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)

A variety of studies have been performed on the preservation of hemostasis by aprotinin during cardiopulmonary bypass (CPB). It appears that the mechanism of aprotinin to preserve hemostasis can be interpreted in different ways. Our previous studies suggested that preservation of platelet glycoprotein Ib (GpIb) antigen, and counteraction of heparin anticoagulation in the extrinsic clotting pathway might partly explain the preservative effect of aprotinin. A clinical study was therefore conducted to evaluate these effects during the use of low dose aprotinin. Improved agglutination by ristocetin (P < 0.05), and improved GpIb antigen expression (P < 0.05) during CPB showed better preserved platelet adhesive capacity in the aprotinin group than in the control group. Glycoprotein Ib antigen expression and the agglutination capacity with ristocetin during CPB were closely related (P < 0.05). Platelet GpIIb/IIIa antigen and adenosine diphosphate (ADP) aggregation were not significantly different between the aprotinin and control groups. Aprotinin had no effect on the extrinsic clotting pathway in the blood, since the thromboplastin clotting time was similar in both groups. These results indicate that the protection of platelet adhesive capacity during CPB is a main function of aprotinin, whereas no evidence was collected for enhanced extrinsic clotting by aprotinin during CPB.
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PMID:Aprotinin effect on platelet function and clotting during cardiopulmonary bypass. 751 34

Platelet activation plays a critical role in thromboembolic disorders, and aspirin remains a keystone in preventive strategies. This remarkable efficacy is rather unexpected, as aspirin selectively inhibits platelet aggregation mediated through activation of the arachidonic-thromboxane pathway, but not platelet aggregation induced by adenosine diphosphate (ADP), collagen and low levels of thrombin. This apparent paradox has stimulated investigations on the effect of aspirin on eicosanoid-independent effects of aspirin on cellular signalling. It has also fostered the search for antiplatelet drugs inhibiting platelet aggregation at other levels than the acetylation of platelet cyclo-oxygenase, such as thromboxane synthase inhibitors and thromboxane receptor antagonists. The final step of all platelet agonists is the functional expression of glycoprotein (GP) IIb/IIIa on the platelet surface, which ligates fibrinogen to link platelets together as part of the aggregation process. Agents that interact between GPIIb/IIIa and fibrinogen have been developed, which block GPIIb/IIIa, such as monoclonal antibodies to GPIIb/IIIa, and natural and synthetic peptides (disintegrins) containing the Arg-Gly-Asp (RGD) recognition sequence in fibrinogen and other adhesion macromolecules. Also, some non-peptide RGD mimetics have been developed which are orally active prodrugs. Stable analogues of prostacyclin, some of which are orally active, are also available. Thrombin has a pivotal role in both platelet activation and fibrin generation. In addition to natural and recombinant human antithrombin III, direct antithrombin III-independent thrombin inhibitors have been developed as recombinant hirudin, hirulog, argatroban, boroarginine derivatives and single stranded DNA oligonucleotides (aptanes). Direct thrombin inhibitors do not affect thrombin generation and may leave some 'escaping' thrombin molecules unaffected. Inhibition of factor Xa can prevent thrombin generation and disrupt the thrombin feedback loop that amplifies thrombin production.
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PMID:Novel antithrombotic drugs in development. 764 2

Apolipoprotein H (ApoH) is a 50 kDa glycoprotein capable of binding to negatively charged phospholipids and is a probable inhibitor of the blood coagulation pathway, platelet aggregation, and platelet prothrombinase activity, as well as being involved in autoimmune disease. We have cloned and sequenced a full length ApoH cDNA clone from a beagle dog liver library. Its derived amino acid sequence shows high cross-species similarity to ApoH from other mammals. Canine ApoH mRNA expression is down regulated during an experimentally induced inflammatory response establishing that it is a negative acute phase reactant.
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PMID:Characterization and acute phase modulation of canine apolipoprotein H (beta 2-glycoprotein I). 768 67

A novel trypsin inhibitor, tentatively named countertrypin, was isolated from mouse plasma in an apparently homogeneous state. Countertrypin is a 53-kDa glycoprotein having about 30% carbohydrate, and did not cross-react immunologically with either mouse alpha 1-antiproteinase (also called alpha 1-proteinase inhibitor or alpha 1-antitrypsin) or contrapsin. Countertrypin had no inhibitory activity against chymotrypsin, pancreatic elastase, neutrophil elastase, thrombin, plasmin, plasma kallikrein, pancreatic kallikrein, clotting factor Xa, or papain. This inhibitory spectrum does not correspond to any of the known plasma proteinase inhibitors that have been well characterized in human or other mammals. NH2-terminal amino acid sequence analysis of the intact molecule and three peptides obtained by CNBr digestion revealed that a total of 93 amino acid residues could be aligned with stretches in human alpha 2-HS glycoprotein, bovine fetuin, and rat pp63 (rat fetuin). Human alpha 2-HS glycoprotein and bovine fetuin prepared without use of ethanol inhibited trypsin and pancreatic and neutrophil elastases. These results indicate that mouse countertrypin is a new member of the mammalian fetuin family, which possibly has the trypsin-inhibiting activity in common.
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PMID:Isolation and characterization of mouse countertrypin, a new trypsin inhibitor belonging to the mammalian fetuin family. 768 30

Beta 2-glycoprotein I (beta 2-GPI) binds negatively charged substances and inhibits intrinsic blood coagulation in the presence of ellagic acid-phospholipid suspension. Beta 2-GPI is thought to be an important protein in the reaction between negatively charged phospholipids and anti-phospholipid antibodies which appear in patients with lupus anticoagulant/antiphospholipid antibody syndrome. We prepared a monoclonal antibody against beta 2-GPI purified from human plasma and obtained beta 2-GPI-depleted plasma using a monoclonal antibody-coupled column. Either partial thromboplastin time or the activation of prekallikrein induced by diluted ellagic acid-phospholipid suspension in beta 2-GPI-depleted plasma was not different from that in control plasma. Beta 2-GPI inhibited the intrinsic blood coagulation only when added to control or beta 2-GPI-depleted plasma in excess (more than physiological concentrations). The intrinsic fibrinolysis in beta 2-GPI-depleted plasma induced by dextran sulfate was not impaired and, again, beta 2-GPI inhibited the intrinsic fibrinolysis only when added to control or beta 2-GPI-depleted plasma in excess. These results indicate that both in vitro Actin-induced intrinsic coagulation and dextran sulfate-induced fibrinolytic activities are significantly inhibited by more than physiological concentrations of beta 2-GPI.
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PMID:Ellagic acid/phospholipid-induced coagulation and dextran sulfate-induced fibrinolytic activities in beta 2-glycoprotein I-depleted plasma. 786 69

Patients with antiphospholipid syndrome, whether primary or secondary to systemic lupus erythematosus, may have thrombocytopenia. Their antibodies to anionic phospholipids might bind to phospholipids on the platelet wall but anionic phospholipids are asymmetrically located in the inner leaflet. In addition, antibodies to anionic phospholipids may require beta 2 glycoprotein I (beta 2GPI) as a cofactor in order to bind to phospholipids. In turn, beta 2GPI has high affinity for anionic phospholipids. Loss of this asymmetry occurs upon platelet activation and could thus permit such antibody-beta 2GPI-platelet interaction. We studied this by flow cytometry using purified beta 2GPI-FITC labelled and similarly labelled affinity-purified polyclonal antibodies to cardiolipin or phosphatidylserine (aPL) obtained from sera of patients with primary antiphospholipid syndrome. Five percent of resting platelets were bound by aPL in the presence of beta 2GPI. Such binding increased when we activated platelets with various agonists, reaching 31% with the concurrent use of thrombin and the calcium ionophore A23187. Platelet activation resulted in the expression of GMP140 but this did not correlate with aPL binding. This probably reflects that the expression of GMP140, which depends on their secretion of alpha granules, has different agonist responses and occurs at different times than do microvesicle formation and expression of prothrombinase activity which coincide with the loss of phospholipid asymmetry on the platelet wall. When we studied the binding of purified beta 2GPI we also found that it binds preferentially to activated platelets and that it seems to be a prerequisite for the binding of aPL onto them. Our findings indicate that aPL from patients with antiphospholipid syndrome may bind to activated platelets through beta 2GPI.
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PMID:Exposure of anionic phospholipids upon platelet activation permits binding of beta 2 glycoprotein I and through it that of IgG antiphospholipid antibodies. Studies in platelets from patients with antiphospholipid syndrome and normal subjects. 791 7

Beta-2-GPI is a 50 kDa glycoprotein which is known to be a serum co-factor, with a role in determining the binding of pathogenic anticardiolipin antibodies to phospholipids. Immunization of naive mice with beta-2-GPI resulted in elevated levels of antibodies directed against negatively charged phospholipids (cardiolipin, phosphotidylserine, phosphatidylinositol). The presence of increased titres of antiphospholipid antibodies in the sera of the mice was later followed by prolonged activated partial thromboplastin time (APTT), thrombocytopenia, and when the mice were mated, by a high percentage of fetal resorptions in the uterus. These data point to the ability of beta-2-GPI to induce pathogenic anti-cardiolipin antibodies following active immunization.
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PMID:Immunization with anticardiolipin cofactor (beta-2-glycoprotein I) induces experimental antiphospholipid syndrome in naive mice. 798 Aug 47

Lupus anticoagulants (LA) have been defined as phospholipid-interfering antibodies. Testing for them has become a frequently requested procedure in coagulation laboratories and new methods have recently become available. Activated partial thromboplastin time (aPTT) reagents with reduced levels or different types of phospholipid provide high sensitivity. Correction procedures resistant to heparin and based on aPTT and dilute Russell's viper venom time (DRVVT) tests with added hexagonal phase phospholipids have improved the specificity of testing. Simplified tests based on venom activators of factor X and prothrombin improve the reliability of LA testing and may facilitate the further categorization of circulating anticoagulants. Recent studies on the mechanism of LA derived from various patients have confirmed their heterogeneity, principally in the protein cofactors involved in their interactions with phospholipids. Perhaps one-third of LA require beta 2-glycoprotein 1 to exert an anticoagulant effect. The remainder may require human prothrombin as suggested from studies with reconstituted clotting factor systems.
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PMID:Some recent developments with lupus anticoagulants. 805 62

Cellular receptors for blood proteases regulate chemotaxis, extracellular proteolysis, and growth behavior of normal and malignant cells. Binding of the coagulation protease factor Xa to leukocytes is contributed by a recently identified molecule, denominated Effector cell Protease Receptor-1 (EPR-1). Monoclonal antibodies were generated against EPR-1+ MOLT13 lymphocytes and selected for reactivity with lymphocyte surface proteins by flow cytometry and with affinity-purified EPR-1 in Western blots. Antibody-based functional cloning of the cDNA for EPR-1 reveals the sequence of a novel molecule encoded by a prominent 1.9-kilobase mRNA. The cDNA predicts a glycoprotein of 337 amino acids, characterized by a unique cysteine-rich extracellular module, a single membrane-spanning domain, and a serine-rich (26%) cytoplasmic tail featuring at least 15 potential phosphorylation sites. Genetically engineered EPR-1 transfectants were recognized by monoclonal antibodies to EPR-1 and bound 125I-factor Xa in a specific and saturable manner (Kd approximately 10-15 nM). In the absence of factor V/Va, EPR-1 transfectants promoted prothrombin activation in a factor Xa concentration-dependent reaction, inhibited by a monoclonal antibody to EPR-1. These findings define EPR-1 as a novel cell surface receptor for factor Xa potentially implicated in protease-dependent cellular effector functions.
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PMID:Molecular cloning of effector cell protease receptor-1, a novel cell surface receptor for the protease factor Xa. 810 47

We used flow cytometry to investigate surface membrane protein expression by platelets and platelet-derived microparticles from normal individuals and a patient with Glanzmann's thrombasthenia. Microparticles were detected by both forward scatter and side scatter using FACScan. The binding of coagulation factors on microparticles was investigated by using monoclonal anti-Factor IX (IXa) and anti-Factor X (Xa) antibodies. Furthermore, the procoagulant activity of microparticles was measured with a chromogenic substrate (S-2222) using a microtiter enzyme-linked immunosorbent assay. Both types of platelets showed similar release of microparticles. Microparticles released from platelets after activation with the calcium ionophore A23187 did not bind factors IXa and Xa, but when purified factors Va and Xa were added to the incubation buffer, factor Xa binding increased markedly in both normal and thrombasthenic platelets. Both normal and thrombasthenic platelets showed a similar time-dependent release of microparticles when activated with A23187. However, the binding of an antibody to granule membrane protein-140 also increased time-dependently in normal microparticles, but was little increased in thrombasthenic microparticles. These findings suggest that glycoprotein IIb/IIIa does not participate in the expression of prothrombinase activity on the surface of activated platelets and microparticles, whereas this glycoprotein appears to have an important role in the movement of granule membrane protein-140 from platelets to microparticles.
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PMID:Flow cytometric analysis of surface membrane proteins on activated platelets and platelet-derived microparticles from healthy and thrombasthenic individuals. 814 98


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