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)

Activated Protein C (APC) resistance, one of the most common genetic risk factors for venous thrombosis, is caused by a single base mutation (G1691-->A) in the factor V (FV) gene resulting in the replacement of Arg506 by Gln at a predominant cleavage site for APC. Great progress in understanding the mechanism of downregulation of FVa activity via the protein C pathway has been achieved by studying APC-mediated inactivation of FVa purified from homozygous APC-resistant individuals. This review briefly summarizes the role of FVa in prothrombin activation and the structure-function relationship of FV and FVa. Subsequently, APC-dependent inactivation of FVa and FVa Leiden and its modulation by protein S and factor Xa in model systems containing purified proteins is discussed. FV also has a function in increasing the inactivation of FVIII/VIIIa by APC. This cofactor activity appears diminished in FV Leiden. Thus, an intricate mechanism of regulation of thrombin formation via the protein C pathway is starting to emerge. Extensive studies in plasma milieu will be needed to gain more insight into the relation between the presence of FV Leiden and impaired downregulation of thrombin formation in APC-resistant individuals.
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PMID:Regulation of thrombin formation by activated protein C: effect of the factor V Leiden mutation. 924 9

The effect of human neutrophil elastase (HNE) on human factor V (F.V) or alpha-thrombin-activated human factor V (F.Va) was studied in vitro by prothrombinase assays, sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), and NH2-terminal sequence analysis. Incubation of F.V (600 nmol/L) with HNE (2 nmol/L) in the presence of Ca2+ resulted in a time-dependent increase in its cofactor activity. In contrast, treatment of F.Va (600 nmol/L) with HNE (60 nmol/L) in the presence of Ca2+ resulted only in a time-dependent decrease in its cofactor activity. Under the conditions of these experiments, the maximum extent of F.V activation accomplished by incubation with HNE was approximately 65% to 70% of that observed with alpha-thrombin in presence of Ca2+. The extent of both the HNE-dependent enhancement in F.V cofactor activity and the HNE-dependent decrease in F.Va cofactor activity was not influenced by the addition of phosphatidylcholine/phosphatidylserine (PCPS) vesicles (50 micromol/L). The HNE-derived cleavage products of F.V, which correlated with increased cofactor activity, as demonstrated by SDS-PAGE under reducing conditions, were different from those generated using alpha-thrombin. Treatment of F.V (600 nmol/L) with HNE (2 nmol/L) in the presence of Ca2+ resulted in the production of three closely spaced doublets of: 99/97, 89/87, and 76/74 kD whose appearance over time correlated well with the increased cofactor activity as judged by densitometry. Treatment of F.Va (600 nmol/L) with HNE (60 nmol/L) in the presence of Ca2+ resulted in the cleavage of both the 96 kD heavy chain and the 74/72 kD light chain into products of: 56, 53, 35, 28, 22, and 12 kD. Although densitometry indicated that both the heavy and light chains of F.Va were hydrolyzed by HNE, cleavage of the 96 kD heavy chain was more extensive during the time period (10 to 30 minutes) of the greatest loss of F.Va cofactor activity. NH2-terminal sequence analysis of F.V treated with HNE indicated cleavage at Ile819 and Ile1484 under conditions during which the procofactor expressed enhanced cofactor activity in the prothrombinase complex. NH2-terminal sequence analysis of F.Va treated with HNE indicated cleavage at Ala341, Ile508, and Thr1767 under conditions, which the cofactor became inactivated, as measured by prothrombinase activity. The activation and inactivation cleavage sites are close to those cleaved by the physiological activator and inactivator of F.V and F.Va, namely alpha-thrombin (Arg709 and Arg1545) and Activated Protein C (APC) (Arg306 and Arg506), respectively. These results indicate that HNE can generate proteolytic products of F.V, which initially express significantly enhanced procoagulant cofactor activity similar to that observed following activation with alpha-thrombin. In contrast, HNE treatment of F.Va resulted only in the loss of its cofactor activity, but again, this is similar to that observed following inactivation by APC.
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PMID:Human neutrophil elastase activates human factor V but inactivates thrombin-activated human factor V. 924 37

The work was aimed to estimate the interrelation and indexes which define the main alterations of hemostatic deviations in the patients with abdominal bleeding. For this reason the authors have analysed interrelations between 31 hemostasis indexes in 30 patients after operations. Fourteen groups of interrelated indications have been revealed. They are as follows: 1. Prothrombin index, activated partial thromboplastin index; 2. Prothrombin's inactive forms (prethrombin-1, decarboxylated prethrombin etc.), ecamulin index; 3. Velocity bend of distraction of fibrin clot, velocity bend of forming of fibrin clot, height of clot using turbidimetric method; 4. Half-lysis time, lysis time, time of fibrin clot using turbidimetric method; 5. Velocity, Intensity, remainder of platelet aggregation induced by ADP 10 mcg/ml, 2.5 mcg/ml, 1.9 mcg/ml; 6. Thrombin time; 7. Protein C; 8. Fibrinogen; 9. Platelet count; 10. Soluble fibrin; 11. Ancystron time; 12. X factor; 13. Antithrombin-III; 14. Fibrin(ogen) degradation products. It was shown how different groups affect hemostasis. The authors have suggested to use the data of mathematical analysis and laboratory tests for the estimation of hemostatic deviations.
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PMID:[Hemostasis in patients operated for abdominal bleeding. I. Estimation of the relationship of hemostasis parameters according to data of the correlation coefficient and factor analysis]. 945 84

Thirteen coagulation tests evaluating hemostatic and fibrinolytic indices and serum cytokine and plasma endotoxin concentrations were obtained in 34 foals with a positive sepsis score (septic group) and 46 age-matched healthy foals. Compared to healthy foals, the prothrombin, activated partial thromboplastin, and whole blood recalcification times were significantly longer in septic foals. The fibrinogen and fibrin degradation products concentrations, percent plasminogen, alpha-2 antiplasmin, and plasminogen activator inhibitor activities, and tumor necrosis factor and interleukin-6 activities were greater in septic foals. Protein C antigen and antithrombin III activity were significantly lower in septic foals. Blood cultures were positive for growth and endotoxin was detected in 19 of 29 and 15 of 30 septic foals, respectively. In septicemic foals with detectable endotoxin in the plasma, the prothrombin and activated partial thromboplastin times were significantly longer and the plasminogen and antithrombin III activities were significantly less than in septic foals in which endotoxin was not detected. Twenty-three of the 34 septic foals did not survive. Septic foals that did not survive were most likely to have a positive blood culture in which a gram-negative organism was isolated. Histopathologic evidence of hemorrhage was evident in 11 foals at postmortem examination and thrombosis was identified in 2 foals. The prothrombin time was significantly longer in foals that had multisite hemorrhage at postmortem examination. The results of this study indicate that clinically relevant alternations in hemostatic and fibrinolytic indices occur in neonatal foals with septicemia and that derangements can be correlated with the presence of endotoxin in plasma. Derangements in hemostatic or fibrinolytic indices were helpful in identification of septic foals with increased risk of coagulopathy, but were not helpful in predicting hemorrhage as compared to thrombus formation. Survival of septicemic foals was correlated with gram-negative bacteremia, but not with the presence of endotoxin or coagulopathy.
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PMID:Hemostatic and fibrinolytic indices in neonatal foals with presumed septicemia. 950 57

We investigated hemostatic parameters in a prospective study of 16 patients who received bone marrow transplants (BMT). We found a significant rise in the levels of fibrinogen, plasmin-alpha2 antiplasmin inhibitor complex, tissue-plasminogen activator.plasminogen activator inhibitor complex (t-PA.PAI), von Willebrand factor antigen, and thrombomodulin on day 14 after transplant compared with values before transplant. Protein C and thrombin-antithrombin III levels did not change significantly. No significant changes in prothrombin time ratio, activated partial thromboplastin time, or protein S were detected. Patients who had grades II-IV graft-versus-host disease (GVHD) (n = 6) showed a significantly higher level of t-PA.PAI on day 14 compared with those with grades 0-I GVHD (n = 10) (P = 0.0062). Three patients with grades II-IV GVHD developed thrombotic microangiopathy (TMA) on days 19, 19 and 62. In these patients, we noted significantly lower levels of fibrinogen (P = 0.0383), and significantly higher levels of t-PA.PAI (P = 0.0008) and thrombomodulin (P = 0.0001) on day 14 compared with those patients who did not develop TMA. These results suggest that prothrombotic states and endothelial damage may be caused by the conditioning regimen and/or acute GVHD during BMT; thrombomodulin values on day 14 post BMT may be useful in surveillance for TMA because of endothelial cell injury.
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PMID:Diagnostic value of hemostatic parameters in bone marrow transplant-associated thrombotic microangiopathy. 957 11

Protein C is a plasmatic inhibitor which regulates the blood coagulation mechanism by modulating the anticoagulant response. The improvement of its bioavailability would be beneficial for the treatment of the disorders caused by its homozygous deficiency or by an other plasmatic inhibitor deficiency. In this context, the protein C encapsulation into biodegradable nanoparticles could be used to approach the problem. However, the method used to prepare the nanoparticles requires the use of ultrasonication and of an organic solvent such as methylene chloride which interferes with protein activity. Sodium dodecyl sulfate polyacrylamide gel electrophoresis showed that neither ultrasonication nor methylene chloride, singly or in combination, led to protein C aggregation or cleavage. Thus, a binding study using an ELISA assay with four characterized monoclonal antibodies was carried out to identify the epitopes damaged by these experimental constraints. The correlation between the immunological assay and a functional one i.e. by the means of the assay of its anticoagulant activity (activated partial thromboplastin time) made it possible to show that protein C amino acids 166-169 of the activation peptide were probably altered after ultrasonication and methylene chloride treatment. Indeed, it is likely that these residues were no longer surface-exposed but had moved inside the protein core.
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PMID:Identification of protein C epitopes altered during its nanoencapsulation. 1069 Nov 88

A 15-year-old woman with a history of transient dysarthria two years before, suddenly developed weakness of right upper extremity, right facial palsy, and dysarthria. She was admitted to our hospital on the third day. She had no hypertension, heart murmur and oedema. On neurological examination, she had mild right hemiparesis including face muscles and mild dysarthria. The right knee jerk was brisk with no Babinski's sign. Ataxia and sensory disturbance were not present. T2-weighted MRI showed a hyperintensity at the posterior limb of the left internal capsule. Cerebral angiography was unremarkable. Ultracardiography and 24-hour electrocardiography were normal. Laboratory data revealed no inflammatory findings, liver dysfunction, hyperglycemia and hyperlipidemia. Antinuclear and anticardiolipin antibodies were negative. Prothrombin time was normal, but activated partial thromboplastin time was slightly prolonged (35.4 sec, normal 25.2-34.4). Protein C, protein S and antithrombin III were normal. Heparin cofactor II (HC II) activity was decreased (44%) with normal HC II antigen (79%) and so she was diagnosed as heparin cofactor II deficiency type II (heparin cofactor II abnormality). Her father manifesting thromboangitis obliterans also had low HC II activity with normal HC II antigen. However, on her genetic analysis, we didn't detect any mutations in the coding region of HC II gene. Until now she has no recurrence of cerebrovascular attacks. On the basis of these results, we suspect that HC II deficiency was a possible risk factor of cerebral infarction in this case because she was so young and had no general risk factors except for HC II. No stroke associated with HC II deficiency type II has been reported up to date. This case is worth considering etiologies of juvenile cerebral infarction.
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PMID:[Juvenile cerebral infarction associated with heparin cofactor II abnormality. A case report]. 1096 62

Protein C is the zymogen of an anticoagulant serine protease and is converted to its active form (activated protein C: APC) by thrombin in the presence of thrombomodulin. APC plays an important role in regulating coagulation and fibrinolysis by inactivating not only blood coagulation factors Va and VIIIa but also type-1 plasminogen activator inhibitor (PAI-1). The aim of the present study was to examine the effect of a human APC product (designated as CTC-111), compared with that of heparin, on the disseminated intravascular coagulation (DIC) induced by lipopolysaccharide (LPS) in rats. LPS (1 mg/kg/h) infusion was performed through a femoral vein for 4 h. One-fifth amount of the total dosage of CTC-111 or heparin was injected into the other femoral vein, followed by a 4-h infusion of the remainder. Both CTC-111 (10,000-100,000 U/kg) and heparin (400-800 IU/kg) inhibited the decrease in platelet count and fibrinogen level equally. The prolonged activated partial thromboplastin time and prothrombin time observed in DIC rats were further elongated in both CTC-111- and heparin-treated rats. But, this prolongation was less in CTC-111-treated rats than in the heparin-treated ones. Heparin inhibited the increase in fibrin and fibrinogen degradation products more prominently than CTC-111. On the other hand, CTC-111 strongly inhibited the increase in PAI-1 activity but heparin did not. These results suggest that CTC-111 may enhance fibrinolysis through its direct inhibitory effect on PAI-1. The parameters for liver or renal damage, i.e., plasma glutamic-oxaloacetic transaminase (GOT), glutamic-pyruvic transaminase (GPT), creatinine (Cre) and blood urea nitrogen (BUN), were significantly increased by LPS infusion. Both CTC-111 (100,000 U/kg) and heparin (800 IU/kg) decreased the increase in GOT and GPT levels significantly, whereas neither affected the increase in Cre or BUN. From these results, the activation of the blood coagulation system might partially contribute to the progression of liver damage caused by LPS, and might be less involved in the progression of renal damage in this model. In conclusion, CTC-111 showed both anticoagulant and profibrinolytic activity in the LPS-induced DIC model without excessive prolongation of coagulation time. From these results, CTC-111 is expected to be a useful remedy for DIC without the risk of bleeding.
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PMID:Effect of activated human protein C on disseminated intravascular coagulation induced by lipopolysaccharide in rats. 1105 Jun 97

We have developed potent and selective thrombin inhibitors with a novel non-peptidic structure. A bicyclic lactam was used as the scaffold on which various P1 and P3 motifs were substituted. Herein, we report the in vitro and in vivo properties of four representatives of this novel class of inhibitors. Their Ki values were less than 10 nM, they inhibited equally both free and clot-bound thrombin, and they displayed high level of specificity for thrombin over other serine proteases (trypsin, factor Xa, activated Protein C, and plasmin). They prolonged the clotting time of human plasma to twice the control value in coagulation assays (TT, APTT, and PT) at a concentration below 3 microM. Their anticoagulant activities using rat plasma were similar to, although slightly weaker, than with human plasma. Furthermore, they inhibited thrombin-induced platelet aggregation (human and rat) at concentrations close to their Ki values for thrombin. These molecules demonstrated similar dose response antithrombotic efficacy in rat arterial and venous thrombosis models when given as i.v. bolus followed by infusion. Antithrombotic efficacy of 85% and greater was observed at a dose of 5-7 microM/kg/hour in each model. Bicyclic lactam inhibitor 3, at a dose which caused a complete inhibition of visible thrombus formation in the venous and arterial models of thrombosis, showed a 1.9-2.1 and a 4.0-4.8-fold shift in APTT and TT, respectively. Unfortunately, the bicyclic lactam inhibitors exhibited low oral bioavailability in rats. Therefore, this novel class of bicyclic lactam thrombin inhibitor has the potential to be promising intravenous antithrombotic agents for the treatment of arterial as well as venous thrombosis and warrants further investigation.
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PMID:In vitro and in vivo properties of bicyclic lactam inhibitors: a novel class of low molecular weight peptidomimetic thrombin inhibitors. 1110 7

Several papers concerning abnormalities of blood coagulation and fibrinolysis during hyperthyroidism, have been published. Increased von Willebrand Factor (vWF) activity and high fibrinogen levels have been reported. However, there is controversy concerning the presence of a hypercoagulable state in hyperthyroidism. We investigated various hemostatic parameters in 41 hyperthyroid patients and compared them to 20 euthyroid controls. Prothrombin time (PT), activated partial thromboplastin time (aPTT), fibrinogen, factors V, VII, VIII, IX and X activities, vWF, antithrombin III (AT III), protein C, protein S, tissue plasminogen activator (t-PA) and tissue plasminogen activator inhibitor-1 (PAI-1), as well as common lipid variables, were measured. The relationships between serum thyroid hormones and these hemostatic parameters were examined. Compared with control subjects, fibrinogen, factor IX, vWF, AT III and PAI-1 were significantly increased in patients (p<0.05, p<0.0001, p<0.05, p<0.01 and p<0.0001; respectively), whereas factor X and t-PA were decreased (p<0.05). We showed that free T4 (FT3) levels were correlated with factor VIII activity (r=0.35, p<0.05). FT4, FT3 and TSH did not correlate with fibrinogen, vWF, AT III, t-PA, or PAI-1. AT III was inversely correlated with factor VII activity (r=-0.48, p<0.01). Protein C and S were correlated with vWF levels (r=0.58, p<0.0001; r=0.55, p<0.0001, respectively). Protein C was inversely correlated with t-PA (r=-0.39, p<0.01). There was a negative correlation between triglycerides, LDL-C and F X (r=-0.45, p<0.05; r=-64, p<0.01, respectively). Mean platelet volume (MPV) was correlated with anti-thyroid peroxidase (TPO) antibodies (in Graves'disease) and F IX activity (r=0.57, p<0.05 and r=0.39, p<0.05; respectively). We found important differences in the coagulatory /fibrinolytic parameters between the hyperthyroid patients and healthy controls. Hyperthyroid patients may experience vascular endothelial dysfunction and decreased fibrinolytic activity in blood. This endothelial activation may represent a situation with a higher thromboembolic potential.
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PMID:Blood coagulation and fibrinolysis in patients with hyperthyroidism. 1203 Jun 6


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