Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: HUMANGGP:027518 (factor Xa)
 5,167 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Magnetic birefringence is used to monitor the kinetics of thrombin-catalyzed fibrin polymerization in model systems of increasing complexity (i.e., fibrinogen solutions, fibrinogen/albumin mixtures, and plasma anticoagulated with citrate) and in plasma containing free calcium which is the physiological condition. The introduction of albumin into fibrinogen solutions shortens the lag period and enhances fiber thickness. The polymerization progress curves are sigmoidal at zero or low albumin concentrations, but at physiological and higher concentrations, they become hyperbola-like from the end of the lag period. High albumin concentration has thus induced a change in the assembly kinetics. The progress curves from plasma in which the cascade is dormant are also hyperbola-like although they round off more quickly because of antithrombin activity. In plasma containing free calcium, thrombin is endogenously produced, and the progress curves are nearly linear; hence, the assembly kinetics are very different from those of the model systems. The curves are not influenced by calcium-dependent cross-linking involving factor XIIIa. The progress curves are also linear when polymerization is induced with Russell's viper venom, which by directly activating factor X circumvents earlier steps in the cascade. This implies that linear polymerization is caused by events posterior to factor X activation and are thus likely to be largely dependent on the functioning of the prothrombinase complex. Addition of thrombin to plasma containing free calcium reduces the lag period. At low exogenous thrombin levels, the polymerization rate is increased, and the progress curves remain linear. However, at higher levels, the curves become more complicated and, paradoxically, full polymerization takes longer.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Fibrin assembly in human plasma and fibrinogen/albumin mixtures. 376 49

The presence of congenital antithrombin deficiency has been consistently shown to predispose patients to venous thrombosis. We have utilized the prothrombin fragment F1+2 radioimmunoassay to quantitate factor Xa activity in the blood of 22 asymptomatic individuals with this clinical disorder not receiving antithrombotic therapy. The mean level of F1+2 was significantly elevated in these patients as compared to normal controls (3.91 vs. 1.97 nM, P less than 0.001). The metabolic behavior of 131 I-F1+2 was found to be similar in antithrombin-deficient subjects and normal individuals. The hemostatic system hyperactivity as measured by the F1+2 assay could be specifically corrected by raising the plasma antithrombin levels of the above asymptomatic individuals into the normal range. This study provides the first demonstration that the prethrombotic state can be biochemically defined as an imbalance between the production and inhibition of factor Xa enzymatic activity within the human circulation. It is known that antithrombin and alpha 1-proteinase inhibitor (PI) are the major inhibitors of factor Xa in human plasma in the absence of heparin. To further evaluate the mechanism by which antithrombin functions as an inhibitor of factor Xa in humans, we studied five patients who exhibited severe congenital deficiencies of alpha 1-PI. Our results indicated that the plasma of these subjects showed virtually identical decreases in plasma antifactor Xa activity in the absence of heparin when compared to antithrombin-deficient individuals, but the plasma F1+2 levels in the alpha 1-PI deficient population were not significantly different than normal. This data suggests that alpha 1-PI does not function as a major inhibitor of factor Xa in vivo, and that a tonically active heparin-dependent mechanism exists in humans for accelerating the neutralization of this enzyme by antithrombin.
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PMID:Elevated factor Xa activity in the blood of asymptomatic patients with congenital antithrombin deficiency. 387 33

The effect of Bacteroides gingivalis W83 on various key components of the human plasma proteinase cascade systems was studied. When purified C1-inhibitor was incubated with the bacterium, the inhibitor was rapidly inactivated by limited proteolytic cleavage. In citrated whole plasma, C1-inhibitor, antithrombin, plasminogen, prekallikrein, prothrombinase complex, the clotting factor X, and most of the alpha 2-antiplasmin were functionally eliminated after 30 min of incubation with the bacterium. Fibrinogen disappeared from the plasma almost immediately upon mixing with the bacterial suspension. In contrast, there was no appreciable decrease in the bulk of other plasma proteins, such as various transport proteins (albumin, prealbumin, transferrin) and immunoglobulins, during 4 h of incubation with the bacterium. Most of the observed effects can be assigned to the proteolytic activity of the bacterium itself, since there was little evidence for generation of intrinsic plasma proteinase activity, despite the loss of proteinase inhibitory activities. B. gingivalis W83 thus seems to be equipped with proteolytic enzyme systems which selectively recognize and rapidly inactivate the most important proteinase inhibitors and proenzymes present in human plasma. This bacterium therefore seems to be able to efficiently paralyze the host's various defenses against invading microorganisms.
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PMID:Inactivation of key factors of the plasma proteinase cascade systems by Bacteroides gingivalis. 390 45

The relative importance of antithrombin and anti-factor Xa activities of heparin fractions required to achieve optimal antithrombotic effects is unknown. To study this, we measured the effects of standard heparin, an octasaccharide heparin fraction (anti-factor Xa activity only), and dermatan sulfate (antithrombin activity only) on the prevention of thrombosis and related this to their anticoagulant effects in vivo in rabbits. Thrombosis was measured as the incorporation of 125I-fibrinogen into tissue thromboplastin-induced thrombi using a Wessler-type model. Ex vivo changes in thrombin clotting time (TCT) were used as an index of antithrombin activity, and a chromogenic anti-factor Xa assay was used to measure anti-factor Xa activity. In addition, the ability of the three sulfated polysaccharides to simultaneously inhibit the generation of thrombin activity and to enhance the inactivation of the factor Xa added to initiate thrombin generation in plasma was determined. Standard heparin, in a dose of 10 anti-factor Xa U/kg, inhibited thrombus formation by 90%, prolonged the TCT by two seconds, and resulted in an anti-factor Xa level of 0.32 U/mL. The octasaccharide heparin fraction, in a dose of 10 anti-factor Xa U/kg, inhibited thrombus formation by 41%, had no effect on the TCT, and resulted in an anti-factor Xa level of 0.28 U/mL. Higher doses of the octasaccharide resulted in a further increase in the anti-factor Xa levels but had no further effect on thrombus formation. Dermatan sulfate, in a dose of 500 micrograms/kg, inhibited thrombus formation by 95%, but had no affect on the TCT. These results indicate that the antithrombotic effect achieved by inhibiting factor Xa is limited and that better antithrombotic effects are achieved by heparin or heparin-like substances capable of influencing the inactivation and/or the generation of thrombin.
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PMID:The relative importance of thrombin inhibition and factor Xa inhibition to the antithrombotic effects of heparin. 396 47

The effect of some sulfated derivatives of chitosan on several blood-coagulant factors was examined in comparison with those of heparin (174 units/mg). The anticoagulant activity (units/mg) with respect to activated partial thromboplastin time was 331-379 for O-sulfated N-acetylchitosan (2), 190-287 for N, O-sulfated chitosan (1), and 21-31 for sulfated O-carboxymethylchitosan (3). The activity (units/mg) with respect to thrombin time was 70-87 for 2, 44-70 for 1, and 14-22 for 3. The activity (units/mg) with respect to antithrombin activity was 4.9-9.0 for 2, 4.7-8.7 for 1, and 3.3-6.0 for 3. No anti-(factor Xa) activity was observed with 1-3. A 6-sulfate group in the hexosaminyl moiety was a main active site; although a 3-sulfate group was not essential, it promoted the activity of the 6-sulfate group. N-Sulfate was not a prerequisite for activity. The biological activities were also related to molecular weight in the sequence 2 (26,000) greater than heparin (21,000) greater than 1 (12,000) greater than 3 (540,000). For the Methylene Blue complexes, 1, but neither 2 nor 3, exhibited a negative, induced Cotton effect similar to that of heparin.
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PMID:Effect of sulfated derivatives of chitosan on some blood coagulant factors. 398 47

Heparin cofactor II (HC II) has been purified from human plasma by a modification of the method described by Tollefsen et al. (J. Biol. Chem., 257, 2162, 1982) and abilities of dextran sulfate and various glycosaminoglycans to activate the antithrombin activities of HC II and antithrombin III (AT III) were studied. By the purification method described here, highly purified HC II with the same specific activity as reported by Tollefsen et al. was obtained with a higher yield and in a shorter purification time. Heparin, dextran sulfate and chondroitin polysulfates 1 and 5 activated both HC II and AT III, while dermatan sulfate activated only HC II. Dextran sulfate was almost as active as heparin in the activation of HC II and AT III, indicating that in the interactions of heparin with HC II and AT III, sulfate groups of heparin are more important than carboxyl groups. When mixed with thrombin in the presence of dermatan sulfate, normal human plasma showed antithrombin activity which was not due to AT III but to HC II only. HC II did not inhibit factor Xa or plasmin in the presence of any glycosaminoglycans or dextran sulfate, suggesting that HC II would be a specific inhibitor of thrombin.
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PMID:Purification and biological property of heparin cofactor II: activation of heparin cofactor II and antithrombin III by dextran sulfate and various glycosaminoglycans. 608 76

Plasma levels of antithrombin-heparin cofactor, determined by heparin-dependent antithrombin assay, and antithrombin III antigen were measured in 22 members of a large kindred predisposed to venous thrombosis. While 11 members had reduced plasma levels of both antithrombin-heparin cofactor and antithrombin III antigen, the levels of antithrombin-heparin cofactor were always greater than the levels of antithrombin III antigen: 66% (+/- 7%) and 49% (+/- 5%) of normal plasma, respectively. Pooled normal plasma and plasma from one of the affected family members (60% antithrombin-heparin cofactor and 47% antithrombin III antigen) were fractionated by heparin-agarose affinity chromatography. Antithrombin-heparin cofactor, which eluted from heparin-agarose with buffer containing 0.4 M NaCl and did not cross-react with antibody specific for antithrombin III and did not inhibit factor Xa at an appreciable rate in the presence of heparin, was designated heparin cofactor A. Antithrombin-heparin cofactor, which eluted from heparin-agarose with buffer containing 2.0 M NaCl, was functionally and antigenically identified as antithrombin III. The concentrations of heparin cofactor A in normal and patient plasma were similar (4.5 x 10(-7) M), while the concentration of antithrombin III in patient plasma (8.0 x 10(-7) M) was only 50% of normal (1.6 x 10(-6) M). The functional properties of both heparin cofactor A and antithrombin III obtained from patient plasma were normal. From the results of the present study it would appear that the antithrombin-heparin cofactor concentrating measured in patient plasma reflects the combined concentrations of heparin cofactor A and antithrombin III. Since heparin cofactor A does not cross-react with antibody to antithrombin III, the concentration of antithrombin III antigen in patient plasma is thus lower than the concentration of antithrombin-heparin cofactor.
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PMID:Heparin cofactor activities in a family with hereditary antithrombin III deficiency: evidence for a second heparin cofactor in human plasma. 618 96

Mucopolysaccharides were isolated from calf cerebral microvasculature and calf aorta. The only complex carbohydrates that exhibited anticoagulant activity were heparin-like components. The biologic potencies of calf cerebral and aortic heparin-like species were 2.92 units/mg of anti-factor Xa activity and 2.85 units/mg of anti-factor IIa activity, as well as 0.56 unit/mg of anti-factor Xa activity and 0.19 unit/mg of anti-factor IIa activity, respectively. Additional experiments revealed that the anticoagulantly active aortic components were significantly present only within the intima. The above populations of heparin-like species were affinity fractionated with antithrombin. The highly active component obtained from calf cerebral microvasculature exhibited an anti-factor Xa activity of 40.7 units/mg as well as an anti-factor IIa activity of 36.8 units/mg, constituted about 4.2% of the initial mass of the starting material, and represented about 75% of the biologic potency of the starting material. The highly active component derived from calf aorta exhibited an anti-factor Xa activity of 55.4 units/mg as well as an anti-factor IIa activity of 11.3 units/mg, constituted about 0.3% of the initial mass of the starting material, and represented about 60% of the biologic potency of the starting material. The highly active cerebral microvascular species possessed a molecular weight and charge density similar to that of heparan sulfate whereas the highly active aortic species displayed a molecular weight and charge density equivalent to that of a hexadecasaccharide fragment of heparin.
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PMID:Anticoagulantly active heparin-like molecules from vascular tissue. 623 50

Steady state kinetic studies have provided evidence for intrinsic prothrombinase activity of human factor X zymogen in a chromogenic assay system. Using a prothrombin substrate, kinetic parameters have been obtained for the action of factors X and Xa. The Km for prothrombin is of a different order of magnitude for the zymogen as compared with the active enzyme. Using a kinetic approach, we have obtained evidence for the binding of factor Xa zymogen to cofactors essential for the coagulant activity of factor Xa. Zymogen enzymatic activity is not inhibited by a specific serine proteinase inhibitor, (p-amidino-phenyl)methanesulfonyl fluoride (p-APMSF), a potent inhibitor of factor Xa. The apparent slow rate of zymogen inhibition by antithrombin III (AT III) as compared with the active enzyme suggests a different kind of zymogen-antithrombin interaction. Blood clotting studies paralleled the kinetic data. Factor X zymogen evidences factor VIII inhibitor bypassing activity (FEIBA) in an in vitro direct clotting system employing factor VIII deficient inhibitor plasma as substrate in both activated or nonactivated partial thromboplastin assay. Most significantly, zymogen coagulant is refractory to inhibition by p-APMSF or AT III. We conclude that a system consisting of factor X zymogen-phospholipid-factor Va can physiologically initiate blood clotting in the presence of inhibitors and may have a major role in the bypass mechanism of therapeutic prothrombin complex concentrate (PCC).
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PMID:Apparent intrinsic prothrombinase activity of human Factor X zymogen: identification with Factor VIII inhibitor bypassing activity (FEIBA). 633 7

With current technological advances, it is now possible to measure in less than 50 microL of plasma picomolar amounts of circulating products of platelet activation, products of protease activation related to coagulation and fibrinolytic pathways, and prostaglandin metabolites formed during a physiologic or pathologic process. Most of these markers, which circulate in blood in nanogram or picogram amounts per milliliter during or after pathologic activation, provide pertinent information on the status of a patient in terms of specificity and early detection, and will be of crucial value in the diagnosis of hemostatic defects and the management of newer antithrombotic drugs that cannot be monitored by currently available assays. Currently, 125I- and 3H-based simple radioimmunoassays are available for platelet factor 4, beta-thromboglobulin, fibrinopeptide A, B beta 15-42 related peptides, thromboxane B2, and the prostaglandins 6-keto-PGF1 alpha and PGE2. Nonisotopic methods such as enzyme-linked immunosorbent assays and fluoroimmunoassays are being developed. Serotonin and ADP, products of platelet activation, are measurable by liquid-chromatographic, immunoenzymatic, and spectrophotofluorometric methods. Analytical methods for fibrin split products (fragments D and E) and serine protease inhibitor complexes such as thrombin-antithrombin-III, factor Xa-antithrombin-III, and kallikrein-C1-esterase are also being developed. We have evaluated all of these methods and found them to be very sensitive to those components of endogenous activation of the hemostatic system listed above.
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PMID:Molecular markers of hemostatic disorders: implications in the diagnosis and therapeutic management of thrombotic and bleeding disorders. 634 55


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