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)

Prekallikrein was purified 1,200-fold in 20% yield from human plasma by DEAE-cellulose, arginyl-triazinyl-aminododecyl-agarose, Cm-Sephadex C-50, and Sephadex G-150 chromatography. Isoelectric focusing of the purified proenzyme gave seven peaks, four major ones at pH 8.6, 8.8, 9.1, and 9.3; and three others at pH 7.9, 8.3, and 9.5. The same IEF profile was obtained from plasma of four individuals of three races and both sexes and from three plasma pools, and was not altered by using diisopropyl fluorophosphate, benzamidine, or EDTA during fractionation. Each major IEF form contained Mr = 88,000 (prekallikrein I) and Mr = 85,000 (prekallikrein II) species, in increasing ratios of I:II from about 20:1 in prekallikrein 8.6 (prekallikrein with pI 8.6) to 1:1 in prekallikrein 9.3. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis of the four zymogens after activation by Hageman factor fragment and reduction gave an Mr = 53,000 H-chain and two L-chains, LI (Mr = 40,000) and LII (Mr = 37,000). Scanning the gels gave LI:LII ratios of 19:1, 5:1, 2:1, and 1:1 for prekallikreins 8.6, 8.8, 9.1, and 9.3, respectively, corresponding to the prekallikrein I:II ratios. The H-chain in turn was split into Mr = 33,000 and 20,000 chains, presumably by autolysis, because the cleavage was prevented by soybean trypsin inhibitor. Each major kallikrein had a pI 0.1-0.2 lower than its zymogen, but the same LI:LII ratio. The four kallikreins were indistinguishable kinetically with human plasma high-molecular weight kininogen and 15 synthetic substrates, and in correcting the activated partial thromboplastin time of prekallikrein-deficient (Fletcher) plasma.
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PMID:Purification and characterization of multiple forms of human plasma prekallikrein. 384 40

From the analysis of 115 cases of primary generalized epilepsies treated for a mean duration of 43 months with sodium valproate as sole therapy, it appears that: the mean effective daily dosage is 21 mg/kg; the efficacy of valproate proved excellent in 82.6% of cases (seizures fully controlled: 74%, seizures occurring exceptionally: 9%); a loss of activity was never observed; in these circumstances of prolonged administration of the drug, no signs of major intolerance were seen; side-effects occurred in 29% of cases, including 20% long-term effects (weight gain, essential tremor); 64 series of laboratory tests including 15 parameters made it possible to evaluate the hematological, hepatic and pancreatic tolerance of valproate: the majority of the tests were normal. The authors believe that during long-term therapy with valproate, monitoring does not need to include the routine performance of liver function tests, but that it would be more advisable, should a suggestive clinical sign be noted, to investigate the platelet count, coagulation (partial activated thromboplastin time) and protein synthesis (fibrinogen).
Sem Hop 1983 Apr 21
PMID:[Monotherapy with sodium valproate in generalized primary epilepsy. 2d phase: Study of long-term efficacy and tolerance]. 619 93

Any diffuse lesion of the liver induces permanent hypercoagulation with subsequent permanent lysis and possible consumption or DIVC/Hemostasis depends on two distinct mechanisms: the platelets, whose functional activity is more important than numbers, and the coagulolytic equilibrium of the plasma. Apart from the activating and inhibiting enzymes of coagulation and lysis, the lungs and liver play an important role. The lungs filter and then determine lysis of the corpuscular agglomerates. The liver produces epuration of the activated factors and prothrombinase, as well as the plasminogen activator. Except in extremely severe cases, however, these functions are rarely involved. Investigations must be complete and include a test of platelet aggregation, a TEG on total blood to analyze whole coagulation, and tests for consumption and lysis. Coagulation and bleeding time tests are of great value during severe hemorrhagic attacks. Pathological examination should evaluate the condition of the vascular state and, more particularly, the presence of fibrin thrombi with the appropriate methods.
Sem Hop
PMID:[Introduction to the study of hemostasis in cirrhotic patients (author's transl)]. 625 23

A comparative clinical trial was undertaken in 2420 patients undergoing thoracic surgery during a 4-year period (1973-1977); 40% of the patients had bronchial cancer. Random allocation was not considered as being possible by the surgeons and was replaced by allocation according to the time of operation. There were three protocol groups: Protocol A: First morning operations (1007 patients): subcutaneous calcium heparin, 5000 units (Ul) 2 hours and 30 minutes before surgery then every 12 hours for 15 days. Protocol B: Second morning operations (932 patients): same dose and duration of treatment; the first injection took place 24 to 72 hours after the surgical procedure. The doses were increased from the fourth day after surgery in order to obtain a moderately prolonged partial thromboplastin time (difference patient-control: 7 to 14 seconds). Protocol 0: 481 patients received no anticoagulant treatment because of a contraindication or minor surgical procedure. Preliminary results showed and increase of per-operative bleeding (p less than 0.01) in treated patients; this was very well accepted by the surgeons. Among the heparin-treated patients, 11 pulmonary emboli out of 13 were observed in patients with bronchial cancer. Of these 13, 10 were fatal with 9 being verified at autopsy. The pulmonary emboli episodes occurred significantly earlier in protocol B than in protocol A. Fatal pulmonary embolism in patients with bronchial cancer was significantly more frequent in protocol B (7 cases) than in protocol A (1 case); P less than 0.01. These results have shown a low frequency of fatal pulmonary emboli in patients without bronchial cancer receiving twice-daily subcutaneous injections of heparin (2 of 1102 operated subjects). The rate was higher in patients with bronchial cancer and this results supports a recommended thrice-daily dose in such patients. In addition, the pre-operative administration of heparin is useful in preventing early post-operative pulmonary embolism.
Sem Hop
PMID:[Prevention of postoperative thrombo-embolic accidents following thoracic surgery by low-dose calcium heparinate: a comparative study (author's transl)]. 626 28

The observation of two cases of thrombophlebitis of the calf which occurred in two sisters within a period of three years is reported. The investigation revealed in both cases the presence of a circulating anticoagulant with anti-prothrombinase activity in association with biological signs of systemic lupus erythematosus (L.E.): anti-DNA antibodies, decreased complement levels, false positive BW reactions. In one patient, the skin biopsy showed a continuous IgM band on immuno-fluorescence. After respectively 4 years and 18 months follow-up both patients are still free from clinical symptoms. A review of the literature is presented and the clinical and etiological significance of the presence of a circulating anticoagulant, its relationship with L.E., particularly with "latent" L.E. (presence of biological signs only), and its association with thrombophlebitis are discussed.
Sem Hop
PMID:[Venous thrombosis, circulating anticoagulant and systemic lupus erythematosus. Two cases reported in two identical HLA sisters (author's transl)]. 627 28

The factor VIII complex is a macromolecule with two distinct components. One is the coagulation factor VIII. The other, known as the Willebrand factor, is a polymer which probably acts as a carrier for serum factor VIII. Hereditary disorders can affect either of these two components. Hemophilia A is a coagulation disorders due to decreased factor VIII coagulant activity. Increase of partial activated thromboplastin time parallels disease severity. Hematomas and hemarthrosis in large joints are the main clinical features. In von Willebrand disease, mucocutaneous bleeding is the main symptom. Diagnosis is established by demonstrating disorders of primary hemostasis: prolonged bleeding time and decreased ristocetin-induced platelet aggregation. Two forms of von Willebrand disease have been described. In the quantitative form, decreased synthesis of von Willebrand factor is often responsible for severe clinical manifestations. The qualitative form probably results from defective polymerization of von Willebrand factor subunits. In both these forms, deficient primary hemostasis is a consequence of decreased platelet adhesion to the vascular wall. Clinical and biological features of hemophilia A and von Willebrand disease, as well as their management, are discussed.
Sem Hop 1982 Sep 30
PMID:[The factor VIII complex: hemophilia A and von Willebrand disease]. 629 93

Antithrombin is an anticoagulant serpin with conformational sensitivity. Mutations and environmental factors may induce its polymerization by a mechanism involving domain swapping, which still requires verification. We have evaluated the functional and conformational effects on antithrombin of citrullination, a post-translational modification catalyzed by peptidylarginine deiminase (PAD), which changes arginine to citrulline. Purified antithrombin (native and latent forms) and plasma were incubated with PAD in the presence and absence of heparin. Citrullines were identified by proteomic analysis. Anti-activated factor X activity determination, IEF, SDS/PAGE and native PAGE were performed. The cleavage pattern with the metalloprotease AspN was studied, and its target residues were identified by Edman sequencing. We confirmed that citrullination of antithrombin abolished its activity; this abolition of activity was accelerated by heparin, which facilitated the early citrullination of Arg393 (P1 residue). Proteomic analyses revealed nine additional citrullines that caused a significant decrease in its electrostatic potential (from 5.95 to 5.06). It was demonstrated that citrullination of antithrombin caused its polymerization. The observation that these polymers, like heat-generated polymers, are cleaved by AspN in helix I is compatible with their linkage by domain swapping from strand 5 to strand 4 of beta-sheet A.
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PMID:Effect of citrullination on the function and conformation of antithrombin. 1984 80

We have recently reported the development and validation of quantum mechanical (QM)-based hydrophobic descriptors derived from the parametrized IEF/PCM-MST continuum solvation model for 3D-QSAR studies within the framework of the Hydrophobic Pharmacophore (HyPhar) method. In this study we explore the applicability of these descriptors to the analysis of selectivity fields. To this end, we have examined a series of 88 compounds with inhibitory activities against thrombin, trypsin and factor Xa, and the HyPhar results have been compared with 3D-QSAR models reported in the literature. The quantitative models obtained by combining the electrostatic and non-electrostatic components of the octanol/water partition coefficient yield results that compare well with the predictive potential of standard CoMFA and CoMSIA techniques. The results also highlight the potential of HyPhar descriptors to discriminate the selectivity of the compounds against thrombin, trypsin, and factor Xa. Moreover, the graphical representation of the hydrophobic maps provides a direct linkage with the pattern of interactions found in crystallographic structures. Overall, the results support the usefulness of the QM/MST-based hydrophobic descriptors as a complementary approach for disclosing structure-activity relationships in drug design and for gaining insight into the molecular determinants of ligand selectivity. Graphical Abstract Quantum Mechanical continuum solvation calculations performed with the IEF/PCM-MST method are used to derived atomic hydrophobic descriptors, which are then used to discriminate the selectivity of ligands against thrombin, trypsin and factor Xa. The descriptors provide complementary view to standard 3D-QSAR analysis, leading to a more comprehensive understanding of ligand recognition.
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PMID:Application of the quantum mechanical IEF/PCM-MST hydrophobic descriptors to selectivity in ligand binding. 2718 23