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

---

Query: EC:3.4.21.5 (thrombin)
33,306 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human oxalated plasma stored at 4 degrees C. until the prothrombin time is increased beyond 60 sec. is a reliable medium for assaying labile factor (factor V) because its response to added labile factor corresponds quantitatively to that of plasma from patients with congenital deficiency of this factor. Such an agreement is not obtained with plasma stored at 37 degrees C. The stability of labile factor is closely associated with ionized calcium. The addition of thrombin to fresh oxalated plasma causes an apparent hyperactivity of labile factor, but this is completely removed by adsorption with Ca(3)(PO)(2). Oxalated plasma when adsorbed with Ca(3)(PO(4))(2) before treatment with thrombin does not develop this adventitious activity, nor does it occur in stored plasma treated with thrombin. The seemingly high labile factor activity in serum can be explained by the activation of this factor which is independent of labile factor but acts synergistically with it. The true labile factor concentration can be determined only after the accelerator is removed by adsorption with Ca(3)(PO(4))(2). A close agreement between the consumption of prothrombin and the loss of labile factor during clotting is observed.
...
PMID:The assay and properties of labile factor (factor V). 1373

Protein Z (PZ) is a 6.2 kDa vitamin K-dependent protein, synthesized in the liver. The gene for human PZ is localized to chromosome 13 at band 34 q. The structure of PZ is very similar to that of factors VII, IX, X and protein C. Very low plasma levels of protein Z were observed under oral anticoagulant treatment. The cause of this phenomenon might be increased protein Z binding on the surface of endothelial cells. Protein Z is consumed during coagulopathy. About 60% of humans suffering from a bleeding tendency of unknown origin presented with decreased plasma levels of protein Z. PZ forms a Ca(2+)-dependent complex with activated factor X (Xa) on phospholipid surfaces, that leads to the inhibition of factor Xa and decrease in thrombin generation. Inhibition of factor Xa may be caused directly by protein Z or indirectly by the activity of protein Z-dependent protease inhibitor (ZPI). ZPI is a 72 kDa member of the serpin family of proteinase inhibitors, synthesized in the liver. ZPI circulates in plasma in complex with protein Z. ZPI in the presence of Ca2+ and phospholipids inhibits factor Xa. The presence of protein Z enhances this process by more than 1000 times. ZPI also inhibits activated factor XI in the absence of protein Z, Ca2+ or phospholipids. Protein Z deficiency may induce bleeding as well as prothrombotic tendencies and might occur as an inherited disorder. Protein Z deficiency may aggravate mild bleeding tendency in subjects with diagnosed borderline decrease in von Willebrand factor and factor VII activity. Patients presenting with factor V Leiden mutation and low protein Z levels show earlier onset and higher frequency of thromboembolic events comparing to patients with normal protein Z levels.
...
PMID:[Protein Z]. 1505 66

Oral contraceptive (OC) use is associated with an increased risk of venous thromboembolism. Previous data reported higher thrombotic risk in women using third-generation combined OC than in those using second generation OC. The difference could be explained by differential effects of progestagens on plasma sensitivity to activated protein C (APC). The main purpose of this cross-sectional study was to assess the influence of a progestagen-only OC (chlormadinone acetate) as well as the effect of several combined OC with different progestagen components on APC resistance. The effect of APC on endogenous thrombin potential (ETP) was investigated in the plasma of healthy women using either combined OC (n=82) or progestagen-only OC (n=28), and in non-users (n=64). Carriers of factor V Leiden were excluded. Compared with non-users, there was no significant change in APC resistance in women using progestagen-only OC. Women who used combined OC were less sensitive to APC than non-users (P < 0.001) and the difference was significantly more pronounced in women using third-generation OC (n=41) than in those who used second-generation OC containing levonorgestrel (n=22) (P < 0.05). Compared with OC containing levonorgestrel, use of norethisterone-containing OC (n = 9) was associated with an increased resistance to APC (P < 0.05). Women who used cyproterone-containing OC (n = 10) were less sensitive to APC than those using third-generation OC (P < 0.05) or second-generation OC containing levonorgestrel (P < 0.05). Protein S, factor II and FVIII levels explained in part the OC-related changes in APC sensitivity variations. ETP-based APC resistance may contribute to explain why different brands of OC can be associated with different levels of thrombogenicity.
...
PMID:Impact of progestagens on activated protein C (APC) resistance among users of oral contraceptives. 1533 36

Raloxifene, a selective estrogen receptor modulator, like hormonal replacement therapy increases the risk of venous thromboembolism in postmenopausal women. A possible explanation for the increased thrombotic risk could be an increase in acquired resistance to activated protein C (APC). In two randomized, placebo-controlled, double-blind studies we determined the effect of raloxifene on the normalized APC sensitivity ratios (nAPCsr). The nAPCsr were determined with the thrombin generation-based APC resistance test. In the first study 83 postmenopausal women (age, 51.1 +/- 2.7 years) randomly received daily 0.625 mg conjugated equine estrogen and 2.5 mg medroxyprogesterone acetate (n=17), 60 mg raloxifene (n=23), 150 mg raloxifene (n=20) or placebo (n=23) for 24 months. At baseline and after 6, 12 and 24 months the nAPCsr were measured. In the second study 30 elderly men (age, 64.4 +/- 2.4 years) randomly received 120 mg raloxifene (n=15) or placebo (n=15) for 3 months. At baseline and after 3 months the nAPCsr and fasting homocysteine levels were measured. In postmenopausal women conjugated equine estrogen/medroxyprogesterone acetate significantly increased the nAPCsr from 1.26 +/- 0.82 to 2.87 +/- 0.86 at 24 months (P <0.0005 compared with placebo). Raloxifene had no significant effect on nAPCsr compared with placebo in both women and men. The results did not change after excluding carriers of factor V Leiden. Also fasting homocysteine levels were not affected by raloxifene in the aging men. It is concluded that raloxifene, in contrast to combined hormonal replacement therapy, does not increase APC resistance.
...
PMID:Effect of raloxifene on activated protein C (APC) resistance in postmenopausal women and on APC resistance and homocysteine levels in elderly men: two randomized placebo-controlled studies. 1561 19

We describe here results from the United Kingdom National External Quality Assessment Scheme (UK NEQAS) Thrombophilia Screening Program, in which an average of 21% of 280 centers reported an incorrect diagnosis for a series of plasma samples. Three case studies are described, showing causes of error in individual laboratories, related to the source of reference plasma or reagents. Methodological bias is also described. For protein C (PC) assays 18% of centers reported PC deficiency in a patient homozygous for factor V Leiden. Studies in the NEQAS laboratory confirmed the effect of activated protein C resistance (APCR) on clot-based PC activity assays. Differences in results obtained for PS-deficient subjects with different protein S (PS) activity kits are reported; several subjects would be misdiagnosed as normal with one kit if the manufacturer's reported reference range was adopted instead of a locally determined reference range. Antithrombin (AT) assays were shown to vary in their sensitivity to different molecular defects in the antithrombin gene; 77% of centers employing human thrombin-based activity assays reported a normal AT level in a patient with antithrombin Cambridge II. Sensitivity of the APC resistance test in the absence of factor V-deficient plasma was shown to be improved through normalization of results, and errors in the genetic diagnosis of factor V Leiden and the P20210A prothrombin gene mutation are described. Errors in the diagnosis of thrombophilic defects can therefore be identified through participation in EQA programs, and following dissemination of information, improvements in diagnosis can be demonstrated.
...
PMID:Multilaboratory testing in thrombophilia through the United Kingdom National External Quality Assessment Scheme (Blood Coagulation) Quality Assurance Program. 1570 77

Women who are using oral contraceptives can acquire APC resistance, measured by the effect of APC on the endogenous thrombin potential (ETP). The objective of our study was to examine whether persistentAPC resistance determined with an ETP-based normalized APC sensitivity ratio (nAPCsr) is a risk marker for venous thromboembolism in women with pregnancy-associated thromboembolism. We determined the activities of antithrombin, protein C, protein S, and performed a genetic analysis of factor V Leiden G1691A, prothrombin mutation G20210A, and methylenetetrahydrofolate reductase mutation (MTHFR C677T) in 65 women with venous thromboembolism during pregnancy or the puerperium and in 114 normal women. A significantly (p<0.05) higher nAPCsr was present in normal women using hormones, in younger women (<or=45 yrs), and in women with carrier status of factorV Leiden. In normal women without factor V Leiden a significant (p<0.05) negative correlation of nAPCsr with age (r=-0.39), antithrombin activity (r=-0.38), protein S activity (r=-0.26), and a significant positive correlation with hormone intake (r=0.36) was present. nAPCsr is influenced by several coagulation parameters, which are modified by the use of oral contraceptives. Consequently, a multivariate analysis of our data did not show a significant association of nAPCsr to venous thromboembolism, neither as a continuous variable (odds ratio 0.8, 95% CI 0.6-1.1, p=0.10) nor using a cutoff value (nAPCsr cut-off 3.1: odds ratio 1.2, 95% CI 0.3-5.3, p=0.77). Our study demonstrates that nAPCsr is not a risk marker for pregnancy-associated venous thromboembolism.
...
PMID:Venous thromboembolism during pregnancy is not associated with persistent elevated activated protein C (APC) sensitivity ratio based on the endogenous thrombin potential. 1571 47

The protein C pathway is a major regulator of blood coagulation, since it controls the conversion of prothrombin to thrombin through a feedback inhibition mechanism. Protein C circulates in plasma as an inactive zymogen and is activated on the surface of endothelial cells by the thrombin-thrombomodulin complex, a process that can be further enhanced when protein C binds to its membrane receptor, the endothelial-cell protein C receptor. Activated protein C (APC) is then released from the complex, binds protein S and inhibits thrombin formation by inactivating coagulation factors Va and VIIIa. The importance of the protein C anticoagulant pathway is emphasized by the increased risk of venous thromboembolism (VTE) associated with protein C and protein S deficiencies, the factor V Leiden mutation, and reduced circulating APC levels. The protein C pathway also plays a significant role in inflammatory processes, since it prevents the lethal effects of E. coli-associated sepsis in animal models and improves the outcome of patients with severe sepsis. APC seems to display anti-apoptotic and neuroprotective activities. Thus, it reduces organ damage in animal models of sepsis, ischemic injury, endothelial cell injury, or stroke. Further research will hopefully widen the current therapeutic perspectives in all these illnesses, where these effects might play a crucial role in their treatment. This review will summarize the mechanisms that contribute to these biological activities of the protein C pathway.
...
PMID:The multifunctional protein C system. 1585 99

The relationship between haemostatic factors and recurrent cardiovascular events was investigated in patients enrolled with acute coronary syndrome (acute non-Q myocardial infarction or unstable angina pectoris). One hundred and fifteen patients, aged 64 +/- 10 years, were included in the study. Haemostatic parameters [prothrombin time, activities of factor VII, factor VIII, factor X, antithrombin (AT) and protein C (PC), and concentrations of free protein S, fibrinogen, D-dimer, prothrombin fragment 1+2, and thrombin-antithrombin complex] were measured four times: within 48 h of hospitalization, at discharge (days 5-8), at 3 months and after 1 year. Screening for factor V Leiden mutation was also performed. Patients were followed for cardiovascular endpoints (new or refractory unstable angina pectoris, non-fatal myocardial infarction, stroke, or death) for an average of 555 days. Of all patients, 35 had an endpoint during the follow-up ("endpoint" group) and 80 patients did not ("no endpoint" group). Analysing the whole follow-up period, PC (P < 0.01) and AT (P < 0.01) were lower in the "endpoint" than in the "no endpoint" group. With 50% percentiles at enrollment, the odds ratio for getting an endpoint in the low (cut-off value < 100%) versus high PC group was 2.72 (95% confidence interval, 1.18-6.29; P < 0.05). Lower levels of AT (P < 0.05) and PC (P < 0.05) during the whole follow-up were associated with a shorter event-free time. In conclusion, lower PC and AT values, even within the normal range, seem to be associated with elevated risk for recurrent cardiovascular events and shorter event-free time in acute coronary syndrome patients.
...
PMID:Low normal level of protein C or of antithrombin increases risk for recurrent cardiovascular events. 1587 May 47

Identifying factors that influence gene transfer efficacy is critical for a successful gene-based clinical study. Here we demonstrate that in vivo AAV-2-mediated gene transfer is efficiently inhibited by unfractionated heparin, but not by a heparin preparation containing mainly low-molecular-weight forms (LMWH). Surprisingly, inhibitors of thrombin or factor Xa (F.Xa) significantly reduced AAV-2 transduction in a dose-dependent manner. These effects were independent of the vector promoter, transgene, or strain of mice. Expression by alternate AAV serotypes 5 and 8 was not affected by anticoagulant drugs, which suggests an AAV-2-specific effect. Moreover, AAV-2-mediated gene expression was diminished in mice with deficiency in thrombin generation (factor IX deficiency) and enhanced in mice with procoagulant phenotype due to factor V Leiden. In addition, inhibitors of F.Xa diminished adenovirus-mediated gene expression. These results demonstrated that coagulation activity itself is critical to ensure optimal viral vector transduction. Since intravascular delivery of vectors often requires the use of anticoagulants, the use of LMWH appears to be safe. These observations are of relevance for approaches using AAV-2 or adenoviral vectors, especially in early phase studies designed to identify the minimum therapeutic doses.
...
PMID:The inhibitory effects of anticoagulation on in vivo gene transfer by adeno-associated viral or adenoviral vectors. 1623 49

The role of factor V Leiden (FVL) as a modifier of the severe hemophilia phenotype is still unclear. We used mice with hemophilia A or B crossed with FVL to elucidate in vivo parameters of hemostasis. Real-time thrombus formation in the microcirculation was monitored by deposition of labeled platelets upon laser-induced endothelial injury using widefield microscopy in living animals. No thrombi formed in hemophilic A or B mice following vascular injuries. However, hemophilic mice, either heterozygous or homozygous for FVL, formed clots at all injured sites. Injection of purified activated FV into hemophilic A or B mice could mimic the in vivo effect of FVL. In contrast to these responses to a laser injury in a microvascular bed, FVL did not provide sustained hemostasis following damage of large vessels in a ferric chloride carotid artery injury model, despite of the improvement of clotting times and high circulating thrombin levels. Together these data provide evidence that FVL has the ability to improve the hemophilia A or B phenotype, but this effect is principally evident at the microcirculation level following a particular vascular injury. Our observations may partly explain the heterogeneous clinical evidence of the beneficial role of FVL in hemophilia.
...
PMID:Factor V Leiden improves in vivo hemostasis in murine hemophilia models. 1635 10


<< Previous 1 2 3 4 5 6 7 8 9 Next >>

---