Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.21.6 (thromboplastin)
13,278 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Optimal timing of vascular clamping to anticoagulation during cardiovascular surgical procedures is poorly defined. This study uses a canine model to determine the effectiveness of three different methods of heparin administration. Heparin sulfate (150 IU/kg) was administered by: injection into the jugular vein 5 minutes before infrarenal aortic clamping (Group 1), injection into the terminal aorta immediately after infrarenal aortic clamping (Group 2), and injection into the jugular vein immediately after infrarenal aortic clamping (Group 3). Thrombin clotting times and partial thromboplastin times were measured in venous blood from the upper and lower extremities before (baseline) heparin administration, and 1, 3, and 5 minutes following heparin administration. Activated clotting times were assessed in lower extremity blood at baseline, and at 1 and 5 minutes after heparin injection. Significant differences existed between groups in both upper and lower extremities. Systemic anticoagulation occurred within 1 minute after intravenous heparin administration in Groups 1 and 2 in the lower extremity, and Groups 1 and 3 in the upper extremity. Delayed anticoagulation in the lower extremity was noted with systemic injection after aortic clamping in Group 3, and after regional intra-aortic administration in the upper extremity of Group 2 subjects. Complete anticoagulation was noted by 5 minutes in all groups in both the upper and lower extremities. These results suggest that the safe time period between heparin administration and vascular clamping varies with the route and the timing of its administration. Intravenous administration prior to aortic cross-clamping provided adequate anticoagulation in this canine model in both the upper and lower extremity blood after 1 minute of heparin circulation.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Time-related effects of heparin sulfate on regional and systemic anticoagulation. 146 Jun 84

Three mechanisms by which sulfated polysaccharides act as anticoagulants and possibly as antithrombotic agents have been described. These are the two heparin cofactor-dependent mechanisms involving the catalysis of the inhibition of various proteases of coagulation by either antithrombin III or heparin cofactor II. The third is a heparin cofactor-independent mechanism involving the inhibition of formation of prothrombinase and tenase complexes. Four sulfated polysaccharides previously shown to have anticoagulant and antithrombotic effects were assessed to determine which of the three mechanisms operate in the expression of their anticoagulant effects. To do this, [125I]prothrombin was added to undiluted human plasma, and the inhibition of [125I]prothrombin activation, or the catalysis of the formation of thrombin-inhibitor complexes was determined in plasma containing one of the four sulfated polysaccharides. Prothrombin activation was demonstrated by the formation of [125I]prothrombin fragment 1.2 and [125I]thrombin. The effect of the thrombin-specific inhibitor, D-Phe-L-Pro-L-ArgCH2Cl (PPACK), on prothrombin activation was also investigated to determine the role of thrombin-dependent feedback reactions on efficient prothrombin activation. Use of PPACK with sulfated polysaccharides also facilitated estimation of the role of the heparin cofactor-independent effects of sulfated polysaccharides on prothrombin activation. Three concentrations of each of the sulfated polysaccharides were used: 0.66, 6.6, and 66 micrograms/ml of plasma. PPACK (1.0 X 10(-6)M) completely inhibited both intrinsic and extrinsic prothrombin activation. The inhibition of prothrombin activation caused by PPACK was abolished when thrombin was added to the plasma before PPACK. These observations indicate that the presence of trace thrombin activity is critical for efficient prothrombin activation by both the intrinsic and extrinsic pathways. All three concentrations of standard heparin completely inhibited the intrinsic activation of prothrombin. This inhibition was only partially abolished when thrombin was added to the plasma before heparin, indicating that heparin inhibits prothrombin activation both by catalyzing the inhibition of thrombin activity and by a heparin cofactor-independent mechanism. Heparan sulfate did not inhibit intrinsic prothrombin activation but catalyzed the inhibition of the thrombin generated by the formation of thrombin-antithrombin III complex. Dematan sulfate inhibited intrinsic prothrombin activation only at the highest concentration. At the two lower concentrations, dermatan sulfate catalyzed formation of thrombin-heparin cofactor II.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Mechanisms for inhibition of the generation of thrombin activity by sulfated polysaccharides. 243 25

The relationship between two anticoagulant actions of glycosaminoglycans (GAGs), namely the catalysis of thrombin inhibition (assessed by thrombin-antithrombin-III and thrombin-heparin-cofactor-II formation) and the inhibition of prothrombin activation, was explored by comparing the effects of heparin, heparan sulfate, and dermatan sulfate on the two reactions in plasma. Heparan sulfate and dermatan sulfate were also resulfated in vitro to yield products with sulfate/carboxylate ratios similar to those of heparin. Their effects on thrombin inhibition and the activation of prothrombin were also determined. The catalytic efficiency of the five GAGs on thrombin inhibition and their inhibitory effects on prothrombin activation decreased in the following order: heparin; resulfated dermatan sulfate; resulfated heparan sulfate; heparan sulfate = dermatan sulfate. These results suggest that the catalytic efficiency of a glycosaminoglycan on thrombin inhibition translates to its inhibitory effect on prothrombin activation, since catalysis of thrombin inhibition results in the inhibition of the thrombin-dependent positive feedback reactions of coagulation which facilitate prothrombinase formation.
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PMID:Plasma anticoagulant mechanisms of heparin, heparan sulfate, and dermatan sulfate. 252 56

Heparan sulphate with no affinity for antithrombin III (ATIII) was observed to cause acceleration of the factor Xa:ATIII interaction by 1100-fold (k2, 7 X 10(7) M-1.min-1) and the prothrombinase:ATIII interaction by 2900-fold (k2, 2.5 X 10(7) M-1.min-1). Although high-affinity heparan sulphate catalyzed higher acceleration and at lower concentration, in natural mixtures of the two forms the activity of the no affinity form predominated. Heparan sulphate had no significant effect on the thrombin:ATIII interaction but inhibited its potentiation by heparin (Kd 0.3 microM). From the estimated concentration of heparan sulphate on the endothelial cell surface it is proposed that the non-thrombogenic property of blood vessels is due to the acceleration of the factor Xa or prothrombinase:ATIII interaction by the greater mass of surface-bound heparan sulphate rather than by the much smaller proportion of heparin-like molecules (with high affinity for antithrombin III) which may be present.
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PMID:Heparan sulphate with no affinity for antithrombin III and the control of haemostasis. 297 92

Heparan with a low affinity for antithrombin III has previously been demonstrated to inhibit thrombin generation in both normal plasma and plasma depleted of antithrombin III. In addition, standard heparin and heparin with a low affinity for antithrombin III have been demonstrated to have equivalent inhibitory actions on thrombin generation in plasma depleted of antithrombin III. These observations prompted the investigation of the effects of four normal vessel wall glycosaminoglycans (heparan sulfate, dermatan sulfate, chondroitin-4-sulfate, and chondroitin-6-sulfate) on the intrinsic pathway generation of thrombin and factor Xa and on the inactivation of thrombin and factor Xa in plasma. Heparan sulfate inhibited thrombin generation and accelerated the inactivation of added thrombin and factor Xa in normal plasma but not in antithrombin III-depleted plasma. In contrast, dermatan sulfate inhibited thrombin generation in both normal and antithrombin III-depleted plasma. In addition, heparan sulfate was an effective inhibitor of factor Xa generation, while dermatan sulfate was not. Neither chondroitin-4-sulfate nor chondroitin-6-sulfate inhibited the generation of thrombin or factor Xa nor did they accelerate the inactivation of factor Xa or thrombin by plasma. These results suggest that heparan sulfate acts primarily by potentiating antithrombin III, while dermatan sulfate acts by potentiating heparin cofactor II. The inhibition of thrombin generation by heparan sulfate and dermatan sulfate thus appears to occur by complementary pathways, both of which may contribute to the anticoagulation of blood in vivo.
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PMID:Heparan sulfate and dermatan sulfate inhibit the generation of thrombin activity in plasma by complementary pathways. 623 72

Heparan sulphate/heparin subfractions with high plasma anti-Xa activity have an unusual uronate composition, i.e. high proportions of both glucuronate and sulphated iduronate. These preparations inhibit the amidase activity of factor Xa in an uncompetitive mode and the prothrombin-activation catalyzed by Xa, both in the absence of antithrombin III. Subfractions of low affinity for antithrombin III are equally potent against Xa. The anti-X activity is destroyed by a 3-h periodate oxidation.
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PMID:Demonstration of a direct anti-factor Xa activity in certain heparin-related glycosaminoglycans. 711 18

Heparin anticoagulation during cardiovascular surgical procedures remains poorly investigated and understood. The objective of this investigation was to assess the effectiveness of three methods of heparin administration. Heparin sulfate (75 IU/kg) administered to patients undergoing aortoiliac surgery was randomised to one of three methods: Group I (n = 9) heparin was injected into a central venous line 5 minutes before infrarenal aortic clamping; Group II (n = 9) heparin was injected into the distal aneurysm immediately after infrarenal aortic clamping; and Group III (n = 8) heparin was injected into a central venous line immediately after infrarenal aortic clamping. Blood samples were analysed for anticoagulant activity from both the upper and lower extremities at 5, 15, 30, 60, and 120 minutes after heparin administration. Anticoagulation, as measured by aPTT, antifactor Xa levels, and ACT, was achieved in all three groups by 5 minutes, but initially with lower heparin activity (measured as antifactor Xa) in the upper extremity (Group II) and lower extremity (Group III), respectively. These differences were also evident in ACT and aPTT determinations. Intravenous heparin administration prior to aortic cross-clamping achieves excellent anticoagulation (anti-factor Xa approximately 1 U/ml) in both upper and lower extremities after 5 minutes. With regional administration, rapid heparin redistribution occurs, but it takes longer to achieve the same level of anticoagulation distant from the site of administration. Nevertheless, from a practical perspective the method of administration does not appear to have a great influence on the eventual achievement of adequate anticoagulation.
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PMID:Time-related anticoagulation after regional and systemic administration of heparin in patients undergoing aortoiliac surgery. 781 23

To understand how 2-O-sulfation of uronic acid residues influences the biosynthesis of anticoagulant heparan sulfate, the cDNA encoding glucosaminyl 3-O-sulfotransferase-1 (3-OST-1) was introduced into wild-type Chinese hamster ovary cells and mutant pgsF-17 cells, which are defective in 2-O-sulfation. 3-OST-1-transduced cells gained the ability to bind to antithrombin. Structural analysis of the heparan sulfate chains showed that 3-OST-1 generates sequences containing GlcUA-GlcN(SO(3))3(SO(3)) and GlcUA-GlcN(SO(3))3(SO(3))6(SO(3)) in both wild-type and mutant cells. In addition, IdoUA-GlcN(SO(3))3(SO(3)) and IdoUA-GlcN(SO(3))3(SO(3))6(SO(3)) accumulate in the mutant chain. These disaccharides were also observed by tagging [6-(3)H]GlcN-labeled pgsF-17 heparan sulfate in vitro with [(35)S]PAPs and purified 3-OST-1. Heparan sulfate derived from the transduced mutant also had approximately 2-fold higher affinity for antithrombin than heparan sulfate derived from the transduced wild-type cells, and it inactivated factor Xa more efficiently. This study demonstrates for the first time that (i) 3-O-sulfation by 3-OST-1 can occur independently of the 2-O-sulfation of uronic acids, (ii) 2-O-sulfation usually occurs before 3-O-sulfation, (iii) 2-O-sulfation blocks the action of 3-OST-1 at glucosamine residues located to the reducing side of IdoUA units, and (iv) that alternative antithrombin-binding structures can be made in the absence of 2-O-sulfation.
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PMID:The effect of precursor structures on the action of glucosaminyl 3-O-sulfotransferase-1 and the biosynthesis of anticoagulant heparan sulfate. 1137 90

Glycosaminoglycans (GAGs) are the portion of a proteoglycan that determine its final shape and function. The molecular structure of predominant GAG species in camel liver and lung is reported for the first time. The one-humped camel survives in an extreme, arid habitat and, thus, offers a good model to study the role of glycomics on homeostasis. Heparan sulfate (HS) from the lung and liver of the one-humped camel were isolated. Characterization of these newly isolated glycosaminoglycans included (1)H NMR spectroscopy and disaccharide compositional analysis. The relative molecular weight of these GAGs was estimated by gradient polyacrylamide gel electrophoresis and their degree of sulfation was also assessed. Anticoagulant activity was determined using an anti-factor Xa assay and the HS from camel lung shows approximately 50% of heparin's activity. The structural differences of camel liver GAGs compared to human and porcine liver heparin and HS is discussed. Camel lung heparan sulfate resembles both heparin and HS in its structure and properties suggesting that it is either a highly sulfated form of HS, a mixture of heparin and HS or an undersulfated heparin.
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PMID:Dromedary glycosaminoglycans: molecular characterization of camel lung and liver heparan sulfate. 1629 50

Heparan sulfate (HS) regulates processing of the amyloid precursor protein by the Alzheimer's beta-secretase (BACE-1). An HS analogue, porcine intestinal mucosal heparin, was systematically modified at the principal positions of O-sulfation and N-sulfation/acetylation and tested for BACE-1 inhibitory and anti factor Xa activities. The derivative with the highest anti-BACE-1 to anti-Xa activity ratio contained N-acetyl and 2-O- and 6-O-sulfates and also exhibited attenuated activities against cathepsin-D and renin, two other structurally related aspartyl proteases.
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PMID:Heparin derivatives as inhibitors of BACE-1, the Alzheimer's beta-secretase, with reduced activity against factor Xa and other proteases. 1700 27


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