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)

Clotting factor V has a dual function in coagulation: after activation, procoagulant factor V stimulates the formation of thrombin, whereas anticoagulant factor V acts as a cofactor for activated protein C (APC) in the degradation of factor VIII/VIIIa, thereby reducing thrombin formation. In the present study, we evaluated whether plasma factor V levels, either decreased or increased, are associated with venous thrombosis. High procoagulant factor V levels may enhance prothrombinase activity and increase the thrombosis risk. Low anticoagulant factor V levels could reduce APC-cofactor activity in the factor VIII inactivation (APC-resistant phenotype), which might also promote thrombosis. Low factor V levels in combination with factor V Leiden could lead to a more severe APC-resistant phenotype (pseudohomozygous APC resistance). To address these issues, we have measured factor V antigen (factor V:Ag) levels in 474 patients with thrombosis and 474 control subjects that were part of the Leiden Thrombophilia Study (LETS). Factor V:Ag levels increased by 7.6 U/dL for every successive 10 years of age. Mean factor V:Ag levels were 134 (range 41 to 305) U/dL in patients and 132 (range 47 to 302) U/dL in controls. Neither high nor low factor V:Ag levels were associated with venous thrombosis. We found that factor V:Ag and factor VIII antigen levels in plasma were correlated, but factor V did not modify the thrombotic risk of high factor VIII levels. The normalized APC ratio was not influenced by the factor V:Ag level in subjects with or without factor V Leiden. We conclude that neither low nor high factor V:Ag levels are associated with venous thrombosis and that factor V:Ag levels do not mediate the thrombotic risk associated with high factor VIII levels.
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PMID:Factor V antigen levels and venous thrombosis: risk profile, interaction with factor V leiden, and relation with factor VIII antigen levels. 1080 57

ProC Global is a new global clotting assay designed to evaluate the functionality of the protein C anticoagulant pathway. It is based on the ability of endogenous activated protein C, generated by activation of protein C by Protac, to prolong an activated partial thromboplastin time, and the results are expressed in protein C activation time normalized ratio (PCAT-NR), after normalization. This multicenter trial involving five European laboratories was designed in order to determine the ability of the ProC Global assay to distinguish patients with and without abnormalities of the protein C pathway. The PCAT-NR was significantly lower in the patients with a thrombotic history not on oral anticoagulant treatment (n = 627) than in the healthy controls (n = 148), even after exclusion from both groups of the patients with abnormality of the protein C pathway. Using receiver operator characteristics analysis, the cut-off level of PCAT-NR = 0.80 was found to provide the best sensitivity-specificity ratio. All the carriers of the factor V Leiden mutation (n = 73), as well as all the patients with activated protein C resistance (n = 42), had a PCAT-NR below 0.80. The ProC Global assay performed well in patients with combined defects (97.0%, n = 33) or protein C deficiency (91.3%, n = 46), but it failed to detect all of them, and one patient with combined defects as well as four patients with a low protein C level had a PCAT-NR above the cut-off level. The sensitivity of the assay for protein S deficiency (n = 58) was weak (only 69.0%) and, surprisingly, more than 40% of the 375 patients without any of these abnormalities of the protein C pathway had a PCAT-NR below the cut-off level.
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PMID:Screening for abnormalities of the protein C anticoagulant pathway using the ProC Global assay. Results of a European multicenter evaluation. 1093 6

Hypercoagulability is observed in patients with inherited thrombophilia, e.g. factor V Leiden (FVL) mutation. Pregnancy represents a hypercoagulable state as well. This study addresses the effects of the FVL mutation on haemostatic activation during pregnancy as indicated by prothrombin fragments (F1+2). 233 pregnant women with no history of venous thromboembolism were studied. Additionally, two patient groups (25 pregnant FVL carriers and 36 pregnant women without thrombophilic diathesis) in whom low molecular weight heparin (dalteparin) was used prophylactically against rethrombosis were investigated. None of the women developed clinical signs of venous thromboembolism during pregnancy or after delivery. Untreated women exhibited substantial hypercoagulability. F1+2 levels were similar in FVL carriers and non-carriers (difference n. s.). After sufficient adjustment for anti-factor Xa activity (> or =0.15; < or =0.4 U/mL), heparinized women without any thrombophilic diathesis had significantly lower levels of F1+2 than untreated pregnant women. This was evident only in the first and second trimenon (p <0.001). F1+2 levels in heparinized FVL carriers were quite similar to the levels observed in untreated pregnant women, however. In conclusion, our data support the thesis that in comparison to asymptomatic patients, thrombin generation is exaggerated in symptomatic FVL carriers. Coagulation activation during pregnancy can be reduced by dalteparin.
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PMID:The impact of dalteparin (Fragmin) on thrombin generation in pregnant women with venous thromboembolism: significance of the factor V Leiden mutation. 1137 68

The activated protein C (APC) resistant-factor V (factor V Leiden) has emerged as the most common inherited risk factor for thrombosis in the Caucasian population. Beside DNA analysis, the laboratory diagnosis is often based on the detection of a poor anticoagulant response to exogenous APC. The ProC Global assay (Dade Behring, Marburg, Germany) is a global clotting assay, which was primarily developed to evaluate the functionality of the protein C anticoagulant pathway. It is based on the ability of endogenous APC, generated by activation of protein C by an extract from Agkistrodon contortrix contortrix venom, to prolong an activated partial thromboplastin time. It was previously found to be highly sensitive for the factor V Leiden mutation and for protein C deficiency, but only moderately sensitivity for protein S deficiency. Here, we evaluated the performance of a modification of the ProC Global assay using a 1 : 5 pre-dilution of patient plasma in factor V-depleted plasma in the screening of the factor V Leiden mutation-related APC resistance. For that purpose, we investigated selected frozen plasma samples from 341 patients with a history of venous thromboembolism. The sensitivity for the factor V Leiden mutation of the modified assay was found to be 100%, as all the carriers of that mutation (five homozygotes and 77 heterozygotes) had a decreased response to the assay, i.e. a normalized ratio below 0.80. Its specificity was also 100% since none of the other tested patients had a decreased response, i.e. isolated protein C (n = 3) or protein S deficiency (n = 50), or without any abnormality of the protein C pathway (n = 143), even those on oral anticoagulant treatment (n = 76). However, it would be preferable that each laboratory defines both its reference range and its cut-off level. Finally, even if larger-scale multicentre studies are needed before definite recommendations could be made, these results suggest that the ProC Global performed using a 1 : 5 pre-dilution of the patient plasma in factor V-depleted plasma could be validly used as a screening assay of the factor V Leiden mutation-related APC resistance in patients with a history of thrombosis.
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PMID:Modification of the ProC Global assay using dilution of patient plasma in factor V-depleted plasma as a screening assay for factor V Leiden mutation. 1168 46

Coagulation factor V has been at the centre of investigation for several years. In addition to factor V Leiden, various other polymorphisms are becoming the object of interest. Different results have been published about the association of the HR2 haplotype with decreased factor V levels and with reduced response to activated protein C (APC). Due to the central position of factor V in the clotting process, its activity can be determined in both thromboplastin-based and activated partial thromboplastin time (aPTT)-based assays. A multitude of assays are known for the determination of APC response. The aim of our study was to investigate whether different methods disclose genotype-dependent differences in factor V activity as well as APC response. Three wild-type carriers, three carriers homozygous for the R2 allele (4070G), and three carriers homozygous for the G allele (2391G, 2663G, 2684G, 2863G) were investigated. For each individual plasma sample, the factor V activity was determined using 12 different reagent combinations of three different thromboplastins, three different aPTT reagents, and two different factor V deficient plasma sources. The determination of factor V activity in the thromboplastin system revealed differences between the genotypes. These differences were independent of the thromboplastin reagent and the factor V-deficient plasma. The aPTT system exhibited a dependency on the aPTT reagent and the factor V-deficient plasma. Analysis of APC response disclosed genomic differences in specific test systems only. One type of assay could be more appropriate than other types in dependence of the position of genomic variations. Therefore, the applied assay is an important influential factor in investigations of functional consequences of genomic variations.
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PMID:Investigation of genotype-dependent differences in factor V activity as well as response to activated protein C by application of different methods. 1173 69

Factor V Leiden with activated protein C resistance is found in up to 5% of the population. It is associated with current adverse pregnancy outcomes. Maternal floor infarction is a lesion in which fibrin is deposited throughout the placenta, leading to necrosis of villi, and (50% of the time) fetal demise. It is also often recurrent. There is no known etiology of maternal floor infarction, nor is there a known treatment. We report a case of a 34-year-old G5, P2 with multiple pregnancy losses, including two fetal deaths. Placental pathology was obtained from one of the losses and was notable for maternal floor infarction. In the index pregnancy, she was evaluated for thrombophilia and found to have a significant protein C resistance of 1.59, consistent with a factor V Leiden. She was treated with low-molecular-weight heparin, enoxaparin, 40 mg twice a day, titrated to achieve an activated factor Xa activity level of 0.2 prior to her next dose. Her pregnancy was unremarkable until 39 weeks, when she developed a decreased amniotic fluid index. A 2995-kg healthy infant was delivered. The placenta showed no evidence of maternal floor infarction. This case demonstrates an association between maternal floor infarction and activated protein C resistance. It is also notable for a successful treatment of recurrent maternal floor infarction with prophylactic heparin. A single case report can only raise a question regarding associations. As we become more familiar with the thrombophilias, we may better understand the association of thrombophilias and placental disease as well as develop successful treatments.
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PMID:Activated protein C resistance associated with maternal floor infarction treated with low-molecular-weight heparin. 1215 46

The effect of caeruloplasmin levels on the sensitivity for activated protein C (APC), measured by a clotting assay based on the activated partial thromboplastin time, was investigated in a large group of healthy individuals without factor V Leiden. A modest inverse association between caeruloplasmin and normalized APC sensitivity ratio was found (regression coefficient beta = -0.33 x 10-2; 95% confidence interval, -0.42 x 10-2 to -0.24 x 10-2). After adjustment for sex and oral contraceptive use, this association weakened (beta = -0.19 x 10-2; 95% CI: -0.34 x 10-2 to -0.05 x 10-2). After additional adjustment for factor VIII levels, which are known to influence the assay, the effect of caeruloplasmin on APC sensitivity completely disappeared.
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PMID:The effect of plasma caeruloplasmin levels on the sensitivity for activated protein C. 1218 Oct 57

Protein Z enhances the inhibition of factor Xa by protein Z-dependent protease inhibitor (ZPI). Thus, diminution of protein Z should induce prothrombotic tendency due to lowered cofactor activity for ZPI. In Factor V Leiden mice, prothrombotic tendency of severe diminution or lack of protein Z was demonstrated. We here present first studies in humans, indicating that diminution of protein Z in factor V Leiden patients aggravates thromboembolic risk.
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PMID:Protein Z influences the prothrombotic phenotype in Factor V Leiden patients. 1229 23

Preeclampsia/HELLP syndrome has been associated with a high incidence of defects in the protein C pathway and increased anticardiolipin-antibodies/lupus anticoagulants. It is also apparent that thrombophilia is responsible for other pregnancy complications, such as recurrent spontaneous abortion, fetal growth restriction, intrauterine fetal death, and abruptio placentae. ProC Global is a new global dotting assay designed to evaluate the abnormalities in the protein C anticoagulant pathway. It is based on the ability of endogenous activated protein C, generated by activation of protein C by Protac, to prolong an activated partial thromboplastin time. A total of 61 patients with a history of severe preeclampsia or HELLP syndrome and 61 normal pregnant women (controls) were evaluated, 15 of whom had factor V Leiden mutation, 12 had protein C/S deficiency, 30 had a repeated lupus anticoagulants, and 27 increased anticardiolipin antibodies (ACA). All carriers of factor V Leiden mutation (N=15) as well as all the patients with low activated protein C (APC) resistance ratio (N=15) had a ProC Global normalized ratio (NR) less than 0.80 (sensitivity 100%). Twenty-four patients positive for the lupus anticoagulants (LA) and 19 patients positive for ACA (>5.0 IgG U/mL) had a ProC Global NR less than 0.8, while six and eight, respectively, had a ProC Global NR greater than 0.8 (sensitivity, 70%-80%). The detection of a reduced protein C/protein S activity (<70%) was low (sensitivity, 33%-44%). In 25 cases with pathologic ProC Global results, a thrombophilic defect (protein S/LA/ACA without APC resistance) was diagnosed in 18 women; but in 7 cases, no known thrombophilic defect was present. ProC Global is a new screening test to identify patients with defects of the protein C system and an activated dotting system in preeclampsia but cannot correctly cover each thrombophilic component.
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PMID:ProC Global assay in the evaluation of women with history of severe preeclampsia or HELLP syndrome. 1251 22

Activated protein C (APC) resistance is a common risk factor for venous thromboembolism (VTE) attributed to various mechanisms, including factor V Leiden (FVL) polymorphism. FVL is considered responsible for up to 95% of APC resistance; however, other factor V polymorphisms and elevated factor VIII levels also have been implicated. We assessed whether additional mechanisms contribute to APC resistance in a blinded case-control study of 65 subjects by measuring APC resistance using 3 methods: 2 activated partial thromboplastin time-based methods with and without dilution in factor V-deficient plasma and 1 Russell viper venom-based assay (RVV). Without factor V-deficient plasma, 24 subjects were APC resistant; with factor V-deficient plasma, the assay identified fewer APC-resistant subjects, as did RVV. All assays detected the 7 heterozygous FVL subjects. Thirteen subjects had factor VIII levels above 150% (1.50). After excluding subjects with FVL or elevated factor VIII levels, 4 subjects still had APC resistance. VTE risk trended higher for subjects with APC resistance in the absence of FVL. Measurement of APC resistance without dilution in factor V-deficient plasma is needed to assess for potentially important thrombotic risk factors other than FVL.
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PMID:Activated protein C resistance assay detects thrombotic risk factors other than factor V Leiden. 1252 Jun 97


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