 1998 Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. JAMA 280:605–613[Abstract/Free Full Text]
  2. Grady D, Herrington D, Bittner V, Blumenthal R, Davidson M, Hlatky M, Hsia J, Hulley S, Herd A, Khan S, Newby LK, Waters D, Vittinghoff E, Wenger N, HERS Research Group 2002 Cardiovascular disease outcomes during 6.8 years of HRT: HERS follow-up. JAMA 288:49–57[Abstract/Free Full Text]
  3. The Writing Group for the Women’s Health Initiative Investigators 2002 Risks and benefits of estrogen plus progestin in healthy menopausal women: principal results from the Women’s Health Initiative randomized controlled study. JAMA 288:32321–32333
  4. Ridker P, Hennekens C, Rifai N, Buring JE, Manson JE 1999 Hormone replacement therapy and increased plasma concentration of C-reactive protein. Circulation 100:713–716[Abstract/Free Full Text]
  5. Cushman M, Legault C, Barrett-Connor E, Stefanick ML, Kessler C, Judd HL, Sakkinen PA, Tracy RP 1999 Effect of postmenopausal hormones on inflammatory-sensitive proteins: the Postmenopausal Estrogen/Progestin Interventions (PEPI) study. Circulation 100:717–722[Abstract/Free Full Text]
  6. Rabbani LE, Seminario NA, Sciacca RR, Chen HJ, Giardina EGV 2002 Conjugated oral estrogen increases plasma von Willebrand factor levels in postmenopausal women. J Am Coll Cardiol 40:1991–1999[Abstract/Free Full Text]
  7. Lip GYH, Blann AD 2000 Thrombogenesis and fibrinolysis in acute coronary syndromes. J Am Coll Cardiol 36:2044–2046[Free Full Text]
  8. Stec JJ, Silbershatz H, Tofler GH, Matheney TH, Sutherland P, Lipinska I, Massaro JM, Wilson PF, Muller JE, D’Agostino Sr RB 2000 Association of fibrinogen with cardiovascular risk factor and cardiovascular disease in the Framingham offspring population. Circulation 102:1634–1638[Abstract/Free Full Text]
  9. Folsom AR, Aleksic N, Park E, Salomaa V, Juneja H, Wu KK 2001 Prospective study of fibrinolytic factors and incident coronary heart disease. The Atherosclerosis Risk in Communities (ARIC) Study. Arterioscler Thromb Vasc Biol 21:611–617[Abstract/Free Full Text]
  10. Thogersen AM, Jansson JH, Boman K, Nilsson TK, Weinehall L, Huhtasaari F, Hallmans G 1998 High plasminogen activator inhibitor and tissue plasminogen activator levels in plasma precede a first acute myocardial infarction in both men and women. Evidence for the fibrinolytic system as an independent primary risk factor. Circulation 98:2241–2247[Abstract/Free Full Text]
  11. Bounameaux H, Kruithof E 2000 On the association of elevated tPA/PAI-1 complex and von Willebrand factor with recurrent myocardial infarction. Arterioscler Thromb Vasc Biol 20:1857–1859[Free Full Text]
  12. Wiman B, Andersson T, Hallqvist J, Reuterwall C, Ahlbom A, deFaire U 2000 Plasma levels of tissue plasminogen activator/plasminogen activator inhibitor-1 complex and von Willebrand factor are significant risk markers for recurrent myocardial infarction in the Stockholm Heart Epidemiology Program (SHEP) study. Arterioscler Thromb Vasc Biol 20:2019–2023[Abstract/Free Full Text]
  13. Johansson L, Jansson JH, Boman K, Nilsson TK, Stegmayr B, Hallmaans G 2000 Tissue plasminogen activator, plasminogen activator inhibitor-1, and tissue plasminogen activator/plasminogen activator inhibitor-1 complex as risk factors for the development of a first stroke. Stroke 31:26–32[Abstract/Free Full Text]
  14. Catto AJ, Carter AM, Barrett JH, Bamford J, Rice PJ, Grant PJ 1997 von Willebrand factor and factor VIII:C in acute cerebrovascular disease: relationship to stroke, subtype and mortality. Thromb Haemost 77:1104–1108[Medline]
  15. Koh KK, Mincemoyer R, Bui MN, Csako G, Pucino F, Guetta V, Waclawiw M, Cannon RO 1997 Effects of hormone-replacement therapy on fibrinolysis in postmenopausal women. N Engl J Med 336:683–690[Abstract/Free Full Text]
  16. Scarabin P-Y, Alhenc-Gelas M, Plu-Bureau G, Taisne P, Agher R, Aiach M 1997 Effects of oral and transdermal estrogen/progesterone regimens on blood coagulation and fibrinolysis in postmenopausal women: a randomized controlled trial. Arterioscler Thromb Vasc Biol 17:3071–3078[Abstract/Free Full Text]
  17. Lip GYH, Blann AD, Jones AF, Gareth Beevers D 1997 Effects of hormone-replacement therapy on hemostatic factors, lipid factors, and endothelial function in women undergoing surgical menopause: implications for prevention of atherosclerosis. Am Heart J 134:764–771[CrossRef][Medline]
  18. Yazdani S, Simon AD, Kovar L, Wang W, Schwartz A, Rabbani LE 1997 Percutaneous interventions alter the hemostatic profile of patients with unstable versus stable angina. J Am Coll Cardiol 30:1284–1287[Abstract]
  19. Ridker PM, Vaughan DE, Stampfer MJ, Manson JE, Hennekens CH 1993 Endogenous tissue-type plasminogen activator and risk of MI. Lancet 341:1165–1168[CrossRef][Medline]
  20. Lijnen HR, Collen D 1996 Impaired fibrinolysis and the risk for coronary heart disease. Circulation 94:2052–2054[Free Full Text]
  21. Salomaa V, Stinson V, Kark JD, Folsom AR, Davis CE, Wu KK 1995 Association of fibrinolytic parameters with early atherosclerosis: the ARIC study. Circulation 91:284–290[Abstract/Free Full Text]
  22. Cortellaro M, Cofrancesco E, Boschetti C, Mussoni L, Donati MD, Cardillo M, Catalano M, Gabrielli L, Lombardi B, Specchia G 1993 Increased fibrin turnover and high PAI-1 activity as predictors of ischemic events in atherosclerotic patients: a case control study. Arterioscler Thromb 13:1412–1417[Abstract/Free Full Text]
  23. Scarabin PY, Plu-Bureau G, Bara L, Bonithon-Kopp C, Guize L, Samama MM 1993 Haemostatic variables and menopausal status: influence of hormone replacement therapy. Thromb Haemost 70:584–587[Medline]
  24. Gebara OC, Mittleman MA, Sutherland P, Lipinska I, Matheney T, Xu P, Welty FK, Wilson PW, Levy D, Muller JE 1995 Association between increased estrogen status and increased fibrinolytic potential in the Framingham Offspring study. Circulation 91:1952–1958[Abstract/Free Full Text]
  25. Shahar E, Folsom AR, Salomaa VV, Stinson VL, McGovern PG, Shimakawa T, Chambless LE, Wu KK 1996 Relation of hormone replacement therapy to measures of plasma fibrinolytic activity: Atherosclerosis Risk in Communities (ARIC) Study Investigators. Circulation 93:1970–1975[Abstract/Free Full Text]
  26. Gilabert J, Estelles A, Cano A, Espana F, Barrachina R, Grancha S, Aznar J, Tortajada M 1995 The effect of estrogen replacement therapy with or without progesterone on the fibrinolytic system and coagulation inhibitors in postmenopausal status. Am J Obstet Gynecol 173:1849–1854[CrossRef][Medline]
  27. Siegbahn A, Odlind V, Hedner U, Venge P 1989 Coagulation and fibrinolysis during the normal menstrual cycle. Ups J Med Sci 94:137–152[Medline]
  28. De Souza C, Jones PP, Seals DR 1998 Physical activity status and adverse age related differences in coagulation and fibrinolytic factors in women. Arterioscler Thromb Vasc Biol 18:362–368[Abstract/Free Full Text]
  29. Giannattasio C, Failla M, Grappiolo A, Stella ML, Bo AD, Colombo M, Mancia G 1999 Fluctuations of radial artery distensibility throughout the menstrual cycle. Arterioscler Thromb Vasc Biol 19:1925–1929[Abstract/Free Full Text]
  30. Westerman RA, Kingwell BA, Paige J, Blombery PA, Sudhir K, Komesaroff PA 2000 Variations in endothelial function and arterial compliance during the menstrual cycle. J Clin Endocrinol Metab 86:5389–5395
  31. Hashimoto M, Akishita M, Eto M, Ishikawa M, Kozaki K, Toba K, Sagara Y, Taketani Y, Orimo H, Ouchi Y 1995 Modulation of endothelium-dependent flow-mediated dilatation of the brachial artery by sex and menstrual cycle. Circulation 92:3431–3435[Abstract/Free Full Text]
  32. Kawano H, Motoyama T, Kugiyama K, Hirashima O, Ohgushi M, Yoshimura M, Ogawa H, Okumura K, Yasue H 1996 Menstrual cyclic variation of endothelium dependent vasodilation of the brachial artery: possible role of estrogen and nitric oxide. Proc Assoc Am Physicians 108:473–480[Medline]
  33. English JL, Jacobs LO, Green G, Andrews TC 1998 Effect of the menstrual cycle on endothelium-dependent vasodilation of the brachial artery in normal young women. Am J Cardiol 82:256–258[CrossRef][Medline]
  34. Kawano H, Motoyama T, Ohgushi M, Kugiyama K, Ogawa H, Yasue H 2001 Menstrual cyclic variation of myocardial ischemia in premenopausal women with variant angina. Ann Intern Med 135:977–981[Abstract/Free Full Text]
  35. Muesing RA, Forman MR, Graubard BI, Beecher GR, Lanza E, McAdam PA, Campbell WS, Olson BR 1996 Cyclic changes in lipoprotein and apolipoprotein levels during the menstrual cycle in healthy premenopausal women on a controlled diet. J Clin Endocrinol Metab 81:3599–3603[Abstract]
  36. Agrawal R, Conway GS, Sladkevicius P, Payne NN, Bekir J, Campbell S, Tan SL, Jacobs HS 1999 Serum vascular endothelial growth factor (VEGF) in the normal menstrual cycle: association with changes in ovarian and uterine Doppler blood flow. Clin Endocrinol (Oxf) 50:101–106[CrossRef][Medline]
  37. Dawson SJ, Wiman B, Hamsten A, Green F, Humphries S, Henney AM 1993 The two allele sequences of a common polymorphism in the promoter of the plasminogen activator inhibitor (PAI-1) gene respond differently to interleukin-1 in HepG2 cells. J Biol Chem 268:10739–10745[Abstract/Free Full Text]
  38. Eriksson P, Kallin B, van’t Hooft FM, Bavenholm P, Hamsten A 1995 Allele-specific increase in basal transcription of the plasminogen-activator inhibitor 1 gene is associated with myocardial infarction. Proc Natl Acad Sci USA 92:1851–1855[Abstract/Free Full Text]
  39. Leander K, Wiman B, Hallqvist J, Sten-Linder, de Raire U 2003 PAI-1 level and the PAI-1 4G/5G polymorphism in relation to risk of non-fatal myocardial infarction. Thromb Haemost 89:1064–1071[Medline]
  40. Ye S, Green FR, Scarabin PY, Nicaud V, Bara L, Dawson SJ, Humphries SE, Evans A, Luc G, Cambou JP 1995 The 4G/5G genetic polymorphism in the promoter of the plasminogen activator inhibitor-1 (PAI-1) gene is associated with differences in plasma PAI-1 activity but not with risk of myocardial infarction in the ECTIM study. Thromb Haemost 74:837–884[Medline]
  41. Grancha S, Estelles A, Tormo G, Falco C, Gilabert J, Espana F, Cano A, Segui R, Aznar J 1999 Plasminogen activator inhibitor-1 (PAI-1) promoter 4G/5G genotype and increased PAI-1 circulating levels in postmenopausal women with coronary artery disease. Thromb Haemost 81:516–521[Medline]
  42. Ridker PM, Hennekens CH, Lindpaintner K, Stampfer MJ, Miletich JP 1997 Arterial and venous thrombosis is not associated with the 4G/5G polymorphism in the promoter of the plasminogen activator inhibitor gene in a large cohort of U.S. men. Circulation 95:59–62[Abstract/Free Full Text]
  43. Hindorff LA, Schwartz SM, Siscovick DS, Psaty BM, Longstreth Jr WT, Reiner AP 2002 The association of PAI-1 promoter 4G/5G insertion/deletion polymorphism with myocardial infarction and stroke in young women. J Cardiovasc Risk 9:131–137[CrossRef][Medline]



This article has been cited by other articles:


Home page
 Hum Reprod UpdateHome page
G. G. Gosman, H. I. Katcher, and R. S. Legro
Obesity and the role of gut and adipose hormones in female reproduction
Hum. Reprod. Update, September 1, 2006; 12(5): 585 - 601.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Submit a related Letter to the Editor
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Giardina, E.-G. V.
Right arrow Articles by Rabbani, L. E.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Giardina, E.-G. V.
Right arrow Articles by Rabbani, L. E.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals