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The coagulation response is a complex interaction involving the vascular surface, blood platelets, and the plasma coagulation factors. These reactions are integrated to give rise to a locally efficient generation of both platelet aggregates and the enzymatic process associated with fibrin formation. Following mechanical, chemical, or biological "damage" to the vascular endothelial surface, coagulation is initiated by a composite of cellular adhesive reactions certainly involving the platelet and potentially also involving other inflammatory cells. The blood coagulation mechanism can be presented as a collection of zymogen-to-enzyme transformations, with each proteases participating with a cofactor protein on a "surface" that gives rise to the competent blood clotting complex. These complexes catalyze the generation of additional enzymes required for succeeding reaction complexes. It is likely that the coagulation reaction system is continuously "on," producing products at some low "idling" rate, with the products of the various reactions being neutralized by the collection of protease inhibitors and cofactor-neutralizing reactions that regulate the blood clotting process. These latter systems include, as principal components, the antithrombin III-heparin anticoagulant and the activated protein C pathway that disables cofactor proteins. Small changes in the concentrations of modulators can cause large effects in response to relatively small inputs. The coagulation process may be regarded as being at an incipient stage, separated from visually observable coagulation by a narrow threshold, which, once crossed, gives rise to the generation of fibrin and other products associated with alpha-thrombin generation.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Potential analytes for the diagnosis of thrombosis. An overview. 134 87

Most of the linkage of atherosclerosis and thrombosis with estrogens is epidemiologic in origin. Although the effects of estrogens on the mechanisms of hemostasis are wide ranging, many are benign; only a few may account for thrombus formation. Platelet function tests have provided extensive but contradictory data, and interpretation is limited because it is uncertain whether a rise in one or more of these parameters is a primary or secondary effect. The most consistent effects of estrogens on coagulation proteins are elevations of fibrinogen; factors II, VII, IX, X, and XII; protein C; and plasminogen. Although these elevations have been attributed to the estrogenic component in oral contraceptives, the progestogen concentration may also influence these increases. Among other coagulation proteins studied, the following are unaffected by oral contraceptive use: factors V, VIII, and XI; prekallikrein; and high-molecular-weight kininogen. In contrast, protein S values are decreased. The plasma concentration of plasmin inhibitor is unchanged, whereas both proteinase inhibitor and macroglobulin are significantly increased by oral contraceptive use. Cl esterase inhibitor is decreased in women taking oral contraceptives and correlates with the increase in Hageman factor. Antithrombin III is one plasma inhibitor for which a decrease in quantity and activity have been associated with a thrombotic tendency in humans. Although data on estrogen-associated changes in the quantity of antithrombin III have been conflicting, the ability of plasma to inhibit factor Xa is significantly reduced in a dose-dependent manner among pre- and postmenopausal estrogen users.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Estrogen-associated thromboembolism. 134 94

The Atherosclerosis Risk in Communities (ARIC) Study is an observational epidemiologic study conducted in four communities. ARIC has two major components: One records the occurrence of myocardial infarction resulting in hospitalization and coronary heart disease death in adults aged 35 to 74 living in the communities; the other is a prospective study of representative cohorts aged 45 to 64. Measurement of hemostatic factors is part of the cohort study, whose major objectives include investigating etiologic factors associated with atherosclerosis and its clinical outcomes. Arterial intimal-medial wall thickness, an index of early atherosclerosis, is measured precisely from ultrasound images of carotid and popliteal arteries. Participants (n = 15,801) completed their first examination, which included measurements of factors associated with coagulation (fibrinogen, factor VII, factor VIII, and von Willebrand factor) and coagulation inhibition (protein C and antithrombin III). Measures of coagulation activation, platelet activation, and fibrinolytic activity will be performed on stored plasma from selected case patients and control subjects.
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PMID:The Atherosclerosis Risk in Communities (ARIC) Study. Introduction and objectives of the hemostasis component. 134 97

Several population studies have shown that plasma levels of fibrinogen and factor VII are significantly associated with ischemic cardiovascular events. However, there is little information regarding the association of hemostatic factors with early atherosclerosis. To evaluate this, we compared the plasma concentrations of several coagulation proteins (fibrinogen, factor VII, factor VIII, von Willebrand factor, protein C, and antithrombin III) between 385 case patients, defined by high-resolution B-mode ultrasonography as having carotid arterial wall thickening, and 385 age-, race-, and sex-matched control subjects. These case patients and control subjects were selected from participants in a prospective population investigation, the Atherosclerosis Risk in Communities (ARIC) Study, who were examined between May 1987 and May 1989. Plasma fibrinogen, factor VII, protein C, and antithrombin III levels were significantly higher in case patients than in control subjects (P < 0.05). Factor VIII and von Willebrand factor were not different. These findings were supported by quartile distribution and univariate analysis. However, only fibrinogen remained significantly associated with carotid atherosclerosis on multivariate analysis taking other atherosclerosis risk factors into consideration. A one standard deviation increase in fibrinogen (67 mg/dL) was associated with a 1.6-fold increase in the odds of carotid atherosclerosis univariately (P < 0.001) and with a 1.3-fold increase in the odds multivariately (P = 0.010). Further analysis revealed that the association of fibrinogen with carotid atherosclerosis was somewhat stronger in cigarette smokers than in nonsmokers. This early case-control analysis of the ARIC Study demonstrates a significant association between plasma fibrinogen concentration and early atherosclerosis in the carotid arteries. In the context of published findings from population studies, our results indicate that plasma fibrinogen concentrations may be a useful marker for identifying individuals at high risk of developing arterial thrombotic disorders.
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PMID:Association of coagulation factors and inhibitors with carotid artery atherosclerosis. Early results of the Atherosclerosis Risk in Communities (ARIC) Study. 134 98

The relations between hemostatic variables and cardiovascular risk factors were examined in a biracial population sample of middle-aged adults. Fibrinogen, factor VII, factor VIII, von Willebrand factor, protein C, and antithrombin III levels varied considerably by age, sex, and race. Hemostatic variables also were associated with several life-style and biochemical risk factors. For the most part, higher levels of the risk factors were associated with higher levels of the hemostatic variables. The findings point to potential confounders that warrant consideration in cardiovascular disease studies, and/or mechanisms by which cardiovascular risk is conferred. They also suggest that modification of the cardiovascular risk factors may have the potential to alter the risk of thrombosis.
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PMID:Relations between hemostasis variables and cardiovascular risk factors in middle-aged adults. Atherosclerosis Risk in Communities (ARIC) Study Investigators. 134 99

Recent epidemiologic studies found that there is a strong association of hemostatic factors with ischemic heart disease. The Atherosclerosis Risk in Communities (ARIC) Intraindividual Variability (IIV) Study was conducted to estimate the various components of variation in hemostasis factors measured in the ARIC Study and to estimate the measures of repeatability of these factors. A total of 39 subjects (16 men, 23 women) were studied. Each had blood collected three times, with a 1- to 2-week interval between each visit. The contributions of between-person variability, within-person (biologic) variability, and processing and assay variability were estimated. Then the reliability coefficient R was estimated as the proportion of total variance accounted for by between-person variance. The reliability coefficient can be interpreted as the correlation between measures made at repeat visits. Among the various analytes, the reliability coefficients were quite high for activated partial thromboplastin time and plasma factor VIII (R = 0.92, 0.86, respectively). Low repeatability was obtained for antithrombin III activity and protein C (R = 0.42, 0.56, respectively). The lack of repeatability for these variables derives mostly from the processing (field center and laboratory) variation. Other analytes--fibrinogen, plasma factor VII, and von Willebrand factor--were intermediate in repeatability. In comparing the analyte-specific high-level to low-level groups, no substantial difference of within-person plus method coefficient of variation between the two groups was found for any analyte except for factor VIII, whereas the corresponding variance components for most analytes were higher for the higher analyte level. Reliability coefficients from this ARIC IIV study are generally higher than those found in other studies, and this is related to the relative variations in populations studied and to the time between measurements.
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PMID:Short-term intraindividual variability in hemostasis factors. The ARIC Study. Atherosclerosis Risk in Communities Intraindividual Variability Study. 134 24

The synthesis of a number of clotting factors takes place in a hepatocyte. Therefore, measurement of these factors in the blood have proved to be of additional value in the diagnosis and follow-up of liver diseases. In the present study we evaluated protein C level in the plasma of patients with liver cell damage due to chronic alcohol consumption. A decrease in plasma protein C concentration which correlated with clinical performance of the patients was found. Significant correlations between the level of protein C and antithrombin III, one-stage prothrombin time, factors VII and X and some biochemical tests reflecting liver cell damage were also stated. The obtained data indicate that plasma protein C level may constitute a useful marker of hepatocellular disease in alcoholics.
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PMID:Plasma protein C as a marker of hepatocellular damage in alcoholic liver disease. 803 40

4 studies involving a combined oral contraceptive devised with norgestimate as the progestin and low-dose ethinyl estradiol as the estrogen, designed to have virtually no androgenic effects, are reviewed. A study of lipid metabolism found that cholesterol rose above desirable limits of 200 mg/dl in only 5% of women and fell within these limits in 25% who surpassed it. Similarly, triglycerides rose above 150 mg/dl in 5% with normal levels and fell in 28% who initially had high levels. 2 other studies documented increases in HDL and decreases in LDL, improving the HDL/LDL ratio. Coagulation factors were followed in a small series: no adverse effects on fibrinopeptide A, antithrombin III, protein C, Fibrinogen, factor VII, or factor VIII were seen in 6 months. No significant changes in mean levels of fasting glucose, insulin, hemoglobin A1C, or glucose tolerance were found. 2% of 2738 women developed abnormal fasting glucose levels after 6 months, while 35% lowered their initially abnormal glucose levels into the normal range after 6 months on the combined pill. Androgenicity was assessed by sex hormone binding globulin (SHBG) and free testosterone levels. The norgestimate pill elevated SHBG about 3-fold, lowering free testosterone. The prevalence of acne in norgestimate pill users is 2%. No change was noted in average blood pressure or weight. Similar results have been reported in studies on a triphasic norgestimate formulation. These results are optimistic for beneficial effects on major risk factors for cardiovascular disease, but large longterm epidemiological studies will have to be done to confirm them.
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PMID:Long-term profile of a new progestin. 136 89

The authors have investigated the effects of double-membrane filtration with hollow fiber membranes made of different artificial materials and low-density lipoprotein (LDL)-adsorbent dextran sulfate cellulose (DS) columns on coagulation-related proteins and complement components to evaluate their hemocompatibility. All membrane filters showed similar sieving effects, which depended upon the molecular weights of the proteins. In the double-membrane filtration system, free protein S, protein C, antithrombin III, and alpha 1-antitrypsin were returned to the intracorporeal circulation, whereas alpha 2-macroglobulin and fibrinogen were almost completely removed from the circulation; C4b-binding protein (C4BP)-protein S complexes were also trapped by the second membrane, and in some instances were even blocked by the first membrane, if it was made of material that activated the classic pathway of the complement system. The DS column adsorbed C4BP-protein S complex, but free protein S was almost completely recovered in the eluate.
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PMID:The effect of low-density lipoprotein apheresis on plasma thrombomodulating factors. 138 16

The plasma concentrations of antithrombin III, protein C and protein S in capillary and venous blood samples obtained simultaneously from 30 neonates were compared in order to determine the suitability of using capillary blood for estimation of these proteins with anticoagulant action. Our findings showed that while capillary and venous blood did not differ significantly in antithrombin III functional activity and protein C antigen levels, the capillary samples had significantly lower protein C functional activity and higher antithrombin III antigen level. Protein S antigen level was also significantly higher in the capillary samples although the difference was relatively small. The capillary and venous concentrations of the binding protein of protein S, C4b binding protein, were almost identical.
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PMID:Comparison of antithrombin III, protein C and protein S levels in capillary and venous blood of newborn infants. 138 30


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