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:3.4.21.5 (thrombin)
33,306 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The distribution of a soluble form of a cell adhesion molecule, P-selectin, in human platelets and cultivated endothelial cells has been studied by enzyme-linked immunosorbent assay (ELISA). The concentration of soluble P-selectin in the blood plasma of healthy donors and patients with abnormal platelet count has also been determined. P-selectin was measured in the Triton X-100 lysate of platelets and endothelial cells (total P-selectin), in the 100,000g supernatant obtained after sedimentation of the membrane fraction from the homogenate of sonicated platelets and endothelial cells (intracellular soluble P-selectin), in the supernatant of activated and nonactivated platelets, and in the culture medium of endothelial cells. A soluble form of P-selectin which did not coprecipitate with the membrane fraction was detected in platelets and accounted for approximately 10% of the total P-selectin. Platelet activation by thrombin, ADP, or a thromboxane A2 analog resulted in the secretion of 30-50% of the intracellular soluble P-selectin. Measurements of P-selectin in endothelial cell culture revealed that endothelium from aorta contained about twofold more P-selectin than endothelium from umbilical vein. Intracellular soluble P-selectin was identified in both types of endothelial cells. In endothelial cells from the umbilical vein this form made up approximately 10% of the total P-selectin. Soluble P-selectin was also detected in the medium of cultivated endothelial cells, where its content correlated with the total cellular P-selectin. Concentration of P-selectin in blood plasma strongly correlated with the platelet count in the blood of healthy donors and patients with thrombocytosis and thrombocytopenia. These data indicate that platelets serve as one of the main source of plasma P-selectin. However, the presence of P-selectin in the plasma of patients with severe thrombocytopenia suggests that endothelium can also be involved in plasma P-selectin production. Thus, in vitro experiments as well as measurements of plasma P-selectin have shown that both platelets and endothelial cells can produce a soluble form of the protein. Platelet-derived soluble P-selectin and plasma P-selectin were shown to react with antibodies against the cytoplasmic domain of P-selectin. These data prove that at least part of soluble P-selectin is produced by synthesis employing special mRNA which lacks the sequence encoding the transmembrane domain, but not by the proteolytic shedding of the extracellular portion of membrane P-selectin.
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PMID:Production of soluble P-selectin by platelets and endothelial cells. 1061 41

Coagulation disorders occur often in cancer patients. Thrombosis or embolism may be the first sign of an underlying malignancy. In addition, subclinical coagulation disturbances have been found in the blood of cancer patients, for example elevated concentrations of tissue factor or thrombin-antithrombin complexes. In 20% of the patients thrombocytosis occurs, and for lung and colon cancer it was found that thrombocytosis is an independent negative prognostic factor for survival. The role of an activated coagulation cascade in tumour growth is not completely clear, but there is strong evidence that the formation of a temporary fibrin matrix stimulates the formation of new blood vessels (angiogenesis) and supports tumour growth and metastasis formation. Preclinical investigations demonstrated that tumour growth and metastasis formation can be inhibited by anticoagulants. Clinical studies suggest a beneficial effect of anticoagulants on the survival of cancer patients, but phase III randomised clinical trials should be performed to determine the effect of longterm administration of anticoagulants.
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PMID:[Coagulation disorders in cancer patients: possible opportunity for therapy]. 1068 17

Flow cytometry can detect platelet activation (CD62p), aggregate formation, microparticle formation, and glycoprotein IIb/IIIa (GP IIb/IIIa) receptor occupancy in one sample at the level of single particles. We studied the effect of GP IIb/IIIa inhibitors on platelet activation with flow cytometry in vitro. Citrated whole blood was incubated with increasing concentrations of three different GP IIb/IIIa inhibitors (c7E3, DMP728, XJ757), then thrombin or adenosine diphosphate (ADP) was added, and after 1 minute the sample was fixed. Samples with thrombin but without c7E3 had a decrease in platelet count, from a mean of 260,000 platelets/microl to 56,000 platelets/microL, and aggregates increased. Samples with concentrations of c7E3 that resulted in 80% or more receptor blockade had no decrease in platelet count, and no aggregates were formed, but the number of CD62p-positive single platelets increased from 1200 to 7400 platelets/microL. The two other inhibitors (DMP 725, XJ757) or ADP instead of thrombin gave similar results. Microparticle formation did not change with platelet activation in the presence of a GP IIb/IIIa inhibitor. With small inhibitor doses resulting in <80% receptor blockade, the number of aggregates did not change or was even higher than that in samples without inhibitor. GP IIb/IIIa inhibitors do prevent aggregate formation but they do not prevent activation of platelets. With GP IIb/IIIa inhibition, more activated single platelets remain in the blood. One may expect an increasing number of circulating, activated platelets with the use of GP IIb/IIIa inhibitors.
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PMID:Effect of glycoprotein IIb/IIIa inhibitors on CD62p expression, platelet aggregates, and microparticles in vitro. 1071 63

Essential thrombocythemia (ET) is one of the less rare variants of the chronic myeloproliferative disorders (MPD). The present review questions the possible link between spontaneous megakaryocytopoiesis, platelet hyperreactivity, and the occurrence of platelet-mediated vascular manifestations in acquired and hereditary ET. In acquired ET, the role of thrombopoietin (TPO) is crucial to the observed hypermegakaryocytopoiesis, which is characterized by an increased proliferation of megakaryocyte (MK) progenitors, even in conditions of culture without addition of any known megakaryocyte colony-stimulating factors. An increased reactivity of megakaryocyte progenitors to TPO remains to be precisely delineated. A defective clearance of TPO by megakaryocytes and platelets because of a reduced number of TPO receptors is possible. TPO is able to enhance platelet aggregation induced by ADP, thrombin, and collagen. A point mutation in the TPO gene as the cause of increased TPO production in hereditary ET can readily explain both spontaneous megakaryocytopoiesis and platelet-mediated microvascular manifestations simulating the phenotype of acquired ET. Nevertheless, to date, no mutation of the TPO structural gene, as shown in two families with hereditary ET, and no mutations in the TPO receptor have been found in patients with acquired ET. There is good evidence that the microvascular circulation disturbances in ET are caused by intravascular activation and aggregation of hypersensitive platelets, with sludging or occlusion of the endarterial microvasculature. In this process, the generation of platelet-derived products, endothelial cell damage, fibromuscular intimal proliferation, and platelet thrombi are essential and can be inhibited by a platelet-specific regimen of aspirin, thus providing a rationale for using low-dose aspirin as an antithrombotic agent in thrombocythemia. In contrast, the generation of thrombin appears not to be essential for the formation of platelet thrombi, thereby explaining the inefficacy of coumadin derivatives and heparin in the treatment and prevention of microvascular circulation disturbances in hereditary and acquired ET.
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PMID:Spontaneous proliferative megakaryocytopoiesis and platelet hyperreactivity in essential thrombocythemia: is thrombopoietin the link? 1074 15

The potential hemocompatibility of radiofrequency glow discharge (RFGD) polymers made by copolymerization of mixtures of hexafluoropropene and ethylene (C(3)F(6)/C(2)H(4)) or acrylic acid and 1,7-octadiene was investigated using in vitro assays for platelet adhesion and platelet catalyzed thrombin generation. Thrombin generation rate normalized to platelet number was used as a measurement of platelet activation (procoagulant activity). RFGD polymers produced by copolymerization of acrylic acid and 1, 7-octadiene contained varying amounts of carboxylic acid species as determined by electron spectroscopy for chemical analysis (ESCA). These polymers induced little variation in platelet adhesion, thrombin generation, or platelet activation. RFGD polymerization of C(3)F(6) and C(2)H(4) resulted in polymers with varying proportions of fluorinated species, as determined by ESCA. Fibrinogen adsorption from plasma was maximal on a polymer made with 25% C(3)F(6) (75% C(2)H(4)) in the feed. However von Willebrand factor (vWF) adsorption was greater on polymers made with increased %C(3)F(6) in the feed. Platelet adhesion decreased with increasing %C(3)F(6) in the feed. Thrombin generation was lowest for platelets adherent to polymers made from both C(3)F(6) and C(2)H(4). Therefore, procoagulant activity of platelets increased for polymers made with increased %C(3)F(6) in the feed, similar to the trend in vWF adsorption. These findings suggest that increased incorporation of fluorinated species into RFGD polymers leads to decreased platelet adhesion and increased platelet activation (which is possibly due to increased vWF adsorption).
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PMID:Platelet adhesion and procoagulant activity induced by contact with radiofrequency glow discharge polymers: roles of adsorbed fibrinogen and vWF. 1088 Jan 15

Activated platelets can express CD40 ligand (CD40L) and trigger inflammatory response and tissue factor (TF) expression in endothelial cells through interaction with CD40. This pathway is also important for T cell-induced monocyte and endothelial cell procoagulant activity. We have studied the potential role of the CD40-CD40L pathway in platelet-induced TF expression in a monocytic cell line and in whole-blood monocytes. In vitamin D(3)-differentiated U-937 cells, thrombin-stimulated platelets increased TF expression as measured by mRNA quantification, flow cytometry, and procoagulant activity. Maximum antigen expression occurred after 2 hours. Neutralizing anti-P-selectin antibody yielded a 50% suppression of procoagulant activity, whereas antibody to CD40L had no effect. In thrombin receptor activator-stimulated citrated blood, monocytes were up to 77% TF-positive, with peak expression after only 15 minutes. However, no TF mRNA was detectable at that time. Anti-P-selectin antibody reduced TF by 50%, whereas antibody to CD40L gave a 17% reduction. Thus, we conclude that P-selectin exposed on activated platelets induces the expression of TF in both U-937 cells and whole-blood monocytes but by different mechanisms. Platelet CD40L does not display any significant effect on U-937 cells but may be of some importance on whole-blood monocytes. This suggests a possible functional difference between U-937 and monocyte CD40. Another important finding in this study is the rapid appearance of surface TF on monocytes without detectable mRNA formation. This indicates that TF may be stored intracellularly in these cells and can be exposed on the surface independent of de novo protein synthesis.
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PMID:Role of platelet P-selectin and CD40 ligand in the induction of monocytic tissue factor expression. 1103 Dec 22

In this study, the protein which stimulates proplatelet formation (PPF) of megakaryocytes was purified from normal human plasma using 7 steps procedures. Two different protease inhibitors were identified based on their amino acid sequences, i.e. antithrombin III (AT III) and C1 inhibitor. They were included in high density lipoprotein (HDL). HDL was necessary for AT III to be active in PPF in vitro. The biological effects of the AT III/HDL or thrombin-AT III (TAT)/HDL were studied in vitro. PPF of murine megakaryocytes was stimulated by negative control (BSA) (1.8 +/- 0.3%), AT III (2.0 +/- 0.4%), HDL (1.2 +/- 0.9%), AT III/HDL (14.8 +/- 2.1%) or TAT/HDL (23.3 +/- 3.5%), respectively. TAT/HDL also had a synergistic effect with the mpl ligand, judging by the acetylcholinesterase (AchE) expression of murine megakaryocytes (2.7 fold increase). In vivo subcutaneous administration of AT III alone or TAT for 3 days significantly stimulated thrombocytosis (136% and 144%, respectively, p<0.05) and AT III/HDL showed rapid and further stimulation (150%, p <0.01). These results and the previous studies indicate that megakaryocytopoiesis is regulated by the mpl ligand, while a protease/protease inhibitor complex such as TAT, which is involved in the coagulation cascade associated with platelet consumption, might be one of the regulators in platelet production.
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PMID:Purification of proplatelet formation (PPF) stimulating factor: thrombin/antithrombin III complex stimulates PPF of megakaryocytes in vitro and platelet production in vivo. 1124 59

Neutrophil P-selectin glycoprotein ligand-1 (PSGL-1) mediates the initial rolling and adhesion of neutrophils to P-selectin on activated endothelium and platelets. Platelet-neutrophil activation and binding occur in the blood of patients with arterial diseases, suggesting that arterial damage leads to these phenomena. We investigated the influence of endothelial surface integrity on circulating platelet activation and binding to neutrophils and the mechanism involved in these interactions. Expression of P-selectin on human platelets and their binding to neutrophils was determined by flow cytometry at baseline after thrombin activation and after exposure for 15 min to intact and damaged arterial surfaces in flow chambers. Expression of platelet P-selectin at baseline and after perfusion over intact endothelium averaged 13.8 +/- 1.2 and 12.7 +/- 1.8%, respectively, and increased significantly to 19.7 +/- 1.8% (P < 0.05) after perfusion over damaged arteries. In mixed neutrophil/platelet suspensions, the percentage of neutrophils that bind platelets increased significantly also, from 10.8 +/- 1.6% at baseline to 39.7 +/- 2.9% (P < 0.05) after perfusion over damaged arteries compared with 69.7 +/- 2.5% with thrombin. This binding was completely inhibited by a recombinant soluble PSGL-1 (rPSGL-Ig) and anti-P-selectin and PSGL-1-blocking monoclonal antibodies. The inhibitory effect of rPSGL-Ig correlated well with its binding to platelets (r = 0.98, P < 0.001). Circulating platelets are activated upon contact with damaged arteries, thereby enhancing their adhesive interactions with neutrophils via P-selectin and PSGL-1. Inhibition of this binding with rPSGL-Ig may constitute a target in the treatment of inflammatory and thrombotic reactions.
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PMID:P-selectin antagonism with recombinant p-selectin glycoprotein ligand-1 (rPSGL-Ig) inhibits circulating activated platelet binding to neutrophils induced by damaged arterial surfaces. 1145 28

Thrombosis and disseminated intravascular coagulation are common complications of cancer. Specific conditions associated with cancer such as stasis due to immobilization or blood flow obstruction, surgery, infections, endothelium damage due to chemotherapeutic agents and abnormalities of blood coagulation contribute to the hypercoagulable and thrombophilic state of cancer patients. This procoagulant state in cancer arises mostly from the capacity of tumor cells to express and release procoagulant activities (cancer procoagulant and tissue factor). Decreased levels of inhibitors of coagulation, impaired fibrinolysis, the presence of antiphospholipid antibodies and an acquired activated protein C resistance contribute to the hypercoagulable state. The activation of coagulation is also implicated in tumor proliferation through interactions of coagulation with inflammation and increased tissue factor pathway inhibitor. Laboratory diagnosis of the thrombophilic state include (1) elevation of clotting factors, fibrinogen/fibrin degradation products, hyperfibrinogenemia and thrombocytosis and (2) elevation of specific markers of activation of coagulation: fibrinopeptide A, fragment 1 + 2, thrombin-antithrombin complexes and D-dimers. However, none of the tests has any predictive value for the occurrence of thrombotic events in one individual patient. In patients with venous thromboembolism a noninvasive screening for occult cancer is able to detect a relatively high incidence of hidden cancer and the search for thrombophilia seems important in patients without known cancer.
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PMID:The thrombophilic state in cancer patients. 1154 75

Thromboembolism is one of the most common causes of death in cancer patients. Among the most frequent thrombotic complications in patients with cancer are disseminated intravascular coagulation, thrombotic thrombocytopenic purpura, and thrombocytosis. Clearly, these complications arise as tumor cells interact with almost all components of the hemostatic system including platelets. Platelets participate in tumor progression by contributing to the metastatic cascade, protecting tumor cells from immune surveillance, regulating tumor cell invasion, and angiogenesis. Platelets contain one of the largest stores of angiogenic and mitogenic factors and the tumor vasculature is leaky, which allows platelets to come in contact with the tumor and deposit multiple angiogenic factors including vascular endothelial growth factor (VEGF) and thrombin to tumor cells, which in turn contributes to tumor progression. This article reviews the recent literature on how platelets contribute to tumor growth, angiogenesis, and metastasis.
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PMID:Platelets and cancer: implications for antiangiogenic therapy. 1188 24


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