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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.

Cardiovascular Diseases↗

Hemostatic responses to maximal exercise in oral contraceptive users.

OBJECTIVE: This study examined the effect of exercise on markers of fibrinolysis and coagulation in users and nonusers of oral contraceptives. STUDY DESIGN: Fourteen oral contraceptive users and 14 nonusers performed a maximal exercise test on a cycle ergometer. Blood samples were collected before and immediately after the completion of the test. A repeated-measures analysis of variance was used for statistical analysis with values considered significant at P =.05. RESULTS: Acute maximal exercise resulted in significant increases in tissue plasminogen activator activity in both groups. There was a trend toward a smaller increase in tissue plasminogen activator activity in oral contraceptive users, but the difference between groups was not statistically significant. Plasminogen activator inhibitor 1 activity was reduced with exercise in both groups but with a significantly greater decrease observed in the nonusers (P <.0001). Prothrombin fragment 1+2 was significantly higher (P <.0001) in the oral contraceptive group but did not change with exercise. Epinephrine levels before and after exercise were similar between the 2 groups, but postexercise norepinephrine concentrations were significantly lower (P =.026) in the oral contraceptive users. CONCLUSION: These data suggest that oral contraceptive use blunts the fibrinolytic response to exercise. This, together with increased coagulation activation in oral contraceptive users, may alter the hemostatic balance during exercise.

Adult↗

Hemostatic effects of smoking and oral contraceptive use.

This review addresses current knowledge of the effects of lower dose oral contraceptives (containing 35, 30, or 20 micrograms of ethinyl estradiol) on hemostasis in smoking and nonsmoking women. Evidence suggests that formulations containing 30 and 35 micrograms ethinyl estradiol induce a significant activation of coagulation, whereas oral contraceptive preparations with 20 micrograms ethinyl estradiol appear to have a negligible effect or no effect. In nonsmokers who take oral contraceptives any procoagulatory effects that may occur are counterbalanced by fibrinolytic effects. In smokers, however, compensatory fibrinolytic effects to offset the procoagulatory effects seen with 30-micrograms ethinyl estradiol oral contraceptive formulations are absent, shifting the hemostatic profile toward a hypercoagulable state. This suggests that a formulation with the lowest dose of ethinyl estradiol may be most suitable for smokers who wish to use this form of contraception.

Blood Coagulation↗

Norwood-type operation with adjustable systemic-pulmonary shunt using hemostatic clip.

The postoperative course of a patient with hypoplastic left heart syndrome after a first-stage Norwood operation is governed to a large extent by the balance between the systemic and pulmonary circulations. Here we describe a simple and convenient technique for establishing an optimally sized systemic-pulmonary shunt by the application of a hemostatic clip. The method has been used in 6 patients.

Aorta, Thoracic↗

Pharmacologic preservation of the hemostatic system during cardiac surgery.

Bleeding after cardiac surgery remains a major potential problem. Numerous pharmacologic approaches to attenuating hemostatic system activation in cardiac surgery patients have been studied to further improve patient management. Therapeutic approaches studied include inhibiting thrombin generation or activation, preserving platelet function, and decreasing the need for transfusion of allogeneic blood products. Pharmacologic approaches to reduce bleeding and transfusion requirements in cardiac surgery patients are based on either preventing or reversing the defects associated with the CPB-induced coagulopathy. The increasing use of platelet inhibitors (clopidogrel and IIb/IIIa receptor antagonists) and new anticoagulants (low-molecular weight heparins, pentasaccharide, recombinant hirudin, bivalirudin, and argatroban) also pose interesting problems in managing cardiac surgery patients. Aprotinin and lysine analogues (epsilon-aminocaproic acid and tranexamic acid) have become mainstay therapeutic agents to prevent bleeding and the potential need for allogeneic transfusion. Newer therapies that are important to consider include the potential of recombinant activated factor VIIa as a therapy for refractory bleeding after cardiac surgery.

Blood Loss, Surgical↗

Preoperative clinical assessment of hemostatic function in patients scheduled for a cardiac operation.

BACKGROUND: Bleeding during and after cardiac operations is usually attributed to inadequate surgical hemostasis or cardiopulmonary bypass-induced disorders of hemostasis. Patient-related factors often are neglected. METHODS: Articles published between 1976 and 1996 on the preoperative assessment of surgical patients were reviewed to determine the clinical elements most likely to predict increased perioperative blood requirements. RESULTS: Preoperative assessment is based on a carefully conducted interview (history of bruising, petechiae, recent or excessive bleeding after operation, chronic drug therapy) and physical examination. A standardized questionnaire to enhance the reliability of the assessment is presented. Thus, patients at high risk of being transfused can be identified early on and may be enrolled in various programs designed to decrease bleeding and the need for allogeneic blood transfusions. CONCLUSIONS: Clinical assessment of hemostatic function before cardiac operations is both effective and efficient. It obviates the need for routine laboratory testing and favors the introduction of blood conservation strategies early on during the process of care.

Cardiac Surgical Procedures↗

Comparison of the lipoprotein, carbohydrate, and hemostatic effects of phasic oral contraceptives containing desogestrel or levonorgestrel.

Desogestrel (DSG) is a less-androgenic progestogen than levonorgestrel (LNG). This difference in androgenicity may be responsible for observed differences in metabolic effects between oral contraceptive (OC) formulations containing almost equivalent estrogen doses but with either DSG or LNG as a progestogen. To test the hypothesis, a prospective 9-month randomized comparison of plasma lipids, glucose, insulin, hemostasis, and sex hormone binding globulin (SHBG) was conducted in 66 healthy women using phasic formulations of OCs containing either DSG (DSG-OC) or LNG (LNG-OC). The study results showed that SHBG increased 3-fold with DSG-OC and 2-fold with LNG-OC. DSG-OC increased HDL-C, HDL(2)-C and HDL(3)-C; LDL-C decreased transiently. LNG-OC decreased HDL(2)-C and increased HDL(3)-C; HDL-C was unchanged and LDL-C decreased transiently. Both formulations increased VLDL-C and triglycerides, more with DSG-OC, but apolipoprotein B levels increased equally. Apo A-I and A-II increased more with DSG-OC than with LNG-OC. Neither formulation altered Lp(a) or fasting glucose and insulin levels. Postprandially, both formulations decreased glucose and increased insulin responses, but to an equivalent degree. Both OCs slightly enhanced procoagulant and profibrinolytic parameters to the same extent except for internally compensating decreases in Factor V and protein S with DSG-OC. In summary, at almost equivalent estrogen doses, a phasic OC containing DSG compared with LNG has a less androgenic effect on lipoproteins and SHBG, similar effects on hemostatic parameters with lower protein S and factor V activity and equivalent effects on carbohydrate metabolism. The lipoprotein, SHBG, and protein S and factor V differences are likely due to the lesser androgenicity of DSG allowing for a greater expression of the dose of estrogen.

Adult↗

Third-generation progestogen type influences hemostatic changes caused by oral contraceptives in Brazilian women.

We compared the effects of two third-generation progestogens, desogestrel (DSG) and gestodene (GSD), on coagulation and fibrinolysis in Brazilian users of oral contraceptives (OCs). Forty-six women were evaluated before treatment and after six cycles of treatment. The coagulation, anticoagulant, and fibrinolytic systems were investigated. During the use of the DSG-containing OC, the activity of factors VII, VIII, IX, X, and XII increased significantly whereas the GSD-containing OC caused no changes in coagulation parameters. Concerning the anticoagulant pathways, the DSG-containing OC increased protein C levels and decreased total protein S levels, and the GSD-containing OC only decreased total protein S. Both OCs increased plasminogen activity, although the DSG-containing OC increased fibrin degradation products levels and decreased the tissue plasminogen activator antigen. In conclusion, we have found that in Brazilian women the effects of DSG and GSD on hemostatic parameters are different and, therefore, third-generation progestogens may not contribute equally to the thrombotic risk.

Adult↗

The effects of seven monophasic oral contraceptive regimens on hemostatic variables: conclusions from a large randomized multicenter study.

We investigated the effects of ethinylestradiol dose (50, 30 and 20 microg) and progestogen type [desogestrel (DSG), gestodene (GSD), levonorgestrel (LNG) and norgestimate (NGM)] in oral contraceptives on 24 hemostatic variables. In a multicenter, randomized, comparative study, 707 healthy, nonsmoking, nulliparous women were treated for six cycles with one of the seven monophasic oral contraceptives tested. Significantly greater increases in prothrombin fragment 1+2 and factor VII (activity and antigen), were found in the DSG, NGM and GSD groups compared to the LNG group. Similarly, significantly lower levels of protein S (free and total) and increased APC-sr (endogenous thrombin potential based) were found in the same groups compared with the LNG group. In addition, the estradiol dose (50 vs. 30 microg) significantly influenced these parameters. All changes were within the normal range and have not been associated with an increased risk of venous thromboembolic event (VTE). However, raised levels of these variables are associated with prothrombotic states such as pregnancy. The significance of the haemostatic changes found in this study in relation to VTE risk remains to be determined, but results of this study probably cannot explain the differences in risk of VTE between OCs containing different progestogens.

Adult↗

Effects on the hemostatic system and liver function in relation to Implanon and Norplant. A prospective randomized clinical trial.

In this prospective randomized clinical trial, two long-term contraceptive implants were studied with respect to hemostasis and liver function in 86 healthy young women. The two implants used were Implanon, containing the progestagen etonogestrel (the biologically active metabolite of desogestrel) and Norplant, the implant containing the progestagen levonorgestrel. The results of the trial showed that both implants had similar small effects on the hemostatic system that are not suggestive of a tendency towards thrombosis. The effect on liver function was characterized by increases in total bilirubin and gamma-glutamyl transferase and decreases in alanine aminotransferase and aspartate aminotransferase.

Adult↗

An open label, randomized study to evaluate the effects of seven monophasic oral contraceptive regimens on hemostatic variables. Outline of the protocol. Oral Contraceptive and Hemostasis Study Group.

Complementary to the epidemiological knowledge on the association between oral contraceptive use and the occurrence of venous thromboembolism, a study was designed to obtain more conclusive data regarding the effect of estrogen dose and progestogen type of oral contraceptives on risk markers for the occurrence of venous thromboembolism. The protocol for this multicenter, randomized, open label, parallel group, comparative study is outlined in the present article. A total of 730 healthy, nonsmoking, mulliparous women were treated for six cycles with one of the seven monophasic oral contraceptives tested in this study. The effects of progestogen type (desogestrel, gestodene, levonorgestrel, and norgestimate) and the effects of ethinyl estradiol dose (50, 30, and 20 micrograms) on various hemostatic variables was assessed, including the key components of the anticoagulant and fibrinolytic system, as well as the coagulation system. The primary outcome variables in the study were prothrombin fragment 1 + 2 and D-dimer.

Blood Coagulation↗

Comparison of avitene, topical thrombin, and gelfoam as sole hemostatic agent in tuboplasties.

Forty-eight virgin guinea pigs were subjected to bilateral sectioning of the uterine horn and cuff type salpingostomy. Avitene, Topical Thrombin, or Gelfoam was used as the sole hemostatic agent in each of three study groups. Bipolar cauterization was used in a control series. These agents were compared with regard to ease of application, degree of adhesion formation, net surface area, and microscopic evaluation of degree of fibrosis and inflammatory reaction. The results revealed no statistically significant differences among the various methods of hemostasis. Data were evaluated by uni- and multivariate analyses. Several trends in the data were noted: the greatest amount of fibrosis was associated with Topical Thrombin and Avitene, and the greatest inflammatory response was associated with Avitene. These agents show no superiority to currently used cautery methods of obtaining hemostasis.

Animals↗

Homocysteine and methylenetetrahydrofolate reductase genotype: association with risk of coronary heart disease and relation to inflammatory, hemostatic, and lipid parameters.

AIM: It has been suggested that homocysteine (tHcy) levels and methylenetetrahydrofolate reductase (MTHFR) genotype are primary risk factors for coronary heart disease (CHD). We performed a case-control study to investigate whether tHcy levels and MTHFR genotype (677 C-->T mutation and 1298 A-->C mutation) are associated with CHD under special consideration of the possibility for confounding. METHODS: German speaking patients aged 40-68 years who underwent coronary angiography at the University of Ulm between April 1996 and November 1997 and who had at least one coronary stenosis greater than 50% were included in the study. Controls were sampled from voluntary blood donors and were matched for sex and age. tHcy levels were measured by high performance liquid chromatography and MTHFR genotype by means of polymerase chain reaction. In addition, C-reactive protein, fibrinogen, plasma viscosity, leukocytes, HDL-cholesterol and Lp(a) were determined. RESULTS: Overall, 312 patients and 479 controls were enrolled in the study (response in patients 78%, in controls 84%). Mean tHcy value was 9.43 micromol/l in CHD patients and 8.91 micromol/l in controls (P=0.145). Prevalence of 677TT-polymorphism was 9.9% in patients and 10.4% in controls (P=0.295). Prevalence of 1298CC-polymorphism was 9.7% in patients and 13.8% in controls (P=0.346). There was a clear association of tHcy-values, but not of 677TT- or 1298CC-genotype with conventional CHD risk factors. After adjustment for these risk factors no increased risk for CHD could be associated with increased tHcy-values, with 677TT or 1298CC-genotype, or with their combination. Also no statistically significant relationships of these parameters to inflammatory, rheologic or hemostatic parameters or lipids were detectable. CONCLUSION: These results do not confirm an independent relationship of tHcy values and MTHFR genotype with risk of CHD in the population studied.

Adult↗

Endotoxin-induced disseminated intravascular coagulation in rabbits: effect of recombinant hirudin on hemostatic parameters, fibrin deposits, and mortality.

We evaluated the effect of r-hirudin on an experimental model of disseminated intravascular coagulation (DIC) in rabbits, through the continuous infusion of 100 microg/kg/hr of Escherichia coli endotoxin for a period of 6 hours. r-Hirudin (0.05, 0.3, and 0.6 mg/kg/hr) as treatment, or saline solution as placebo, were administered simultaneously with endotoxin. Severe DIC in the endotoxin control group was shown by impairment in hemostatic parameters, kidney fibrin deposition, and a high mortality rate. Medium and high doses of r-hirudin led to an improvement in such DIC-related parameters as platelet numbers and fibrinogen and protein C concentrations. High-dose r-hirudin also reduced consumption of antithrombin III (ATIII). All doses of r-hirudin prevented decreases in tissue plasminogen activator (t-PA) and reduced the increase in plasminogen activator inhibitor-1 (PAI-1) activity observed at 2 hours after endotoxin administration. A significant reduction in kidney fibrin deposition was seen in medium- and high-dose r-hirudin groups. Additionally, the mortality rate in rabbits receiving medium- and high-dose r-hirudin was 10%, and that in rabbits receiving low-dose r-hirudin was 20%, as compared with a mortality rate of 70% in the control group. Protein C activity was significantly lower (p < 0.001) in nonsurviving rabbits. Moreover, there was a strong positive correlation (r = 0.68, p < 0.001) between protein C consumption and kidney fibrin deposition. We conclude that r-hirudin can be a useful drug in the clinical treatment of DIC.

Animals↗

Comparative study of microfibrillar collagen hemostat (Colgel) and oxidized cellulose (Surgicel) in high transfusion-risk cardiac surgery.

OBJECTIVE: The effects of microfibrillar collagen hemostat (Colgel) and oxidized cellulose (Surgicel) on bleeding and allogeneic transfusions were compared in cardiac operations with a predicted high risk of bleeding. METHODS: Between August 1999 and November 2001, 71 patients undergoing elective, high risk of bleeding operations were studied after giving informed consent. The procedures included repeat cardiac operations (aorta-coronary bypass operations or valvular operations), ascending aortic aneurysm repair necessitating deep hypothermic circulatory arrest, and ascending aortic grafting without deep hypothermic circulatory arrest. Subjects were excluded if they had recent (<5 days) acetylsalicylic acid ingestion, thrombolytic therapy, or anticoagulant therapy (heparin <4 hours preoperatively or warfarin <3 days preoperatively). Consenting subjects were randomized to receive either Colgel or Surgicel. RESULTS: Chest tube drainage in the first 24 hours was 373 +/- 143 mL in the Colgel group and 571 +/- 144 mL in the Surgicel group (P =.01). Total postoperative chest tube drainage was 423 +/- 154 mL (range, 280-1100 mL) in the Colgel group and 677 +/- 128 mL (range, 285-1350 mL) in the Surgicel group (P =.01). In addition, chest tube drainage was compared between the 2 groups every 3 hours after operation. Blood loss in the first 3 postoperative hours was significantly less in the Colgel group (132 +/- 41 vs 228 +/- 57 mL, P <.001). In the following 3-hour interval, this significant difference persisted (67 +/- 24 vs 121 +/- 49 mL, P <.001). CONCLUSIONS: In conclusion, the easy application, low cost, and significant blood-loss reduction effect of microfibrillar collagen powder renders this agent attractive for cardiac operations associated with high risk of bleeding.

Blood Transfusion↗

Hemostatic disturbances observed in patients with snakebite in south China.

To investigate the hematological disorders after snakebite, we measured the maximum platelet aggregation rate (MAR), antithrombin III (AT-III) activity, alpha(2)-plasmin inhibitor (alpha(2)-PI) activity, concentration of fibrinogen (Fg) and fibrin degradation products (FDP) in 25 samples from 17 patients with snakebite in south China. The results obtained in the patients before application of antivenom and patients with Ophiophagus hannah (Oh.) bite were as follows: (1) the mean MAR values were significantly decreased in the case of the snakebites from Vipera russellii (Vr.) and Trimeresurus mucrosquamatus (Tm.); (2) the mean activities of AT-III were decreased in all patients in the present study; 3) the mean activities of alpha(2)-PI were significantly decreased in patients bitten by Deinagkistrodon acutus (Da.), Agkistrodon halys (Ah.), Vr., Trimeresurus stejnegeri (Ts.), Tm. and Naja naja atra (Nn.); (4) the mean concentrations of Fg were markedly decreased in patients bitten by Da., Ah., Vr., Ts. and Tm.; and (5) the mean levels of FDP were significantly increased in cases of Da., Vr. and Ts. bite, but not in Ah., Tm., Nn. and Oh. bite. The results of the present study indicate that disorders of platelet aggregation and the coagulation-fibrinolysis system are liable to occur in patients with snakebite from Da., Ah., Vr., Ts., Tm. and Nn. Furthermore, it appeared that disseminated intravascular coagulation (DIC) was evoked in some patients. Specific antivenom was found to be useful for improving the hemostatic disturbances after snakebite from Ah. and Nn.

Adolescent↗

Hemostatic alterations in patients with benign and malignant colorectal disease during major abdominal surgery.

We determined sensitive markers of coagulation and fibrinolysis in plasma of 20 patients with malignant colorectal disease as compared to 17 patients with benign colorectal disease. Thrombin/antithrombin III complex (TAT), soluble fibrin (SF), total fibrinogen and fibrin degradation products (TDP), plasminogen activator inhibitor type-1 (PAI-1), urokinase-type plasminogen activator (uPA) and uPA receptor (uPAR) were measured preoperatively, starting anesthesia, during surgery and postoperatively. The purpose was to verify the supposed hypercoagulable state of cancer patients. In addition, we investigated whether the hemostatic alterations induced by general anesthesia and major abdominal surgery differed between the two groups. Patients with colorectal cancer showed initially an altered balance of hemostasis with a preponderance of procoagulant activity and fibrinolytic inhibition, as noted by marginally elevated TAT and PAI-1 plasma levels. The stimulus of anesthesia induction alone was sufficient to trigger not only activation of coagulation in these patients but also further activation of fibrinolysis and increased fibrinolytic inhibition. The marked activation of coagulation and fibrinolysis and enhanced fibrinolytic inhibition during surgery was more pronounced in patients with malignancy as compared to the control group. Postoperatively, a shift of the normal balance of hemostasis with a slight preponderance of fibrinolytic inhibition was observed, as evidenced by a marginally elevated PAI-1 plasma levels. The results of this study strengthen the hypothesis of a hypercoagulable state in patients with colorectal malignancy that may favor the development of thrombosis in this patient group.

Adult↗

Hemostatic markers with bolus versus prolonged heparin after carotid artery stenting.

BACKGROUND: The evolving technique of carotid stenting (CS) requires optimal antithrombotic strategies to reduce periinterventional thromboembolic risk. In animal models of balloon injury, tissue factor (TF) was shown to be the major procoagulant of the atherosclerotic plaque mediating prolonged procoagulant activity. METHODS: We analyzed TF and TF-dependent hemostatic markers before and 2, 6 and 24 h after CS with two antithrombotic drug regimens. Group A (n=20) received prolonged unfractionated heparin (UFH) for 18-20 h starting at intervention next to aspirin and thienopyridine. In group B (n=16), single bolus UFH was administered next to combined antiplatelet therapy. Natural anticoagulants were determined at baseline. RESULTS: Patients with symptomatic and asymptomatic cerebrovascular disease did not differ in plasma TF levels. Furthermore, no statistically significant difference for TF, TFPI/Xa-complex and prothrombin fragment F1.2 was observed between bolus and prolonged heparin treatment. No significant change was found in time course for these parameters. Two patients (5.5%; one in each treatment group) suffered periinterventional minor stroke associated with increased levels of F1.2 and TFPI/Xa-complex. Both were resistant to activated protein C (APC ratio<1.9) due to heterozygous factor V Leiden mutation. CONCLUSIONS: No significant activation of the TF pathway was seen with both antithrombotic regimens suggesting that single bolus UFH combined with antiplatelet therapy is generally sufficient to control TF-dependent procoagulant activity after CS. However, patients with resistance to activated protein C may be at increased periinterventional stroke risk.

Aged↗