Home About us Contact
|
Home About us Contact | ||
|
|
||
U dL (u + dl)
Selected AbstractsIn vivo recovery of factor VIII and factor IX: intra- and interindividual variance in a clinical settingHAEMOPHILIA, Issue 1 2007S. BJÖRKMAN Summary., In vivo recovery (IVR) is traditionally used as a parameter to characterize the pharmacokinetic properties of coagulation factors. It has also been suggested that dosing of factor VIII (FVIII) and factor IX (FIX) can be adjusted according to the need of the individual patient, based on an individually determined IVR value. This approach, however, requires that the individual IVR value is more reliably representative for the patient than the mean value in the population, i.e. that there is less variance within than between the individuals. The aim of this investigation was to compare intra- and interindividual variance in IVR (as U dL,1 per U kg,1) for FVIII and plasma-derived FIX in a cohort of non-bleeding patients with haemophilia. The data were collected retrospectively from six clinical studies, yielding 297 IVR determinations in 50 patients with haemophilia A and 93 determinations in 13 patients with haemophilia B. For FVIII, the mean variance within patients exceeded the between-patient variance. Thus, an individually determined IVR value is apparently no more informative than an average, or population, value for the dosing of FVIII. There was no apparent relationship between IVR and age of the patient (1.5,67 years). For FIX, the mean variance within patients was lower than the between-patient variance, and there was a significant positive relationship between IVR and age (13,69 years). From these data, it seems probable that using an individual IVR confers little advantage in comparison to using an age-specific population mean value. Dose tailoring of coagulation factor treatment has been applied successfully after determination of the entire single-dose curve of FVIII:C or FIX:C in the patient and calculation of the relevant pharmacokinetic parameters. However, the findings presented here do not support the assumption that dosing of FVIII or FIX can be individualized on the basis of a clinically determined IVR value. [source] Successful use of recombinant factor VIIa in a patient with inhibitor secondary to severe factor XI deficiencyHAEMOPHILIA, Issue 2 2002P. LAWLER Factor XI (FXI) inhibitors are a rare complication of inherited FXI deficiency. We report the successful use of recombinant factor VIIa (FVIIa) in a patient with a high-responding inhibitor undergoing cataract extraction. At the time of surgery there were limited available data on the optimal management of patients with FXI deficiency. A 62-year-old Ashkenazi Jewish woman had a lifelong history of excessive bleeding secondary to severe FXI deficiency (2 U dL,1), and received FXI concentrate (FXI:C) when she underwent a colposuspension procedure. She was subsequently diagnosed with a FXI inhibitor of 16 Bethesda units (BU) when she developed a poor response to FXI:C at the time of total hip replacement. Two months later she was admitted for cataract extraction. The FXI level was < 1 U dL,1 with an inhibitor titre of 48 BU. She received 90 ,g kg,1 of FVIIa immediately preoperatively followed by continuous infusion at a rate of 20 ,g kg,1 h,1 for 24 h. The cataract extraction was successful and there was no excess bleeding during surgery or in the postoperative period. Mutation analysis of the FXI gene showed that the patient was homozygous for the type II genotype [exon 5, Glu117,Ter]. The reason for the low prevalence of inhibitor formation in patients with FXI deficiency is unclear but may reflect a number of factors including reporting bias, the rarity of absent circulating FXI:C activity, and the infrequent use of FXI replacement therapy. [source] Prerequisites for recombinant factor VIIa-induced thrombin generation in plasmas deficient in factors VIII, IX or XIJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 1 2006T. LIVNAT Summary.,Background:,Recombinant factor VIIa (rFVIIa) used for the treatment of hemophilia A or B patients with an inhibitor is hemostatically effective because it induces thrombin generation (TG), despite grossly impaired FVIII- and FIX-dependent amplification of FX activation. Tissue factor (TF) and or activated platelets were shown to be essential for the rFVIIa activity. Objective: To evaluate the relative effects of TF and phospholipids on rFVIIa-induced TG in FVIII-, FIX- and FXI-deficient plasmas. Methods: Phospholipids had an independent effect that was augmented by TF. The contribution of blood-borne TF in FVIII-, FIX- and FXI-deficient plasma to rFVIIa-induced TG was demonstrated by removing microparticles and use of anti-TF antibodies. Results: At increasing concentrations of rFVIIa, the dependence of rFVIIa-induced TG on TF declined, but the presence of phospholipids was essential. rFVIIa was also shown to activate purified FIX and FX in the presence of phospholipids and absence of TF. rFVIIa-induced TG was dramatically augmented in FVIII- or FIX-deficient plasma in which the level of FVIII or FIX was increased to 1 or 2 U dL,1. Conclusions: The data indicate that rFVIIa-induced TG is affected by TF, phospholipids, rFVIIa concentration, and the presence of FVIII and FIX. [source] A multicenter pharmacokinetic study of the B-domain deleted recombinant factor VIII concentrate using different assays and standardsJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 11 2003M. Morfini Summary., When the one-stage clotting assay is used in comparison with the chromogenic and immunological assays, plasma levels of factor (F)VIII are underestimated by 40,50% after infusion of B-domain deleted recombinant FVIII (BDD-rFVIII) in patients with hemophilia. A possible way to counteract the underestimation of FVIII levels by the one-stage assay is the adoption of a recombinant FVIII reference standard instead of a plasma standard. To evaluate the usefulness of such a standard [ReFacto® Laboratory Standard (RLS)], the pharmacokinetic parameters of a single dose of BDD-rFVIII (25 U kg,1) were evaluated in a multicenter study carried out in 18 patients with severe hemophilia A. The very low in vivo recovery, obtained with the combination of the one-stage assay and plasma reference standard, was increased up to the values obtained by the chromogenic assay when the results were expressed in terms of RLS. When the plasma standard was used, the one-stage/chromogenic ratio was 0.82 ± 0.12 for FVIII levels above 25 U dL,1 and 1.42 ± 0.99 for FVIII levels below 25 U dL,1. Using the RLS, the one-stage/chromogenic ratio increased to 1.01 ± 0.19 at FVIII levels above 25 U dL,1, as a consequence of a complete overlap of the two decays; however, at FVIII levels below 25 U dL,1, the one-stage/chromogenic ratio was still 1.6 ± 0.85. After the twelfth hour, FVIII concentrations obtained by chromogenic assay were always lower than those resulting from the one-stage clotting assay, independently of the standard used. Results obtained by chromogenic assay were not affected by the type of standard used. Compared with those obtained by the one-stage assay, higher values of clearance, lower volume of distribution area and shorter plasma half-life or mean residence time were obtained by chromogenic assay because of a shape change of the decay curve due to a shift to higher values in the first part (time interval 0,12 h) and to lower values in the second part of the decay curve (time interval 12,48 h). As a consequence, the slope of the decay curve obtained by means of chromogenic assay was steeper. In conclusion, the more homogeneous results of in vivo recovery and pharmacokinetic analysis, due to the decrease of discrepancy between the two methods when RLS was used, make the cheaper and more widely used one-stage assay preferable to the more expensive chromogenic assay, on condition that the ReFacto specific standard has used. [source] | ||||||||||