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E Berntorp

Publications and source records attributed to E Berntorp.

At least 19 recordsLinked to original sources
PubMed2007

Impact of different inhibitor reactivities with commercial factor VIII concentrates on thrombin generation.

In order to describe the haemostatic role of a variation in inhibitor reactivity with different factor VIII (FVIII) concentrates, we have compared inhibitor titres against a panel of FVIII concentrates and correlated titre with the capacity to inhibit thrombin generation. Three plasma-derived concentrates were tested in vitro in mixing experiments with inhibitor plasmas from 11 patients with severe haemophilia A: Fanhdi, which contains von Willebrand factor (VWF) with a final ratio of approximately 1:1 (VWF IU per IU FVIII:C); Haemate-P with a ratio of 2.5:1 and Hemofil-M containing only trace amounts of VWF. In addition, the recombinant FVIII concentrate Kogenate Bayer containing no VWF was included. Inhibitor titres and the capacity to generate thrombin were measured. A statistically significant difference in measured titres was found with the highest titres recorded against Hemofil-M. The inhibitor titres needed to inhibit 50% maximum thrombin generation were the lowest for Kogenate Bayer and the highest and similar for Fanhdi and Haemate-P with intermediate titres needed for inhibition of Hemofil-M. In this study, the thrombin generation assay provides additional indications for the role of VWF in the treatment of patients with inhibitors. The VWF-containing concentrates Fanhdi and Haemate-P, added to FVIII-deficient plasma with the presence of inhibitor, generate more thrombin than do the purified concentrates Hemofil-M and Kogenate Bayer.

Antigen-Antibody Reactions↗
PubMed2007

In vivo recovery of factor VIII and factor IX: intra- and interindividual variance in a clinical setting.

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 dL1 per U kg1) 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.

Adolescent↗
PubMed2006

Von Willebrand's disease: clinical management.

The aim of treatment of von Willebrand's disease (VWD) is to correct the dual defect of haemostasis, i.e. the abnormal platelet adhesion due to reduced and/or dysfunctional von Willebrand factor (VWF) and the abnormal coagulation expressed by low levels of factor VIII (FVIII). Desmopressin (DDAVP) is the treatment of choice for type 1 VWD because it can induce release of normal VWF from cellular compartments. Prospective studies on biological response versus clinical efficacy of DDAVP in VWD type 1 and 2 are in progress to further explore its benefits and limits as therapeutic option. In type 3 and in severe forms of type 1 and 2 VWD, DDAVP is not effective and for these patients plasma virally inactivated concentrates containing VWF and FVIII are the mainstay of treatment. Several intermediate- and high-purity VWF/FVIII concentrates are available and have been shown to be effective in clinical practice (bleeding and surgery). New VWF products almost devoid of FVIII are now under evaluation in clinical practice. Although thrombotic events are rare in VWD patients receiving repeated infusions of concentrates, there is some concern that sustained high FVIII levels may increase risk of postoperative venous thromboembolism. Dosage and timing of VWF/FVIII administrations should be planned to keep FVIII level between 50 and 150 U/dL. Appropriate dosage and timing in repeated infusions are also very important in patients exposed to secondary long term prophylaxis for recurrent bleedings.

Deamino Arginine Vasopressin↗
PubMed2006

Tyr2105Cys mutation in exon 22 of FVIII gene is a risk factor for the development of inhibitors in patients with mild/moderate haemophilia A.

We report the case of a patient with mild haemophilia A, due to a Tyr2105Cys mutation in exon 22 of the C1 domain, who developed a high-titre factor VIII inhibitor (maximum titre 1600 BU) with recurrent severe haemorrhages and fatal intracranial bleeding. Based on published data, it appears that although this mutation occurs rarely in patients with mild or moderate haemophilia A, it is frequently associated with the development of high-titre inhibitors.

Blood Coagulation Factor Inhibitors↗
PubMed2006

Inhibitor treatment in haemophilias A and B: summary statement for the 2006 international consensus conference.

Participants in an international conference on the management of haemophilia patients with inhibitors developed a jointly authored summary of the findings and conclusions of the conference. Current knowledge of the genetic and immunologic mechanisms underlying inhibitor development was briefly summarized. Concerning the purported treatment-related risk factors, conference participants commented on the limitations of the available evidence and the need for more rigorous prospective research in a fully genotyped population. Other clinical considerations discussed included the unproved utility of routine surveillance, the need for assay standardization, the management of acute bleeding and approaches to joint disease prophylaxis and immune tolerance induction (ITI). A number of issues were identified as needing further investigation in larger prospective studies, ideally through international cooperation. Such studies should enroll cohorts that have been scrupulously defined in terms of mutation status and treatment exposure. Finally, conference participants urged their colleagues to participate in the currently ongoing international trials of ITI.

Blood Coagulation Factor Inhibitors↗
PubMed2006

Options for treating acute bleeds in addition to bypassing agents: extracorporeal immunoadsorption, FVIII/FIX, desmopressin and antifibrinolytics.

Inhibitor patients do not always respond satisfactorily to treatment with bypassing agents, and options to the standard practice are sometimes needed. Temporary inhibitor removal may be achieved using extracorporeal immunoadsorption. This technique uses a column system including either protein A or antihuman IgG. Immunoadsorption may be used as part of an immune tolerance protocol, or in the case of acute bleeds or prior to surgery, thus rendering the patient more responsive to ordinary replacement therapy with factor VIII or factor IX. Desmopressin is a valuable haemostatic agent in many situations and can be especially recommended in mild haemophilia complicated by an inhibitor. Antifibrinolytics are often administered as an adjunct therapy to the treatment protocol and have also been reported to have a direct anti-inhibitor effect.

Antifibrinolytic Agents↗
PubMed2006

The 80th anniversary of von Willebrand's disease: history, management and research.

The history of von Willebrand's disease (VWD) is fascinating because it demonstrates how good clinical observations, genetic studies and biochemical skills can improve basic understanding of a disease and its management. The continuous efforts of scientists and clinicians during the last 80 years have significantly improved the knowledge of von Willebrand factor (VWF) structure and function and the management of VWD. Diagnosis of phenotype and genotype is now available in many countries and treatment is becoming more specific according to the VWD type. Any therapeutic agents must correct the dual defect of haemostasis, i.e. the abnormal platelet adhesion due to reduced and/or dysfunctional and low levels of factor VIII (FVIII) associated with VWF defects. Desmopressin (DDAVP) is the treatment of choice for type 1 VWD because it induces release of VWF from cellular compartments. Plasma virally inactivated VWF concentrates containing FVIII are effective and safe in patients unresponsive to DDAVP. There are advanced plans to develop a recombinant VWF but this product will require the concomitant administration of FVIII for the control of acute bleeds. Basic research studies on cellular biology, biochemistry and immunology have confirmed the role of VWF as a crucial participant in both haemostasis and thrombosis as its main biological activity is to support platelet adhesion-aggregation in the circulation. Retrospective and prospective clinical research studies, including bleeding history and laboratory markers for diagnosis as well as the use of DDAVP and VWF concentrates to manage or prevent bleeds in patients with VWD have been essential to provide general guidelines for VWD management. The large number of publications quoting VWD and VWF emphasizes the important role of VWF in medicine.

Clinical Trials as Topic↗
PubMed2005

Pharmacokinetic studies on Wilfactin, a von Willebrand factor concentrate with a low factor VIII content treated with three virus-inactivation/removal methods.

OBJECTIVE: In order to correct the primary von Willebrand factor (VWF) defect and avoid supra-physiologic plasma levels of factor VIII, a pure VWF concentrate almost devoid of FVIII was developed and used in France since 1989. METHODS: The pharmacokinetic (PK) profile of the most recent version of this concentrate (Wilfactin; LFB, Les Ulis, France), treated with three virus-inactivation/removal methods (solvent/detergent, 35 nm filtration, dry heat treatment), was investigated in 25 patients. Seventeen patients with various types of clinically severe von Willebrand disease (VWD) were included in a crossover, randomized trial carried out in five European centers and comparing Wilfactin with concentrates containing both FVIII and VWF (FVIII/VWF). Eight type 3 VWD patients were included in another trial carried out in six French centers comparing Wilfactin with its previous version (Facteur Willebrand-LFB; LFB) that adopted one virus-inactivation method only. RESULTS: For both the measurements evaluated in this study (VWF antigen, VWF:Ag; and VWF ristocetin co-factor activity, VWF:RCo), Wilfactin had a PK profile similar to that of the FVIII/VWF concentrates and of Facteur Willebrand-LFB. VWF:RCo and VWF:Ag recoveries were 2.1 +/- 0.3 and 1.8 +/- 0.3 per IU kg(-1), respectively, and the half-lives were 12.4 +/- 1.8 and 15.9 +/- 1.5 h. The FVIII synthesis rate was 5.8 +/- 1.0 IU dL(-1) h(-1), with a half-life of 15.8 +/- 2.4 h. CONCLUSION: The PK of VWF and FVIII have not been altered by the three virus-inactivation/removal steps during the manufacturing of Wilfactin.

Adult↗
PubMed2004

Elective orthopedic surgery for hemophilia patients with inhibitors: New opportunities.

We report a series of 108 elective orthopedic surgical procedures in hemophilia patients with inhibitors, comprising 88 cases in which radiosynoviorthesis was performed and 20 cases in which major orthopedic procedures were carried out. Hemostatic cover was provided by recombinant factor VIIa (rFVIIa, NovoSeven(R), Novo Nordisk, Bagsvaerd, Denmark) in 17 cases, and by FVIII anti-inhibitor product (FEIBA, Baxter Corp, Toronto, Canada) in the remaining three procedures. A total of 51 patients from nine centers worldwide were included. The results of the procedures were characterized as good (82 procedures), fair (15), or poor (11). Postoperative bleeding complications requiring further surgical intervention occurred in three (15%) of the 20 major orthopedic procedures; all three procedures used rFVIIa as a hemostatic agent. Despite these complications, however, our study has shown that rFVIIa allows hemophilic patients with high inhibitor titers to undergo elective orthopedic surgery (EOS) with a greater expectation of success, leading to an improved quality of life. Thorough analysis of each case as part of a multidisciplinary team will help to identify further inhibitor patients in whom EOS can be performed both safely and effectively.

Blood Coagulation Factor Inhibitors↗
PubMed2004

Economic evaluation: what are we looking for and how do we get there?

The interest in economic evaluation of alternative strategies for haemophilia treatment has increased through the years. Few studies have actually been undertaken, however, and most of them have been simple cost-minimization or cost-effectiveness analyses. From the perspective of the binational project 'Treatment strategies for severe haemophilia-prophylaxis vs. on-demand', the present paper discusses the pros and cons of different methods for economic evaluation and their data requirements. Severe haemophilia is a rare disease that requires lifelong treatment. In addition, treatment has both short- and long-term effects which are likely to differ between strategies. Accordingly, regardless of the chosen evaluation method, data requirements are non-trivial. Hence, the various problems connected to the generation of data, as well as how they may be addressed, are also discussed.

Cost Savings↗
PubMed2004

Clinical evaluation of an advanced category antihaemophilic factor prepared using a plasma/albumin-free method: pharmacokinetics, efficacy, and safety in previously treated patients with haemophilia A.

The efficacy and safety of an advanced category recombinant antihaemophilic factor produced by a plasma- and albumin-free method (rAHF-PFM) was studied in 111 previously treated subjects with haemophilia A. The study comprised a randomized, double-blinded, crossover pharmacokinetic comparison of rAHF-PFM and RECOMBINATE rAHF (R-FVIII); prophylaxis (three to four times per week with 25-40 IU kg(-1) rAHF-PFM) for at least 75 exposure days; and treatment of episodic haemorrhagic events. Median age was 18 years, 96% of subjects had baseline factor VIII <1%, and 108 received study drug. Bioequivalence, based on area under the plasma concentration vs. time curve and adjusted in vivo recovery, was demonstrated for rAHF-PFM and R-FVIII. Mean (+/-SD) half-life for rAHF-PFM was 12.0 +/- 4.3 h. Among 510 bleeding events, 473 (93%) were managed with one or two infusions of rAHF-PFM and 439 (86%) had efficacy ratings of excellent or good. Subjects who were less adherent to the prophylactic regimen had a higher bleeding rate (9.9 episodes subject(-1) year(-1)) than subjects who were more adherent (4.4 episodes subject(-1) year(-1); P < 0.03). One subject developed a low titre, non-persistent inhibitor (2.0 BU) after 26 exposure days. These data demonstrate that rAHF-PFM is bioequivalent to R-FVIII, and suggest that rAHF-PFM is efficacious and safe, without increased immunogenicity, for the treatment of haemophilia A.

Adolescent↗
PubMed2004

Costs of on-demand and prophylactic treatment for severe haemophilia in Norway and Sweden.

The expected annual cost (in the year 2000 prices) for a 30-year-old patient with average individual and treatment characteristics for on-demand EUR 51,832 (95% CI: 44,324-59,341) and for prophylaxis EUR 146,118 (95% CI: 129,965-162,271), was obtained from panel-data analysis of an 11-year retrospective panel of 156 patients with severe haemophilia in Norway and Sweden. Costs included haemophilia-related treatment costs within the health-care sector (factor concentrate, doctors' visits, diagnostic procedures, hospitalisation, invasive procedures, etc.) and cost for haemophilia-related resource use in other sectors (lost production, use of special equipment, adaptation of workplace and domicile, etc). Although costs of lost production, reconstructive surgery and hospitalisation were higher for on-demand, they did not balance out the higher costs of factor-concentrate consumption in prophylaxis. The cut-off risk of premature death, where on-demand and prophylaxis would have been equally costly, was 3.7 percentage units higher for on-demand than for prophylaxis. Such a great risk difference has not been reported elsewhere to our knowledge. Estimated cost-elasticities indicated that annual costs of prophylaxis would increase by approximately the same proportion as a potential increase in the price of factor concentrate and decrease less than proportionately with a reduction in prescribed dose kg(-1). For on-demand, the annual costs would increase by approximately the same proportion as an increase in the prescribed dose kg(-1).

Adult↗
PubMed2004

Willingness to pay for on-demand and prophylactic treatment for severe haemophilia in Sweden.

The objective of the present paper was to provide an estimate of the benefits of on-demand and prophylaxis treatment strategies for severe haemophilia in monetary terms. Using the contingent-valuation method, which simulates a missing market by asking people about their willingness to pay (WTP), we asked a representative sample (n = 609) of the Swedish population if they would be willing to pay a specific amount (bid) so that patients with severe haemophilia could receive on-demand treatment and another bid for prophylactic treatment. Different respondents were offered different bids and the bid vector ranged from 71 Euro cents to EUR 130. The order of the bid questions was randomized so that half of the respondents were asked first about their WTP for on-demand treatment, and then about their WTP for prophylaxis, while the order was reversed for the other half of the respondents. The mean estimated WTP (year 2002) was EUR 39 (95% CI 31-47) for on-demand and EUR 65 (95% CI 55-73) for prophylaxis. Our sensitivity analysis showed that the ranking of the two treatment alternatives was robust in that the WTP was greater for prophylaxis in all possible subsets. The point estimates of WTP varied somewhat in subsets defined by individual characteristics, but confidence intervals always overlapped that of the main results. The WTP for on-demand and prophylaxis exceeded the calculated cost of treatment per taxpayer of providing on-demand and prophylactic treatment, respectively, based on our previous results.

Adult↗
PubMed2004

A 6-year follow-up of dosing, coagulation factor levels and bleedings in relation to joint status in the prophylactic treatment of haemophilia.

The primary aim of this study was to investigate the possible relationship between coagulation factor level and bleeding frequency during prophylactic treatment of haemophilia after stratification of the patients according to joint scores. The secondary aim was to obtain a systematic overview of the doses of coagulation factors prescribed for prophylaxis at the Malmo haemophilia treatment centre during a 6-year period. A retrospective survey of medical records for the years 1997-2002 and pharmacokinetic study results from the 1990s was complemented by collection of blood samples for coagulation factor assay when needed. Information on the dosing and plasma levels of factor VIII or factor IX, joint scores and incidence of bleedings (joint bleeds and 'other bleeds') was compiled. The patients were stratified by age (0-6, 7-12, 13-18, 19-36 and >36 years) and joint score (0, 1-6 and >6). Individual pharmacokinetic parameters of plasma coagulation factor activities (FVIII:C and FIX:C) were estimated. Trough levels during the treatment were calculated, as well as the number of hours per week of treatment during which plasma FVIII:C/FIX:C fell below a 1, 2 or 3% target level. Fifty-one patients with haemophilia A (two moderate, 49 severe) and 13 with haemophilia B (all severe) were included, yielding data for 364 patient-years of treatment. There was a wide range of dosing schedules, the most common ones being three times a week or every other day for FVIII and twice a week or every third day for FIX. The overall relationship between FVIII:C/FIX:C levels and incidence of joint bleeding was very weak, even after stratification of the patients according to joint score. There was no relationship between coagulation factor level and incidence of other bleeds. In this cohort of patients on high-dose prophylactic treatment, dosing was based more on clinical outcome in terms of bleeding frequency than on the aim to maintain a 1% target level of FVIII:C/FIX:C. Some patients did not bleed in spite of a trough level of <1% and others did in spite of trough levels >3%. The practical implication of our findings is that dosing in prophylactic treatment of haemophilia should be individualized. Thus, proposed standard regimens should be implemented only after careful clinical consideration, with a high readiness for re-assessment and individual dose tailoring.

Adolescent↗
PubMed2003

Experience with a new percutaneous port system, Percuseal, for intravenous injection in patients with haemophilia, von Willebrand disease and severe alpha1-antitrypsin deficiency.

We have implanted a new port system (Percuseal) in altogether 13 patients with haemophilia A, B, von Willebrand disease and alpha1-antitrypsin deficiency in order to facilitate venous access. The Percuseal system differs from subcutaneous ports, such as Port-a-Cath, in that the upper part of the device protrudes above the skin. In this way, the patient can easily puncture the port membrane under the guidance of his eyes without penetrating the skin. In the present study cohort, a number of complications occurred. These were mainly caused by repeated local infections (in five patients), which made it necessary to replace the ports in three of the patients and to permanently remove the ports as the first option in two of the patients. In one patient, the port was removed because of inconvenience when doing physical exercise. In one additional patient, a severe systemic infection occurred, causing spondylitis. Despite the high infection rate, most patients considered the device very convenient to use. Because of the side-effects seen in our study, the Percuseal port in its present form is not to be recommended for regular use. A reconstruction of the port, making it smaller and giving it an antibacteriostatic cap, may possibly make this kind of port system a feasible alternative to use in order to improve pharmacoeconomics in the prophylactic treatment of haemophilia and patients with alpha1-antitrypsin deficiency.

Adult↗
PubMed2003

The pharmacokinetics of clotting factor therapy.

Clotting factor preparations are expensive and not readily available in all parts of the world. We are still facing shortages due to limited production. Thus, it is obvious that clotting factor therapy should be optimised as far as possible. The judicious use of pharmacokinetic principles should be one of the fundaments of dosing. There are several pitfalls in studies of clotting factor pharmacokinetics, such as discrepancies between assays, inadequate blood sampling protocols, problems to define the administered dose, uncertainty in the estimation of plasma volume for in vivo recovery calculation, and post-infusion activation of the clotting factor. Thus, while the pharmacokinetics of factor VIII is well characterised there are some discrepancies in the literature on factor IX. Recombinant factor VIIa is useful to treat haemorrhages in haemophilia complicated by inhibitors. The pharmacokinetics of VIIa has been investigated, however, the relationship between plasma level of VIIa and effect needs further exploration. Important applications of clotting factor pharmacokinetics include optimising the treatment and improving its cost-effectiveness during long-term prophylaxis as well as during bleeding episodes and surgery.

Blood Coagulation Factors↗