Search PubMed⌕ Search

Biomedical subjects

J Astermark

Publications and source records attributed to J Astermark.

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

Current use of by-passing agents in Europe in the management of acute bleeds in patients with haemophilia and inhibitors.

The ultimate goal of treatment for patients with inhibitory antibodies should be to permanently eradicate the inhibitor by immune tolerance induction therapy (ITI). However, ITI procedures fail in a substantial number of patients and in many countries ITI is not even offered owing to its high cost. How patients with inhibitors are managed in different European countries is evaluated with a special focus on the use of by-passing agents, i.e. recombinant FVIIa (rFVIIa) and activated prothrombin complex concentrates (aPCC), as well as the type of monitoring performed. Investigators from 22 large haemophilia centres participating within the network of the European Haemophilia Therapy Standardisation Board (EHTSB) were asked to complete a questionnaire. rFVIIa was routinely used in all centres for both children and adults at dosages ranging from 90 to 250 mug kg(-1) at an interval of 2-4 h. aPCC was used in 85% of the centres in adults and in 25% of the centres in children with haemophilia A at dosages of 50-100 IU kg(-1) every 6-12 h. The corresponding figures for children and adults with haemophilia B were 40% and 15% of the centres, respectively. Higher dosages of both agents were considered in the case of life-threatening bleeds. General recommendations were developed, based on the information provided by the survey. The results clearly indicate the need for well-designed comparative studies to optimize the use of by-passing agents.

Acute Disease↗
PubMed2006

Why do inhibitors develop? Principles of and factors influencing the risk for inhibitor development in haemophilia.

The formation of inhibitory alloantibodies is, in the postinfectious era, the most severe and costly complication of replacement therapy in patients with haemophilia. The complexity of the immune response to the infused factor becomes more and more obvious as knowledge in the area increases. Antibodies develop as a result of a complex multi-factorial interaction between antigen-presenting cells, T- and B-lymphocytes. Genetic susceptibility of cell surface molecules, such as the major histocompatibility complex, the T-cell receptor and cytokine receptors, as well as various immunomodulatory molecules have a major impact on the outcome. In addition, environmental factors probably influence the risk of inhibitor development. The current concept of inhibitor development is reviewed. A better understanding of the pathophysiological mechanisms involved will facilitate improvement of therapy in the future, and hopefully provide an opportunity to prevent this complication of treatment.

Blood Coagulation Factor Inhibitors↗
PubMed2006

Current European practice in immune tolerance induction therapy in patients with haemophilia and inhibitors.

The management of patients with inhibitors is an important challenge in haemophilia care. The lack of randomized controlled trials means that clinical decisions are generally based on subjective opinions, and purchasers' attention is likely to focus on the costs of treatment. In order to assess the current management of inhibitor patients and use of immune tolerance induction therapy (ITI) in Europe, we performed a survey within a European network of 21 comprehensive care centres from 14 countries (the European Haemophilia Therapy Standardisation Board). The survey identified a total of 381 patients with inhibitors attending the centres, 211 (55.4%) of whom had never been exposed to ITI. Between 1998 and 2003, the centres performed 233 procedures and 114 (48.9%) were successful. The survey demonstrated that dosing, which is the time to start and stop the ITI, the type of concentrate to use and the definition of success varied among the centres. Well-designed trials are warranted to guide decision-making, but in the absence of these studies we have developed consensus guidance for the management of inhibitor patients based on current clinical practice, as identified by the survey, and review of the literature.

Adult↗
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

Basic aspects of inhibitors to factors VIII and IX and the influence of non-genetic risk factors.

The appearance of polyclonal antibodies inhibiting the function of exogenous factors VIII (FVIII) and IX (FIX) continues to be a major challenge in the treatment of patients with congenital haemophilia. Why these inhibitors develop in 10-20% of patients with haemophilia A, and in 1-5% of patients with haemophilia B, remains largely unexplained. The antibodies, however, are characterized by several features that may have implications for the immune process by which they occur. The FVIII antibodies are mainly directed towards the A2, A3 and C2 domains, thereby interfering with the function of the factor Xase complex, the binding of FVIII to von Willebrand factor, and the binding of FVIII to phospholipid membranes. The FIX epitopes are localized to the NH(2)-terminal gamma-carboxyglutamic acid region and the serine protease domain. Genetic risk factors are known to be of importance in the development of inhibitors, whereas the impact of non-genetic factors is less clear. However, based on studies of related subjects, it is obvious that non-genetic factors are of importance as well. Putative factors currently debated include age at the start of treatment, treatment in association with immune challenges, the type of product, and the mode of administration. Most of the findings reported to date, however, derive from small cohorts that have not been sufficiently well characterized with respect to genetic risk profile. Therefore, additional studies are required to quantify the impact of non-genetic factors on the pathophysiologic process of inhibitor development.

Antibodies↗
PubMed2003

Impact of inhibitor epitope profile on the neutralizing effect against plasma-derived and recombinant factor VIII concentrates in vitro.

The inhibitory capacity of plasma samples from 24 patients with severe haemophilia A and high-responding inhibitors were evaluated in a concentrate-based assay using two plasma-derived (Haemate and Monoclate-P) and three recombinant (Helixate, Recombinate and ReFacto) factor VIII concentrates and correlated with the corresponding epitope profile. In most, but not all, inhibitor plasmas with a relatively low reactivity against the von Willebrand-containing product Haemate, the main epitopes were located in the FVIII light chain. The reactivities within the group of recombinant products varied in that the reactivity against the B-domain deleted ReFacto was in general higher than that against Recombinate and Helixate. This difference did not correlate with any particular epitope profile and indicates that the B-domain, type of formulation and/or purification procedures may have an impact on the inhibitor reactivity in vitro. The ratio between the inhibitor titres in the concentrate-based assay and the Bethesda assay was dependent on the inhibitor plasma and concentrate used. Taken together, our results show that the reactivity of inhibitor plasmas varies considerably between different FVIII concentrates and that it does not fully correlate with the epitope profile. Potential clinical implications of the observed differences in inhibitor reactivity are discussed.

Autoantibodies↗
PubMed2003

When to start and when to stop primary prophylaxis in patients with severe haemophilia.

Primary prophylactic treatment of patients with severe haemophilia has been shown to reduce the number of bleeding episodes and to minimize the development of arthropathy. However, since the use of clotting factor concentrates is associated with considerable cost and not all patients with severe haemophilia have a severe bleeding phenotype, there is still no consensus about when to start prophylaxis, which dosing regimen to use, and if or when the treatment should be stopped when the patient becomes elderly. Some care providers are also concerned about the use of central venous lines in very young children. Even though most available data indicate that prophylaxis should be started during the first years of life, it may be possible to adjust the dose and dose interval depending on the bleeding pattern. The use of an individualized prophylactic regimen may also improve cost-effectiveness and make the use of this treatment modality more feasible. Studies to further address this issue are warranted.

Adolescent↗
PubMed2003

Consensus perspectives on prophylactic therapy for haemophilia: summary statement.

Participants in an international conference on prophylactic therapy for severe haemophilia developed a consensus summary of the findings and conclusions of the conference. In the consensus, participants agreed upon revised definitions for primary and secondary prophylaxis and also made recommendations concerning the need for an international system of pharmacovigilance. Considerations on starting prophylaxis, monitoring outcomes, and individualizing treatment regimens were discussed. Several research questions were identified as needing further investigation, including when to start and when to stop prophylaxis, optimal dosing and dose interval, and methods for assessment of long-term treatment effects. Such studies should include carefully defined cohorts, validated orthopaedic and quality-of-life assessment instruments, and cost-benefit analyses.

Consensus Statements as Topic↗
PubMed2003

Thrombosis in inherited factor VII deficiency.

Thrombosis in congenital factor (F) VII deficiency was investigated through extensive phenotypic and molecular-genetic studies. Patients with a history of thrombosis among 514 entries in the FVII Deficiency Study Group database were evaluated. Thrombotic events were arterial in one case, disseminated intravascular coagulation in another and venous in seven. Gene mutations were characterized in eight patients: three were homozygous, three compound heterozygous and two heterozygous. FXa and IIa generation assays were consistent with the genetic lesions. One patient was heterozygous for the FV Leiden and one for the FIIG20210A mutation. In seven patients, surgical interventions and/or replacement therapies had a close temporal relationship with thrombosis, while in the remaining, events were apparently spontaneous. Thromboses were not associated with any specific age, phenotype, mutation zygosity or thrombophilic abnormalities. In particular, severe FVII deficiency did not seem to offer protection from strong thrombosis risk factors such as surgery and replacement therapy.

Adolescent↗
PubMed2003

Monitoring the bioavailability of FEIBA with a thrombin generation assay.

BACKGROUND: Hemophilia A patients with inhibitors are generally treated with preparations containing activated coagulation factors to achieve hemostasis by bypassing factor (F)VIII. OBJECTIVES: We developed an assay for monitoring the kinetic of thrombin generation in human FVIII inhibitor plasma reconstituted in vitro with activated prothrombin complex concentrate, FEIBA, and in plasma samples from hemophilia A patients taken after FEIBA treatment. PATIENTS AND METHODS: For pharmacokinetic studies three patients with severe hemophilia A and with a high-titer inhibitor received a single dose of FEIBA. Repeated FEIBA treatment was monitored in one patient with acquired hemophilia A. Coagulation was triggered in citrated plasma by adding a low concentration of tissue factor/phospholipid complex and CaCl2 in the presence of a fluorogenic thrombin substrate. The intensity of the fluorescence signal (FU) was continuously monitored, and the rate of increase in the fluorescence signal for every time point, which reflects the actual thrombin concentrations, was calculated. RESULTS: The maximum rate of substrate conversion, which indicates the highest thrombin concentration, was approximately 1900 FU min(-1) in a normal plasma pool. Practically no thrombin generation was observed in the FVIII inhibitor plasma, but when it was spiked with FEIBA, the rate and the peak of thrombin generation increased dose-dependently to close to normal. Plasma samples from FVIII inhibitor patients treated with a single dose of FEIBA had an improved thrombin maximum within an hour after treatment, which gradually returned to baseline values with a half-life of 4-7 h. Changes in the characteristic parameters of thrombin generation coincided with the repeated administration of FEIBA in a patient with acquired hemophilia A. CONCLUSIONS: This assay enables the pharmacodynamic and pharmacokinetic properties of bypassing therapies to be monitored, thus helping to optimize treatment.

Adult↗
PubMed2003

Factor VIII inhibitor-bypassing agents act by inducing thrombin generation and can be monitored by a thrombin generation assay.

Factor VIII (FVIII)-bypassing agents have complex modes of action but all control bleeding in inhibitor patients by triggering the generation of thrombin. No routine test is available for monitoring this therapy in patients with inhibitors against FVIII. We present an assay that records FEIBA- or FVIIa-mediated changes in thrombin generation (TG) in FVIII inhibitor plasma samples. In plasma samples spiked with FEIBA TG was normalized above 0.4 U/ml, while for recombinant FVIIa (rFVIIa) more than 12.5 microg/ml were required to induce TG in the absence of tissue factor (TF). Addition of TF increased the TG potential of rFVIIa in vitro. This assay seems suitable for monitoring the pharmacokinetics of inhibitor bypassing agents during treatment and possibly for predicting responses to treatment.

Autoantibodies↗
PubMed2002

The prognostic value of global haemostatic tests in the intensive care unit setting.

BACKGROUND: Global haemostatic tests are often abnormal in critically ill patients, secondary to activation or consumption of coagulation factors or inhibitors. Methods for analysing plasma levels of these factors are, however, not widely available, and the predictive value of global tests is not known. We examined the clinical applicability to predict the outcome of the global haemostatic tests used at most hospitals. METHODS: Blood was collected from patients within 6 h of admission to an intensive care unit (ICU) and tested regarding platelet count, International Normalized Ratio (INR), and activated partial thromboplastin time (APTT). Ninety-two patients with platelet counts <100 x 10(9) l(-1), INR > 1.36 and/or APTT >45 s were included in a study group, and an additional 92 patients with a comparable age and sex distribution, but not fulfilling these laboratory criteria, constituted a control group. The following data were recorded for each patient: number of days in the ICU and hospital; alive or deceased when released from the ICU and hospital; survival at 30 days and 180 days. RESULTS: Survival upon discharge from the ICU and hospital was significantly reduced in the study group. This was especially pronounced in patients with medical disorders, whereas the survival rate was slightly higher in surgery patients. Expressing the survival predicting ability of the screening tests as odds ratios for all patients (study and control groups together) indicated that prolonged APTT in particular foretold a lower survival rate at studied time-points after admission to the ICU. CONCLUSIONS: The global haemostatic tests INR and APTT can predict survival in critically ill patients, and prolonged APTT in particular seems to be associated with a negative prognosis.

Aged↗
PubMed2002

Prophylactic treatment for severe haemophilia: comparison of an intermediate-dose to a high-dose regimen.

A multicentre study was performed in Sweden and the Netherlands, comparing effects of two prophylactic regimens in 128 patients with severe haemophilia, born 1970-90. 42 Swedish patients (high-dose prophylaxis), were compared with 86 Dutch patients (intermediate-dose prophylaxis). Patients were evaluated at the date of their last radiological score according to Pettersson. Annual clotting factor consumption and bleeding frequency were registered for a period of three years before evaluation. Patients in the high-dose group were younger at evaluation (median 15.2 vs. 17.9 years), started prophylaxis earlier (median 2 vs. 5 years), and used 2.19 times more clotting factor kg-1 year-1. Patients treated with high-dose prophylaxis had fewer joint bleeds (median 0.3 year-1 vs. 3.3 year-1) and the proportion of patients without arthropathy as measured by the Pettersson score was higher (69% vs. 32%), however, the age-adjusted difference in scores (median 0 points vs. 4 points) was small and at present not statistically significant. Clinical scores and quality of life were similar. These findings suggest that, compared with intermediate-dose prophylaxis, high-dose prophylaxis significantly increases treatment costs and reduces joint bleeds over a period of 3 years, but only slightly reduces arthropathy after 17 years of follow-up.

Adolescent↗
PubMed2001

Anti- and procoagulant activities in factor VII-deficient subjects.

The clinical feature in patients with congenital factor VII deficiency is in part dependent on the underlying genetic defect, but the mechanisms influencing the genotype-phenotype correlation remain to be fully elucidated. In addition, thromboembolic events have been reported. Compensatory mechanisms involving vitamin K-dependent factors have been suggested. We have measured anticoagulant activities in 25 factor VII-deficient subjects (factor VII activity < or =36%) and 23 age-matched controls and correlated these to the vitamin K-dependent procoagulant activities. Two of the patients had a history of thromboembolism. The factor VII-deficient patients were found to have a significantly lower protein C activity than the controls [0.84 U/ml (95% CI 0.78; 0.89) vs. 0.98 U/ml (95% CI 0.91; 1.05), P=.004]. In addition, the protein C activity was correlated to that of factor VII (r=.36; P=.014), factor IX (r=.45; P=.002) and factor X (r=.50; P=.0006), respectively. The level of prothrombin fragment 1+2 was correlated to the protein C (r=.40; P=.012) and to the factor VII activity (r=.42; P=.011). No differences between patients and controls were seen regarding total and free protein S, antithrombin, plasminogen activator inhibitor-1 (PAI-1) and tissue factor pathway inhibitor (TFPI). Seven of the patients were found to have the Factor V Leiden mutation, but none of them had experienced any thromboembolic event. The present data support the notion that compensatory hemostatic mechanisms might exist in that the protein C activity was found to be decreased in the factor VII-deficient subjects. Whether this could influence the clinical feature, including the risk of thromboembolic events in association with replacement therapy, remains to be evaluated.

Activated Protein C Resistance↗
PubMed2001

The Malmö International Brother Study (MIBS): further support for genetic predisposition to inhibitor development in hemophilia patients.

The issue of factors predisposing for inhibitor development in haemophilia patients is still largely unresolved. In an attempt to address this problem, we initiated a registry in 1996 of siblings with haemophilia and with or without a history of inhibitors. Four hundred and sixty families have accrued, of whom 388 suffer from haemophilia A and 72 haemophilia B. Twenty-five of the brother pairs are twins. The inhibitor incidence in all families with severe haemophilia A was 31.7%. The corresponding figure in the caucasian patients was 27.4%, whereas a higher incidence of inhibitors was reported in the black subjects (55.6%). Twins were reported in six of the 100 inhibitor families, for whom monozygocity was confirmed in three cases. In 32 families (32%), at least two brothers had a history of inhibitors. In 22 (69%) of these families, the inhibitor was also of the same type, i.e. either high- or low-responding. The overall concordance within the severe haemophilia A families was found to be 78.3% (195/249) compared to an expected figure of 68.0% and 58.0% using an inhibitor incidence of 20 and 30%, respectively (P < 0.0001). The corresponding figure for the twins was 88.2% (15/17). Moreover, the risk for inhibitor development in families with a previous inhibitor history was found to be 48% (95% confidence interval [CI] 35-62%), whereas the risk in families with no previous known inhibitor was only 15% (95% CI 11-21%) corresponding to a relative risk of 3.2 (95% CI 2.1-4.9). Immune-tolerance induction was reported in 24 families, of whom 13 siblings were successfully treated. Our data clearly support the concept that a genetic predisposition for inhibitor development exists. However, the markers of this predisposition remain to be elucidated and we believe that the MIBS registry will be useful for this purpose.

Chi-Square Distribution↗