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)

Mitogenesis, cell differentiation and immune-inflammatory responses are regulated by the coordinated assembly of proteases with specific cellular receptors. We have investigated the possibility that immune effector cells may express a high-affinity protease receptor. To address this hypothesis, we have generated mAb to factor V and its activated form Va, a circulating plasma protein that binds the serine protease of the coagulation cascade, factor Xa. Further, by flow microfluorimetry screening, we have isolated a panel of these mAb that recognize a surface molecule expressed on transformed monocytic cells. We now show that these mAb bind to blood monocytes, to CD3- CD16+ CD56+ NK cells, and with considerable heterogeneity, to neutrophils. A small subset of CD3+ cells (5 to 10%) was also identified by these probes and further phenotypically characterized by two-color flow microfluorimetry as predominantly coexpressing CD2, CD4 or CD8, CD57, CD11b, and alpha/beta TCR. This subset of CD3+ cells was expanded in vitro by both lectin- or Ag-specific stimulation. In addition, long term alloreactive stimulation resulted in approximately 8- to 10-fold increased expression of the molecule recognized by these mAb. Functional analyses were performed on a selected T cell clonal derivative of the transformed cell line HuT 78. These cells bound 125I-factor Xa in a specific reaction saturated at 194,000 +/- 26,000 molecules/cell with a Kd approximately 10 to 20 nM and inhibited by the mAb panel described above. These data suggest that immune effector cells express a dynamically regulated protease receptor that is immunologically related to the plasma coagulation protein factor V and its activated form Va. We propose the term effector cell protease receptor-1 to tentatively identify this molecule, and we speculate on its possible involvement in specialized protease-mediated effector functions.
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PMID:Identification of effector cell protease receptor-1. A leukocyte-distributed receptor for the serine protease factor Xa. 216 87

Curdlan sulfate (CRDS) is a semi-synthetic sulfated polysaccharide which has anti-HIV activity in vitro, and inhibits attachment of the virus to T-cells. After two weeks of exposure of virus and cells to CRDS, there is complete inhibition of virus replication. CRDS is also active against cytomegalovirus. The favorable toxicological profile of CRDS in animals suggested clinical trials. In this study, doses of 0.014, 0.14, 0.42, 1.42, 2.84 and 4.26 mg/Kg (hereinafter referred to as 1, 10, 30, 100, 200 and 300 mg/body, respectively, for convenience) were administered to three HIV-positive patients at each dose level for four hours intravenously. Activated partial thromboplastin times (APTT) were measured hourly. Unexpectedly, single doses of CRDS produced marked, dose-related, increases in CD4 lymphocytes in HIV-infected patients. There were no clinical side effects seen at any dose tested. All laboratory parameters were normal except for prolongation of APTT in the 200 and 300 mg dose group. Two patients in the 300 mg dose group had a doubling of the APTT during the four hour infusion, which was the termination point of the trial according to the protocol. The half-life of CRDS was estimated to be 2 to 3 hours from the APTT data and from the blood level assays (not shown). CRDS was well tolerated in the study with the APTT levels being a convenient monitoring basis for dosing. Marked increases in CD4 levels were seen at higher doses, which, if confirmed and extended, may have therapeutic implications. CRDS is considered safe for multiple dosing with monitoring of APTT.
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PMID:A phase I study of curdlan sulfate--an HIV inhibitor. Tolerance, pharmacokinetics and effects on coagulation and on CD4 lymphocytes. 799 61

Curdlan sulfate (CRDS) is a semi-synthetic sulfated polysaccharide which inhibits the attachment of HIV to T-cells, and also has intracellular anti-HIV activity. In Phase I clinical trials, CRDS was found in 4 hr i.v. infusions, to be well tolerated up to 200 mg/70 kg and unexpectedly to produce marked, dose-related increases in CD4 lymphocytes in HIV-infected patients. Prolongation of bleeding time is expected to be the dose limiting toxicity, but no episodes of bleeding were seen. In one of the studies in this report, CRDS was administered i.v. daily for 7 days to HIV patients at doses of 40, 100, 140 and 180 mg/70 kg/day. At the higher doses, marked increases in CD4 and CD8 lymphocytes were observed. These increases mainly returned to baseline after 24 hr. To further delineate the pharmacokinetics of these changes in CD4 and CD8 lymphocytes, another Phase I study was done in which CRDS was infused i.v. over a 30 min period in HIV patients at single doses of 25, 50, 75, 100, 125, 150, 175 and 200 mg/70 kg/day. The drug was well tolerated in all cases and marked increases in CD4 lymphocytes were again seen at the higher doses, in some cases amounting to increases of 500 cells/mm3 after a single dose. The half-life of CRDS in man was found to be about two hours, as measured by activated partial thromboplastin time (APTT) and by plasma assays.
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PMID:Further clinical studies of curdlan sulfate (CRDS)--an anti-HIV agent. 855 1

The chemokine RANTES (regulated on activation, normal T cell expressed and secreted) is a potent regulator of leukocyte trafficking. RANTES preferentially attracts mature CD4 cells as well as macrophages and eosinophils, but not neutrophils. In total, 128 children with meningococcal disease were prospectively studied, and the role of RANTES in the pathophysiology of meningococcal disease was assessed. Plasma RANTES, interleukin (IL)-8, IL-6, IL-1 receptor agonist, and tumor necrosis factor-alpha were measured at admission. Severity of disease was stratified by the Glasgow meningococcal septicemia prognostic score (GMSPS). RANTES levels correlated significantly with IL-8 levels, admission lactate levels, platelets, prothrombin time, and activated partial thromboplastin time. RANTES levels were lower in children with severe disease (GMSPS>/=8; P=.001), in those with septic shock (P<.0005), and in nonsurvivors (P=.048; Mann-Whitney test). RANTES is a potential mediator in the pathophysiology of meningococcal disease.
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PMID:The role of RANTES in meningococcal disease. 1088 26

Many aspects of acquired immunodeficiency syndrome (AIDS) have been described in detail in the literature. However, there have been very few articles on the phenomenon of deep vein thrombosis (DVT) in the lower extremities of human immunodeficiency virus (HIV)/AIDS patients. The objective of this communication is to record the incidence of DVT in HIV/AIDS patients and the risks for development of embolic events and to emphasize the need for prevention and for the vigorous treatment of this complication. We conducted a retrospective review of HIV/AIDS-infected patients with DVT admitted to Mount Sinai School of Medicine/Cabrini Hospital in New York during the last 5 years. Analysis includes demographic data; risk factors for HIV/AIDS infection; associated medical problems; recent surgery; and laboratory findings including CD4 counts, platelet counts, prothrombin times, partial thromboplastin times, and plasma albumin levels; and image studies. From January 1995 to January 2000 4752 HIV/AIDS-infected patients were admitted. Of those admitted to the hospital 45 (0.95%) were found to have DVT. There were 36 males and nine females (mean age 43 years). Of the 45 patients 38 had infectious complications and 13 developed a malignancy. The distribution of the thromboses were the femoral vein in 23 patients, the popliteal vein in 20 patients, and the iliofemoral system in 2 patients. Twelve patients had recurrent DVT and three patients developed a pulmonary embolism. HIV/AIDS infection is a considerable risk for development of DVT in the lower extremity. Statistically DVT in HIV/AIDS is approximately 10 times greater than in the general population. Emphasis upon prevention and vigorous treatment of DVT is recommended.
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PMID:HIV/AIDS and the risk of deep vein thrombosis: a study of 45 patients with lower extremity involvement. 1145 Jul 80

Aside from their critical role in thrombosis, activated coagulation factors also have inflammatory properties and these may be important during delayed xenograft rejection (DXR). This study assessed whether porcine EC could be activated by factor Xa (FXa) and thrombin (FIIa) and whether expression of tissue factor pathway inhibitor (TFPI)-CD4 and hirudin-CD4 fusion proteins could prevent such activation. Incubation of porcine EC with human FXa and FIIa induced cell surface expression of E-selectin, VCAM and tissue factor (TF) in a time-dependent and concentration-dependent manner. In contrast, porcine EC transfected with a human TFPI-CD4 fusion protein were selectively resistant to these pro-inflammatory effects of FXa but not FIIa. Likewise, the transfectants expressing the hirudin-CD4 fusion protein were selectively resistant to the pro-inflammatory effects of FIIa but not those of FXa. When combined, the FXa and FIIa had an additive effect on the activation of control EC. In contrast, coexpression of both hirudin-CD4 and TFPI-CD4 fusion proteins completely inhibited the upregulation of VCAM with the FXa/FIIa mix. These results indicate that expression of novel anticoagulant fusion proteins on the surface of porcine EC can protect against EC activation induced by human coagulation factors FXa and FIIa. In vivo, we anticipate that expression of these fusion proteins on the endothelium of transplanted xenografts, besides preventing intravascular thrombosis, will also protect against EC activation induced by trace amounts of FIIa and FXa, thereby further protecting the grafts from DXR.
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PMID:Human thrombin and FXa mediate porcine endothelial cell activation; modulation by expression of TFPI-CD4 and hirudin-CD4 fusion proteins. 1173 51

The implantation of nonautologous cells encapsulated in immunoprotective microcapsules provides an alternative nonviral method for gene therapy. This strategy was successful in reversing the disease phenotypes of dwarfism and a lysosomal storage disease, mucopolysaccharidosis VII, in murine models. In this article we implanted transgenic hemophilic B mice with microcapsules enclosing factor IX-secreting C2C12 myoblasts to study the clinical potential of this approach in the treatment of hemophilia. Treated mice showed increased plasma factor IX levels as high as 28 ng of human factor IX per milliliter of plasma and decreased activated thromboplastin times (reduced by 20% to 29%). However, the level of factor IX decreased to baseline levels by day 7, coinciding with emergence of anti-human factor IX antibody, the titer of which increased greater than 10-fold by day 28. Monoclonal anti-CD4 antibodies were used to deplete CD4+ T cells to suppress the immune response against the recombinant factor IX. In the treated hemophilic mice, the anti-factor IX antibody response was totally suppressed to beyond day 28 accompanied by a significant decrease in activated thromboplastin time compared with that seen in untreated hemophilic mice. When the microcapsules were recovered from the intraperitoneal cavity after 38 days of implantation, the encapsulated cells continued to secrete factor IX at preimplantation levels, but both cell viability and microcapsule mechanical stability were reduced. Hence although the polymer chemistry of the microcapsules and cell viability may need to be improved for long-term delivery, nonautologous gene therapy with microencapsulated cells has been shown to be effective, at least for the short-term, in alleviating the hemophilic hemostatic anomaly. Coadministration of an immunosuppressant is effective in inhibiting antibody development against the delivered factor IX and should be considered for recipients at risk of inhibitor development.
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PMID:Treatment of hemophilia B in mice with nonautologous somatic gene therapeutics. 1187 43

Severe acute respiratory syndrome (SARS) is a highly infectious disease with a significant morbidity and case fatality. The major clinical features include persistent fever, chills/rigor, myalgia, malaise, dry cough, headache and dyspnoea. Less common symptoms include sputum production, sore throat, coryza, dizziness, nausea, vomiting and diarrhoea. Older subjects may present with decrease in general well-being, poor feeding, fall/fracture and delirium, without the typical febrile response. Common laboratory features include lymphopenia with depletion of CD4 and CD8 lymphocytes, thrombocytopenia, prolonged activated partial thromboplastin time, elevated D-Dimer, elevated alanine transminases, lactate dehydrogenase and creatinine kinase. The constellation of compatible clinical and laboratory findings, together with the rather characteristic radiological features especially on HRCT and the lack of clinical response to broad-spectrum antibiotics, should quickly arouse suspicion of SARS. The positivity rates of urine, nasophargyngeal aspirate and stool specimen have been reported to be 42%, 68% and 97%, respectively, on day 14 of illness, whereas serology for confirmation may take 28 days to reach a detection rate above 90%. Recently, quantitative measurement of blood SARS CoV RNA with real-time RT-PCR technique has been developed with a detection rate of 80% as early as day 1 of hospital admission but the detection rates drop to 75% and 42% on day 7 and day 14, respectively.
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PMID:SARS: clinical features and diagnosis. 1501 29

Immune coagulation is a major contributor to the pathogenesis of xenograft rejection, viral-induced hepatocellular injury and cytokine-induced fetal loss syndrome. In this study, we investigated the contribution of the novel gene product, fibrinogen-like protein 2 (fgl2) prothrombinase, in mediating immune injury in experimental and human acute allograft rejection. Using a mouse heterotopic cardiac transplant model, mouse fgl2(mfgl2)/fibroleukin mRNA transcripts and protein were highly expressed in macrophages, CD4- and CD8-positive T lymphocytes, and endothelial cells in rejecting cardiac allografts in association with deposits of fibrin. Although mfgl2-deficient mice rejected allografts at similar rates to littermate controls, survival of grafts from mfgl2-deficient mice were prolonged and deposition of intravascular fibrin was diminished. Treatment of wild-type mice with a neutralizing anti-fgl2 Ab ameliorated histological evidence for allorejection and intravascular fibrin deposition, and resulted in an increase in graft survival. To address further the relevance of fgl2 in acute allograft rejection, we examined kidney biopsies from patients who had undergone renal transplantation. Human fgl2 mRNA transcripts and protein were markedly expressed mainly in renal tubule cells, infiltrating lymphoid cells including macrophages, CD8(+) T cells, mature B cells (plasma cells), and endothelial cells. Dual staining showed fibrin deposition was localized mainly to blood vessels, in the glomerulus and interstitium and the lumen of tubules, and occurred in association with human fgl2 expression. These data collectively suggest that fgl2 accounts for the fibrin deposition seen in both experimental and human allograft rejection and provide a rationale for targeting fgl2 as adjunctive therapy to treat allograft rejection.
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PMID:Role of fibrinogen-like protein 2 prothrombinase/fibroleukin in experimental and human allograft rejection. 1590 89

There are still controversies concerning the role of immunological mechanisms engaged both in recurrent abortions (RA) and pre-eclampsia (PE). According to some opinions, recurrent miscarriage is comparable to organ-specific autoimmune disease. Analysis of immune reactions shows that graft rejection shares many similar mechanisms with RA and PE. This fact allows us to conclude that rejection of transplanted alloantigenic organs and pregnancy loss have probably the same evolutionary origin. Subsets and functions of immunocompetent cells (T CD4, suppressor gammadeltaT, cytotoxic T CD8, Treg, Tr1, uterine NK cells), over-activation of innate immunity (activation of NK cytotoxic cells, macrophages, neutrophils and complement), changes of Th1/Th2 cytokine balance (IL-2, IL-12, IL-15, IL-18, IFNgamma, TNFalpha vs. IL-4, IL-10, TGFbeta), importance of HLA-G molecule, CD200/CD200R interaction, over-expression of adhesion molecules, fgl2 prothrombinase activation and stimulation of IDO and HO expression, all suggest that RA and PE are syndromes of fetal allograft rejection, and not organ-specific autoimmune diseases. According to that supposition, an analogy might exist between acute graft rejection and recurrent abortion, and between chronic graft rejection and pre-eclampsia.
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PMID:Immunological analogy between allograft rejection, recurrent abortion and pre-eclampsia - the same basic mechanism? 1682 4


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