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:3.4.21.69 (APC)
16,337 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Deep vein thrombosis (DVT) is a frequent event in patients with spinal cord injury, even with prophylactic anticoagulant therapy. Lower limb paralysis is a known major risk factor for venous thrombosis, supposedly due to the venostasis in relation with total immobility. The main goal of this study was to evaluate the endothelial response to anoxia to determine whether recovery of fibrinolytic potential occurs in patients subjected to forced bedrest because of a spinal cord injury and whether this recovery is related to the incidence and/or evolution of DVT. We evaluated vascular endothelium reactivity in the lower limbs no longer submitted to the hydrostatic pressure of the erected position in 15 patients with paraplegia or tetraplegia and in 10 normal volunteers after venous occlusion produced by the application of 10 cm Hg pressure to the lower limb for 15 min comparatively to the upper limb used as reference. Among the 15 patients, 10 whose spinal cord injury had occurred 1 to 6 months earlier were still receiving prophylactic anticoagulant therapy, whereas the five other patients were not receiving prophylactic anticoagulants because the injury dated back 6 months or more. After venostasis, tissue plasminogen activator (tPA) increased significantly in both patients and controls in the upper limb (tPA levels twofold and threefold respectively in controls and patients) but showed no significant changes in the lower limb; prolonged immobility did not allow recovery in the lower limbs of a level of fibrinolytic responsiveness identical to that in the upper limbs. The plasminogen activator inhibitor (PAI1) remained unchanged after anoxia, although wide interindividual variations were seen. Natural coagulation inhibitors and circulating blood stigmates of hypercoagulability were measured. None of the patients had abnormally low levels of coagulation inhibitors (ie, antithrombin III, protein C and protein S levels were normal). Seventy-five per cent of patients (prophylactically anticoagulated or not) had very high levels of fibrin degradation products (D. Dimer levels sevenfold to eightfold those of the controls), but all patients had normal levels of thrombin-antithrombin complexes and prothrombin fragments 1 + 2. The permanence of the thrombotic process characterized by an increase in D. Dimer levels without recovery of fibrinolytic potential suggests a proposal for the patients an indefinite antithrombotic treatment at curative doses.
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PMID:Endothelial fibrinolytic reactivity and the risk of deep venous thrombosis after spinal cord injury. 907 65

We examined hemostatic molecular markers in various thrombotic disorders. The efficacy of treatment in relation to the disseminated intravascular coagulation (DIC) score when the treatment was begun showed that greater efficacy was achieved in Pre-DIC than in DIC patients. The outcome was poorer with increasing DIC score, suggesting that early treatment is important. The sensitivity in some of molecular markers was high for both DIC and Pre-DIC. Receiver operating characteristic analysis suggest that soluble fibrin monomer level could be the most useful marker for the diagnosis of DIC. In examination of these markers in deep vein thrombosis, pulmonary embolism, acute myocardial infarction, and cerebral infarction, plasminogen activator inhibitor-1 and activated protein C-protein C inhibitor complex were useful marker for the diagnosis. Increased plasma GMP-140 was suggested to be the activation of platelets. The patients with high levels of plasma thrombomodulin (TM) considered to be a marker of vascular endothelial injuries became poor outcome. We will term these patients with high TM as systemic vascular endothelium injuries syndrome, and treat those by protecting the vascular endothelium.
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PMID:[Study of hemostatic molecular marker]. 913 93

The identification of many biologic anomalies is progressively realized in nephrotic children, thanks to adult studies and to scientific advances. The number of anomalies and the intensity of alterations vary from one patient to another and during flare-ups in the same patient. Their severity is usually a function of the severity of the nephrotic syndrome (NS). The responsibility of each anomaly per se in triggering thrombotic complications is not yet known and today it is understood that the coexistence of several factors is necessary to induce these complications. Thus, the NS presents a true model because it can gather multiple thrombogenic anomalies. It might be more satisfying to characterize all of the mechanisms that could be responsible for a thrombosis rather than to assay all of the biologic components in one patient. When the main balances during the childhood NS are broken-pro- versus anticoagulant forces, pro- versus antifibrinolytic forces, platelet/vessel wall interactions-one cannot evaluate with accuracy the possible impact of acquired interrelations such as a decrease of antithrombin versus an increase of protein C. Among the present unknown factors, a major one is related to the effects, if any, of the proteinuric factor (recently discovered) on the vascular endothelium and the central question is: would it be capable of changing the thromboresistant phenotype to a thrombogenic one? No absolute correlation has been found between the many biologic abnormalities and the occurrence of thromboembolic (TE) complications. However, it is of great interest to have the best evaluation of the TE risks in nephrotic children. The criteria that are commonly used are: albuminuria, and plasma levels of fibrinogen and antithrombin. One can suggest adding to these criteria the D-dimer assay, a molecular marker of coagulation activation, and the factor V Leiden workup because it represents a genetic predisposition for TE complications. As far as prevention of TE complications is concerned, the standard but basic guidelines of nephrotic patients must be followed. Furthermore, vitamin K antagonists should be administered as soon as the risk criteria are gathered, but only after a careful evaluation of the benefits/risks ratio. As to the treatment of TE events, one should follow the present recommendations for children. A better future regarding prevention of TE accidents is based not only on the necessity of multicentric prospective studies but also on basic research that will allow discovery of the "primum movens" of childhood NS.
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PMID:Thromboembolic risks and complications in nephrotic children. 925 8

Solid-phase enzyme immunoassay estimated S and C protein levels in 10 patients with nonspecific aortic arteritis (NAA). Lowered concentrations of total protein S (< 70%) occurred in 8 (80%) of 10 NAA patients, in 3 of them protein C was also low. Isolated reduction of protein C was encountered only in one patient. Four patients (44%) of 9 had antibodies to phospholipids, as a rule, in low concentrations. 3 of them had low total protein S concentrations against normal C protein. 4 patients (40%) showed elevated concentrations of WF antigen concentrations. No relationship was noted between a fall in total protein S, C concentrations and clinical presentation of NAA, the disease activity, presence of antibodies to neutrophil cytoplasm and antibodies to endothelial cells. Thus, a reduction in the levels of total protein S in NAA patients is induced by endothelial dysfunction unrelated to production of antibodies to phospholipids, neutrophil cytoplasm and vascular endothelium.
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PMID:[The clinical importance of determining protein C and protein S in patients with nonspecific aortoarteritis]. 932 92

We describe a subset of peripheral CD14+ cells, coexpressing the CD34 progenitor marker and able to migrate across endothelial cell monolayers. On culture with granulocyte-macrophage-CSF, this population differentiated into dendritic cells expressing CD83, CD80, HLA-DR(bright), CD86, and CD54. These dendritic cells were immunostimulatory, in that they induced proliferation of allogenic and tetanus toxoid-specific T lymphocytes. The CD14+ CD34+ population expressed higher levels of platelet endothelial cell adhesion molecule-1 (PECAM-1) and alpha4beta1 integrin than the CD14+ CD34- counterpart, being dull positive for other integrins. Using stably transfected PECAM-1+, VCAM-1+, or ICAM-1+ cells, we found that PECAM-1 and, to a lesser extent, VCAM-1, could support transmigration of CD14+ CD34+ cells, whereas the alphaL-ICAM-1 interaction was involved in cell adhesion. PECAM-1-driven transmigration was conceivably dependent on a haptotactic gradient, as it was reduced by 80% across NIH3T3 cells transfected with the PECAM-1-delta cyto deletion mutant. This mutant lacks the cytoplasmic tail and displays a reduced tendency to localize at the intercellular junctions, thus failing to form a molecular junctional gradient. Once differentiated, dendritic cells derived from CD14+ CD34+ precursors retained their transendothelial migratory capability, using both PECAM-1 and ICAM-1 for transmigration. We suggest that a subset of CD14+ CD34+ circulating leukocytes can localize to peripheral tissues and differentiate into functional dendritic cells, thus representing a functional reservoir of potential APC. PECAM-1, constitutively expressed on vascular endothelium, is likely to play a relevant role in the egress of this population from the bloodstream.
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PMID:CD14+ CD34+ peripheral blood mononuclear cells migrate across endothelium and give rise to immunostimulatory dendritic cells. 951 Jan 66

A comparative study of thrombomodulin (TM), a potent natural anticoagulant, was performed in first trimester and term human placentae. Immunoreactive TM was observed on fetal vascular endothelium and syncytiotrophoblast at both gestational ages. Staining was stronger in term than in early placentae, particularly along the microvillous apical membrane of the syncytiotrophoblast. Similarly, a higher level of TM mRNA was detected by RT-PCR (P<0.02) and Northern blot analysis in extracts of whole term placentae. The localization of TM on syncytial microvilli was confirmed by electron microscopy after immunogold labelling. When isolated microvilli were compared at both gestational ages; a significant 2.3-fold increase in TM protein was observed in term microvilli as compared to first trimester microvilli by Western blot analysis (P<0.005) and ELISA (P<0.05). This higher level of TM in term microvilli was associated with an increase in its ability to activate protein C, from 3.7 +/- 1.2 to 8.7 +/- 4.2 mOD/min/microg protein +/- s.d. (P<0.01) in first trimester and term microvilli, respectively. The modulation of biologically active TM at the syncytial membrane exposed to maternal blood according to the length of gestation suggests that TM may be involved both in maternal haemostasis within the intervillous spaces, and also in the trophoblast differentiation process.
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PMID:Increase in expression and activity of thrombomodulin in term human syncytiotrophoblast microvilli. 963 21

Upon encountering the relevant vascular bed, lymphocytes attach to endothelial adhesion molecules, transmigrate out of circulation, and localize within tissues. Lymphocytes may then be retained at microanatomic sites, as in tissues, or they may continue to migrate to the lymphatics and recirculate in the blood. Lymphocytes also interact transiently, but with high avidity, with target cells or APC that are infected with microbes or have taken up exogenous foreign Ags. This array of adhesive capabilities is mediated by the selective expression of lymphocyte adhesion molecules. Here, we developed the 6F10 mAb, which recognizes a cell surface glycoprotein designated lymphocyte endothelial-epithelial cell adhesion molecule (LEEP-CAM), that is distinct in biochemical characteristics and distribution of expression from other molecules known to play a role in lymphocyte adhesion. LEEP-CAM is expressed on particular epithelia, including the suprabasal region of the epidermis, the basal layer of bronchial and breast epithelia, and throughout the tonsillar and vaginal epithelia. Yet, it is absent from intestinal and renal epithelia. Interestingly, it is expressed also on vascular endothelium, especially high endothelial venules (HEV) in lymphoid organs, such as tonsil and appendix. The anti-LEEP-CAM mAb specifically blocked T and B lymphocyte adhesion to monolayers of epithelial cells and to vascular endothelial cells in static cell-to-cell binding assays by approximately 40-60% when compared with control mAbs. These data suggest a role for this newly identified molecule in lymphocyte binding to endothelium, as well as adhesive interactions within selected epithelia.
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PMID:Lymphocyte adhesion to epithelia and endothelia mediated by the lymphocyte endothelial-epithelial cell adhesion molecule glycoprotein. 1041 64

Accelerated thrombin generation is central to the development of hemostatic abnormalities during cardiopulmonary bypass (CPB) that are associated with both thromboembolic complications and serious, abnormal bleeding. Thrombin not only converts fibrinogen to fibrin, but also activates platelets and coagulation factors V, VIII, and XI and causes release of von Willebrand factor from vascular endothelium. Thrombin can also downregulate the hemostatic system by inducing formation of platelet inhibitory agents, such as nitric oxide and prostacyclin, and release of tissue plasminogen activator, facilitating activation of protein C, and releasing tissue factor pathway inhibitor. Excessive thrombin activity may also result in substantial consumption of platelets, fibrinogen, and labile coagulation factors and abnormal bleeding. Elevated tissue plasminogen activator levels secondary to activation of the contact system and surgery catalyze the formation of plasmin, which also consumes or internalizes platelet glycoprotein receptors and coagulation factors V, VIII, and fibrinogen. Heparin can reduce the generation of and mediate neutralization of excessive and CPB-associated thrombin activity. Heparin anticoagulation is commonly monitored with the activated clotting time (ACT). However, the ACT may be prolonged by factors other than heparin during CPB, such as hemodilution and hypothermia, and therefore may not accurately reflect the extent of anticoagulation by heparin. Aprotinin, a nonspecific serine protease inhibitor used with CPB, can also prolong celite-based ACT values, rendering it less reliable for monitoring heparin anticoagulation. Therefore, several alternative anticoagulation strategies have been recommended when aprotinin is used, such as a higher celite ACT trigger (>750 seconds), monitoring of whole blood heparin concentrations (eg, >2.7 U/mL), or administration of heparin based on a CPB duration-dependent, fixed-dose regimen. Administration of heparin doses higher than those generally recommended, as guided by predetermined, patient-specific whole blood heparin concentration measurements during bypass, can reduce excessive thrombin-mediated consumption of platelets and coagulation factors as well as post-CPB blood loss and blood component transfusions. New modalities of improving suppression of excess thrombin generation during CPB include use of heparin-bonded CPB circuits, heparin cofactor II or related analogs, supplemental antithrombin III, direct thrombin inhibitors (eg, hirudin, argatroban), and inhibitors of the contact and tissue factor pathways. The safety and efficacy of these approaches remains to be established by additional, appropriately powered, prospective studies.
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PMID:Anticoagulation and anticoagulation reversal with cardiac surgery involving cardiopulmonary bypass: an update. 1046 45

The vascular endothelium influences not only the three classically interacting components of hemostasis: the vessel, the blood platelets and the clotting and fibrinolytic systems of plasma, but also the natural sequelae: inflammation and tissue repair. Two principal modes of endothelial behaviour may be differentiated, best defined as an anti- and a prothrombotic state. Under physiological conditions endothelium mediates vascular dilatation (formation of NO, PGI2, adenosine, hyperpolarizing factor), prevents platelet adhesion and activation (production of adenosine, NO and PGI2, removal of ADP), blocks thrombin formation (tissue factor pathway inhibitor, activation of protein C via thrombomodulin, activation of antithrombin III) and mitigates fibrin deposition (t- and scuplasminogen activator production). Adhesion and transmigration of inflammatory leukocytes are attenuated, e.g. by NO and IL-10, and oxygen radicals are efficiently scavenged (urate, NO, glutathione, SOD). When the endothelium is physically disrupted or functionally perturbed by postischemic reperfusion, acute and chronic inflammation, atherosclerosis, diabetes and chronic arterial hypertension, then completely opposing actions pertain. This prothrombotic, proinflammatory state is characterised by vaso-constriction, platelet and leukocyte activation and adhesion (externalization, expression and upregulation of von Willebrand factor, platelet activating factor, P-selectin, ICAM-1, IL-8, MCP-1, TNF alpha, etc.), promotion of thrombin formation, coagulation and fibrin deposition at the vascular wall (expression of tissue factor, PAI-1, phosphatidyl serine, etc.) and, in platelet-leukocyte coaggregates, additional inflammatory interactions via attachment of platelet CD40-ligand to endothelial, monocyte and B-cell CD40. Since thrombin formation and inflammatory stimulation set the stage for later tissue repair, complete abolition of such endothelial responses cannot be the goal of clinical interventions aimed at limiting procoagulatory, prothrombotic actions of a dysfunctional vascular endothelium.
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PMID:Endothelial function and hemostasis. 1079 71

Raloxifene is a nonsteroidal selective estrogen receptor modulator (SERM) that mimics the effects of estrogen on some plasma lipids and may have direct effects on the vascular wall. The objective of this study was to determine the effects of 17beta-estradiol, raloxifene, and LY139,478 (a related benzothiophene SERM) on the anticoagulant protein C pathway. In human vascular endothelial cells activated with interleukin-1 (IL-1), we demonstrated decreased thrombomodulin-dependent protein C activation. 17beta-estradiol reduced the anticoagulant properties of both unstimulated and IL-1-activated endothelial cells by decreasing thrombomodulin expression. In contrast, raloxifene and LY139,478 enhanced the anticoagulant properties of both unstimulated and IL-1-activated endothelial cells through upregulation of thrombomodulin. Regulation of the protein C pathway via thrombomodulin on vascular endothelium may be a novel mechanism by which SERMs could potentially confer cardioprotective effects and reduce the thrombotic risk associated with HRT in compromised patients.
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PMID:17beta-estradiol, but not raloxifene, decreases thrombomodulin in the antithrombotic protein C pathway. 1101 48


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