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)

Antiphospholipid antibodies (APA) are a family of immunoglobulins that react with anionic phospholipids, or anionic phospholipids-protein complexes. Recent evidence would support the latter definition. Lupus anticoagulants (LA) inhibit in vitro phospholipid dependent coagulation tests [e.g., activated partial thromboplastin time (APTT), prothrombin time (PT), and dilute Russell viper venom time (dRVVT)]. This inhibition appears to be specific for reagent phospholipids. The addition of freeze-thawed platelets or activated platelets will result in correction of the LA-induced abnormality. Anticardiolipin antibodies (ACA) are related to LA but appear to be distinct. ACA are detected by solid phase assays (ELISA, RIA) and require a plasma cofactor: beta 2 Glycoprotein-I (beta 2 GPI). ACA and LA activities can be separated in individual patient plasmas by affinity chromatography. In some instances they are of differing isotypes. Preliminary evaluation of beta 2 GPI in coagulation assays suggests it may function as a cofactor for LA activity. Recent work also suggests human prothrombin may represent a necessary cofactor for in vitro LA activity. Paradoxically, patients with LA/ACA may sustain thromboembolic events involving both venous and arterial sites. The prothrombotic properties of LA/ACA have not been satisfactorily characterized. A number of proposals have been reported, including inhibition of prostacyclin (PGI2) generation by endothelial cells, decreased activity of the protein C system, impaired fibrinolysis, and inhibition of beta 2GPI. Among these various hypotheses, down regulation of the protein C system appears most plausible. Also, LA/ACA may interfere with the phospholipase A2-phospholipid substrate complex involved in the generation of arachidonic acid from membrane phospholipids.
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PMID:Antiphospholipid antibodies: proposed mechanisms of action. 128 81

We examined the effect of the lipoproteins on the activation of human factor X in an in vitro system containing purified human factor VII, low levels of tissue factor and calcium ions. In the absence of the lipoproteins the maximum activation was achieved within 10 min of the start of incubation; after this period the formation of factor Xa ceases. When very low-density lipoproteins, low-density lipoproteins or high-density lipoproteins were present at normal or subnormal plasma concentrations, the factor Xa generated was almost doubled after 10 min. This increase could be abolished by treating each lipoprotein subfraction with the phospholipase A2; hence, the treated lipoproteins lowered the factor Xa activity. We conclude that the phospholipids favor factor Xa formation and protect the tissue factor/factor VIIa/factor Xa complex from a potent inhibitor contained in the lipoprotein subfractions.
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PMID:The effects of lipoproteins on the tissue factor-dependent activation of factor X. 150 4

The asymmetric distribution of phospholipids in the erythrocyte membrane during the intracellular development of the human malaria parasite Plasmodium falciparum was studied. Infected cells of high parasitaemia were treated with phospholipase A2 or sphingomyelinase C, followed by isolation of the host red cell membrane using the Affigel (731) bead method. Additionally, phosphatidylserine on the surface of infected cells was probed using a phosphatidylserine-sensitive prothrombinase assay. Trophozoite-infected cells showed an increase in phosphatidylethanolamine and phosphatidylserine and a decrease in phosphatidylcholine in the outer leaflet. In addition to the changes already present in trophozoite-infected cells, schizont-infected cells showed a decrease in sphingomyelin as well as a further increase in phosphatidylserine in the outer leaflet. The results are discussed with respect to possible mechanisms and consequences of these changes.
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PMID:Alterations in erythrocyte membrane phospholipid organization due to the intracellular growth of the human malaria parasite, Plasmodium falciparum. 185 85

Lipopolysaccharide (LPS) stimulation of human monocytes in heparinized whole blood in vitro as expressed by induced activity of thromboplastin, has been studied. An essential role of arachidonic acid (20:4) release was found. 2,4'-Dibromoacetophenone, a phospholipase A2 inhibitor, totally blocked the induced synthesis of thromboplastin activity. Furthermore, nordihydroguaiaretic acid (NDGA), a lipoxygenase inhibitor, had an effect on the LPS-induced thromboplastin synthesis which varied from no inhibition in individuals insensitive to LPS ('low responders'), up to 80% inhibition in the person with the highest response ('high responder') to LPS. Platelets were found to be partially responsible for this difference. Thus, monocytes from high responders cross-combined with platelets from low responders were much less prone to LPS stimulation than they were in the presence of high responder platelets. Intake of acetylsalicylic acid caused a 50% increment of LPS-induced thromboplastin synthesis, and this effect was mediated by platelets.
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PMID:The role of arachidonic acid release and lipoxygenase pathway in lipopolysaccharide-induced thromboplastin activity in monocytes. 212 91

The human placental proteins PP4 and PP4-X, belonging to the annexin protein family, were expressed in Escherichia coli at high yield. The proteins were purified to homogeneity. The physicochemical parameters of the recombinant proteins were determined and compared with those of their natural placental counterparts. Except for a minor change in the pI, the proteins appeared to be indistinguishable by several criteria. Both recombinant PP4 and recombinant PP4-X were biologically active in a thromboplastin inhibition test and in a phospholipase A2 inhibition test.
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PMID:Annexin proteins PP4 and PP4-X. Comparative characterization of biological activities of placental and recombinant proteins. 214 60

The three phospholipase A2 isoenzymes from Naja nigricollis venom inhibit blood coagulation with different potencies. The strongly anticoagulant basic isoenzyme CM-IV inhibits the prothrombinase complex, whereas the weakly anticoagulant isoenzymes CM-I and CM-II do not. To determine the role of enzymatic activity of the phospholipases in the inhibition of prothrombinase, we varied the time of incubation of each of these isoenzymes with the prothrombinase complex. The inhibition by CM-IV did not increase with time of incubation. CM-I and CM-II failed to inhibit the complex, even with complete hydrolysis of phospholipids in the assay mixture. After alkylation of its active-site histidine, CM-IV lost 97% of its enzymatic activity but retained 60% of its inhibitory potency on prothrombinase. CM-IV also inhibited prothrombinase activity in the absence of phospholipids, whereas CM-I and CM-II did not. The inhibition of the prothrombinase complex by CM-IV is thus not due to its binding to or hydrolysis of phospholipids. The kinetics of CM-IV inhibition of the prothrombinase complex in both the presence and absence of phospholipids was noncompetitive. This inhibition can be explained by binding of CM-IV to either factor Va or Xa, or both, to inhibit the complex. CM-IV differs from previously described nonenzymatic anticoagulants that are proteinase inhibitors or that inhibit the coagulation complexes by interfering with the binding of clotting factors to phospholipids. We conclude that the basic enzyme, CM-IV, inhibits the prothrombinase complex by a novel mechanism independent of enzymatic activity.
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PMID:The basic phospholipase A2 from Naja nigricollis venom inhibits the prothrombinase complex by a novel nonenzymatic mechanism. 227 32

The transbilayer distribution of glycerophospholipids in the plasma membrane of Plasmodium knowlesi infected erythrocytes was studied by using lysine-116-epsilon-N-palmitoyl amidinated pancreatic phospholipase A2. As a consequence of its superior membrane penetrating capacities, this modified enzyme rapidly degrades its substrates in the outer membrane leaflet of intact erythrocytes, a property that makes the enzyme an excellent tool to study the malaria parasitized red cell. The modified phospholipase A2 caused a nonlytic hydrolysis of up to 12-15% of the phosphatidylethanolamine and none of the phosphatidylserine in the red cell membrane, irrespective of whether the cells harboured trophozoite and schizont stages of parasites or no parasites at all. The absence of phosphatidylserine at the exterior surface of Plasmodium infected erythrocytes was confirmed by applying the prothrombinase assay on Plasmodium falciparum infected human erythrocytes. Consequently, the results from these and previous studies indicate that the plasma membrane of Plasmodium infected erythrocytes exhibit a normal transbilayer phospholipid asymmetry.
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PMID:Phospholipid asymmetry in the plasma membrane of malaria infected erythrocytes. 234 3

An anticoagulant protein was purified from the EDTA extract of human placental tissue. The purified protein had a molecular weight of 73,000 on sodium dodecyl sulfate polyacrylamide gel electrophoresis under both reducing and non-reducing conditions. Because this protein had the ability to bind phospholipids such as phosphatidylserine, phosphatidylinositol, and cardiolipin in the presence of Ca2+, this protein was designated as calphobindin II (CPB-II). CPB-II prolonged the clotting time of normal plasma when coagulation was induced by tissue factor, cephalin and ellagic acid or recalcification, but did not affect thrombin-initiated fibrin formation. CPB-II also inhibited the activation of prothrombin by the complete prothrombinase complex or factor Xa-phospholipid-Ca2+ but not that by phospholipid-free factor Xa. In addition, CPB-II had an inhibitory activity against phospholipase A2.
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PMID:Isolation and characterization of an anticoagulant protein from human placenta. 252 73

Crosslinking of membrane skeletal proteins such as spectrin by oxidation of their SH-groups can be provoked by treatment of intact erythrocytes with diamide. Shortly after exposure of human erythrocytes to diamide and despite the transverse destabilization of the lipid bilayer that was observed in these cells (Franck, P.F.H., Op den Kamp, J.A.F., Roelofsen, B. and Van Deenen, L.L.M. (1986) Biochim. Biophys. Acta 857, 127-130), no abnormalities could be detected regarding the asymmetric distribution of the phospholipids when probed by either the prothrombinase assay or brief exposure of the cells to a modified phospholipase A2 with enhanced membrane penetrating capacity. This asymmetry appeared to undergo dramatic changes however, when the ATP content of the cytosol had decreased to less than 10% of its original level during prolonged incubation of the treated cells. These observations indicate that the initial maintenance of phospholipid asymmetry in diamide-treated erythrocytes can be solely ascribed to the action of the ATP-dependent aminophospholipid translocase. This view is supported by experiments involving radiolabeled phospholipids of which trace amounts had been inserted into the outer membrane leaflet of diamide-treated red cells and which still showed a preferential translocation of both aminophospholipids in favour of the inner monolayer, be it that the efficiency of the translocase was found to be impaired when compared to control cells.
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PMID:Involvement of ATP-dependent aminophospholipid translocation in maintaining phospholipid asymmetry in diamide-treated human erythrocytes. 271 70

Treatment of platelets with fluoride (10 mM) was found to result in a transient increase in Ca2+-permeability of the platelet plasma membrane. This phenomenon was used to provide supplementary evidence for the suggestions made earlier (Comfurius et al. (1985) Biochim. Biophys. Acta 815, 143; Verhallen et al. (1987) Biochim. Biophys. Acta 903, 206), that cytoskeletal disrupture by calpain is involved in the process leading to transbilayer movement of phosphatidylserine during expression of platelet procoagulant activity. This was achieved by relating both calpain activity and exposure of phosphatidylserine with platelet procoagulant activity. It was found that only upon addition of extracellular Ca2+ to fluoride-treated platelets, procoagulant activity, expressed as prothrombinase activity, and calpain activity, estimated from protein patterns after gel electrophoresis, were generated. Both Ca2+-inducible prothrombinase activity and calpain activity followed an identical time-course during incubation with fluoride: after a time-lag of about 10 min they sharply increased towards a peak level. Upon further incubation with fluoride, both activities decreased towards a final plateau, still above basal level. The presence of leupeptin during incubation with fluoride was found to inhibit Ca2+-inducible calpain activity and prothrombinase activity in an identical way. Ca2+-inducible exposure of phosphatidylserine, as determined with extracellular phospholipase A2, showed a similar pattern as Ca2+-inducible calpain activity and prothrombinase activity. From the strict parallelism between prothrombinase activity, calpain activity and exposure of phosphatidylserine, it is concluded that calpain plays an important role in the activation-dependent transbilayer movement of phosphatidylserine during expression of platelet procoagulant activity. It is suggested that degradation of the platelet membrane-skeleton by calpain disturbs the structural organization of the lipid bilayer of the platelet plasma membrane leading to enhanced transbilayer movement of phospholipids and appearance of phosphatidylserine at the platelet outer surface.
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PMID:Fluoride-dependent calcium-induced platelet procoagulant activity shows that calpain is involved in increased phospholipid transbilayer movement. 283 83


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