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)

The aim of the present study was to investigate the reactivity of immunoreagents developed for clinical applications in humans in different animal species (hen, mouse, rat, rabbit, guinea-pig, dog, pig, sheep, baboon). Prothrombin fragment 1 + 2, thrombin-antithrombin III complex and fibrinopeptide A were tested for coagulation, platelet factor 4 and beta-thromboglobulin for platelet activation, glycoprotein IIb-IIIa, glycoprotein Ib and P-selectin for platelet membrane glycoproteins, D-dimers for fibrinolysis, thrombomodulin for activation of endothelial cells and thrombospondin and von Willebrand factor for adhesive proteins. Prothrombin fragment 1 + 2, platelet factor 4, beta-thromboglobulin and D-dimers were revealed only in baboons. Fibrinopeptide A was well detected in baboons but weakly in mice, dogs, pigs and sheep. Whereas glycoprotein IIb-IIIa was revealed on guinea-pig, dog and sheep platelets and glycoprotein Ib on rabbit and dog platelets, P-selectin and thrombomodulin were never detected. Thrombospondin was revealed in hens, mice, rats, guinea-pigs, pigs, sheep and baboons and von Willebrand factor in mice, rats, guinea-pigs, dogs, pigs, sheep and baboons. Interestingly, thrombin-antithrombin III complex (TAT) was detected in all species tested except the hen. A time- and dose-dependent increase in TAT was observed when rats, dogs or pigs were infused with thromboplastin (4.5-450 microliters/kg/h), while administration of hirudin (1 mg/kg) abolished this TAT generation. Thus, the TAT immunoassay could provide a tool for the screening of antithrombotic drugs in a number of animal species. However, the possibility of using a wider panel of human immunoreagents would appear to be restricted to baboons which display good species cross-reactivity.
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PMID:Cross-reactivity of human molecular markers for detection of prethrombotic states in various animal species. 858 12

We employed flow cytometry and monoclonal antibodies (MoAb) to study the surface membrane protein of shed particles (small vesicles, SV) that were released from vascular endothelial cells (EC) by agonists such as a Ca ionophore (A23187) and thrombin. After stimulation of EC by A23187, CD9 antigens disappeared entirely from the EC surface in a time- and concentration-dependent manner; they subsequently moved onto the SV surface. Von Willebrand factor (vWF) and P-selectin from Weibel-Palade (W-P) bodies were expressed rapidly on the EC surface after thrombin stimulation, but not on the SV surface. P-selectin may have some effect on maintenance of hemostasis on the EC surface. We demonstrated that the surfaces of SV and EC significantly supported prothrombinase activity and confirmed that A23187-induced SV from EC express binding sites for factors IXa and Xa. These results suggest that the SV are an important factor in a novel controlling mechanism of the coagulation system on the EC surface.
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PMID:Expression of prothrombinase activity and CD9 antigen on the surface of small vesicles from stimulated human endothelial cells. 861 Feb 73

To investigate whether there are differences in haematology and coagulation indices in arterial and venous plasma, and whether those changes related to damage to the endothelium in atherosclerosis, we obtained blood samples from 22 subjects undergoing diagnostic angiography. There were no differences in any of the 15 routine haematological indices measured. There were no differences in prothrombin time, activated partial thromboplastin time, fibrinogen, tissue plasminogen activator, D-dimer, leucocyte elastase, soluble P-selectin or von Willebrand factor. In venous samples, von Willebrand factor was lower in serum than in plasma (p < 0.0001). Levels of the tissue plasminogen activator/plasminogen activator inhibitor-1 (tPA/PAI-1) complex were markedly higher in arterial blood than in venous blood (p = 0.004) and plasma viscosity was higher in venous blood (p = 0.0014). Consequently, with the exception of viscosity and the tPA/PAI complex, we can find no differences in arterial blood compared to venous blood which can contribute to the debate regarding the mechanism of damage to arterial endothelial cells but the relative protection of venous endothelial cells from injury in atherosclerosis.
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PMID:Haematology and coagulation indices in paired samples of arterial and venous blood from patients with arterial disease. 911 85

The membrane attack complex of complement (C) in sublytic concentrations stimulates endothelial cells (EC) to express adhesion molecules and to release biologically active products. We have examined the ability of a cytolytically inactive form of this complex, which is incapable of inserting into the cell membrane, to upregulate the expression of adhesion molecules and of tissue factor (TF) procoagulant activity. The inactive terminal C complex (iTCC) was prepared by mixing C5b6, C7, C8, and C9 and was purified by fast protein liquid chromatography on a Superose 12 column. Binding of this complex to EC was found to be dose dependent and was inhibited by anti-C9 antibodies, as assessed both by ELISA using an mAb anti-C9 neoantigen and by measuring cell-bound 125I-labeled iTCC. Exposure of EC to iTCC resulted in a dose- and time-dependent expression of endothelial leukocyte adhesion molecule 1, intercellular adhesion molecule 1, and vascular cell adhesion molecule 1 accompanied by increased levels of the corresponding mRNA, but not in the rapid expression of P-selectin. Inactive TCC also induced increased TF activity evaluated by a chromogenic assay that measures the formation of factor Xa. These effects were inhibited by anti-C9 antibodies. The data support the conclusion that iTCC may induce proinflammatory and procoagulant activities on EC.
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PMID:The cytolytically inactive terminal complement complex activates endothelial cells to express adhesion molecules and tissue factor procoagulant activity. 915 99

A biodegradable polymer, poly(D,L-lactide-co-glycolide) RESOMER RG756, was modified by surface immobilization of recombinant hirudin (r-Hir) with glutaraldehyde as coupling reagent to improve the blood contacting properties of the polymer. The activity of immobilized hirudin on the polymer was estimated by a chromogenic assay to about 2.5 ATU r-Hir cm-2. The improvement of the haemocompatibility of the modified RG756 was evaluated in terms of platelet adhesion/activation, whole blood clotting times and clot formation rate. Fluorescence microscopy revealed that surface modification with r-Hir resulted in decreased platelet adhesion and activation. An ELISA for P-selectin, a marker of platelet activation, was used to confirm this result. Clotting time experiments demonstrated significantly prolonged non-activated partial thromboplastin times, and a decreased clot formation rate of whole blood in contact with r-Hir modified RG756 compared with the plain polymer. Comparison of immobilized r-Hir with bound heparin yielded equivalent improvement of blood-contacting properties of the investigated polymers. These in vitro investigations indicate that the immobilization of r-Hir on RG756 is a useful method to improve the blood contacting properties of polylactides/polyglycolides and other polymers as well.
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PMID:Covalent immobilization of hirudin improves the haemocompatibility of polylactide-polyglycolide in vitro. 942 79

Herpes simplex virus type 1 and cytomegalovirus alter the phenotype of the endothelium in vitro from anticoagulant to procoagulant, thereby promoting the adherence of neutrophils and platelets to the endothelium. Virus infection of the endothelium induces the expression of viral glycoproteins and adhesion molecules, which promote neutrophil and monocyte adhesion. Herpes simplex infection of the endothelium promotes prothrombinase assembly, allowing more efficient thrombin generation. Excess thrombin generation causes translocation of P-selectin. Viral infection also induces the procoagulant molecule, tissue factor, in endothelial cells. These enhanced procoagulant effects are associated with the loss of anticoagulants, including thrombomodulin, prostacyclin and tissue plasminogen activator. These studies support the speculation that virus infection in vivo promotes vascular injury and thrombosis, which may contribute to disease states such as atherosclerosis.
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PMID:Effects of viral activation of the vessel wall on inflammation and thrombosis. 966 64

Lymphocyte adhesion to endothelial cells and the extravascular deposition of fibrin are 2 important processes during pathologic situations such as allograft rejection. Tissue factor (TF) expression was therefore measured on human umbilical vein endothelial cells (HUVECs) after coculture with allogeneic lymphocytes (PBLs) by a factor Xa generation assay. When cocultured with PBLs, HUVECs expressed strong procoagulant activity related to the TF/factor VII-dependent pathway, which was enhanced when endothelial cells were treated with interferon-gamma (IFN-gamma). The highest TF activity was measured when 10(5) lymphocytes were incubated with 10(4) HUVECs (ratio 10: 1) for 4 hours, a time-dependent course similar to that obtained with tumor necrosis factor-alpha (TNF-alpha), and direct contact between the 2 cell types was necessary. PBL-induced TF activity was inhibited by cycloheximide or actinomycin D, indicating active protein synthesis that was confirmed by the increase in TF mRNA detected by reverse transcription-polymerase chain reaction. It was then demonstrated that 1 of the primary signaling pathways leading to endothelial cell TF expression was a rapid initial interaction between membrane TNF expressed on PBLs and the 75-kd TNF receptor, with subsequent involvement of platelet-activating factor and P-selectin. Finally, we showed that the transduction of external signals involving the activation of protein kinase C and protein tyrosine kinases also contributed to the regulation of TF expression.
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PMID:Human allogeneic lymphocytes trigger endothelial cell tissue factor expression by a tumor necrosis factor-dependent pathway. 985 44

Polyethylene glycol (PEG)-hirudin is a derivative of hirudin with a long plasma half-life. We have compared the efficacy of PEG-hirudin with unfractionated heparin (UH) in preventing arterial thrombosis. Arterial thrombus formation was induced ex vivo in 12 healthy human volunteers by exposing a tissue factor-coated coverslip positioned in a parallel-plate perfusion chamber to flowing nonanticoagulated human blood drawn directly from an antecubital vein at an arterial wall shear rate of 2600 s-1 for 3.5 minutes. PEG-hirudin, UH, or saline (as control) were administered ex vivo through a heparin-coated mixing device positioned proximal to the perfusion chamber. Platelet and fibrin deposition was quantified by immunoenzymatic measure of the P-selectin and D-dimer content of dissolved plasmin-digested thrombi, respectively. UH was administered to a plasma concentration of 0.35 IU/mL. This concentration prolonged the activated partial thromboplastin time from 32+/-1 seconds to 79+/-4 seconds (P<0.01). UH did not significantly prevent platelet deposition. However, fibrin deposition was reduced by 39% (P<0.05). PEG-hirudin in plasma concentrations of 0.5, 2.5, and 5 microg/mL prolonged the activated partial thromboplastin time to 48+/-2, 87+/-4, and 118+/-4 seconds, respectively. In contrast to UH, PEG-hirudin prevented both platelet and fibrin deposition in a dose-dependent manner with a >80% reduction at 5 microg/mL (P<0.01). Furthermore, the plasma level of PEG-hirudin required to significantly prevent fibrin deposition (0.5 microg/mL) corresponded to a much shorter prolongation of activated partial thromboplastin time (48+/-2 seconds) than that needed for UH (79+/-4 seconds). Thus, our results are compatible with the view that thrombin is greatly involved in recruitment of platelets in evolving thrombi, and that PEG-hirudin is an effective agent for preventing arterial thrombosis in a human ex vivo experimental model.
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PMID:Comparison of the antithrombotic effect of PEG-hirudin and heparin in a human ex vivo model of arterial thrombosis. 1032 89

Low molecular weight heparins (LMWHs) are obtained from unfractionated heparin by diverse chemical and enzymatic processes and findings with one LMWH cannot be extrapolated to another. Functional assays performed in vitro, evaluating antiprotease activity mediated via antithrombin III, heparin cofactor II interactions, antithrombin III binding, and plasma protein binding, showed wide variations between LMWHs, indicating that compositional differences among the LMWHs have a major impact on function. Evaluation in vitro showed varying potency in United States Pharmacopeia (USP) and anti-Xa assays. LMWHs tested at anti-Xa-adjusted concentrations exhibited varying potencies with anti-IIa, Heptest, and activated partial thromboplastin time (APTT) assays. Evaluation of these assays showed differences between LMWHs and a link with molecular weight. Each LMWH also varied in the in vitro neutralization by platelet factor 4, thrombin, and heparinase. LMWHs also varied in platelet interactions as assessed by whole blood clotting, thromboelastography and P-selectin expression, and in tissue factor pathway inhibitor release in cell culture. It was concluded that compositional variations in LMWHs give each product a unique biochemical profile. This profile, plus varying endogenous interactions and pharmacokinetic profiles may give rise to the clinical differences observed with LMWHs in specific indications.
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PMID:In vitro studies on the biochemistry and pharmacology of low molecular weight heparins. 1054 13

The GAIT (Genetic Analysis of Idiopathic Thrombophilia) Project is a family-based study dedicated to elucidating the genetic basis of hemostasis-related phenotypes and thrombosis risk. In this paper, we have examined several lesser-studied hemostasis-related phenotypes in the 21 GAIT families: levels of vitamin B 12, serum folate, whole blood folate, alpha2-antiplasmin, prekallikrein, beta2-glycoprotein I, soluble P-selectin, factor XIII A and B subunits and a new coagulation measurement based on thromboplastin time in the presence or absence of thrombomodulin. Using the variance component method, we estimated the relative contributions of genetic and environmental influences on these phenotypes. In addition, we calculated the genetic correlations between thrombosis risk and each of these phenotypes. All 12 phenotypes showed significant genetic contributions with genes accounting for 22% to 78% of the variance after correction for covariate effects. Four phenotypes (three traits involving thromboplastin-thrombomodulin mediated coagulation time and serum folate) exhibited significant genetic correlations with thrombosis. Thus, some of the genes that influence quantitative variation in these physiological phenotypes also influence the risk of thrombosis. The high heritabilities and significant genetic correlations between thrombosis and some risk factors suggest that joint consideration of correlated quantitative phenotypes will aid in identifying susceptibility genes.
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PMID:Thromboplastin-thrombomodulin-mediated time and serum folate levels are genetically correlated with the risk of thromboembolic disease: results from the GAIT project. 1184 58


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