Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.21.69 (APC)
 16,337 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Patients affected by inflammatory bowel disease (IBD) frequently suffer from thromboembolic events. Aims of this study were to investigate hemostatic system and the presence of antiphospholipid antibodies (aPL) in IBD patients. Forty-one patients affected by Crohn's disease (CD) and 19 by ulcerative colitis (UC) were studied, compared to 40 healthy control subjects. Platelet count (PLT), PT, aPTT, fibrinogen (Fib), prothrombin fragment F1+2, antithrombin (AT), protein C (PC), protein S (PS), factor XIII (FXIII), plasminogen (PLG), plasminogen activator inhibitor (PA1), spontaneous platelet aggregation in platelet-rich plasma (PRP-SPA) and in whole blood (WB-SPA), and antiphospholipid antibodies (aPL) were evaluated. PLT, Fib, F1+2 and WB-SPA were significantly increased in IBD patients (p at least <0.05) both in active and inactive phases; aPL positivity was more frequent (p<0.05) and FXIII was significantly decreased (p<0.05) in comparison to control subjects. The thrombophilic state of IBD patients is not related to the degree of activity of the disease or to previous thrombotic events; aPL express the immunological alterations connected with IBD and are not the main cause of thrombotic events.
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PMID:Hemostatic abnormalities in inflammatory bowel disease. 916 67

Vipera lebetina fibrinogenase (VlF) was shown to render fibrinogen incoagulable and to solubilize fibrin. The fibrinogenolytic activity of this enzyme was found to be 33 mg fibrinogen/min/mg protein. The study of the specificity of this enzyme revealed that it has no effect on purified factor X, prothrombin and protein C and on the specific chromogenic substrates of their active form. Plasminogen was not activated by VlF but slightly degraded. We have also compared the effect of VlF and plasmin on fibrinogen and shown that these two enzymes have a different sites of cleavage. This enzyme inhibited human platelet aggregation on PRP initiated by ADP and collagen but was without effect on the aggregation of washed rabbit platelets using thrombin as agonist. Administration of VlF in rat did not show any necrosis or hemorrhage in treated rats organ's. We therefore, examined the thrombolytic activity of VlF in a rat model of venous thrombosis. Thrombus was produced in the posterior vena cava by injection of human fibrinogen and thrombin. Injection of 5 mg/Kg body weight showed an evident flow restoration after one hour and measurement of the fibrinogen level a decrease of about 30% after 3 hrs. VlF's action is not dependent on plasminogen activators and may act synergistically with them, thereby providing an intriguing potential clinical application for dissolution of blood clots.
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PMID:Further characterization and thrombolytic activity in a rat model of a fibrinogenase from Vipera lebetina venom. 917 44

The zinc endopeptidases mutalysin I (100 kDa) and mutalysin II (22.5 kDa) have been previously isolated from bushmaster (Lachesis muta muta) snake venom. Hemorrhagic activity was observed with as little as 0.5 microg (2000 units/mg) and 17.8 microg (56.2 units/mg) for mutalysin I and II, respectively. Additionally, the proteases hydrolyse the Aalpha>Bbeta chain of fibrinogen without clot formation. The specific fibrinogenolytic activity was estimated as 5. 25 and 16.3 micromol fibrinogen/min/micromol protein for mutalysin I and II, respectively. In vitro, the enzymes act directly on fibrin and are not inhibited by serine proteinase inhibitors (SERPINS). Analysis by SDS-PAGE of fibrin hydrolysis by both enzymes showed that mutalysin II (0.22 microM) completely digested the alpha- and gamma-gamma chains and partially the beta-chain (in 120 min incubation). In contrast, mutalysin I (three fold higher concentration than mutalysin II) hydrolyzed selectively the alpha-chain of fibrin leaving the beta and gamma-gamma chains unaffected. Unlike with the plasminogen activator-based thrombolytic agents (e.g., streptokinase), mutalysins do not activate plasminogen. Neither enzyme had an effect on protein C activation. Mutalysin II does not inhibit platelet aggregation in human PRP induced by collagen or ADP. However, mutalysin I showed a selective inhibitory effect on collagen-induced aggregation of human PRP; it did not affect platelet aggregation with ADP as the agonist. The present investigation demonstrates that both native and EDTA-inactivated mutalysin I dose dependently blocked aggregation of human PRP elicited by 10 microg/mL of collagen with an IC(50) of 180 and 580 nM, respectively. These studies suggest that, in addition to the metalloprotease region of mutalysin I, the disintegrin-like domain also participates in the inhibitory effect. The proteolytic activity of mutalysin II against dimethylcasein and fibrin was completely abolished by alpha2-macroglobulin (alpha2-M). The stoichiometry of inhibition was 1.0 mol of enzyme per mol of alpha2-M. In contrast, the proteolytic effect of mutalysin I against the same substrates was not significantly inhibited by alpha2-M. Therefore, the data explain why mutalysin I contributes significantly not only to local but also to systemic bleeding associated with the observed pathological effects of the venom.
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PMID:Action of metalloproteinases mutalysin I and II on several components of the hemostatic and fibrinolytic systems. 1096 87

Calibrated automated thrombography displays the concentration of thrombin in clotting plasma with or without platelets (platelet-rich plasma/platelet-poor plasma, PRP/PPP) in up to 48 samples by monitoring the splitting of a fluorogenic substrate and comparing it to a constant known thrombin activity in a parallel, non-clotting sample. Thus, the non-linearity of the reaction rate with thrombin concentration is compensated for, and adding an excess of substrate can be avoided. Standard conditions were established at which acceptable experimental variation accompanies sensitivity to pathological changes. The coefficients of variation of the surface under the curve (endogenous thrombin potential) are: within experiment approximately 3%; intra-individual: <5% in PPP, <8% in PRP; interindividual 15% in PPP and 19% in PRP. In PPP, calibrated automated thrombography shows all clotting factor deficiencies (except factor XIII) and the effect of all anticoagulants [AVK, heparin(-likes), direct inhibitors]. In PRP, it is diminished in von Willebrand's disease, but it also shows the effect of platelet inhibitors (e.g. aspirin and abciximab). Addition of activated protein C (APC) or thrombomodulin inhibits thrombin generation and reflects disorders of the APC system (congenital and acquired resistance, deficiencies and lupus antibodies) independent of concomitant inhibition of the procoagulant pathway as for example by anticoagulants.
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PMID:Calibrated automated thrombin generation measurement in clotting plasma. 1698 60

To enhance the practical applicability of the calibrated automated thrombogram (CAT) we investigated whether frozen-thawed platelet-rich plasma (ft-PRP) can be used to assess the function of the protein C inhibitory pathway, while preserving the natural phospholipid composition. Recalcified ft-PRP triggered with 0.5 pM recombinant human tissue factor shows a median thrombin potential of 1,779 nM x min, against 1,576 nM x min for fresh PRP. To obtain approximately 70% inhibition, 6.7 nM activated protein C (APC) has to be added, instead of 25 nM in fresh PRP; so the relative APC resistance of PRP appears to depend upon the presence of intact platelets. Factor VIII, added to normal ft-PRP to obtain a concentration of 3.3 U/ml, increases the thrombin potential in the presence of APC 1.5-fold, from 524 to 808 nM x min, in keeping with previously published increases in thrombotic risk in patients with high factor VIII levels. We conclude that thrombography in ft-PRP, with and without added APC, can be used to assess known risk factors for thrombosis, which allows the design of large clinical studies aimed at proving the relationship between thrombin potential and clinical outcome.
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PMID:Calibrated automated thrombin generation in frozen-thawed platelet-rich plasma to detect hypercoagulability. 1285 9

The respective use of random (RPC) and apheresis (APC) platelet concentrates is highly heterogeneous among countries, ranging from 10 to 98% RPC in countries supposed to provide a similar transfusion service to patients. Moreover, when considering each country in the past 10 years, one can observe that some have changed their policy, switching from a majority of APC to RPC or vice versa. This presentation intends to analyse which factors may impact such decisions. For many years, the only available platelet component was a RPC obtained from whole blood donation by a two centrifugation steps process, the "platelet rich plasma" or PRP method. Since the beginning of the 1970s, APCs became available, with in fact many different techniques leading to many APCs that may not be equivalent. Since the end of the 1980s, a new method of RPC preparation was developed, using the buffy-coat (BC-PC), providing a blood component with highly preserved platelet functions as compared to RPCs prepared by the PRP technique. Finally, the use of each of these components either native, or leuco-reduced, or suspended in a storage solution, or processed with a pathogen inactivation technique adds new layers of complexity to compare them. Innumerable references can be found in the literature describing in vitro functional parameters of platelet concentrates. Although it is clear that BC-RPC retain much more their in vitro functions than PRP-RPC, indicating that no one should use the latter any more, it is much more difficult to distinguish differences between other PCs. Conversely, only a very few studies have been published related to a comparison of clinical efficacy of RPC versus APC, the endpoints being mainly CCI. Similarly to the in vitro studies, although RPC prepared with the PRP method show the lowest CCIs, no clear difference exists between "modern" RPC and APC. Another factor that may impact policy decision is the occurrence of adverse reactions in recipients. When considering only comparable data, for example leuco-reduced RPC versus leuco-reduced APC, there is now evidence that the latter is more associated with adverse reactions in recipients: data from hemovigilance in France show that, although no difference is noted for febrile non haemolytic transfusion reactions, nor for bacteria contamination, the incidence of allergic adverse reactions is about four times higher with APC as compared with RPC. Other aspects may impact the decision: the fact that using APC in place of RPC reduces the total donor exposure of patients was considered critical in some countries to reduce the risk of transmission of blood transmissible disease. Finally, the cost of the components, much higher for APC may be considered.
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PMID:Use of random versus apheresis platelet concentrates. 1841 1

Spinal cord injury (SCI) results in substantial oligodendrocyte death and subsequent demyelination leading to white-matter defects. Cell replacement strategies to promote remyelination are under intense investigation; however, the optimal cell for transplantation remains to be determined. We previously isolated a platelet-derived growth factor (PDGF)-responsive neural precursor (PRP) from the ventral forebrain of fetal mice that primarily generates oligodendrocytes, but also astrocytes and neurons. Importantly, human PRPs were found to possess a greater capacity for oligodendrogenesis than human epidermal growth factor- and/or fibroblast growth factor-responsive neural stem cells. Therefore, we tested the potential of PRPs isolated from green fluorescent protein (GFP)-expressing transgenic mice to remyelinate axons in the injured rat spinal cord. PRPs were transplanted 1 week after a moderate thoracic (T9) spinal cord contusion in adult male rats. After initial losses, PRP numbers remained stable from 2 weeks posttransplantation onward and those surviving cells integrated into host tissue. Approximately one-third of the surviving cells developed the typical branched phenotype of mature oligodendrocytes, expressing the marker APC-CC1. The close association of GFP cells with myelin basic protein as well as with Kv1.2 and Caspr in the paranodal and juxtaparanodal regions of nodes of Ranvier indicated that the transplanted cells successfully formed mature myelin sheaths. Transplantation of PRPs into dysmyelinated Shiverer mice confirmed the ability of PRP-derived cells to produce compact myelin sheaths with normal periodicity. These findings indicate that PRPs are a novel candidate for CNS myelin repair, although PRP-derived myelinating oligodendrocytes were insufficient to produce behavioral improvements in our model of SCI.
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PMID:Platelet-derived growth factor-responsive neural precursors give rise to myelinating oligodendrocytes after transplantation into the spinal cords of contused rats and dysmyelinated mice. 2240 83