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)

The intensity of warfarin therapy for prevention of primary and secondary thromboembolic complications in paediatric patients, is extrapolated from guidelines for adults, which may not be optimal. Therefore, we assessed thrombin regulation ex vivo and in vitro in plasmas from 40 children (1 to 18 years old with a median age of 13 years) and 27 adults receiving warfarin with an international normalized ratio of 2 to 3 (child: 2.5 +/- 0.15; adult: 2.4 +/- 0.14). Ex vivo concentrations of prothrombin fragment 1.2 were significantly lower in children (0.30 +/- 0.03 nM) compared to adults (0.45 +/- 0.04 nM; p <0.01). Thrombin generation in defibrinated plasmas (Arvin) was decreased and delayed for children compared to adults when activated by either activated partial thromboplastin time (child = 32 +/- 1.7, adult = 45 +/- 1.9 microM x s) or prothrombin time (child = 35 +/- 0.7, adult = 46 +/- 1.0 microM x s) reagents (p <0.01 for both). Although plasma concentrations of factors (F) II, FVII, FIX, F X, protein C and protein S were similar, more of the thrombin generated was complexed to alpha2 macroglobulin (alpha2M) at times close to peak thrombin activity (60 s) in plasma from children (general linear analysis of variance; p <0.03). Thus, increased alpha2M levels may enhance thrombin regulation in paediatric compared to adult patients receiving warfarin, suggesting that clinical trials in children, using less intense warfarin treatment, may be required to determine optimum therapy.
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PMID:Enhanced thrombin regulation during warfarin therapy in children compared to adults. 979 71

High levels of recombinant activated factor VII (rFVIIa; NovoSeven, Novo Nordisk, Bagsvaerd, Denmark) have been found to be effective in providing haemostasis in haemophiliacs and in normal individuals with acquired inhibitors to factor VIII (FVIII) or FIX. However, the mechanism of this therapeutic effect of FVIIa is unclear. Opinion is divided over whether high-dose FVIIa therapy works primarily by a tissue factor (TF)-dependent or -independent mechanism. Our group originally favoured a TF-dependent mechanism; however, we have recently found that, at levels comparable with those attained therapeutically, FVIIa activates enough FX on activated platelets to restore platelet surface thrombin generation. These data now lead us to favour a primarily (although not necessarily exclusively) TF-independent mechanism for the haemostatic effect of high-dose FVIIa. We believe that a platelet surface localization of FVIIa activity explains both its safety and efficacy, as well as its haemostatic effect in patients with thrombocytopenia and platelet function defects. Localization on activated platelets would tend to restrict the activity of FVIIa to sites of injury. Activation of FX on the platelet surface in haemophiliacs would provide FXa in a favourable location to escape inhibition by plasma protease inhibitors and be incorporated into platelet prothrombinase complexes. Activation of FIX and FX on platelet surfaces in thrombocytopenia would result in more thrombin generation per platelet, possibly leading to formation of a stable fibrin network even in the absence of an optimal initial platelet plug.
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PMID:Activated factor VII activates factors IX and X on the surface of activated platelets: thoughts on the mechanism of action of high-dose activated factor VII. 981 30

By virtue of a severely prolonged aPTT with a normal thromboplastin time (prothrombin time) and a normal thrombin time, severe FXII deficiency has been diagnosed in a woman without a bleeding diathesis or a history of thromboembolic complications. A deficiency of a factor of the contact activation system (FXII, prekallikrein, high molecular weight kininogen) is usually diagnosed during routine coagulation tests demonstrating a prolonged aPTT. The severe and partial deficiency of FXII, of prekallikrein or high molecular weight kininogen is not associated with a bleeding tendency. In contrast, severely factor XI deficient subjects may suffer from a mild hemorrhagic diathesis, whereas FVIII deficiency (hemophilia A, autoimmune "hemophilia", von Willebrand disease) and FIX deficiency (hemophilia B) are associated with a bleeding tendency of varying severity, depending on the clotting activity of FVIII or FIX, respectively. An isolated prolongation of the aPTT due to a lupus anticoagulant, however, is frequently associated with arterial and/or venous thrombosis. Therefore, in case of a prolongation of the aPTT, its cause has to be determined.
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PMID:[A patient with isolated prolongation of aPTT without hemorrhagic diathesis anamnesis: severe, hereditary factor XII deficiency]. 1051 21

The pharmacokinetics and pharmacodynamics (PK/PD) of a humanized anti-Factor IX IgG1 monoclonal antibody (SB 249417, FIX mAb) were studied in Cynomolgus monkeys. Single i.v. bolus doses of 1, 3, or 10 mg/kg of FIX mAb were administered. The total FIX mAb concentration, activated partial thromboplastin time (aPTT), and Factor IX activity were monitored for up to 4 weeks after dosing. In the monkey, FIX mAb had a plasma clearance of 0.6 ml/h/kg and a steady-state volume of distribution of approximately 70 ml/kg. The elimination phase half-life (3.8 days) was considerably less than other humanized IgG1 mAbs in the monkey, for which there is no binding to endogenous antigen. The suppression of Factor IX activity and the prolongation of aPTT were rapid and dose dependent. The time for aPTT values to return to basal levels (25-170 h) increased with increasing dose. A mechanism-based PK/PD model consistent with the stoichiometry of binding (2:1) was developed to describe the Factor IX activity and aPTT response time course. The model incorporated Factor IX synthesis and degradation rates that were interrupted by the sequestration of Factor IX by the antibody. aPTT values were related to free Factor IX activity. This model was able to describe the PD profiles from the three dose levels simultaneously. The estimated Factor IX half-life was 11 h and the third-order association rate constant was 3.96 x 10(3) microM(-2) h(-1). The PK/PD modeling was useful in summarizing the major determinants (endogenous and antibody-ligand binding) controlling FIX mAb-related effects.
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PMID:Pharmacokinetics and pharmacodynamics of a humanized monoclonal antibody to factor IX in cynomolgus monkeys. 1064 Mar 22

Inherited hemophilia dog and other transient hemophilic animal models have been used for evaluation of hemostatic agents for use in treatment of hemophilia. We established the first nonhuman primate hemophilic model by immunizing cynomolgus monkeys with human FIX (hFIX) in adjuvants. FIX activities of all three hFIX-immunized monkeys decreased transiently to less than 10% in accordance with prolongation of activated partial thromboplastin time (APTT). Forty micrograms of human factor VIIa (hFVIIa) per kilogram body weight (that was reported to be clinically effective) was administered to the monkey with the highest inhibitor titer to evaluate its usefulness as a hemophilia inhibitor model. Results of thromboelastography (TEG) after the injection demonstrated that the hemostatic effect of FVIIa in this model would be similar to that in hemophiliacs with inhibitors. The antibodies purified from the monkey's plasma by hFIX-immobilized gel were composed of two types: Ca(2+)-dependent and -independent antibodies, with features of IgG(1) and IgG(4). Both types of antibodies reacted to cynomolgus FIX, and only Ca(2+)-dependent antibodies also expressed inhibitory activity against cynomolgus FIX. Immunoblotting analyses of Ca(2+)-dependent antibodies using hFIX and its derivatives suggested that they recognized the Ca(2+)-dependent conformation related to the gamma-carboxyglutamic acid (Gla) domain. Comparison of FIX cDNA from human, cynomolgus monkey, and other species, and the results of immunization of various animals (goats, beagle dogs, rabbits, and rats) with hFIX in adjuvants strongly suggested that the development of acquired FIX inhibitors in the monkeys might be due to high cross-reactivity of the antibodies to molecular mimic antigens, hFIX, and cynomolgus FIX.
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PMID:Induction of acquired factor IX inhibitors in cynomolgus monkey (Macaca fascicularis): a new primate model of hemophilia B. 1136 29

Blood coagulation has been thought to be composed of both intrinsic and extrinsic pathways. Recent evidence strongly supports the critical role of the extrinsic pathway in the initiation of blood coagulation. This investigation established an assay that examines the role of FXI in the thromboplastin-initiated (extrinsic) coagulation based on this new concept. Plasma clotting times were measured at different concentrations of thromboplastin with activated FXII inhibited (FXIIa-inhibited Diluted Thromboplastin Time, FXIIaiDTT). Only at low concentrations of thromboplastin was FXIIaiDTT of FXI-deficient plasma significantly prolonged than that of normal plasma. Depletion of FXI from normal plasma prolonged its FXIIaiDTT and replenishment of FXI shortened it. FXIIaiDTTs of both FVIII-deficient and FIX-deficient plasma were remarkably prolonged, and addition of normal plasma dose-dependently shortened it. Furthermore, earlier alpha-thrombin inhibition was directly correlated with decreasing FXa generation. The amount of FXa production was: platelet-rich plasma > platelet-poor plasma > FXI-deficient plasma. Therefore, our findings from the FXIIaiDTT assays not only support the critical role of extrinsic pathway in blood coagulation initiation, but also demonstrate the importance of FXI as an amplifier of thrombin generation in thromboplastin-initiated coagulation.
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PMID:The role of factor XI in a dilute thromboplastin assay of extrinsic coagulation pathway. 1143 84

Using a cell-based model system of coagulation, we performed a systematic examination of the effect of varying individual procoagulant proteins (over the range of 0-200% of pooled plasma levels) on the characteristics of thrombin generation. The results revealed a number of features unique to the different coagulation factors, as well as common features allowing them to be grouped according to the patterns observed. Variation of those factors contributing to formation of the tenase complex, factor (F)VIII, factor (F)IX and factor (F)XI, primarily affected the rate and peak of thrombin production, but had little to no effect on total thrombin production. The effect of decreased FXI was milder than seen with decreased FVIII or FIX, and more variable between platelet donors. In contrast, varying the concentration of factors that contribute to formation of the prothrombinase complex, prothrombin or factor (F)V (with FV-deficient platelets), significantly affected all three measures of thrombin production: rate, peak and total. Additionally, while no thrombin generation was observed with no factor X, only very small amounts (between 1% and < 10% of normal plasma levels) were required to normalize the measured parameters. Finally, our results with this cell-based system highlight differences in thrombin generation on cell surfaces (platelets) compared with phospholipids, and suggest that platelets contribute more than simply a surface for the generation of thrombin.
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PMID:Impact of procoagulant concentration on rate, peak and total thrombin generation in a model system. 1500 54

This study assessed the effect on coagulation tests of fresh frozen plasma (FFP), given according to guidelines compared with higher doses in critically ill patients. Group 1 (10 patients) received 12.2 ml/kg and group 2 (12 patients) 33.5 ml/kg FFP. Prothrombin time, activated partial thromboplastin time and factors I-XII were measured before and after FFP infusion. Factor levels of 30 IU/dl (1 g/l for fibrinogen) were considered haemostatic. A retrospective review showed 10 of 22 (five in group 1 and five in group 2) patients had not required FFP. Of those that needed FFP, one of five in group 1 and seven of seven in group 2 had coagulation factor levels above the target post-FFP. Increments for group 1 versus 2 were: fibrinogen 0.4 vs. 1.0 g/l, FII 16 vs. 41*, FV 10 vs. 28*, FVII 11 vs. 38*, FVIII 10 vs. 17, FIX 8 vs. 28*, FX 15 vs. 37*, FXI 9 vs. 23 and FXII 30 vs. 44 IU/dl* (*P < 0.01). In vivo recovery of coagulation factors was the same for both groups and the observed increments correlated with the dose of FFP. In conclusion, coagulation screens were poor predictors of coagulation factor levels and current guidelines on the use of FFP result in predictably small increments in coagulation factors in critically ill patients and should be reviewed.
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PMID:Efficacy of standard dose and 30 ml/kg fresh frozen plasma in correcting laboratory parameters of haemostasis in critically ill patients. 1501 71

FEIBA (factor eight inhibitor bypassing activity) has a history of more than 30 years of successful use in controlling bleeding in haemophilic patients who have developed inhibitory antibodies against factor (F)VIII or FIX. Recently it was shown that FEIBA contains the proenzymes of the prothrombin complex factors, prothrombin, FVII, FIX and FX, but only very small amounts of their activation products, with the exception of FVIIa, which is contained in FEIBA in greater amounts. FEIBA controls bleeding by induction and facilitation of thrombin generation, a process for which FV is crucial. A number of biochemical in vitro and in vivo studies have shown that FXa and prothrombin play a critical role in the activity of FEIBA. Consequently, they are considered to be key components of this product. The prothrombinase complex has been found to be a major target site for FEIBA. Apart from prothrombin and FXa, FEIBA contains other proteins of the prothrombin complex, which could also facilitate haemostasis in haemophilia patients with inhibitors.
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PMID:FEIBA: mode of action. 1538 40

Activated recombinant human factor VIIa (rFVIIa) has been used as a hemostatic agent in patients with hemophilia and acquired inhibitors. Other indications for rFVIIa may include liver disease, warfarin sodium (Coumadin) overdose, or trauma. Monitoring patients on this treatment with standard laboratory testing is problematic. Bleeding risk does not correlate well with the prothrombin time (PT) or the activated partial thromboplastin time (aPTT) during therapy with rFVIIa. In addition, there is no identifiable literature on the effect of rFVIIa on assays of inhibitors in this patient group. Monitoring inhibitors may be important during interventions aimed at acutely reducing inhibitor levels, such as during plasma exchange or protein adsorption. We performed factor assays and evaluated inhibitor levels in plasma from 3 patients with deficiencies in FVIII (2 patients) or FIX (1 patient) and inhibitors (titer range, 5.8-17.4 Bethesda units) before and after adding rFVIIa (range, 0.25-8 microg/mL) in vitro. Additionally, we performed assays of factors of both intrinsic and extrinsic systems to determine the impact of rFVIIa on these tests. We found that both factor levels and inhibitor titers from patients with hemophilia A or B could be measured accurately, even in the presence of suprapharmacologic doses of rFVIIa (8 microg/mL). We also obtained accurate measurements for other assays of the intrinsic coagulation system (FXI and FXII) based on the aPTT. Conversely, we found that assays of the extrinsic system based on the PT (FII, FV, and FX) produced results that were unreliable. FVII results were very high but reproducible. These results suggest that assays based on the PT are inaccurate and should be avoided during FVIIa treatment. Conversely, FVIII and FIX levels and inhibitor titers can be accurately monitored in hemophilia patients receiving rFVIIa according to results of aPTT-based coagulation tests.
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PMID:Effect of activated recombinant human factor 7 (Niastase) on laboratory testing of inhibitors of factors VIII and IX. 1602 35


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