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

Thrombin regulation in newborns remains incompletely understood. We studied tissue factor-initiated thrombin formation in cord plasma in vitro, and the effects of Factor V(Leiden) (FVL) heterozygosity on thrombin regulation both in vitro and in vivo in newborns. Pregnant women with known thrombophilia (n=27) were enrolled in the study. Cord blood and venous blood at the age of 14 days were collected from 11 FVL heterozygous newborns (FVL-positive) and from 16 FVL-negative newborns. Prothrombin fragment F1 +2 and coagulation factors were measured. Tissue factor-initiated thrombin formation was studied in cord platelet-poor plasma (PPP) of FVL-negative and -positive newborns, and in both PPP and platelet-rich plasma (PRP) of healthy controls. The endogenous thrombin potential (ETP) in cord PPP or PRP was approximately 60% of that in adult plasma, while thrombin formation started approximately 55% and approximately 40% earlier in cord PPP and PRP, respectively. Further, in FVL-positive newborns thrombin formation started significantly earlier than in FVL-negative newborns. Exogenous activated protein C (APC) decreased ETP significantly more in cord than in adult PRP. In FVL-negative cord plasma 5 nM APC decreased ETP by 17.4+/-3.5% (mean+/-SEM) compared with only 3.5+/-3.8% in FVL-positive cord plasma (p=0.01). FVL-positive newborns showed similar levels of F1 +2 but significantly decreased levels of factorV compared with FVL-negative newborns both in cord plasma (FV 0.82+/-0.07 U/ml vs. 0.98+/- 0.05 U/ml, p=0.03) and at the age of two weeks (FV 1.15+/-0.04 U/ml vs. 1.32+/- 0.05 U/ml, p=0.03). In conclusion, newborn plasma showed more rapid thrombin formation and enhanced sensitivity to APC compared with adult plasma. FVL conveyed APC resistance and a procoagulant effect in newborn plasma. Lack of elevated F1+2 levels in FVL-positive infants, however, suggested the existence of balancing mechanisms; one could be the observed lower level of factor V in FVL heterozygous newborns.
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PMID:The procoagulant effects of factor V Leiden may be balanced against decreased levels of factor V and do not reflect in vivo thrombin formation in newborns. 1652 70

Prolonged sitting and thrombophilia may compound the risk of venous thromboembolism. In order to investigate suspected local lower limb venous procoagulant changes associated with prolonged sitting-induced venous stasis in a man heterozygous for factor V Leiden (participant X), we qualitatively compared venous coagulability in lower and upper limb plasma in this participant and three other male Caucasians over 8 h of sitting. Of the four participants, participant X had the highest baseline values of prothrombin fragments 1 and 2, thrombin-antithrombin III complexes, tissue plasminogen activator, plasminogen activator inhibitor 1, D-dimer and soluble thrombomodulin. Over time, in participant X, venous prothrombin fragments 1 and 2, thrombin-antithrombin III complexes, and soluble thrombomodulin decreased in both limbs; D-dimer decreased in the lower limbs but increased in the upper limbs; the tissue plasminogen activator/plasminogen activator inhibitor 1 molar ratio increased in both limbs; and minimal changes were noted in haematocrit. A foot volume increase was associated with vague symptoms towards the end of the study. Overall, these changes were similar to those observed in other participants. It is concluded from this case comparison that prolonged sitting of 8 h duration under normal atmospheric conditions did not result in local, as well as systemic, procoagulant haemostatic responses in a heterozygote for factor V Leiden when compared with other healthy volunteers. However, this observed, possibly adaptive, response is more likely to be compromised in factor V Leiden subjects during continued or increased venous endothelial stress or in the presence of other venous thromboembolism risk factors.
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PMID:Prolonged seated immobility-associated venous coagulability in a factor V Leiden heterozygote: a case-comparative study. 1657 56

Systemic lupus erythematosus (SLE) is a chronic inflammatory disorder with a high prevalence of cardiovascular disease due to accelerated atherosclerosis, as well as an increased risk of venous thromboembolism. Many of these clinical features have been attributed to the high prevalence of autoantibodies that are directed against phospholipid-bound antigens and that induce prothrombotic effects and disturb endothelial cell function. We conducted a case-control study in a cohort of female patients with SLE and in age-matched and sex-matched normal individuals. Patients had significantly higher levels of plasma inflammatory markers, but their overall coagulation status assessed by prothrombin fragment 1 + 2 and D-dimer plasma levels was not different from controls. Resistance against activated protein C (APC), assessed by a thrombin generation-based as well as an activated partial thromboplastin time-based method, however, was increased in patients. This defect was neither due to factor V Leiden carriership or to the use of oral contraceptives. This acquired form of APC resistance was due to proinflammatory changes associated with lower plasma levels of free protein S. In conclusion, acquired APC resistance may be an important determinant of the risk of thrombosis in patients with SLE, probably due to an active cross-talk between inflammation and coagulation systems.
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PMID:The inflammation and coagulation cross-talk in patients with systemic lupus erythematosus. 1717 22

The consequences of an erroneous thrombophilia diagnosis may be serious if it is used to determine clinical management. Therefore careful selection, assessment, and control of laboratory tests for thrombophilia are essential. As for other coagulation tests, the pre-analytical phase must be carefully controlled with attention to the specific problems associated with each type of assay. The investigator must then recognize that for most laboratory tests of thrombophilia, there are a number of assay types available, often based on different principles of analysis. This creates the potential for different users to obtain varying results depending on the technique employed. Such problems can occur in assays of antithrombin activity, depending on whether the assay employs factor Xa, human thrombin, or bovine thrombin. In clot-based assays of protein C and protein S, there can be specificity problems related to interference by factor V Leiden (FVL), antiphospholipid antibodies, and other substances. Even genetic tests can give erroneous results and should not automatically be seen as absolute without supporting evidence and careful quality-control measures. Whatever technique is selected, it is mandatory to incorporate sufficient concurrent quality-control samples to validate the results of thrombophilia tests. These should include assessment of the parameter at normal and abnormal levels to give confidence in results across the measurement range that would normally be encountered in routine practice. This should be used in conjunction with regular participation in external quality assessment (EQA) (which has been linked to improved laboratory performance in thrombophilia testing). Larger EQA programs can provide information concerning the relative performance of analytical procedures, including the method principle, reagents, and instruments. Herein, we describe many of the methodologic effects in detail. We use specific examples to illustrate the general principle that, in performing laboratory testing for thrombophilia, one must always consider the performance characteristics and limitations of the assay in use.
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PMID:Quality assurance issues and interpretation of assays. 1743 4

Measurement of endogenous thrombin potential (ETP) detects hypercoagulability and can be used to identify activated protein C resistance due to factor V Leiden (FVL). However, not all carriers of FVL suffer thrombosis and therefore we sought to determine if the test for ETP could be modified in such a way as to enable detection of FVL patients who were at increased risk of venous thromboembolism. Protac, an activator of both protein C and factor V, was incorporated into the traditional thrombin generation reaction and ratios (reaction with Protac:reaction without Protac) were calculated. Plasma samples from 42 FVL heterozygotes (12 with a history of thrombosis and 30 with no prior thrombosis) and 38 controls (non-FVL with no history of thrombosis) were analysed. The mean ETP ratio was significantly higher in FVL heterozygotes (0.90 +/- 0.06) compared to normal controls (0.41 +/- 0.10; p = 0.00004). Multivariate analysis indicated that the average ETP ratio was significantly and inversely correlated with factor V levels in FVL heterozygotes (p = 0.002) but not controls. Within the FVL group, patients with a history of thrombosis had higher ETP ratios (0.92 +/- 0.06) compared to those without (0.89 +/- 0.05), however, this did not reach statistical significance (p = 0.09). Further investigation into the use of ETP for detecting risk of thrombosis in people who are genetically predisposed is warranted. The recent introduction of diagnostic ETP measurements in the form of the calibrated automated thrombin generation from Thrombinoscope and the TechnoThrombin from Baxter should facilitate such studies.
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PMID:Endogenous thrombin potential for predicting risk of venous thromboembolism in carriers of factor V Leiden. 1756 36

The thrombin generation test appears to be a highly sensitive and specific test in the detection of thrombophilia in patients with venous thromboembolism. We aimed to determine the accuracy of the thrombin generation test to detect factor V Leiden and/or other prothrombotic states in first-degree relatives of patients with venous thromboembolism and factor V Leiden. Sixty-two first-degree relatives of 21 index cases were tested for factor V Leiden, the G20210A prothrombin gene mutation and thrombin generation. Information about oestrogen therapy and previous VTE was also collected. The normalized Thrombomodulin sensitivity ratio (n-TMsr) was defined as the ratio of endogenous thrombin potential determined in the presence and absence of thrombomodulin which was normalized against the same ratio determined in normal control plasma. The mean n-TMsr was 1.37 (+/- 0.33) in the 45 relatives with one or more prothrombotic state (factor V Leiden, G20210A prothrombin mutation, oestrogen therapy or hormonal therapy) and 1.02 (+/- 0.34) in the 17 relatives without prothrombotic state (p = 0.001). The positive predictive value was 90.3 (95%CI, 73.1-97.4). In relatives with an abnormal n-TMsr, the adjusted odds ratio for having a prothrombotic state was 8.3 (95%CI, 1.9-36.9) and the adjusted odds ratio for having the factor V Leiden was 14.3 (95%CI, 2.9-71.2). An abnormal thrombin generation test appears highly predictive for having factor V Leiden and/or other prothrombotic states in first-degree relatives of patients with venous thromboembolism and factor V Leiden.
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PMID:Thrombin generation in first-degree relatives of patients with venous thromboembolism who have factor V Leiden. A pilot study. 1821 58

Increased thrombin generation in the presence of activated protein C (APC) is known to be an independent risk factor for thrombosis. Although commercially available methods for measuring thrombin generation are available, none measure sensitivity to APC. We have developed an automated thrombin generation based APC sensitivity test, for use with defibrinated plasma using the automated coagulometer (ACL9000). A chromogenic substrate that is cleaved by thrombin at a slow rate, 7 pm tissue factor and 20 mum phospholipid (DOPC : DOPE : DOPS, 60 : 20 : 20) with and without 5 nm APC. Thrombin generation with [endogenous thrombin potential (ETP)(+APC)] and without APC (ETP), was expressed as a ratio relative to pooled normal plasma. Normal reference ranges were established in 30 normal subjects: ETP 0.73-1.06; ETP(+APC) 0.42-1.07. ETP(+APC) was found to be sensitive to factor V Leiden, oral contraceptive use, low levels of protein S and tissue factor pathway inhibitor and increased plasma factor VIII.
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PMID:Measuring thrombin generation based sensitivity to activated protein C using an automated coagulometer (ACL 9000). 1866 22

Factor V (FV; proaccelerin or labile factor) is the plasma cofactor for the prothrombinase complex that activates prothrombin to thrombin. FV deficiency can be caused by mutations in the FV gene or in genes encoding components of a putative cargo receptor that transports FV (and factor VIII) from the endoplasmic reticulum to the Golgi. Because FV is present in platelet alpha-granules as well as in plasma, low FV levels are also seen in disorders of platelet granules. Additionally, acquired FV deficiencies can occur in the setting of rheumatologic disorders, malignancies, and antibiotic use and, most frequently, with the use of topical bovine thrombin. FV levels have limited correlation with the risk of bleeding, but overall, FV-deficient patients appear to have a less severe phenotype than patients with haemophilia A or B. The most commonly reported symptoms are bleeding from mucosal surfaces and postoperative haemorrhage. However, haemarthroses and intramuscular and intracranial haemorrhages can also occur. Because no FV-specific concentrate is available, fresh frozen plasma remains the mainstay of treatment. Antifibrinolytics can also provide benefit, especially for mucosal bleeding. In refractory cases, or for patients with inhibitors, prothrombin complex concentrates, recombinant activated FVIIa, and platelet transfusions have been successfully used. Some patients with inhibitors may also require immunosuppression.
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PMID:Factor V deficiency: a concise review. 1914 Nov 56

Observations that hepatic inflammation and cirrhosis are associated with the presence of thrombi within the hepatic microvasculature and fibrin-fibrinogen deposition have led to epidemiologic studies showing that carriage of the factor V Leiden mutation, protein C deficiency, and increased expression of factor VIII are associated with rapid progression to cirrhosis in a chronic hepatitis C virus. Additional data suggest that this process may extend more broadly to progression in many forms of chronic liver disease. This article discusses the evidence for a role for coagulation cascade activity in hepatic fibrogenesis and explores the proposed pathogenic mechanisms including the downstream events of thrombin activation. Interference with either the generation of thrombin or its downstream activity may reduce hepatic fibrosis. Also examined are the implications for future therapeutic intervention.
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PMID:Parenchymal extinction: coagulation and hepatic fibrogenesis. 1915 Mar 16

The HemosIL ThromboPath assay (Instrumentation Laboratory) is a new chromogenic assay designed to globally evaluate the functionality of the protein C (PC) pathway. It is based on the ability of endogenous APC generated after activation of PC by a snake venom extract (Protac) to reduce the thrombin generation induced by a reagent containing tissue factor. The aim of this multicenter study involving three laboratories was to evaluate the test sensitivity to PC pathway abnormalities by retrospectively testing frozen plasma samples obtained in the different laboratories. Test results were significantly lower (p < 0.0001) in subjects who presented with any confirmed PC pathway abnormality than in those without. The cut-off value, defined in each participating center as the mean value minus one standard deviation of test results obtained in 30 normal samples, was found to provide a sensitivity-to-specificity ratio similar to that obtained using ROC-analysis. The assay performed well in carriers of the factor V Leiden mutation (n = 81), patients with PC deficiency (n = 40), combined defects (n = 55) or lupus anticoagulant (n = 44), with test results below the locally defined cut-off values in 97.5%, 95.0%, 100% and 100% of the tested subjects, respectively. The assay sensitivity for PS deficiency (n = 62) was 87.1%. Only 13.6% of the 272 subjects without any PC pathway abnormality had a decreased test result. So, using the locally defined cut-off values, the overall test sensitivity to all tested PC pathway abnormalities was 95.0% (95%CI = 91.8-97.3), its specificity 86.4% (95%CI = 81.8-90.2), its negative predictive value 94.4% (95%CI = 90.8-96.9) and its positive predictive value 87.9% (95%CI = 83.7-91.3).
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PMID:A new chromogenic assay (HemosIL ThromboPath) is sensitive to major prothrombotic risk factors affecting the protein C pathway. Results of a multicenter study. 1915 24


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