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)

Asparaginase (ASNase) is a widely used and successful agent against childhood acute lymphoblastic leukemia (ALL). Asparaginase cleaves asparagine (Asn) to give aspartic acid and ammonia, thereby depleting free Asn in the blood. However, treatment with ASNase has been implicated in significant reduction of plasma levels of the coagulation serine protease inhibitor (serpin) antithrombin III (AT3), predisposing patients to thromboembolic complications. Our investigation was designed to delineate the biochemical mechanism of AT3 depletion that can occur in the plasma of ALL patients undergoing ASNase therapy. SDS-PAGE showed no cleavage of purified AT3 following treatment with ASNase. Furthermore, purified AT3 treated with ASNase demonstrated no decrease in inhibitory activity. Human plasma and whole blood treated with approximate therapeutic concentrations of ASNase showed no loss of AT3 activity as detected by a plasma-based factor Xa inhibition assay. Treatment of a confluent monolayer of HepG2 (hepatocarcinoma) cells with ASNase showed no gross loss in AT3 message levels detected by rtPCR. However, a decrease of cell viability was observed in cultures treated with ASNase. Interestingly, medium from HepG2 cells treated with ASNase showed a marked decrease in secretion of AT3 and another serpin, heparin cofactor II. Collectively, these data show that ASNase has no direct effect on AT3 in blood or plasma, but that ASNase may affect plasma levels of AT3 by interfering with translation and/or secretion of the protein in liver cells.
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PMID:Insight into the mechanism of asparaginase-induced depletion of antithrombin III in treatment of childhood acute lymphoblastic leukemia. 1086 29

A large east Texas family with autosomal dominant inheritance of a novel bleeding disorder has been identified. The disorder is characterized clinically by easy bruising, life-threatening bleeding with trauma or surgery, and menorrhagia in affected women. Laboratory studies demonstrated prolongation of the prothrombin time and activated partial thromboplastin time in affected individuals. Paradoxically, assays of known coagulation factors are all within normal limits. To determine the molecular basis of this disease, a candidate gene linkage analysis in this kindred was done. Initially it was hypothesized that the cause of the disease in this family could be an antithrombin III (AT3) mutation that resulted in a constitutively active AT3 in the absence of heparin binding. Linkage studies using DNA from the family and an intragenic polymorphic marker within the AT3 gene showed that the disease mapped to this locus. The coding region and intron/exon junctions of AT3 were sequenced using the proband's DNA, but this analysis failed to identify a mutation. Additional family members were recruited for the study, and 16 polymorphic markers around the AT3 gene were analyzed. Using 2 recombinants, the critical interval for the defective gene was narrowed to approximately 1.5 Mb, centromeric to AT3. The factor V (FV) gene was mapped into the disease interval and sequenced; there were no mutations found. Elucidation of the genetic defect causing the bleeding disorder in this family may reveal a novel protein involved in the coagulation cascade.
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PMID:Characterization of a novel autosomal dominant bleeding disorder in a large kindred from east Texas. 1123 89

The transfusion of fresh-frozen plasma (FFP) is suggested to minimize dilution coagulopathy when applied instead of colloids during paediatric craniofacial surgery (pCFS). We prospectively compared plasmatic haemostaseologic function between volume replacement with FFPs versus human albumin (HA) in a pilot study. Thirty infants with primary craniosynostosis were scheduled for pCFS. In 15 of those, FFPs were available from the identical donor as for packed red blood cells (pRBC), and were thus employed for intraoperative volume replacement. The remaining 15 infants were infused with HA-5% instead. Haemoglobin(Hb)-values, global coagulation parameters (activated partial thromboplastin time-aPTT; prothrombin time-PT), selected clotting factors (F) (VIII, XI, XIII), antithrombin-AT, fibrinolytic factors (fibrinogen; plasminogen; alpha2-antiplasmin-alpha2A), and activation parameters (thrombin-antithrombin-complex-TAT; plasmin-antiplasmin-complex-PAP; D-dimers) were assessed and compared between both groups after induction of anaesthesia, before transfusion of pRBC, and at the end of surgery. Patients and treatment characteristics were balanced between both groups. Prolongation of aPTT and decreases of PT, FXI, FXIII, AT3, and fibrinolytic factors were more pronounced in the HA-group. Increases in F VIII activity, activation parameters, and the course of Hb-values were similar among both groups. There was no difference regarding clinical endpoints (peri-/postoperative pRBC-transfusions, postoperative blood loss). In conclusion, the application of HA was associated with a more distinct dilution of procoagulant factors, AT3, and fibrinolytic factors than the use of FFPs. However, the course of activation markers suggested a similar extent of clotting and fibrinolytic activation with the use of both transfusion regimens, and there were no differences with regard to clinical endpoints.
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PMID:Intraoperative fresh-frozen plasma versus human albumin in craniofacial surgery--a pilot study comparing coagulation profiles in infants younger than 12 months. 1759 10

Protein Z-dependent protease inhibitor (ZPI) and antithrombin III (AT3) are members of the serpin superfamily of protease inhibitors that inhibit factor Xa (FXa) and other proteases in the coagulation pathway. While experimental structural information is available for the interaction of AT3 with FXa, at present there is no structural data regarding the interaction of ZPI with FXa, and the precise role of this interaction in the blood coagulation pathway is poorly understood. In an effort to gain a structural understanding of this system, we have built a solvent equilibrated three-dimensional structural model of the Michaelis complex of human ZPI/FXa using homology modeling, protein-protein docking and molecular dynamics simulation methods. Preliminary analysis of interactions at the complex interface from our simulations suggests that the interactions of the reactive center loop (RCL) and the exosite surface of ZPI with FXa are similar to those observed from X-ray crystal structure-based simulations of AT3/FXa. However, detailed comparison of our modeled structure of ZPI/FXa with that of AT3/FXa points to differences in interaction specificity at the reactive center and in the stability of the inhibitory complex, due to the presence of a tyrosine residue at the P1 position in ZPI, instead of the P1 arginine residue in AT3. The modeled structure also shows specific structural differences between AT3 and ZPI in the heparin-binding and flexible N-terminal tail regions. Our structural model of ZPI/FXa is also compatible with available experimental information regarding the importance for the inhibitory action of certain basic residues in FXa.
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PMID:A computational modeling and molecular dynamics study of the Michaelis complex of human protein Z-dependent protease inhibitor (ZPI) and factor Xa (FXa). 1917 19