Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.21.6 (thromboplastin)
 13,278 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The M(r) of the complexes formed when factor Xa reacts with antithrombin III (ATIII) in plasma were estimated by gel filtration and SDS-polyacrylamide electrophoresis. The predominant species of factor Xa-ATIII detected after plasma and plasma to which factor Xa had been added were gel filtered on Sephadex G-200 and Sepharose 4B had apparent M(r) > 200,000, in which factor Xa-ATIII was associated with vitronectin. Addition of factor Xa-ATIII to ATIII-depleted plasma also resulted in the formation of factor Xa-ATIII-vitronectin complexes with M(r) > 200,000. Using polyclonal antibodies to human factor Xa-ATIII and ATIII as the capture and detector antibodies, respectively, a sensitive and specific enzyme-linked immunosorbent assay was developed to quantify factor Xa-ATIII in plasma. The relationship between factor Xa-ATIII production and prothrombinase activity in vivo was investigated by quantifying factor Xa-ATIII and prothrombin fragment 1 + 2 endogenous to the plasmas of blood donors and patients with Hodgkin's and non-Hodgkin's lymphoma. Whereas the concentrations of prothrombin fragment 1 + 2 in the 84 normal plasmas increased with age, those of factor Xa-ATIII (mean +/- SD of 34.7 +/- 13.8 pM) did not, and no correlation existed between the concentrations of the two parameters in normal plasmas. In contrast, a highly significant correlation between the concentrations of these two parameters was found in the plasmas of the cancer patients which coincidentally also had higher concentrations of both factor Xa-ATIII and prothrombin fragment 1 + 2 than the normal plasmas. Thus, ATIII may differentially influence prothrombinase formation and activity in normal individuals and cancer patients.
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PMID:Measurement of factor Xa-antithrombin III in plasma: relationship to prothrombin activation in vivo. 764 8

Cytotoxic drugs may potentiate the thrombotic complications in patients with malignancies and platelet function abnormalities have been reported after initiation of cisplatin therapy. This report describes a prolonged activation of platelets over 6-24 h co-culture with peripheral blood mononuclear cells (PBM) by pharmacological doses of cisplatin. Cisplatin had no direct effect on platelets and depended on PBM to produce aggregation which was apparently not mediated by products of the cyclooxygenase or lipoxygenase pathways, by platelet activation factor (PAF) or by thrombin. Although platelet aggregation normally involves the binding of fibrinogen to the beta 3 integrin, GP IIb-IIIa, on activated platelets, the cisplatin-dependent platelet aggregation observed in the co-culture experiments was not inhibited by an anti-GP IIb-IIIa monoclonal antibody which blocks fibrinogen-dependent aggregation nor by an adhesive peptide containing the RGDS integrin recognition sequence. Rather, aggregation appeared to involve a novel 140 kD granule membrane protein (GMP-140) mediated mechanism since aggregation was almost completely blocked by Fab fragments of an antibody to GMP-140 and was inhibited by fluid-phase GMP-140. At concentrations of cisplatin, adriamycin, and LPS that induced equivalent levels of tissue factor of blood monocytes, prothrombinase activity was significantly greater in cultures containing cisplatin. Prothrombinase activity was dependent on the presence of platelets and the rate of thrombin formation was enhanced by factor Xa generated by the tissue factor-factor VIIa complex. These studies suggest that the vascular and thrombotic complications associated with cisplatin therapy are mediated, at least in part, by platelet activation and aggregation and monocyte procoagulant activity.
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PMID:Cisplatin-induced platelet activation requires mononuclear cells: role of GMP-140 and modulation of procoagulant activity. 768 17

The human melanoma cell line M24met expresses tissue factor, the cellular initiator of the blood coagulation cascade. Blocking of the coagulation pathways at the level of tissue factor, factor Xa, or thrombin inhibits hematogenous M24met metastasis in SCID mice, implicating a role for thrombin generation in this process. Dependent on cell surface tissue factor activity, M24met cells generate thrombin in vitro. Thrombin and the thrombin receptor agonist peptide TRP-14 activate a signaling pathway in M24met cells that involves an increase in intracellular calcium and induces cell proliferation. Immunofluorescence evidences expression of the signaling thrombin receptor on these cells. Thus, M24met melanoma cells express both the initiating cell surface receptor for the coagulation pathways and the central signaling receptor of the coagulation system, suggesting the in situ generation of proliferative signals which can contribute to the malignant phenotype.
Cancer Res 1995 Apr 15
PMID:Tissue factor-initiated thrombin generation activates the signaling thrombin receptor on malignant melanoma cells. 771 65

Giroline (RP 49532A) is a new protein-synthesis inhibitor with broad antitumor activity in experimental models. In the present phase I study, Giroline was given by 24-h i.v. infusion every 3 weeks at doses ranging from 3 to 15 mg/m2 to 12 patients with advanced refractory solid tumors. The dose-limiting toxic effects were delayed hypotension and severe asthenia. The maximum tolerated dose (MTD) was 15 mg/m2. Transient nausea and vomiting during infusion were reported at all dose levels. Mild reversible prolongation of prothrombin time and activated partial thromboplastin time was observed in most patients at dose levels above 3 mg/m2. No antitumor activity was observed. The toxicity profile of Giroline precludes further evaluation in cancer patients.
Cancer Chemother Pharmacol 1995
PMID:Phase I study of RP 49532A, a new protein-synthesis inhibitor, in patients with advanced refractory solid tumors. 780 84

Recently, an increased frequency of thromboembolic events has been reported after the administration of anticancer drugs. The precise mechanism by which these vascular phenomena occur is unknown. The current work aims at evaluating the alterations of the coagulation and the fibrinolysis systems during the administration of antineoplastic agents by means of newly developed markers of haemostasis. This investigation comprised 25 lung cancer patients treated with multidrug combination chemotherapy. D-dimer, plasmin-alpha 2-antiplasmin complex, fibrin degradation products, fibrinogen, antithrombin III, thrombin-antithrombin III complex, prothrombin time and activated partial thromboplastin time were measured from samples taken before and on days 2, 5, 7, 14 and 21 after the administration of antineoplastic drugs. A significant reduction in plasma concentration of fibrinolytic activity markers, DD and PAP, was observed on days 5 and 7, and on days 2, 5, 7 and 14, respectively, following the administration of chemotherapeutic drugs. Statistically significant shortening of PT and APTT on days 2, 5, 7 and 14, as well as significant elevation of the thrombin generation marker TAT were observed on days 5 and 7 after chemotherapy. These results show that relatively higher levels of coagulation activation and a lower fibrinolytic activity occur during cytotoxic drug therapy compared with basal values. Small variations of haemostatic values and a short follow-up period may explain why no thrombotic events were observed during this study. Although further studies must be done to clarify these findings, the results of this investigation suggest that an imbalance of the coagulation-fibrinolysis system might be a contributing factor in the pathogenesis of thrombotic complications during chemotherapy.
Eur J Cancer 1994
PMID:Alteration of coagulation and fibrinolysis systems after multidrug anticancer therapy for lung cancer. 799 12

Severe thrombotic alterations, such as veno-occlusive disease of the liver, may occur in the early phase following high-dose chemoradiotherapy and BMT. In this study, performed in patients with hematological malignancies subjected to allogeneic (10 cases) and autologous (20 cases) BMT, we have monitored laboratory hemostatic parameters to better understand the pathogenetic mechanism of thrombosis and particularly of veno-occlusive disease. Prothrombin time, activated partial thromboplastin time, plasma fibrinogen, markers of hypercoagulability (thrombin-antithrombin complex and prothrombin fragment F1+2); natural anticoagulants (protein C, protein S and antithrombin) together with fibrinolytic parameters (plasminogen, alpha 2-antiplasmin, tissue-plasminogen activator, plasminogen activator inhibitor and D-dimer) were assessed before transplant, on day 0 and weekly for 1 month thereafter. A hypercoagulability state, not related to an impairment of the anticoagulant and fibrinolytic systems, was documented before and after autologous and allogeneic transplant. Two patients developed veno-occlusive disease: they did not show any difference from the other patients before transplant while they presented a decrease of the natural anticoagulants along with altered fibrinolytic parameters only at the clinical onset of veno-occlusive disease. In conclusion, in this study a state of marked hypercoagulability was documented in BMT patients and the hemostatic laboratory parameters evaluated were not able to predict the occurrence of the thrombotic complications.
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PMID:Hypercoagulability in patients undergoing autologous or allogeneic BMT for hematological malignancies. 824 85

Using a one-stage kinetic chromogenic assay, we studied the procoagulant activity (PCA) of prostatic tissue in an experimental model of prostate cancer in the rat. PCA was present in homogenates of rat prostate glands containing either benign or malignant tumours. The procoagulant activated factor X directly and was provisionally characterised as a tissue factor-factor VIIa complex. There was no significant differences in PCA between control rats and rats exposed to carcinogens that did not develop tumour. Levels in rats that developed tumours were significantly higher (P < 0.01) than all other groups and there was a positive correlation between tumour weight and PCA (r = 0.85, P < 0.001). Furthermore, prostatic PCA levels were higher in the metastasis (P < 0.02). We conclude that PCA reflects the malignant phenotype in this animals, the PCA of the primary tumour was compared with that of the corresponding secondary deposit and levels were higher in the metastasis (P < 0.02). We conclude that PCA reflects the malignant phenotype in this model of experimental prostate cancer and suggest that this parameter is worth evaluating as a potential tumour marker in the human disease.
Br J Cancer 1994 Feb
PMID:Procoagulant activity may be a marker of the malignant phenotype in experimental prostate cancer. 829 26

Malignant diseases have been shown to cause hypercoagulable states. Elevated prothrombin fragment F 1 + 2 plasma levels occur, when prothrombin is converted into thrombin by factor Xa. In order to evaluate the role of prothrombin fragment F 1 + 2 as an indicator for hemostatic disorders in patients with gynecologic malignancies, plasma levels of 76 patients with various malignancies of the female genital tract and those of 25 healthy subjects were investigated. Fifty-two of 76 (68.4%) patients with malignant diseases showed elevated F 1 + 2 plasma concentrations, whereas no elevated plasma levels were observed in the control group. Mean values of F 1 + 2 in the study group and the controls were 1.94 +/- 1.63 and 0.89 +/- 0.07 nmol/liter, respectively (P < 0.01). These results provide further evidence that gynecologic malignancies can induce hypercoagulable states.
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PMID:Prothrombin fragment F 1 + 2 plasma concentrations in patients with gynecologic malignancies. 802 Aug 31

Specific antibodies to tissue factor pathway inhibitor (TFPI) were used in immunohistochemical procedures to determine the distribution of TFPI in normal and neoplastic human tissues. TFPI was restricted to megakaryocytes and the endothelium of the microvasculature in normal and abnormal tissues, but was not found in the endothelium of larger vessels or in hepatocytes. TFPI was also detected in macrophages in the villi of term placenta. Tumor-associated macrophages in several types of malignancy that we have shown previously to express a complete tissue factor-initiated pathway of coagulation and thrombin generation also manifested TFPI. By contrast, malignant cells in small cell carcinoma of the lung, renal cell carcinoma, and malignant melanoma that we have shown previously to express coagulation factors together with tumor cell-associated fibrin formation failed to stain for TFPI. We postulate that TFPI may be lacking from the latter malignancies because of the absence of the appropriately configured tissue factor-factor VIIa-factor Xa complex required for TFPI binding.
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PMID:Distribution of tissue factor pathway inhibitor in normal and malignant human tissues. 849 49

While heparin has been the standard treatment in established deep vein thrombosis (DVT), it carries associated potential hazards of hemorrhage and induction of thrombocytopenia. Enoxaparin (Rhone-Poulenc Rorer Pharm. Inc., France) is a low molecular weight heparin which has antithrombotic properties, and has been demonstrated effective in prophylaxis of DVT, apparently without severe treatment related bleeding complications. Six patients with genital malignancies, presenting with Doppler sonography confirmed deep venous thrombosis, were treated with Enoxaparin. A uniform dosage of 2 mg/kg/day in two divided doses was administered subcutaneously for 10 days during hospitalization and then continued on an out-patient basis. The clinical symptoms of venous thromboses diminished in all six patients. Enoxaparin represents an effective treatment of DVT, with the potential advantage of a lessening hemorrhagic complications. With administration of low molecular heparin, the activated partial thromboplastin time (aPTT) is not dramatically altered, making laboratory monitoring unnecessary. Our clinical findings demonstrate an easily applied therapy for gynecologic oncology patients, which is potentially safer to use, less costly, and less dependent on laboratory monitoring than the normal regimen.
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PMID:Low molecular heparin (Enoxaparin) as an alternative treatment of acute deep venous thrombosis in gynecologic oncology patients. 893 32


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