© 1996 American Heart Association, Inc.
Articles |
Sex Differences in Coagulation and Fibrinolysis in White Subjects With Non–Insulin-Dependent Diabetes Mellitus
From the Diabetes and Thrombosis Research Group, Division of Medicine, Leeds (United Kingdom) General Infirmary.
Correspondence to Dr Michael W. Mansfield, Diabetes and Thrombosis Research Group, Division of Medicine, Leeds General Infirmary, Leeds LS1 3EX, UK. E-mail michaelm@pathology.leeds.ac.uk.
 |
Abstract |
|---|
 Top Abstract IntroductionMethods Results Discussion References |
|---|
Abstract The increase in cardiovascular risk associated with having non–insulin-dependent diabetes mellitus (NIDDM) is far greater in women than men. Conventional risk factors do not account for this excess, and attention has focused on the possible contribution of abnormalities of fibrinolysis and coagulation in NIDDM. In the general population a number of hemostatic factors have been shown to predict the occurrence or progression of coronary artery disease. To investigate sex differences in coagulation and fibrinolysis in NIDDM, we measured levels of fibrinogen, factor VII:C, von Willebrand factor, plasminogen activator inhibitor-1, and tissue plasminogen activator in 213 NIDDM subjects (124 men and 89 women) who were not receiving insulin therapy. The women had higher levels of factor VII:C (144% versus 120.5% in men, P<.0005) and plasminogen activator inhibitor-1 activity (25.6 versus 17.0 U/mL), and these differences remained significant when account was taken of the higher body mass index (29.6 versus 28.0 kg/m2, P=.02), glycosylated hemoglobin (7.2% versus 6.8%, P<.05), and cholesterol levels (6.3 versus 5.7 mmol/L, P<.0005) in women than men. In contrast, levels of fibrinogen (3.2 versus 3.1 g/L), tissue plasminogen activator antigen (10.6 versus 11.2 ng/mL), and von Willebrand factor (1.27 versus 1.23 IU/mL) were no different between women and men, respectively. These results suggest that elevated levels of plasminogen activator inhibitor-1 and factor VII:C may contribute to the increased cardiovascular risk of NIDDM that is particularly marked in women.
Key Words: fibrinolysis • coagulation • non–insulin-dependent diabetes mellitus • women
|
Introduction |
|---|
|
TopAbstractIntroductionMethods Results Discussion References |
|---|
Clinical disease resulting from large vessel atherosclerosis is responsible for most of the increased mortality of NIDDM. The risk of clinical macrovascular disease is increased twofold to threefold in subjects with diabetes; however, this increase has a greater effect in diabetic women. In the Framingham study the age-adjusted increase in the risk of cardiovascular death with diabetes was twofold for men and nearly fivefold for women.1
The mechanisms by which diabetes increases vascular risk and particularly so in women are incompletely understood. In contrast to the clear evidence from prospective studies of the microvascular complications of diabetes,2 the evidence that hyperglycemia contributes to large vessel atherogenesis is less convincing. Furthermore, despite the clustering of established cardiovascular risk factors in diabetes and particularly NIDDM, these risk factors alone do not fully account for the increased vascular risk.3 As results from a number of large prospective studies in general population groups have identified various hemostatic markers for the subsequent development4 5 6 7 or progression8 9 of large vessel atherosclerosis, attention has turned to abnormalities in coagulation and fibrinolysis in diabetes that may contribute to increased vascular risk.
To investigate whether abnormalities in fibrinolysis and coagulation may contribute to the increased vascular risk of NIDDM in a sex-specific fashion, we examined levels of five components of the coagulation and fibrinolytic systems that have been reported to be elevated in subjects with NIDDM and have been associated with atherosclerotic disease in the general population (fibrinogen, vWF, FVII:C, PAI-1, and TPA) in men and women with NIDDM.
|
Methods |
|---|
|
TopAbstractIntroductionMethods Results Discussion References |
|---|
Two hundred thirteen white subjects (124 men and 89 women) with NIDDM as defined by World Health Organization criteria aged 30 years or more at diagnosis were recruited from the diabetes clinic at the General Infirmary in Leeds. Each subject attended the department between 8 and 9:15 AM after an overnight fast of at least 10 hours and abstention from cigarette smoking. After 20 minutes of rest, free-flowing blood samples were taken with a 19-gauge butterfly needle from an antecubital vein. Blood was taken into 0.9% citrate (pH 8.8) on ice in the ratio of 9 parts blood to 1 of citrate for assay of PAI-1 and TPA and into lithium heparin on ice for analysis of insulin levels. These samples were centrifuged at 2560g and 4°C for 30 minutes. Blood taken into 0.9% citrate at room temperature for analysis of FVII:C, vWF, and fibrinogen was spun at 2560g and room temperature for 20 minutes. Plasma was aliquoted from the spun samples, snap-frozen, and stored at -40°C until assay. Blood was also collected into lithium fluoride for plasma glucose estimation, lithium heparin for plasma lipid analysis, and EDTA for HbA1C estimation. Blood pressure was measured with subjects sitting and to the nearest 2 mm Hg. Systolic and diastolic pressures were calculated from the mean of three readings. BMI was calculated as weight in kilograms divided by height in meters squared. Current smoking habit was recorded and note taken of current drug therapy. Each subject gave informed consent; the study was approved by the United Leeds Teaching Hospitals (NHS) Trust Research Ethics Committee.
PAI-1 activity was measured by chromogenic assay (Spectrolyse, Biopool) and TPA antigen by enzyme-linked immunosorbent assay (Imulyse, Biopool). Plasma FVII:C was assayed with an ACL 3000 plus (Instrumentation Laboratory), with factor VII–deficient plasma and rabbit thromboplastin (Instrumentation Laboratory) as reagents. FVII:C was expressed as a percentage of activity given by calibration plasma. Fibrinogen was measured by the Clauss method,10 vWF by an enzyme-linked immunosorbent assay (Dako), and plasma insulin levels by a radioimmunoassay kit (Medgenix). Interassay and intra-assay coefficients of variation were 10.5% and 7.0%, respectively, for TPA antigen, 8% and 5% for PAI-1 activity, 2.0% and 2.5% for fibrinogen, 4.7% and 2.8% for vWF, and 10.5% and 8.4% for the insulin assay. Measurements of plasma glucose (by a glucose oxidase method), cholesterol, and triglyceride were made with a Hitachi 747 autoanalyzer (Boehringer Mannheim). HbA1C was measured by a Glycomat autoanalyzer (Ciba Corning), with a reference range of 4.5% to 6.5%.
As circulating levels of FVII:C show a strong association with genotype at a coding (Arg-Gln) polymorphism in the eighth exon of the factor VII gene,11 genotype at this polymorphism was determined by polymerase chain reaction amplification of genomic DNA and Msp I restriction as described by Green et al.11
In view of the frequent use of antihypertensive agents, hypertension was defined as being present if the mean blood pressure was greater than 160 mm Hg systolic or 90 mm Hg diastolic or the subject was previously diagnosed as hypertensive and was receiving antihypertensive therapy. Those subjects receiving antihypertensive medication for other indications such as ischemic heart disease could not be classified on this basis. An estimate of the prevalence of symptomatic coronary artery disease in each sex group was determined from a clinical history of angina, myocardial infarction, or coronary revascularization and case-note review.
Subjects' ages and disease duration were not normally distributed and
are shown as median (range). The Mann-Whitney U test was
used to compare values of these between the two groups. The
2 test was used to compare the frequency of
clinical coronary disease and hypertension between sexes.
Values for BMI, plasma insulin, lipids, glucose,
HbA1C, PAI-1, and fibrinogen showed a positive skew
and were log transformed to normalize their distribution and permit use
of parametric statistical analyses. Values for vWF were
skewed to the right, and square-root transformation resulted in a
normal distribution. Values for FVII:C and TPA were distributed
normally. The Kolmogorov-Smirnov statistic and Lilliefors significance
values were used to confirm normality of the distribution of values
(after transformation where appropriate). Unpaired Student's
t test was used to compare mean values of these
variables between men and women. Where mean values of a hemostatic
parameter differed between men and women, factorial ANOVA
was performed entering age, BMI, smoking habit,
HbA1C, and levels of plasma insulin,
triglyceride, and cholesterol as covariates.
For factor VII levels, genotype at the coding polymorphism
was entered into the factorial ANOVA model as a code, in which those
subjects with the most common Arg/Arg genotype were coded as 2
and those carrying the less frequent Gln allele as 1. Current
smoking was considered a categorical variable. All statistical
analyses were performed with SPSS for Windows Version 6.1.
|
Results |
|---|
|
TopAbstractIntroductionMethods Results Discussion References |
|---|
The clinical and metabolic characteristics of the 124 men and 89 women studied are shown in Table 1
. The
groups were of similar ages and disease duration, with approximately 1
in 7 subjects smoking cigarettes in each group. A quarter of the
subjects of each sex gave a clinical history of ischemic heart
disease (angina, myocardial infarction, or coronary
revascularization). Despite being of similar age
and disease duration, the women showed a greater frequency of
hypertension as defined above and a significantly higher BMI compared
with the men. These changes were also associated with increased
cholesterol levels and HbA1C in the women and a
trend toward higher insulin and triglyceride that did not
reach standard levels of significance. At the factor VII Msp
I polymorphism, 21% of the subjects carried the Gln allele,
and there was no difference in this frequency between the men (19%)
and women (22%).
|
As shown in Table 2, PAI-1 activity and FVII:C levels
were significantly higher in the women; fibrinogen and vWF levels were
very similar in each group; and there was a nonsignificant trend toward
lower TPA levels in the women.
|
In the factorial ANOVA models, sex remained a significant and independent predictor of both PAI-1 activity and FVII:C levels. Geometric mean levels of PAI-1 activity adjusted for age, BMI, smoking habit, HbA1C, and levels of insulin, triglyceride, and cholesterol were 18.0 U/mL for men and 24.6 U/mL for women (P=.003); FVII:C levels adjusted for these same covariates and factor VII Msp I genotype were 123.5% in men and 141% in women (P=.003). Sex accounted for some 4% and 7% of the interindividual variance of PAI-1 and FVII:C levels, respectively, in these models, which had R2 values of .35 and .58, respectively. Fibrinogen and vWF levels remained similar in men and women when allowing for differences in these other covariates. However, the trend toward lower TPA antigen levels in women was exaggerated in the ANOVA model, reaching statistical significance with adjusted TPA antigen levels being 11.5 ng/mL in men and 10.0 ng/mL in women (P=.005). In this model, sex accounted for 4% of interindividual variance in TPA antigen levels. The outcome of these ANOVA models was not altered by inclusion of other covariates and was consistent when applied to randomly selected 75% subgroups of the population.
|
Discussion |
|---|
|
TopAbstractIntroductionMethods Results Discussion References |
|---|
Abnormalities of both coagulation and fibrinolysis have been described in NIDDM, with increased levels of fibrinogen,12 factor VII,13 vWF,14 PAI-1,15 and TPA antigen.15 A prothrombotic state resulting from elevated levels of clotting factors and suppression of fibrinolysis by elevated levels of PAI-1 could theoretically increase the risk of vascular occlusion and thereby coronary events and death in NIDDM. In support of this, levels of each of these factors have been implicated as predictors of coronary disease in prospective studies of healthy subjects or subjects with angina. Fibrinogen has emerged as an important and independent predictor of cardiovascular disease and coronary events in a number of prospective studies, including the Northwick Park Heart Study,4 the Speedwell/Caerphilly Study,5 the Framingham Study,6 and the Prospective Cardiovascular Münster (PROCAM) Study.7 . The Northwick Park Heart Study also found that FVII:C levels independently predicted fatal coronary events, with a 1 SD increase in levels being associated with a 62% increase in risk over 5 years.4 In the European Concerted Action on Thrombosis and Disabilities (ECAT) study, vWF levels as well as fibrinogen and TPA antigen levels were identified as independent and significant predictors of myocardial infarction or sudden death in patients with angina pectoris.9 Increased levels of PAI-1 itself have been found to relate to the severity of coronary disease16 and in survivors of myocardial infarction to predict subsequent recurrence.8
The increase in vascular risk in NIDDM is multifactorial, and changes in hemostasis may represent just one component of a profile of cardiovascular risk factors involving metabolic, constitutional, and behavioral factors. Reaven17 recognized that particular cardiovascular risk factors tend to cluster in certain individuals. These factors include increased BMI, with male-pattern obesity; high circulating levels of insulin and triglyceride; and low levels of HDL cholesterol, with glucose intolerance and systolic hypertension. These have all been related to peripheral tissue resistance to the actions of insulin, that is, insulin resistance. This syndrome of insulin resistance is manifest in a spectrum of individuals with minimal impairment of glucose tolerance, through overtly impaired glucose tolerance to frank NIDDM, in which pancreatic insulin production is insufficient to overcome the tissue insulin resistance. More recently, data have accumulated indicating that suppression of fibrinolysis through increased PAI-1 levels should be added to the syndrome,18 19 20 21 and there is emerging evidence that in NIDDM, FVII:C levels also correlate strongly with these metabolic features.22 Evidence that elevated vWF levels relate to the syndrome of insulin resistance is conflicting.14 23
Clearly, the identification of this clustering of recognized cardiovascular risk factors and hemostatic abnormalities may go a long way in explaining the increase in vascular disease in NIDDM. Furthermore, if these metabolic and hemostatic factors are causally involved in vascular disease, then the presence of sex-related differences in the levels of these factors in subjects with NIDDM would suggest a mechanism for the particular increase in vascular risk of diabetic women.
In the present study we found significantly higher FVII:C and PAI-1 levels in women compared with men with NIDDM that were associated with higher BMI and cholesterol levels, with a consistent trend toward higher levels of the other features of insulin resistance, that is, insulin and triglyceride. As levels of these factors are known to correlate in NIDDM,22 24 25 26 the increased FVII:C and PAI-1 levels may indicate increased expression of the syndrome of insulin resistance in the women from this population of NIDDM subjects. Despite these associations, in the ANOVA models for both PAI-1 and FVII:C, sex remained an independent and significant predictor of levels. This suggests an influence of sex on PAI-1 and FVII:C levels, in addition to its association with the features of insulin resistance, although clearly, care must be taken in the interpretation of such statistical models.
Large cross-sectional studies of healthy subjects, predominantly from Scandinavia, suggest that PAI-1 levels are similar in men and women although there are reports of higher levels in men in some age brackets.27 28 Our finding of higher PAI-1 levels in diabetic women therefore may indicate an important sex-specific interference in the hemostatic system by diabetes that could increase vascular risk.
A mechanism independent of insulin resistance by which female sex could be associated with higher PAI-1 levels in NIDDM is not clear. Differences caused by sex hormone levels do not explain the findings. Although in hyperlipidemic men PAI-1 and testosterone levels correlate negatively,29 in women higher estrogen levels are associated with lower PAI-1 levels; in healthy postmenopausal women not receiving estrogen replacement, PAI-1 levels are no higher than in men of the same age.30 In the present study no assessment was made of sex hormone levels although examination of the age range of the women studied suggests that a large majority were postmenopausal. Investigation of the relationship among female hormonal status, fibrinolytic variables, and the features of insulin resistance in premenopausal and postmenopausal NIDDM women may help in the evaluation of the importance of estrogens and PAI-1 in vascular risk in women with NIDDM.
The results of our study contrast with those of a smaller study of 38 lean and obese NIDDM subjects in which PAI-1 activity levels were significantly higher in the male than the female subjects.31 Although subjects in that study were stratified into two groups according to BMI, it is unclear whether the PAI-1 values for each sex were adjusted for differences in BMI. Furthermore, small cross-sectional studies of PAI-1 levels are vulnerable to the marked intraindividual variability of PAI-1 levels, and the inclusion of subjects from differing racial backgrounds in that study may have accentuated this. These factors may account for the disparity in results between the two studies.
Levels of TPA antigen are generally found to be elevated in NIDDM, a paradoxical finding in view of the suppression of fibrinolysis. This has been interpreted either as reflecting the increased presence of circulating TPA–PAI-1 complexes nonspecifically detected by the TPA antigen assay9 or as indicating release of both TPA and PAI-1 from diseased arterial endothelium. In the present study we found a tendency toward lower TPA antigen levels in the women with NIDDM than the men, and this difference was exaggerated by adjustment for the influence of covariates. While taken at face value these findings are compatible with a further suppression of fibrinolysis in women compared with men with NIDDM, in view of PAI-1 activity levels being higher in the women, they may simply indicate that levels of TPA–PAI-1 complexes were lower in the women. Given the uncertainty of how TPA antigen assays relate to measures of fibrinolysis and that our unadjusted data showed only a trend toward lower levels in women with NIDDM, care must be taken in applying any of these interpretations to our results. Studies of TPA antigen levels in healthy subjects give differing results, some finding similar levels in men and women27 and others finding higher levels in men.32
Higher FVII:C levels in women than men have been described in a healthy population,33 and our finding with regard to FVII:C may simply indicate that in NIDDM, FVII:C levels are generally increased from healthy population levels in both sexes, remaining higher in women. Our results for FVII:C are in accord with a recent study of newly diagnosed NIDDM subjects of Chinese ethnicity in whom FVII:C levels were higher in female than male subjects.34
In contrast to FVII:C and PAI-1, we found no differences in fibrinogen, vWF, and TPA levels between men and women with NIDDM. As in healthy subjects fibrinogen levels are reported to be higher in female than male subjects,35 our findings of similar levels in men and women indicate that altered fibrinogen levels are unlikely to contribute to the increased coronary risk of NIDDM in women. For fibrinogen, our results differ from those found in Chinese NIDDM subjects, in whom fibrinogen levels were higher in females than males.34 Apart from the obvious ethnic differences, this disparity may relate to younger age and lower BMI of the Chinese diabetic subjects studied.
Studies of vWF in healthy white subjects14 and subjects with angina36 show no sex differences, and as our results show equal levels of both in men and women, the increase due to NIDDM appears not to be altered by sex.
Our findings may throw some light on the causes of the particular increase in vascular risk seen in women with NIDDM. However, while only 25% of the subjects studied gave a clinical history of angina, myocardial infarction, or coronary revascularization, coronary disease is often clinically silent in NIDDM, and it is probable that ascertainment by electrocardiography or angiography would reveal a much higher prevalence. As the hemostatic variables studied may be synthesized and released in response to vascular damage, the vascular disease burden of the subjects studied is a confounding variable in this study. It is therefore possible that our findings may represent an effect rather than a cause of diabetic macrovascular disease. Furthermore, the high mortality from coronary disease in NIDDM may have led to exclusion from the study, through premature death, of subjects with the most severe coronary disease.
These major limitations of this retrospective study indicate the need for a prospective study to confirm sex differences in PAI-1 and FVII:C levels in which stratification of male and female subjects by levels of obesity, lipids, smoking, and other factors known to influence these levels can also be undertaken. As diabetic macrovascular disease is often present at the time of diagnosis of NIDDM, such a study might have to be begun in younger, nondiabetic subjects identified as having a high subsequent risk of developing NIDDM.
In summary, in this study of white subjects with NIDDM, PAI-1 and FVII:C levels were higher in women than men, and fibrinogen, vWF, and TPA levels were similar in both groups. Whereas PAI-1 and FVII:C levels associate with the features of insulin resistance in NIDDM, the evidence that vWF and fibrinogen relate to insulin resistance is conflicting. These results suggest that the elevated PAI-1 and FVII:C levels may contribute to the increased macrovascular risk of NIDDM in a sex-specific way, with a greater increase seen in female NIDDM subjects related at least partly to increased expression of the syndrome of insulin resistance in diabetic women. These observations may help account for the particularly marked increase in cardiovascular risk found in women with NIDDM.
|
Selected Abbreviations and Acronyms |
|---|
|
|
Acknowledgments |
|---|
This study was funded by the British Heart Foundation and the United Leeds Teaching Hospitals Special Trustees.
Received June 27, 1995; accepted October 24, 1995.
|
References |
|---|
|
TopAbstractIntroductionMethods Results Discussion References |
|---|
1. Kannal WB, McGee DL. Diabetes and cardiovascular disease, the Framingham Study. JAMA. 1979;241:2035-2038.
2.
The Diabetes Control and Complications Trial Research
Group. The effect of intensive treatment of diabetes on the development
and progression of long-term complications in insulin-dependent
diabetes mellitus. N Engl J Med. 1993;329:977-986.
3. Pyörälä K. Relationship of glucose tolerance and plasma insulin to the incidence of coronary heart disease: results from two population studies in Finland. Diabetes Care. 1979;2:131-141. [Abstract]
4. Meade TW, Mellows S, Brozovic M, Miller GJ, Chakrabarti RR, North W, Haines AP, Stirling Y, Imeson JD, Thompson SG. Haemostatic function and ischaemic heart disease: principal results of the Northwick Park Heart Study. Lancet. 1986;2:533-537. [Medline] [Order article via Infotrieve]
5.
Yarnell J, Baker IA, Sweetnam PM, Bainton D, O'Brien
JR, Whitehead PJ, Elwood PC. Fibrinogen, viscosity, and white
blood cell count are major risk factors for ischaemic heart disease:
the Caerphilly and Speedwell Collaborative Heart Disease
Studies. Circulation. 1991;83:836-844.
6.
Kannal WB, Wolf PA, Castelli WP, D'Agostino
RB. Fibrinogen and risk of cardiovascular
disease: the Framingham Study. JAMA. 1987;258:1183-1186.
7.
Heinrich J, Balleisen L, Schulte H, Assmann G, van de
Loo J. Fibrinogen and factor VII in the prediction of
coronary risk: results from the PROCAM Study in healthy
men. Arterioscler Thromb. 1994;14:54-59.
8. Hamsten A, de Faire U, Walldius G, Dahlén G, Szamosi A, Landou C, Blombäck M, Wiman B. Plasminogen activator inhibitor in plasma: risk for recurrent myocardial infarction. Lancet. 1987;2:3-9. [Medline] [Order article via Infotrieve]
9.
Thompson SG, Kienast J, Pyke S, Haverkate F, van de
Loo J. Haemostatic factors and the risk of myocardial infarction
or sudden death in patients with angina pectoris. N
Engl J Med. 1995;332:635-641.
10. Marbet GA, Duckert F. Fibrinogen. In: Jespersen J, Bertina RM, Haverkate F, eds. ECAT Assay Procedures. A Manual of Laboratory Results. Dordrecht, Netherlands: Kluwer; 1992:47-55.
11.
Green F, Kelleher C, Wilkes H, Temple A, Meade T,
Humphries S. A common genetic polymorphism associated with
lower coagulation factor VII levels in healthy individuals.
Arterioscler Thromb. 1991;11:540-546.
12. Ostermann H, Van de Loo J. Factors of the haemostatic system in diabetic patients. Haemostasis. 1986;16:386-390. [Medline] [Order article via Infotrieve]
13. Fuller JH, Keen H, Jarrett RJ, Omer T, Meade TW, Chakrabarti R, North W, Stirling Y. Haemostatic variables associated with diabetes and its complications. BMJ. 1979;2:964-966.
14. Conlan MG, Folsom AR, Finch A, Davis CE, Sorlie P, Marcucci G, Wu KK. Associations of factor VIII and von Willebrand factor with age, race, sex, and risk factors for atherosclerosis: the Atherosclerosis Risk in Communities (ARIC) study. Thromb Haemost. 1993;70:380-385. [Medline] [Order article via Infotrieve]
15. Gough S, Grant PJ. The fibrinolytic system in diabetes mellitus. Diabet Med. 1991;8:898-905. [Medline] [Order article via Infotrieve]
16.
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.
17. Reaven GM. Role of insulin resistance in human disease. Diabetes. 1988;37:1595-1607. [Abstract]
18. Potter van Loon BJ, Kluft K, Radder JK, Blankenstein MA, Meinders AE. The cardiovascular risk factor plasminogen activator inhibitor type 1 is related to insulin resistance. Metabolism. 1993;42:945-949. [Medline] [Order article via Infotrieve]
19. Landin K, Stigendal L, Eriksson E, Krotkiewski M, Risberg B, Tengborn L, Smith U. Abdominal obesity is associated with an impaired fibrinolytic activity and elevated plasminogen activator inhibitor-1. Metabolism. 1990;39:1044-1048. [Medline] [Order article via Infotrieve]
20. Landin K, Tengborn L, Smith U. Elevated fibrinogen and plasminogen activator inhibitor (PAI-1) in hypertension are related to metabolic risk factors for cardiovascular disease. J Intern Med. 1990;227:273-278. [Medline] [Order article via Infotrieve]
21. Juhan-Vague I, Alessi MC. Plasminogen activator inhibitor 1 and atherothrombosis. Thromb Haemost. 1993;70:138-143. [Medline] [Order article via Infotrieve]
22. Heywood DM, Mansfield MW, Grant PJ. Factor VII:C Msp I genotype, factor VII:C levels, and features of insulin resistance in non-insulin-dependent diabetes mellitus: a link with vascular risk. Diabet Med. 1995;12(suppl 1):S35. Abstract.
23. Nilsson TK, Boman K, Bjerle P, Hallmans G, Hellsten G. von Willebrand factor and fibrinolytic variables are differently affected in the insulin resistance syndrome. J Intern Med. 1994;235:419-423. [Medline] [Order article via Infotrieve]
24. Mansfield MW, Stickland MH, Grant PJ. Environmental and genetic factors in relation to elevated circulating levels of plasminogen activator inhibitor-1 in Caucasian patients with non-insulin-dependent diabetes mellitus. Thromb Haemost. 1995;74:842-847. [Medline] [Order article via Infotrieve]
25. Panahloo A, Mohamed-Ali V, Lane A, Green F, Humphries SE, Yudkin JS. Determinants of plasminogen activator inhibitor 1 activity in treated NIDDM and its relation to a polymorphism in the plasminogen activator inhibitor 1 gene. Diabetes. 1995;44:37-42. [Abstract]
26. 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;61:370-373. [Medline] [Order article via Infotrieve]
27. Eliasson M, Evrin PE, Lundblad D, Asplund K, Rånby M. Influence of gender, age and sampling time on plasma fibrinolytic variables and fibrinogen. Fibrinolysis. 1993;7:316-323.
28. Rånby M, Sundell IB, Johnson O, Ledin M-C, Dahlen G. Activity of plasminogen activator inhibitor-1 (PAI-1) in a population in Northern Sweden. Fibrinolysis. 1990;4(suppl 2):54-55.
29. Glueck CJ, Glueck HI, Stroop D, Spiers J, Hamer T, Tracy T. Endogenous testosterone, fibrinolysis, and coronary heart disease risk in hyperlipidemic men. J Lab Clin Med. 1993;122:412-420. [Medline] [Order article via Infotrieve]
30.
Gebara OC, Mittleman MA, Sutherland P, Lipinska I,
Matheney T, Xu P, Welty FK, Wilson PW, 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.
31. McGill JB, Schneider DJ, Arfken CL, Lucore CL, Sobel BE. Factors responsible for impaired fibrinolysis in obese subjects and NIDDM patients. Diabetes. 1994;43:104-109. [Abstract]
32. Siegert G, Bergmann S, Jaross W. Relationship of plasminogen activator inhibitor activity and tissue-type plasminogen activator concentration with age, sex, risk factors for coronary heart disease and life style. Fibrinolysis. 1994;8:34-36.
33. Balliesen L, Bailey J, Epping PH, Schulte H, Van de Loo J. Epidemiological study on factor VII, factor VIII and fibrinogen in an industrial population, 1: baseline data on the relation to age, gender, body-weight, smoking, alcohol, pill-using, and menopause. Thromb Haemost. 1985;54:475-479. [Medline] [Order article via Infotrieve]
34. Chan P, Pan WH. Coagulation activation in type 2 diabetes mellitus: the higher coronary risk of female diabetic patients. Diabet Med. 1995;12:504-507. [Medline] [Order article via Infotrieve]
35. Ernst E. Fibrinogen: its emerging role as a cardiovascular risk factor. Angiology. 1994;45:87-93.
36. 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;73:561-567.[Medline] [Order article via Infotrieve]
This article has been cited by other articles:
 |
|
 |
|
  J. F. Arenillas, P. Sandoval, N. Perez de la Ossa, M. Millan, C. Guerrero, D. Escudero, L. Dorado, E. Lopez-Cancio, J. Castillo, and A. Davalos The Metabolic Syndrome Is Associated With a Higher Resistance to Intravenous Thrombolysis for Acute Ischemic Stroke in Women Than in Men Stroke, February 1, 2009; 40(2): 344 - 349. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Smith, C. Patterson, J. Yarnell, A. Rumley, Y. Ben-Shlomo, and G. Lowe Which Hemostatic Markers Add to the Predictive Value of Conventional Risk Factors for Coronary Heart Disease and Ischemic Stroke?: The Caerphilly Study Circulation, November 15, 2005; 112(20): 3080 - 3087. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Barrett-Connor, E.-G. V. Giardina, A. K. Gitt, U. Gudat, H. O. Steinberg, and D. Tschoepe Women and Heart Disease: The Role of Diabetes and Hyperglycemia Arch Intern Med, May 10, 2004; 164(9): 934 - 942. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. Stangl, G. Baumann, and K. Stangl Coronary atherogenic risk factors in women Eur. Heart J., November 2, 2002; 23(22): 1738 - 1752. [Full Text] [PDF]
|
|
|
|
 |
|
 F. Samad, M. Pandey, and D. J. Loskutoff Regulation of tissue factor gene expression in obesity Blood, December 1, 2001; 98(12): 3353 - 3358. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Samad, M. Pandey, and D. J. Loskutoff Tissue factor gene expression in the adipose tissues of obese mice PNAS, June 23, 1998; 95(13): 7591 - 7596. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. W. Mansfield, D. M. Heywood, and P. J. Grant Circulating Levels of Factor VII, Fibrinogen, and von Willebrand Factor and Features of Insulin Resistance in First-Degree Relatives of Patients With NIDDM Circulation, November 1, 1996; 94(9): 2171 - 2176. [Abstract] [Full Text]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||