Factor VIIc Research Articles

Dilatation of common carotid artery is strongly associated with cerebral ischemic stroke with or without the presence of carotid atherosclerosis

P147 Background: Dilatation of common carotid artery (CCA) was related to age, sex, and body height in population studies. It was also considered a compensatory mechanism to carotid atherosclerotic stenosis. The present study examined the risk of CCA dilatation associated with ischemic stroke (IS) and its relations to carotid atherosclerosis, hypertension, hyperglycemia, fibrinogen, cholesterol, HDL-cholesterol (HDL-C), smoking, and alcohol consumption. Methods: A case-control study was carried on 251 first-ever IS patients (age≥40) excluding previous history of myocardial infarction and cancer and 242 non-stroke outpatients. Intraluminal diameter of middle portion of CCA, and plaque thickness in CCA, bulb, internal and external carotid arteries were measured. Information on hypertension and diabetes status and data of life-styles such as smoking and alcohol consumption were collected. Levels of fibrinogen, factor VIIIc, cholesterol, HDL-C and glucose were obtained. Results: CCA dilatation was a strong factor for IS (OR=4.13, P=0.0001). It was also associated with hypertension, hyperglycemia, smoking, alcohol consumption, low HDL-C, and high levels of fibrinogen, factor VIIIc, cholesterol, and plaque score. The association remained significant with or without each of the following conditions: hypertension (p=0.0001, p=0.0007), hyperglycemia (p=0.0446, p=0.0001), elevated fibrinogen (p=0.0104, p=0.0001) or factor VIIIc (p=0.2458, p=0.0001), hypercholesterolemia (p=0.0238, p=0.0001), decreased HDL-C (p=0.0012, p=0.0001) and presence of plaque score (p=0.0263, p=0.0003). Adjusting above risk factors, odds ratios of elevated diameter could associated with IS, before (OR=2.21, P=0.0066) and after (OR=6.63, p=0.0055) excluding subjects with plaque. Conclusion: Dilatation of CCA is a strong risk factor for IS. The fact the association remained significant without ultrasonic evidence of carotid plaque indicates that IS in Chinese involved a mechanism of active vasculopathy, not just a passive compensatory process to extracranial atherosclerosis.

Fibrin D-dimer, Markers of Coagulation Activation and the Risk of Major Ischaemic Heart Disease in the Caerphilly Study

We have previously reported that plasma fibrin D-dimer (a marker of turnover of cross-linked fibrin) showed a strong and independent association with incident ischaemic heart disease (IHD) in the Caerphilly Study cohort of 1,998 men aged 49-65. To establish the specificity of this finding, we assayed plasma samples from this cohort with a more specific assay for fibrin D-dimer: this showed an association with incident IHD which was at least as strong and independent as that for the original assay (odds ratio, OR for top fifth compared to bottom fifth 3.79; 95% CI 1.77-8.10; p < 0.0001). To establish potential causes of the increased fibrin turnover, we also assayed several potential markers of coagulation activation or thrombotic tendency (prothrombin fragment F1+2, thrombin-antithrombin complexes, factor VIIc, activated partial thromboplastin time [APTT] and activated protein C resistance): none of these variables were associated with incident IHD in this cohort. We suggest that further studies are required to establish the causes of increased cross-linked fibrin turnover, which is associated with incident IHD in the general population when measured by a specific assay.

Localization of Blood Coagulation Factors In Situ in Pancreatic Carcinoma

Blood coagulation is activated commonly in pancreatic carcinoma but the role of the tumor cell in this activation is undefined. Immunohistochemical procedures were applied to fixed sections of 22 cases of resected adenocarcinoma of the pancreas to determine the presence of components of coagulation and fibrinolysis pathways in situ. Tumor cell bodies stained for tissue factor: prothrombin: and factors VII, VIIIc, IX, X, XII, and subunit "a" of factor XIII. Fibrinogen existed throughout the tumor stroma, and tumor cells were surrounded by fibrin. Staining for tissue factor pathway inhibitor, and plasminogen activators was minimal and inconsistent. Plasminogen activator inhibitors -1, -2, and -3 were present in the tumor stroma, and on tumor cells and vascular endothelium. Extravascular coagulation activation exists associated with pancreatic carcinoma cells in situ that is apparently unopposed by naturally occurring inhibitors or the plasminogen activator-plasmin system. We postulate that such local coagulation activation may regulate growth of this malignancy. These findings provide a rationale for testing agents that modulate the blood coagulation/fibrinolytic system (that inhibit tumor growth in other settings) in pancreatic carcinoma.

Effects of Diets Containing Olive Oil, Sunflower Oil, or Rapeseed Oil on the Hemostatic System

Various studies have already shown that the fatty acid composition of dietary fat has different effects on hemostasis and platelet function. However, knowledge on this topic is incomplete. In the present study, fifty-eight healthy students received either a 4-week rapeseed oil [high content of monounsaturated fatty acids (MUFA) and high n-3/n-6 PUFA ratio], an olive oil (high content of MUFA, low n-3/n-6 PUFA ratio) or a sunflower oil (low content of MUFA, low n-3/n-6 PUFA ratio) diet. In each group, effects on hemostatic parameters were compared with a wash-in diet rich in saturated fatty acids with respect to intermediate-time effects on the hemostatic system and platelet function. With the olive oil diet, a reduction of coagulation factors VIIc, XIIc, XIIa, and Xc was found, whereas sunflower oil led to lower values of coagulation factors XIIc, XIIa, and IXc. In all study groups levels of plasmin-alpha2-antiplasmin were lower in week 4 than at baseline. Lower fibrinogen binding on platelets was found after the sunflower oil diet, whereas expression of CD62 and spontaneous platelet aggregation were slightly higher after the olive oil diet. However, given the major differences in the fatty acid compositions of the diets, the differences between the groups with respect to hemostasis tended to be small. Therefore, the clinical significance of the present findings remains to be evaluated.

A single (investigator)-blind randomised control trial comparing the effects of quinapril and nifedipine on platelet function in patients with mild to moderate hypertension

The effect of quinapril and nifedipine on platelet aggregation, vascular endothelial function and coagulation system activity, was compared in a parallel-group, investigator-blind study carried out on patients with mild to moderate hypertension but no other diseases or receiving medication which might affect platelet function, vascular endothelium or coagulation. Forty patients (two groups of 20 patients each) and 20 control subjects were recruited. Patients were randomised to receive either quinapril or nifedipine retard and the dose escalated to control hypertension. Platelet aggregation studies were assessed serially and g -thromboglobulin, angiotensin-converting enzyme (ACE), von Willebrand factor (vWF) coagulation factors VIIIc, XII and fibrinogen were measured at the beginning and end of the 12-week period. Blood pressure was adequately controlled in all patients in both groups. Platelet function was impaired in certain parameters (slope of the reaction with ADP and collagen and maximum aggregation with collagen) in the patient group compared to controls before treatment and this improved in patients on quinapril but not on nifedipine; likewise g -thromboglobulin was higher in the patient group and fell significantly in the quinapril group but not those on nifedipine. Measurements of endothelial function and coagulation were normal before treatment and showed no alteration during the study, except in the expected fall in plasma ACE in the quinapril group. The results indicate that the ACE inhibitor, quinapril, has a beneficial effect on platelet function unlike the calcium channel blocker, nifedipine.

Acetaminophen causes an increased International Normalized Ratio by reducing functional factor VII.

Acetaminophen may increase International Normalized Ratio (INR) in patients taking anticoagulation medication, and in patients with acetaminophen poisoning without hepatic injury. The objective of this study was to describe and investigate the effect of acetaminophen on INR. The authors studied patients admitted to a regional toxicology treatment center with acetaminophen poisoning with INR and without potentially confounding coingestion or hepatic injury. Exposed and nonexposed (control) cohorts were recruited from admissions with acetaminophen poisoning and psychotropic drug poisoning, respectively. From 1,437 acetaminophen poisonings, after exclusions, there were 143 admissions with 205 estimations of INR. INR showed a time-dependent increase. Fifty percent of all patients and 66% of those with an extrapolated 4-hour acetaminophen concentration > or = 150 mg/L had an abnormal INR at some time. Dose ingested (p = 0.01) and nomogram-based risk (p for trend = 0.005) were correlated with the effect. N-acetylcysteine had a protective effect. Functional factor VII was lower (p = 0.005) in exposed patients (n = 30) than controls (n = 8), and less than antigenic factor VII in exposed patients (p = 0.03). Factor IX was lower (p = 0.02). Factor VIIIc was not significantly different. The authors concluded that an isolated, small rise in INR is common after acetaminophen poisoning without hepatic injury. It appears to be caused by inhibition of Vitamin K-dependent activation of coagulation factors. This effect suggests a possible mechanism for the observed interaction between acetaminophen and warfarin.

Determinants of haemostatic risk factors for coronary heart disease in obese children and adolescents.

To investigate the contribution of serum lipids, parameters of glucose metabolism, body composition and cardiovascular fitness to the variance of several haemostatic risk factors for coronary heart disease (CHD) in obese children and adolescents. Forty-two healthy, obese children and adolescents (20 male, 22 female, age 12.6 +/- 3.2y; body mass index (BMI), 30.4 +/- 5.3 kg/m2), were screened for haemostatic and metabolic risk factors for CHD. Thirty-five of the participants (18 male, age 13.5 +/- 2.9y; BMI, 29.9 +/-4.5kg/m2; 17 female, age 12.8+/-2.1 y, BMI, 31.1 +/- 5.3 kg/m2) were assessed for cardiovascular fitness by means of incremental cycle ergometer exercise. After adjustment for age, fat mass correlated significantly with plasminogen activator inhibitor-1 antigen (PAI-1-Ag) in boys and girls and factor VIIc only in girls. Children with lower power output (< or = 2.77W/kg) showed significantly higher values for factor VIIc, fibrinogen and tissue-type plasminogen activator antigen (tPA-Ag). Neither body composition nor cardiovascular fitness contributed independently to the variance of the determined haemostatic risk factors, except PAI-1-Ag, which has been shown to be determined by fat mass. In multiple linear regression analysis, triglycerides and PAI-1-Ag explained significant independent proportions of the variance of tPA-Ag. Factor VIIc was explained by C-peptide, insulin and fibrinogen. Von Willebrand factor antigen (vWF-Ag) was significantly related to glucose and insulin. The results suggest that in obese children and adolescents the haemostatic risk factors factor VIIc, vWF-Ag and tPA-Ag are mainly determinated by plasma insulin and triglyceride concentrations, but are primarily independent of body composition and cardiovascular fitness.

Effect of niacin, warfarin, and antioxidant therapy on coagulation parameters in patients with peripheral arterial disease in the Arterial Disease Multiple Intervention Trial (ADMIT)

Background Patients with peripheral arterial disease (PAD) have high rates of cardiovascular morbidity and mortality, including that caused by associated coronary heart disease and cerebrovascular disease. Previous studies have shown that coagulation parameters are altered in PAD and that altered coagulation may play a critical role in the susceptibility to cardiovascular complications in PAD. It is therefore important to assess the effect of secondary prevention measures on coagulation in patients with PAD. The Arterial Disease Multiple Intervention Trial (ADMIT), a multicenter, randomized, placebo-controlled trial, was conducted to determine the feasibility of a combined lipid-modifying, antioxidant, and antithrombotic treatment regimen in patients with PAD. The objective of this study was to assess the effect of the ADMIT interventions on coagulation. Methods ADMIT participants were randomly assigned to low-dose warfarin, niacin, and antioxidant vitamin cocktail or corresponding placebos in a 2 × 2 × 2 factorial design. Specialized coagulation studies were performed in a subset of 80 ADMIT participants at baseline and after 12 months of treatment. Results Low-dose warfarin (1 to 4 mg/d) resulted in a significant decrease in factor VIIc (P < .001) and in plasma F1.2 (P = .001). Unexpectedly, niacin treatment also resulted in significant decrease in both fibrinogen (48 mg/dL; P < .001) and F1.2 (P = .04). von Willebrand factor increased after antioxidant vitamin treatment (P = .04). Conclusions A regimen of low-dose warfarin effectively modifies coagulation in patients with PAD. Niacin also favorably modifies fibrinogen and plasma F1.2. Niacin, in addition to its lipid effects, modifies abnormal coagulation factors that accompany PAD. (Am Heart J 2000;140:631-6.)

High Plasma Concentration of Factor VIIIc Is a Major Risk Factor for Venous Thromboembolism

Established risk factors, including deficiencies of protein C, protein S or antithrombin and the factor V Leiden and prothrombin mutation, are present in about one third of unselected patients with venous thromboembolism. In addition to these inherited thrombophilic defects, elevated plasma levels of factor VIIIc have been suggested to be important in the pathogenesis of (recurrent) venous thromboembolism. The objective of this study was to assess the relevance of factor VIIIc plasma concentration in consecutive patients with venous thromboembolism. We studied the prevalence of elevated plasma levels of factor VIIIc in 65 patients with a proven single episode and in 60 matched patients with documented recurrent venous thromboembolism. The reference group consisted of 60 age- and sex-matched patients who were referred for suspected venous thromboembolism, which was refuted by objective testing and long-term clinical follow-up. To minimalize the influence of the acute phase, blood was obtained at least 6 months after the thromboembolic event and results were adjusted for fibrinogen and C-reactive protein. Factor VIIIc was re-determined several years after the first measurement in a subset of patients to evaluate the variability over time. To study a possible genetic cause, a family study was done. In the control, single and recurrent episode group, the prevalences of plasma levels of factor VIIIc above 175 IU/dl (90th percentile of controls) were 10% (95% CI: 4 to 21%), 19% (95% CI: 10 to 30%) and 33% (95% CI: 22 to 47%), respectively. For each 10 IU/dl increment of factor VIIIc, the risk for a single and recurrent episode of venous thrombosis increased by 10% (95% CI: 0.9 to 21%) and 24% (95% CI: 11 to 38%), respectively. Both low and high plasma levels of factor VIIIc were consistent over time (R = 0.80, p = 0.01). A family study indicated a high concordance for elevated factor VIIIc plasma concentrations among first degree family members. Adjustment for fibrinogen, C-reactive protein and known thrombophilic risk factors did not change the observed association of elevated factor VIIIc with thrombosis. Elevated plasma levels of factor VIIIc are a significant, prevalent, independent and dose-dependent risk factor for venous thromboembolism. It also predisposes to recurrent venous thromboembolism.

Abstracts of literature

Abstracts of literature

Actividad coagulante del factor VII (FVIIc) en ancianos con cardiopatía isquémica

The coagulant activity of factor VII increases with age and is a risk factor in middle aged subjects. Its role in elderly people is still unknown. The aim of this study was to evaluate whether or not FVIIc is a risk factor in such population. cases and controls study. The group of cases consisted of 79 subjects fulfilling the following criteria: a) age between 65 and 85 years, and b) admission in the Valle de los Pedroches Hospital of Pozoblanco (Córdoba, Spain) due to a myocardial infarction and/or unstable angina, 2 or 6 months before their enrollment. The control group consisted of 81 subjects of similar age, chosen at random from the municipal registry, and excluding those with coronary heart disease. Factor VIIc was measured by conventional methods. Plasma samples were diluted with deficient plasma in FVIIc, and coagulation times were measured after adding thromboplastin and calcium. The measures were compared with a <<control>> plasma and the results were presented as a percentage. There were no significant differences in the FVIIc between cases (118.3 [SD 22.2]) and controls (116.5 [24.4]; p = 0.630) in the total group. When classified according to their age, it was observed that within the group of more than 75 years old, cases had a higher FVIIc than controls (124.1 [18.2] vs 113.3 [23.5]; p < 0. 05). When the classification was carried out according to sex, male presented similar results than the total group. Bivariable analysis showed, in subjects with coronary diseases, that FVIIc was related to total cholesterol, cLDL, apoprotein B, body mass index, HbA1c, and age. Factors related to FVIIc in the multivariable analysis were basal glucose serum level, body mass index; cHDL was negatively related. FVIIc is higher in very old subjects with coronary diseases so it may be a significant coronary risk factor in this age group.

Two Novel Anti–von Willebrand Factor Monoclonal Antibodies

Von Willebrand Factor is a multimer produced by endothelial cells and megakaryocytes, being stored in intracellular organelles, such as the Weibel-Palade bodies and α-granules in endothelial cells and platelets, respectively. This molecule acts as a carrier protein for factor VIIIc, involved in the intrinsic pathway of blood coagulation maintaining its stability in circulation. Von Willebrand Factor also plays an important role in platelet aggregation and adhesion to injured vessel wall. It interacts with platelets through two distinct glycoproteins, GPIb and GPIIb/IIIa. We raised two monoclonal antibodies, ECA-3 and ECA-4, against human umbilical vascular endothelial cells that recognize and immunoprecipitate von Willebrand Factor. Interestingly, ECA-4 monoclonal antibody is able to completely inhibit platelet agglutination induced by ristocetin, suggesting that it binds to von Willebrand Factor close to platelet GPIb binding site. The use of monoclonal antibodies to identify von Willebrand Factor binding regions to factor VIII or platelets has been reported by others. In pulmonary hypertension, abnormalities have been detected on the multimeric structure of the molecule as well as on its proteolytic fragments, by using monoclonal antibodies. Moreover, monoclonal antibodies raised against specific regions of von Willebrand Factor molecule may allow studies of functional abnormalities of this protein in inherited and acquired disorders like subtypes of von Willebrand's disease.

Relationship between Triglycerides and Factor VIIc and Plasminogen Activator Inhibitor Type-1: Lack of Threshold Value

Increased factor VIIc (FVIIc) and plasminogen activator inhibitor type 1 (PAI-1) levels may lead to a thrombotic state and subsequently to a higher risk of myocardial infarction. The relationships between triglycerides and plasma levels of both PAI-1 and FVIIc were established in previous studies. However, there is no data assessing whether there is a threshold value of triglycerides above which FVIIc and PAI-1 levels increase or whether the relationship is continuous. Therefore, we measured triglycerides, FVIIc, and PAI-1 levels in a large group of 1254 asymptomatic patients with hyperlipoproteinemia. Our results showed that both FVIIc and PAI-1 levels increase linearly in parallel to triglyceride levels p=0.0001 . In the multiple regression analysis, the relationship between log triglycerides and FVIIc was significantly independent of total cholesterol, body mass index, fasting glycemia, gender, and age; the relationship between log triglycerides and PAI-1 was significantly independent of body mass index, fasting glycemia, gender, and age. Interestingly, we found that the correlation coefficients between triglycerides and the haemostatic parameters measured were almost identical in different subgroups of subjects: males, females, nonobese, and normoglycemic, as well as nonalcoholic. We conclude that the relationships between triglyceride levels and FVIIc, as well as PAI-1, are continuous without threshold value of triglycerides.

Fibrinogen and factor VII levels are related to adiposity but not to fetal growth or social class in children aged 10-11 years.

Factors operating in fetal life or during childhood may be important in determining fibrinogen and factor VII concentrations in adult life, and particularly in explaining social gradients in cardiovascular disease risk. In 1994, the authors measured fibrinogen and factor VIIc levels in 641 children aged 10-11 years (61% response rate) from schools in five towns in England and Wales. Birth weight was obtained by maternal recall, and other data on measures of fetal growth were obtained from birth records. Fibrinogen levels were higher in girls (258.8 mg/dl) than in boys (245.4 mg/dl) (95% confidence interval (CI) for difference: 5.5, 21.5). Fibrinogen and factor VIIc levels were linearly related to adiposity, rising by 37.1 mg/dl (95% CI: 24.7, 49.5) and 13.0% of standard (95% CI: 6.3, 19.7), respectively, between the bottom and top quintiles of ponderal index (weight (kg)/height (m)3). Fibrinogen was independently related to heart rate (p < 0.001) and was negatively but nonsignificantly related to measures of physical activity. Factor VIIc was positively correlated with total cholesterol (p < 0.001). No relations were found with measures of fetal growth or social class. These data do not support the concept that fibrinogen or factor VII levels are determined in utero or by social factors in childhood. Adiposity and physical training appear to be the important determinants of fibrinogen and factor VII levels in childhood.

Prospective study of markers of hemostatic function with risk of ischemic stroke. The Atherosclerosis Risk in Communities (ARIC) Study Investigators.

Several markers of hemostatic function and inflammation have been associated with increased risk of coronary heart disease, but prospective evidence for their role in ischemic stroke is scant. The Atherosclerosis Risk in Communities (ARIC) Study measured several of these markers in more than 14 700 participants 45 to 64 years old who were free of cardiovascular disease and were followed up for 6 to 9 years for occurrence of ischemic stroke (n=191). There was no apparent association between ischemic stroke incidence and factor VIIc, antithrombin III, platelet count, or activated partial thromboplastin time. After adjustment for multiple cardiovascular risk factors, von Willebrand factor, factor VIIIc, fibrinogen, and white blood cell count were positively associated and protein C was negatively but nonsignificantly associated with ischemic stroke incidence in regression analyses based on either continuous variables or fourths of the variable distributions. The adjusted relative risk (and 95% CI) for ischemic stroke in those in the highest versus lowest fourth were: von Willebrand factor, 1.71 (1.1 to 2.7); factor VIIIc, 1.93 (1.2 to 3.1); white blood cell count, 1.50 (0.9 to 2.4); fibrinogen, 1.26 (0.8 to 2.0); and protein C, 0.65 (0.4 to 1.0). This study offers modest support for the hypothesis that some markers of hemostatic function and inflammation can identify groups of middle-aged adults at increased risk of stroke. These factors may play a role in the pathogenesis of ischemic stroke.

High apolipoprotein AI concentrations are associated with lower mortality and myocardial infarction five years after coronary artery bypass graft surgery

OBJECTIVETo examine mortality and myocardial infarction five years after coronary artery bypass graft (CABG) surgery and the association with different lipid fractions and haemostatic, glycaemic, and demographic risk factors.SETTINGA regional...

EFFECT OF CHANGES IN PHYSICAL ACTIVITY ON MARKERS OF BLOOD COAGULATION AND FIBRINOLYSIS

1135 We examined the effects of changes in physical activity (PA) on markers of blood coagulation and fibrinolysis in 108 adults in the Seasonal Variation of Cholesterol Study [56% men, age=49±12.5 yrs, BMI=27.3±4.6 kg·m−2 (mean±SD)]. Fasting morning blood samples and PA measures were collected at baseline and then every 3 months for 1 year. Three 24-hour PA recalls were obtained at each assessment point to estimate total (TA), household (HA), occupational (OA), and leisure-time activity (LA) in MET-hrs·d−1. Baseline values of fibrinogen (FIBR), factor VIIc activity (FVIIc), and unbound plasminogen activator inhibitor-1 (PAI-1) were (mean ±SD); 306±83 mg·dl−1, 107±22%, and 55±43 ng·ml−1, respectively. Random effects models quantifying the slope (b) of the relationship between change in PA and change in FIBR, PAI-1, and FVIIc revealed that subjects reporting increases in TA had reductions in FIBR [b(men)=−0.65, (−1.7, 0.4); b(women)=−2.51, (−4.4, −0.6); (b, (95%CI)]. Increased LA was also associated with favorable reductions of FIBR in both men [b= −1.97, (−4.8, 0.4)] and women [b=−1.84, (−5.0, 1.3)]. In women only, increased OA and HA were associated with reduced FIBR levels [b=−2.05, (−5.8, 1.7) and b=−3.05, (−5.6, −0.5), respectively]. No associations were observed between any PA measure and PAI-1 or FVIIc. In conclusion, increased PA at home, at work, and during leisure-time may lower risk of cardiovascular events by favorably reducing basal levels of FIBR. Support: ACSM Fellowship for Epidemiological Research and NIH ROI HL-52745.

Hormone replacement therapy, inflammation, and hemostasis in elderly women.

Lipid-lowering by postmenopausal hormone therapy (HRT) explains only partly the assumed coronary risk reduction associated with therapy. To explore other possible mechanisms, we studied associations of HRT use with inflammation and hemostasis risk markers in women >/=65 years of age. Subjects were selected from 3393 participants in the fourth year examination of the Cardiovascular Health Study, an observational study of vascular disease risk factors. After excluding women with vascular disease, we compared levels of inflammation and hemostasis variables in the 230 women using unopposed estrogen and 60 using estrogen/progestin, with those of 196 nonusers selected as controls. Compared with nonusers, unopposed estrogen use was associated with 59% higher mean C-reactive protein (P<0.001), but with modestly lower levels of other inflammation indicators, fibrinogen, and alpha-1 acid glycoprotein (P<0.001). Factor VIIc was 16% higher among estrogen users (P<0.001), but this was not associated with higher thrombin production (prothrombin fragment 1-2), or increased fibrin breakdown (D-dimer). Concentration of plasminogen activator inhibitor-1 was 50% lower in both using groups (P<0.001) compared with nonusers, and this was associated with higher plasmin-antiplasmin complex: 8% higher in estrogen and 18% higher in estrogen/progestin users (P<0. 05). Relationships between the markers and hormone use were less pronounced in estrogen/progestin users, with no association for C-reactive protein except in women in upper 2 tertiles of body mass index (P for interaction, 0.02). The direction and strength of the associations of HRT use with inflammation markers differed depending on the protein, so it is not clear whether HRT confers coronary risk reduction through an inflammation-sensitive mechanism. Associations with hemostasis markers indicated no association with evidence of procoagulation and a possible association with increased fibrinolytic activity.

Relationship of plasmin generation to cardiovascular disease risk factors in elderly men and women.

Plasmin-alpha2-antiplasmin complex (PAP) marks plasmin generation and fibrinolytic balance. We recently observed that elevated levels of PAP predict acute myocardial infarction in the elderly, yet little is known about the correlates of PAP. We measured PAP in 800 elderly subjects who were free of clinical cardiovascular disease in 2 cohort studies: the Cardiovascular Health Study and the Honolulu Heart Program. Median PAP levels did not differ between the Cardiovascular Health Study (6.05+/-1.46 nmol/L) and the Honolulu Heart Program (6.11+/-1.44 nmol/L), and correlates of PAP were similar in both cohorts. In CHS, PAP levels increased with age (r=0. 30), procoagulant factors (eg, factor VIIc, r=0.15), thrombin activity (prothrombin fragment F1+2, r=0.29), and inflammation-sensitive proteins (eg, fibrinogen, r=0.44; factor VIIIc, r=0.37). PAP was associated with increased atherosclerosis as measured by the ankle-arm index (AAI) (P for trend, </=0.001). PAP was negatively related to factors associated with the insulin resistance syndrome (IRS) (eg, fasting insulin, r=-0.26; body mass index, r=-0.26), possibly reflecting an association with plasminogen activator inhibitor-1 (r=-0.29). Although our study did not have sufficient power to detect a significant interaction, PAP and AAI appeared to be more weakly associated in subjects with more manifestations of the IRS: PAP appeared more strongly associated with AAI in the subgroup with 0 or 1 metabolic disorders (P</=0.001; slope estimate, -0.14) compared with the subgroup with 2 or more metabolic disorders (P=0.10; slope estimate, -0.08) and in those with non-insulin-dependent diabetes mellitus (P=0.46; slope estimate, -0.04). Although PAP reflects reactive fibrinolysis and is associated with subclinical atherosclerosis, this relationship may be weaker in populations with characteristics of the IRS, possibly reflecting the inhibitory effects of plasminogen activator inhibitor-1 on PAP. Decreased fibrinolysis in the presence of subclinical disease in subjects with hyperinsulinemia or glucose intolerance is consistent with the premise that depressed plasmin generation may enhance the progression of atherosclerosis in these people.

Effects of hormone replacement therapy on hemostatic cardiovascular risk factors

Objectives: From observational studies, there is evidence that hormone replacement therapy in postmenopausal women causes a decrease in cardiovascular events. It remains unknown, however, precisely by which mechanisms this reduction is achieved. The primary aim of this work was to study the effects of hormone replacement therapy on established hemostatic risk factors during 1-year treatment of healthy postmenopausal women. The secondary aim was to investigate whether there was any significant difference in these risk factors between hormone replacement therapy administered as a cyclic estrogen/sequential progestogen or continuous estrogen/sequential progestogen regimen. Study Design: Sixty postmenopausal women were randomized to treatment with estradiol valerate 2 mg/day either continuously or cyclic (days 1 to 21; placebo on days 21 to 28). Both groups received cyproterone acetate 1 mg/day on days 12 to 21. Blood samples were collected before treatment and on cycle days 17 to 22 in cycles 3, 6, and 12. Thirty women with basic characteristics identical to the women included in the treatment group were included as a reference group. Blood samples were collected after 0, 6, and 12 months of observation. Results: Hormone replacement therapy during 1 year caused a marginal but significant increase in plasma concentration of factor VIIc after 12 months of treatment ( P < .05), a significant decrease in fibrinogen, and a significant decrease in the protein concentrations of tissue-type plasminogen activator, plasminogen activator inhibitor-1, and lipoprotein(a) after 3, 6, and 12 months of treatment ( P < .05). Possible differences in the integrated response between the reference group and the hormone replacement therapy group were evaluated by comparison of the area under the curve as estimated in each individual on the basis of each analyte in the sampling periods. The area under the curve of fibrinogen was significantly lower in the hormone replacement therapy group than in the reference group ( P < .03), whereas other variables did not deviate significantly between the groups. The areas under the curve did not deviate significantly between the group that received cyclic estrogen/sequential progestogen and the group that received continuous estrogen/sequential progestogen. Conclusions: One-year treatment with hormone replacement therapy influenced favorably a number of prognostic cardiovascular risk factors in healthy women. The most important effect was the lowering of fibrinogen. Furthermore, in this study the effect of hormone replacement therapy on hemostasis did not deviate between a cyclic estrogen/sequential progestogen regimen and a continuous estrogen/sequential progestogen regimen. (Am J Obstet Gynecol 1999;180:283-9.)