92 results on '"Rolf Ljung"'
Search Results
2. Detection of mosaics in hemophilia A by deep Ion Torrent sequencing and droplet digital PCR
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Eric Manderstedt, Rosanna Nilsson, Rolf Ljung, Christina Lind‐Halldén, Jan Astermark, and Christer Halldén
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factor VIII ,hemophilia A ,high‐throughput nucleotide sequencing ,mosaicism ,polymerase chain reaction ,Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Abstract Background The occurrence of mosaicism in hemophilia A (HA) has been investigated in several studies using different detection methods. Objectives To characterize and compare the ability of AmpliSeq/Ion Torrent sequencing and droplet digital polymerase chain reaction (ddPCR) for mosaic detection in HA. Methods Ion Torrent sequencing and ddPCR were used to analyze 20 healthy males and 16 mothers of sporadic HA patients. Results An error‐rate map over all coding positions and all positions reported as mutated in the F8‐specific mutation database was produced. The sequencing produced a mean read depth of >1500X where >97% of positions were covered by >100 reads. Higher error frequencies were observed in positions with A or T as reference allele and in positions surrounded on both sides with C or G. Seventeen of 9319 positions had a mean substitution error frequency >1%. The ability to identify low‐level mosaicism was determined primarily by read depth and error rate of each specific position. Limit of detection (LOD) was 1% require repeated testing and mononucleotide repeats with more than four repeat units need an alternative analysis strategy. Mosaicism was detected in 1 of 16 mothers and confirmed using ddPCR. Conclusions Deep sequencing using an AmpliSeq/Ion Torrent strategy allows for simultaneous identification of disease‐causing mutations in patients and mosaicism in mothers. ddPCR has high sensitivity but is hampered by the need for mutation‐specific design.
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- 2020
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3. Silent variant in F8:c.222G>T (p.Thr74Thr) causes a partial exon skipping in a patient with mild hemophilia A
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Anna Letelier, Rolf Ljung, Anna Olsson, and Nadine G. Andersson
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exon skipping ,F8 gene ,hemophilia A ,silent mutation ,Genetics ,QH426-470 - Abstract
Abstract One of the challenges of genetic testing in patients with hemophilia A is the interpretation of sequence variants. Here we report a silent variant found in exon 2 in the F8 gene in a 47‐year‐old patient with a previous von Willebrand disease (VWD) type 1 diagnosis. Clinically he had mild bleeding symptoms restricted to prolonged bleeding from minor wounds. Sanger sequencing of F8 gene using genomic DNA showed a hemizygous silent variant in exon 2: c.222G>T, p.Thr74Thr. When applying ACMG criteria, the variant was predicted to be “likely benign” in the analyzing software or VUS after curating. Sanger sequencing of the patient's cDNA after nested polymerase chain reaction showed that the patient had both a normal transcript containing exons 1–4 and a defect transcript lacking exon 2. These findings explain the patient's low FVIII:C level and led to the diagnosis of mild hemophilia A instead of VWD type 1. This case illustrates that mRNA work‐up may be needed to clarify a patient's phenotype–genotype.
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- 2022
- Full Text
- View/download PDF
4. Inhibitor incidence in an unselected cohort of previously untreated patients with severe haemophilia B: a PedNet study
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Christoph Male, Nadine G. Andersson, Anne Rafowicz, Ri Liesner, Karin Kurnik, Kathelijn Fischer, Helen Platokouki, Elena Santagostino, Hervé Chambost, Beatrice Nolan, Christoph Königs, Gili Kenet, Rolf Ljung, Marijke van den Berg, and PedNet study group
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
The incidence of FIX inhibitors in severe hemophilia B (SHB) is not well defined. Frequencies of 3-5% have been reported but most studies to date were small, including patients with different severities, and without prospective follow-up for inhibitor incidence. Study objective was to investigate inhibitor incidence in patients with SHB followed up to 500 exposure days (ED), the frequency of allergic reactions, and the relationship with genotypes. Consecutive previously untreated patients (PUPs) with SHB enrolled into the PedNet cohort were included. Detailed data was collected for the first 50 ED, followed by annual collection of inhibitor status and allergic reactions. Presence of inhibitors was defined by at least two consecutive positive samples. Additionally, data on factor IX gene mutation was collected. 154 PUPs with SHB were included; 75% were followed until 75 ED, and 43% until 500 ED. Inhibitors developed in 14 patients (7 high-titre). Median number of ED at inhibitor manifestation was 11 (IQR 6.5-36.5). Cumulative inhibitor incidence was 9.3% (95%CI 4.4-14.1) at 75 ED, and 10.2% (5.1-15.3) at 500 ED. Allergic reactions occurred in 4 (28.6%) inhibitor patients. Missense mutations were most frequent (46.8%) overall but not associated with inhibitors. Nonsense mutations and deletions with large structural changes comprised all mutations among inhibitor patients and were associated with an inhibitor risk of 26.9% and 33.3%, respectively. In an unselected, well-defined cohort of PUPs with SHB, cumulative inhibitor incidence was 10.2% at 500 ED. Nonsense mutations and large deletions were strongly associated with the risk of inhibitor development. The PedNet Registry is registered at clinicaltrials.gov; identifier: NCT02979119
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- 2020
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5. Mode of delivery in hemophilia: vaginal delivery and Cesarean section carry similar risks for intracranial hemorrhages and other major bleeds
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Nadine G. Andersson, Elizabeth A. Chalmers, Gili Kenet, Rolf Ljung, Anne Mäkipernaa, and Hervé Chambost
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
The optimal mode of delivery for a pregnant hemophilia carrier is still a matter of debate. The aim of the study was to determine the incidence of intracranial hemorrhage and other major bleeds in neonates with moderate and severe hemophilia in relationship to mode of delivery and known family history. A total of 926 neonates, 786 with severe and 140 with moderate hemophilia were included in this PedNet multicenter study. Vaginal delivery was performed in 68.3% (n=633) and Cesarean section in 31.6% (n=293). Twenty intracranial hemorrhages (2.2%) and 44 other major bleeds (4.8%) occurred. Intracranial hemorrhages occurred in 2.4% of neonates following vaginal delivery compared to 1.7% after Cesarean section (P=not significant); other major bleeds occurred in 4.2% born by vaginal delivery and in 5.8% after Cesarean section (P=not significant). Further analysis of subgroups (n=813) identified vaginal delivery with instruments being a significant risk factor for both intracranial hemorrhages and major bleeds (Relative Risk: 4.78-7.39; P
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- 2019
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6. Targeted re-sequencing of F8, F9 and VWF: Characterization of Ion Torrent data and clinical implications for mutation screening.
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Eric Manderstedt, Rosanna Nilsson, Christina Lind-Halldén, Rolf Ljung, Jan Astermark, and Christer Halldén
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Medicine ,Science - Abstract
Mutations are not identified in ~5% of hemophilia A and 10-35% of type 1 VWD patients. The bleeding tendency also varies among patients carrying the same causative mutation, potentially indicating variants in additional genes modifying the phenotype that cannot be identified by routine single-gene analysis. The F8, F9 and VWF genes were analyzed in parallel using an AmpliSeq strategy and Ion Torrent sequencing. Targeting all exonic positions showed an average read depth of >2000X and coverage close to 100% in 24 male patients with known disease-causing mutations. Discrimination between reference alleles and alternative/indel alleles was adequate at a 25% frequency threshold. In F8, F9 and VWF there was an absolute majority of all reference alleles at allele frequencies >95% and the average alternative allele and indel frequencies never reached above 10% and 15%, respectively. In VWF, 4-5 regions showed lower reference allele frequencies; in two regions covered by the pseudogene close to the 25% cut-off for reference alleles. All known mutations, including indels, gross deletions and substitutions, were identified. Additional VWF variants were identified in three hemophilia patients. The presence of additional mutations in 2 out of 16 (12%) randomly selected hemophilia patients indicates a potential mutational contribution that may affect the disease phenotype and counseling in these patients. Parallel identification of disease-causing mutations in all three genes not only confirms the deficiency, but differentiates phenotypic overlaps and allows for correct genetic counseling.
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- 2019
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7. Bleeding before prophylaxis in severe hemophilia: paradigm shift over two decades
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Annelies Nijdam, Carmen Altisent, Manuel D. Carcao, Ana R. Cid, Ségolène Claeyssens-Donadel, Karin Kurnik, Rolf Ljung, Beatrice Nolan, Pia Petrini, Helen Platokouki, Anne Rafowicz, Angela E. Thomas, and Kathelijn Fischer
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2015
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8. BAY 81-8973 Efficacy and Safety in Previously Untreated and Minimally Treated Children with Severe Hemophilia A: The LEOPOLD Kids Trial
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Rolf Ljung, Anthony K. C. Chan, Heidi Glosli, Olubunmi Afonja, Bastian Becker, Despina Tseneklidou-Stoeter, Maria Elisa Mancuso, Sonata Saulyte-Trakymiene, and Gili Kenet
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Hematology - Abstract
Introduction BAY 81–8973, a full-length recombinant factor VIII for hemophilia A treatment, has been extensively evaluated in previously treated patients in the LEOPOLD (Long-Term Efficacy Open-Label Program in Severe Hemophilia A Disease) clinical trials. Aim To assess BAY 81–8973 efficacy and safety when used for bleed prophylaxis and treatment in previously untreated/minimally treated patients (PUPs/MTPs). Methods In this phase III, multicenter, open-label, uncontrolled study, PUPs/MTPs ( Results Fifty-two patients were enrolled, with 43 patients (mean age: 13.6 months) treated. Median (interquartile range) ABR for all bleeds within 48 hours of prophylaxis infusion was 0.0 (0.0–1.8) among patients without inhibitors (n = 20) and 0.0 (0.0–2.2) among all patients. As expected, inhibitors were the most frequent treatment-related adverse event (high titer: 17 [39.5%] patients; low titer: 6 [13.9%] patients). Six of 12 patients who underwent ITI treatment in the extension phase (high titer [n = 5], low titer [n = 1]) achieved a negative inhibitor titer. Conclusion BAY 81–8973 was effective for bleed prevention and treatment in PUPs/MTPs. The observed inhibitor rate was strongly influenced by a cluster of inhibitor cases, and consequently, slightly higher than in other PUP/MTP studies. Overall, the BAY 81–8973 benefit–risk profile remains unchanged and supported by ongoing safety surveillance. Immune tolerance can be achieved with BAY 81–8973.
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- 2023
9. Haemophilia A and B – evaluation of the Swedish prophylactic regimen by magnetic resonance imaging
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Björn Lundin, Fariba Baghaei, Margareta Holmström, Pia Petrini, Gunilla Müller, Sven Månsson, and Rolf Ljung
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Pediatrik ,factor IX ,factor VIII ,haemophilia A ,haemophilia B ,magnetic resonance imaging ,Hematology ,General Medicine ,Pediatrics ,Genetics (clinical) - Abstract
IntroductionSweden has been a pioneer in the prophylactic treatment of haemophilia. Magnetic resonance imaging (MRI) can detect small changes in joints and can therefore give an indication of a risk of developing arthropathy. AimTo use MRI to evaluate the outcome of the Swedish high-dose regimen and correlate the findings to age, bleeds, joint score and physical activity. MethodsThe study group comprised 48 Swedish male patients, mean age 25 years (range 12-33 years), with severe or moderate haemophilia A or B. Data on the Haemophilia Joint Health Score (HJHS) were available and physical activity was evaluated by a self-reported questionnaire. ResultsMRI score was recorded in 188 joints. Twenty out of 48 patients had a score of >= 1 (range 1-13) in 31 joints of which 3/31 scores were in the knees and 28/31 in the ankles. No correlation was found between the number of recorded bleeds and the MRI score or between HJHS and MRI score. There was no correlation between the physical activity and the number of joint bleeds per se, but a trend (OR 3.0) that those most physically active (19/48; 39.6%), more frequently had an MRI score of >= 1 with an overweight for the right ankle. ConclusionThe Swedish prophylactic model offers protection against haemophilia joint arthropathy but will still not prevent osteochondral changes in some patients at young age. MRI of the ankles can signal risk of future arthropathy and indicate need to modify the prophylactic regimen. Funding Agencies|Baxter Sweden AB (now part of Takeda)
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- 2022
10. Primary prophylaxis in children with severe haemophilia A and B-Implementation over the last 20 years as illustrated in real-world data in the PedNet cohorts
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Rolf Ljung, H. Marijke Van den Berg, and Marloes Stephanie De Kovel
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Hematology ,General Medicine ,Genetics (clinical) - Abstract
The prophylactic regimen in children with severe haemophilia is suggested in various publications and guidelines. Few data exist on its implementation in clinical practice.To investigate the implementation of primary prophylaxis based on real-life data from PedNet during the last 20 years.All children from the PedNet cohort (n = 1260) with severe haemophilia A (SHA) or severe haemophilia B (SHB), FVIII/IX .01 IU/mL, born between 2000 and 2009 (Cohort I; SHA n = 662; SHB n = 88) and 2010-2019 (Cohort II; SHA n = 598; SHB n = 94) were included.In SHA, the median age at start of prophylaxis was 17.3 months (IQR; 12.5-26.1) in Cohort I which decreased to 13.1 months (IQR; 10.4-19.1) in Cohort II (p .000). "Once-a-week" prophylaxis at start increased from 49% to 68% (SHA) and 38% to 70% (SHB). FVIII doses were reduced from median 43.5 (IQR; 34.6-49.0) to 30.9 IU/kg (IQR; 26.3-46.3), while dosing with FIX did not change. After 2010 approximately 60% of the patients with SHA and SHB started prophylaxis before any joint bleed. The number of CVADs needed in both cohorts was around 30%. Incidences of inhibitors were unchanged: SHA (∼31%) and SHB (∼10%). Sporadic cases were diagnosed significantly later (median 8.3 months; IQR; 3.7-11.9) and they had more joint bleeds before start of prophylaxis.Primary prophylaxis nowadays starts at an earlier age: before any joint bleed (60% of patients with SHA and SHB). Approximately 70% started on a once-weekly schedule with significantly reduced doses in SHA but unchanged in SHB.
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- 2022
11. Autologous cell therapy - A new concept to eradicate inhibitors in haemophilia
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Hanjing Xie, Rolf Ljung, Jan Astermark, and Terese Hylander
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Factor VIII ,Cell- and Tissue-Based Therapy ,Humans ,Hematology ,General Medicine ,Hemophilia A ,Genetics (clinical) - Published
- 2022
12. Trial in Progress: An Open-Label, Multi-Center, First in Human, Phase 1/2a Trial to Evaluate the Safety and Preliminary Efficacy of Autologous Tolerogenic Dendritic Cells Ex Vivo Loaded with Recombinant Factor VIII (FVIII) in Adults with Congenital Hemophilia a (HA) with Neutralizing Antibodies to FVIII and Having Failed Immune Tolerance Induction (ITI)
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Jan Astermark, Rolf Ljung, Eva Karlsson, and Hanjing Xie
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
13. Detection of F8 int22h inversions using digital droplet PCR and mile‐post assays
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Christer Halldén, Rolf Ljung, Christina Lind-Halldén, Eric Manderstedt, and Jan Astermark
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Mutation ,Factor VIII ,Wild type ,Intron ,Locus (genetics) ,Hematology ,030204 cardiovascular system & hematology ,Biology ,Hemophilia A ,medicine.disease_cause ,Polymerase Chain Reaction ,Molecular biology ,Introns ,law.invention ,03 medical and health sciences ,0302 clinical medicine ,law ,Genetic linkage ,Chromosome Inversion ,medicine ,Humans ,Repeated sequence ,Polymerase chain reaction ,Digital droplet pcr - Abstract
BACKGROUND: Inversions involving intron 22 (Inv22) of F8 are detected in approximately 45% of all severe hemophilia A patients. Diagnosis is complicated by the large size of the ~9.5 kb int22h repeated sequence which generates the inversions. Methods such as long-range PCR and inverse-shifting PCR are currently used diagnostically, but suffer from low PCR efficiencies and are difficult to standardize.OBJECTIVES: To design and validate a sensitive and robust assay for the detection of F8 int22h inversions.METHODS: Digital droplet PCR using mile-post assays was used to investigate archival DNA samples.RESULTS: The detection of linkage as a function of physical distance between loci was investigated using an anchor locus and mile-post loci located at 1, 6, 12 and 15 kb distances from the anchor locus. The proportion of linked molecules decreased with increasing distance between loci and showed 30-40% linked molecules for loci 12-15 kb apart. Mile-post assays specific for wild type and Inv22 type 1 and 2 chromosomes were then designed and optimized. All three assays showed high specificities and sensitivities, with coefficients of variation < 5% for all assays. Analysis of 106 patients and 20 carrier mothers showed complete concordance with previously known mutation status. The analysis demonstrated the robustness of the assays versus input DNA concentration (6 ng and higher) and level of fragmentation.CONCLUSIONS: Digital droplet PCR and mile-post assays can be used to detect F8 int22h inversions. The assay systems are technically simple to perform, highly efficient and robust. (Less)
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- 2020
14. Genetic screening of children with suspected inherited bleeding disorders
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Maria Rossing, Migle Gabrielaite, Eva Leinoe, Nadine G. Andersson, Rolf Ljung, Eva Norström, Eva Zetterberg, Marcus Fager Ferrari, and Annika Mårtensson
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Male ,medicine.medical_specialty ,Pediatrics ,Adolescent ,Platelet disorder ,Functional testing ,Disease ,030204 cardiovascular system & hematology ,03 medical and health sciences ,Blood Coagulation Disorders, Inherited ,0302 clinical medicine ,Informed consent ,Internal medicine ,Humans ,Medicine ,Genetic Predisposition to Disease ,Genetic Testing ,Family history ,Child ,Genetics (clinical) ,Hematology ,business.industry ,Infant, Newborn ,Infant ,Cancer ,General Medicine ,medicine.disease ,Bleeding diathesis ,Child, Preschool ,Female ,business ,030215 immunology - Abstract
INTRODUCTION: Genetic screening using high-throughput DNA sequencing has become a tool in diagnosing patients with suspected inherited bleeding disorders (IBD). However, its usefulness and diagnostic efficacy in children is unclear.AIM: To evaluate the diagnostic efficacy of genetic screening for IBD in children and downstream further testing.METHODS: After informed consent, children (
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- 2020
15. Silent variant in F8 :c.222G>T (p.Thr74Thr) causes a partial exon skipping in a patient with mild hemophilia A
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Anna Letelier, Rolf Ljung, Anna Olsson, and Nadine G. Andersson
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Male ,Factor VIII ,Clinical Report ,silent mutation ,Exons ,QH426-470 ,Clinical Reports ,F8 gene ,hemic and lymphatic diseases ,Genetics ,Humans ,hemophilia A ,Molecular Biology ,Genetics (clinical) ,exon skipping - Abstract
One of the challenges of genetic testing in patients with hemophilia A is the interpretation of sequence variants. Here we report a silent variant found in exon 2 in the F8 gene in a 47‐year‐old patient with a previous von Willebrand disease (VWD) type 1 diagnosis. Clinically he had mild bleeding symptoms restricted to prolonged bleeding from minor wounds. Sanger sequencing of F8 gene using genomic DNA showed a hemizygous silent variant in exon 2: c.222G>T, p.Thr74Thr. When applying ACMG criteria, the variant was predicted to be “likely benign” in the analyzing software or VUS after curating. Sanger sequencing of the patient's cDNA after nested polymerase chain reaction showed that the patient had both a normal transcript containing exons 1–4 and a defect transcript lacking exon 2. These findings explain the patient's low FVIII:C level and led to the diagnosis of mild hemophilia A instead of VWD type 1. This case illustrates that mRNA work‐up may be needed to clarify a patient's phenotype–genotype., A patient with low FVIII levels was first misdiagnosed as von Willebrand disease. Genetic analysis revealed a silent variant in F8:c.222G>T.Sanger sequencing of the patient's cDNA after nested polymerase chain reaction showed that the patient had both a normal transcript containing exons 1–4 and a defect transcript lacking exon 2. The patient could be diagnosed with mild hemophilia A due to partial exon skipping.
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- 2021
16. Registries and databases—A European perspective
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Rolf Ljung
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Core set ,Databases, Factual ,business.industry ,Hematology ,General Medicine ,030204 cardiovascular system & hematology ,Hemophilia A ,Haemophilia ,medicine.disease ,Europe ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Humans ,Observational study ,Registries ,Medical emergency ,business ,Merge (version control) ,Genetics (clinical) ,030215 immunology ,Cohort study - Abstract
Registries will enable cohort studies to be performed, which are usually considered to be the best quality of observational studies. The quality of data of registries can be increased if is it possible to merge results ('crosstalk') between registries. A prerequisite for that is an agreed uniform core set of data to be collected and uniform definitions on the items to be collected. This paper discusses problems and barriers with existing registries and provides recommendations from an EMA workshop (European Medicines Agency), for core common data sets and how to secure the quality of data collected. The PedNet registry including >2200 children with haemophilia is presented as an example of a registry/cohort study.
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- 2020
17. Principles of care for acquired hemophilia
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Cedric Hermans, Silva Zupančić Šalek, Hermann Eichler, Víctor Jiménez-Yuste, Elena Santagostino, Gary Benson, Rolf Ljung, Debra Pollard, Gerry Dolan, Annette E. Bowyer, UCL - SSS/IREC/CARD - Pôle de recherche cardiovasculaire, and UCL - (SLuc) Service d'hématologie
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diagnosis ,Health Personnel ,media_common.quotation_subject ,principles ,Care ,Hemophilia A ,Haemophilia ,Appropriate use ,Promotion (rank) ,Multidisciplinary approach ,Health care ,Diagnosis ,medicine ,Humans ,care ,health care economics and organizations ,media_common ,treatment ,Health professionals ,business.industry ,Original Articles ,Hematology ,General Medicine ,medicine.disease ,Patient management ,Acquired hemophilia ,Management ,Treatment ,Original Article ,Medical emergency ,acquired hemophilia ,business ,Delivery of Health Care ,Principles ,management - Abstract
Objective To establish clear priorities for the care of patients with acquired hemophilia A (AHA) by proposing 10 key principles of practical, holistic AHA management. Method These principles were developed by the Zürich Haemophilia Forum, an expert panel of European hemophilia specialists comprising physicians and nursing and laboratory specialists. Results The 10 proposed principles for AHA care are as follows: (a) Improving initial diagnosis of AHA; (b) Differential diagnosis of AHA: laboratory assessment of patients with unusual bleeding; (c) Effective communication between laboratories, physicians, and specialists; (d) Improving clinical care: networking between healthcare professionals in the treating hospital and specialist hemophilia centers; (e) Comprehensive assessment of bleeding; (f) Appropriate use of bypassing agents; (g) Long‐term follow‐up and monitoring for efficacy and safety of immunosuppressive treatment; (h) Inpatient/outpatient settings; (i) Access to innovative and disruptive treatments; (j) Promotion of international collaborative research. Conclusion The proposed principles for holistic AHA care aim to ensure swift diagnosis and optimal patient management. Key to achieving this goal is training for healthcare personnel in non‐specialist hospitals and collaboration between different specialists. We hope these principles will increase awareness of AHA in the wider medical community and catalyze efforts toward improving its practical, multidisciplinary management.
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- 2021
18. Droplet digital PCR and mile-post analysis for the detection of F8 int1h inversions
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Eric Manderstedt, Christer Halldén, Jan Astermark, Christina Lind-Halldén, and Rolf Ljung
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polymerase chain reaction ,030204 cardiovascular system & hematology ,Biology ,Hemophilia A ,Polymerase Chain Reaction ,law.invention ,03 medical and health sciences ,Exon ,chemistry.chemical_compound ,0302 clinical medicine ,genetic linkage ,Genetic linkage ,law ,Biomedicinsk laboratorievetenskap/teknologi ,Gene duplication ,Humans ,Digital polymerase chain reaction ,Biomedical Laboratory Science/Technology ,Copy-number variation ,Gene ,Polymerase chain reaction ,sequence inversion ,Factor VIII ,Hematology ,Molecular biology ,Introns ,chemistry ,Chromosome Inversion ,Mutation ,hemophilia A ,DNA - Abstract
Background F8 int1h inversions (Inv1) are detected in 1-2% of severe hemophilia A (HA) patients. Long-range polymerase chain reaction (PCR) and inverse-shifting PCR have been used to diagnose these inversions. Objectives To design and validate a sensitive and robust assay for detection of F8 Inv1 inversions. Methods Archival DNA samples were investigated using mile-post assays and droplet digital PCR. Results Mile-post assays for Inv1 showing high specificities and sensitivities were designed and optimized. Analysis of four patients, two carrier mothers and 40 healthy controls showed concordance with known mutation status with one exception. One patient had a duplication involving exons 2-22 of the F8 gene instead of an Inv1 mutation. DNA mixtures with different proportions of wild type and Inv1 DNA correlated well with the observed relative linkage for both wild type and Inv1 assays and estimated the limit of detection of these assays to 2% of the rare chromosome. Conclusions The mile-post strategy has several inherent control systems. The absolute counting of target molecules by both assays enables determination of template quantity, detection of copy number variants and rare variants occurring in primer and probe annealing sites and estimation of DNA integrity through the observed linkage. The presented Inv1 mile-post analysis offers sensitive and robust detection and quantification of the F8 int1h inversions and other rearrangements involving intron 1 in patients and their mothers.
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- 2021
19. Inhibitor incidence in an unselected cohort of previously untreated patients with severe haemophilia B: a PedNet study
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Christoph Male, Nadine G. Andersson, Anne Rafowicz, Ri Liesner, Karin Kurnik, Kathelijn Fischer, Helen Platokouki, Elena Santagostino, Hervé Chambost, Beatrice Nolan, Christoph Königs, Gili Kenet, Rolf Ljung, Marijke Van den Berg, null PedNet study group, Medizinische Universität Wien = Medical University of Vienna, Skane University Hospital [Malmo], Lund University [Lund], Hôpital Bicêtre, Great Ormond Street Hospital for Children [London] (GOSH), University of Munich Medical Center, Partenaires INRAE, University Medical Center [Utrecht], Sophia Children's Hospital, CHU Milan, Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Our Lady's Children's Hospital Crumlin (OLCHC), J.W.Goethe University Hospital, Chaim Sheba Medical Center, PedNet Haemophilia Research Foundation, Lucas, Nelly, and Department of Paediatrics, Medical University of Vienna, Vienna
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medicine.medical_specialty ,Nonsense mutation ,030204 cardiovascular system & hematology ,Gene mutation ,Hemophilia A ,Hemophilia B ,Gastroenterology ,[SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract ,Article ,03 medical and health sciences ,0302 clinical medicine ,Risk Factors ,Internal medicine ,medicine ,Humans ,Missense mutation ,Haemophilia B ,Prospective Studies ,Factor IX ,Factor VIII ,Hematology ,business.industry ,Incidence ,Incidence (epidemiology) ,medicine.disease ,3. Good health ,Cohort ,[SDV.MHEP.PSR] Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract ,business ,030215 immunology ,medicine.drug - Abstract
The incidence of factor IX (FIX) inhibitors in severe hemophilia B (SHB) is not well defined. Frequencies of 3-5% have been reported but most studies to date have been small, including patients with different severities, and without prospective follow up for inhibitor incidence. The study objective was to investigate the inhibitor incidence in patients with SHB followed up for to 500 exposure days (ED), the frequency of allergic reactions, and the relationship with genotypes. Consecutive previously untreated patients (PUP) with SHB enrolled into the PedNet cohort were included. Detailed data was collected for the first 50 ED, followed by the annual collection of the inhibitor status and allergic re-actions. The presence of inhibitors was defined by at least two consecutive positive samples. Additionally, data on FIX gene mutation was collected. One hundred and fifty-four PUP with SHB were included; 75% were followed up until 75 ED, and 43% until 500 ED. Inhibitors developed in 14 patients (seven high-titer). The median number of ED at inhibitor manifestation was 11 (interquartile range [IQR]: 6.5-36.5). The cumulative inhibitor incidence was 9.3% (95% Confidence Interval [CI]: 4.4-14.1) at 75 ED, and 10.2% (95% CI: 5.1-15.3) at 500 ED. Allergic reactions occurred in four (28.6%) inhibitor patients. Missense mutations were most frequent (46.8%) overall but not associated with inhibitors. Nonsense mutations and deletions with large structural changes comprised all mutations among inhibitor patients and were associated with an inhibitor risk of 26.9% and 33.3%, respectively. In an unselected, well-defined cohort of PUP with SHB, the cumulative inhibitor incidence was 10.2% at 500 ED. Nonsense mutations and large deletions were strongly associated with the risk of inhibitor development. The ‘PedNet Registry’ is registered at clinicaltrials.gov; identifier: NCT02979119.
- Published
- 2021
20. Practical considerations for nonfactor-replacement therapies in the treatment of haemophilia with inhibitors
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Thierry Lambert, Silva Zupančić Šalek, Elena Santagostino, Gerry Dolan, Gary Benson, Víctor Jiménez-Yuste, Cedric Hermans, Günter Auerswald, Massimo Morfini, Rolf Ljung, UCL - SSS/IREC/CARD - Pôle de recherche cardiovasculaire, and UCL - (SLuc) Service d'hématologie
- Subjects
medicine.medical_specialty ,medicine.drug_class ,Haemophilia A ,Hemorrhage ,030204 cardiovascular system & hematology ,Antibodies, Monoclonal, Humanized ,Hemophilia A ,Haemophilia ,Hemophilia B ,Hemostatics ,03 medical and health sciences ,0302 clinical medicine ,Tissue factor pathway inhibitor ,Internal medicine ,Antibodies, Bispecific ,medicine ,Humans ,Haemophilia B ,Intensive care medicine ,Genetics (clinical) ,Emicizumab ,Factor VIII ,Hematology ,business.industry ,Inhibitors ,Prophylaxis ,Antithrombin ,Anticoagulant ,General Medicine ,medicine.disease ,Nonfactor-replacement therapies ,business ,030215 immunology ,medicine.drug - Abstract
New therapeutic agents for haemophilia with inhibitors that are in development or already licensed are expected to provide transformative treatment options. Many of these new therapies are not based on simply replacing the missing factor; new strategies include bispecific antibody technology that mimics factor VIII coagulation function (emicizumab), and inhibition of anticoagulant proteins such as tissue factor pathway inhibitor (eg PF-06741086) and antithrombin (eg fitusiran). These agents are administered subcutaneously and should significantly reduce treatment burden and increase the ability to deliver prophylaxis for patients. Limited real-world data and validated practical guidance on these recently licensed/upcoming treatments resulted in the authors convening to discuss recommendations on their use. Emicizumab is currently the only licenced nonfactor therapy; thus, our recommendations focus on this product. Target candidates for emicizumab prophylaxis are difficult-to-treat patients with haemophilia A and inhibitors and/or venous access issues, frequent bleeds and target joints. In case of breakthrough bleeding while receiving emicizumab, patients still require treatment with bypassing agents; the adjunct treatment of choice is recombinant activated factor VII. This treatment is also recommended to prevent bleeds in patients with inhibitors undergoing surgery. Our recommendations on suitable laboratory assays and monitoring new products, as well as the benefit of patient-reported outcomes (such as pain and physical activity levels), are included. We also briefly discuss future treatment options for patients with haemophilia B and inhibitors. Although these nonfactor treatments offer great promise, further data and real-world evidence are needed.
- Published
- 2021
21. Detection of mosaics in hemophilia A by deep Ion Torrent sequencing and droplet digital PCR
- Author
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Rosanna Nilsson, Eric Manderstedt, Christer Halldén, Christina Lind-Halldén, Rolf Ljung, and Jan Astermark
- Subjects
Genetics ,polymerase chain reaction ,Read depth ,factor VIII ,hemophilia A ,high-throughput nucleotide sequencing ,mosaicism ,Hematology ,Ion semiconductor sequencing ,Biology ,high‐throughput nucleotide sequencing ,Deep sequencing ,law.invention ,Repeated testing ,law ,Original Articles ‐ Hemostasis ,Biomedicinsk laboratorievetenskap/teknologi ,Mutation database ,In patient ,Digital polymerase chain reaction ,Diseases of the blood and blood-forming organs ,Biomedical Laboratory Science/Technology ,Original Article ,RC633-647.5 ,Polymerase chain reaction - Abstract
Background: The occurrence of mosaicism in hemophilia A (HA) has been investigated in several studies using different detection methods. Objectives: To characterize and compare the ability of AmpliSeq/Ion Torrent sequencing and droplet digital polymerase chain reaction (ddPCR) for mosaic detection in HA. Methods: Ion Torrent sequencing and ddPCR were used to analyze 20 healthy males and 16 mothers of sporadic HA patients. Results: An error-rate map over all coding positions and all positions reported as mutated in the F8-specific mutation database was produced. The sequencing produced a mean read depth of >1500X where >97% of positions were covered by >100 reads. Higher error frequencies were observed in positions with A or T as reference allele and in positions surrounded on both sides with C or G. Seventeen of 9319 positions had a mean substitution error frequency >1%. The ability to identify low-level mosaicism was determined primarily by read depth and error rate of each specific position. Limit of detection (LOD) was 1% require repeated testing and mononucleotide repeats with more than four repeat units need an alternative analysis strategy. Mosaicism was detected in 1 of 16 mothers and confirmed using ddPCR. Conclusions: Deep sequencing using an AmpliSeq/Ion Torrent strategy allows for simultaneous identification of disease-causing mutations in patients and mosaicism in mothers. ddPCR has high sensitivity but is hampered by the need for mutationspecific design.
- Published
- 2020
22. Continued benefit demonstrated with BAY 81-8973 prophylaxis in previously treated children with severe haemophilia A: Interim analysis from the LEOPOLD Kids extension study
- Author
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Victor S. Blanchette, Bryce A. Kerlin, Rolf Ljung, Nikki Church, Valentina Uscatescu, Sonata Saulytė Trakymienė, L. Rusen, Despina Tseneklidou-Stoeter, Horst Beckmann, and Gili Kenet
- Subjects
Pediatrics ,medicine.medical_specialty ,Haemophilia A ,Hemorrhage ,030204 cardiovascular system & hematology ,Haemophilia ,Hemophilia A ,clinical trial ,full-length factor VIII ,haemophilia A ,long-term observation ,prophylaxis ,recombinant proteins ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Humans ,Adverse effect ,Child ,Factor VIII ,business.industry ,Hematology ,Bleed ,medicine.disease ,Interim analysis ,Clinical trial ,Treatment Outcome ,Quartile ,030220 oncology & carcinogenesis ,business ,Bay - Abstract
Introduction BAY 81-8973 (Kovaltry®), a recombinant factor VIII (rFVIII) product, was efficacious and well tolerated in paediatric previously treated patients (PTPs) with severe haemophilia A for ≥50 exposure days (EDs) in the LEOPOLD Kids study. Because long-term prophylaxis (≥100 EDs) can provide substantial patient benefits, FVIII products should demonstrate long-term safety and efficacy. Aim To demonstrate long-term (≥100 EDs) efficacy and safety of BAY 81-8973 in paediatric PTPs. Methods PTPs aged ≤12 years with severe haemophilia A without inhibitors could continue in the ongoing open-label extension study after completing ≥50 EDs in the LEOPOLD Kids main study. Patients received BAY 81-8973 for prophylaxis (25–50 IU/kg ≥2×/week), bleed treatment, and surgery. Bleeds were documented in electronic patient diaries. Inhibitor development was monitored every 6 months. Results At the August 2017 interim data cutoff, 46 patients (median [range] age at enrolment, 6.0 [1.0–11.0] years) had spent a median (range) of 602.5 (148–1069) EDs and 4.6 (1.0–5.9) years in the main plus extension studies. Median (quartile [Q]1; Q3) annualised bleeding rate for bleeds within 48 h after a prophylaxis infusion and total bleeds was 1.0 (0.2; 1.9) and 2.0 (0.4; 3.6), respectively. Most (>94%) bleeds were mild or moderate; 71.8% were treated with ≤1 infusion. BAY 81-8973 was also well tolerated with only one treatment-related adverse event (transient, low-titre inhibitor which did not require treatment adjustment). Conclusion BAY 81-8973 was efficacious for prophylaxis and treatment of bleeds during >4.5 years in paediatric PTPs with severe haemophilia A.
- Published
- 2019
23. Predicting Thrombosis Recurrence in Children: The Role of Thrombophilia Testing
- Author
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Rolf Ljung and Bader Allahyani
- Subjects
Pediatrics ,medicine.medical_specialty ,business.industry ,Deep vein ,Immunology ,Antithrombin ,Cell Biology ,Hematology ,medicine.disease ,Thrombophilia ,Biochemistry ,Thrombosis ,medicine.anatomical_structure ,Cohort ,medicine ,Coagulation testing ,Medical history ,cardiovascular diseases ,business ,Protein C ,medicine.drug - Abstract
Background: The role of inherited thrombophilia testing in predicting a recurrence of deep vein thrombosis (DVT) after an incident of the first DVT in children remains unclear Objectives: To investigate the association between inherited thrombophilia and DVT recurrence. Design/Method: We conducted a retrospective regional study of all consecutive ICD10 codes of venous thromboembolism (VTE) in children over 15 years (January 1, 2000, to December 31, 2015) in a regional catchment area of southern Sweden using an electronic diagnosis registry. Eligible subjects were children aged 1-18 years presenting with DVT diagnosed with imaging and having undergone complete inherited thrombophilia workup after the first DVT event. Of the 174 patients diagnosed with DVTs, 139 were eligible for inclusion. Data regarding subject demographics and medical history, location of DVT and imaging method, coagulation studies at primary investigation including at least plasma concentrations of protein C, protein S, antithrombin, resistance to activated protein C, and the genotypes FVG1691A and FIIG20210A. Also, plasma values for coagulation factors, VIII and XI, D-dimer, INR, and cardiolipin antibodies, were analyzed. Results: A total of 139 patients had inherited thrombophilia workup after the incident of the first DVT. Inherited thrombophilia was found in 30 % of patients, the prevalence of minor thrombophilia among these 139 patients was 23 % (n = 32), whereas major thrombophilia accounted for 7 % (n = 10) of abnormal results. Anticoagulants as treatment were administered in 92 % of the first DVT. The majority of the cohort treated with anticoagulation therapy for 12 weeks. Patients with minor inherited thrombophilia treated for at least 24 weeks, whereas the patients with major inherited thrombophilia were continued on anticoagulation therapy for the long term. The incidence rate of recurrent thromboembolic events was 6.5 % (n = 9) of patients after their incident of the first thrombotic event. Recurrent thrombosis in patients with spontaneous DVT and proven inherited thrombophilia found in only 1 %. Conclusion: Inherited thrombophilia was not predictive of recurrent DVT among our cohort patients. Our findings suggest that Inherited thrombophilia testing may not predict risk for the recurrence of DVT, although it may help for adjustment of the duration of the anticoagulation therapy. Figure Disclosures No relevant conflicts of interest to declare.
- Published
- 2020
24. Intracranial haemorrhage in children and adolescents with severe haemophilia A or B - the impact of prophylactic treatment
- Author
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Kaan Kavakli, Marianne Hoffmann, Rosario Perez Garrido, Amy L. Dunn, Angelo Claudio Molinari, Karin Fijnvandraat, Amy D. Shapiro, Karin Kurnik, Chris Barnes, Nadine G. Andersson, Rainer Kobelt, Runhui Wu, Anne Mäkipernaa, Gili Kenet, Marilyn J. Manco-Johnson, Maria Elisa Mancuso, Ri Liesner, Manuel Carcao, Beatrice Nolan, Helen Platokouki, Rolf Ljung, Pia Petrini, Günter Auerswald, ARD - Amsterdam Reproduction and Development, ACS - Amsterdam Cardiovascular Sciences, Paediatric Infectious Diseases / Rheumatology / Immunology, and ACS - Pulmonary hypertension & thrombosis
- Subjects
Adult ,Male ,Pediatrics ,medicine.medical_specialty ,Adolescent ,Haemophilia A ,Population ,haemophilia A ,haemophilia B ,030204 cardiovascular system & hematology ,Haemophilia ,Hemophilia A ,Hemophilia B ,Severity of Illness Index ,03 medical and health sciences ,0302 clinical medicine ,children ,medicine ,Humans ,Haemophilia B ,Prospective Studies ,cardiovascular diseases ,10. No inequality ,Prospective cohort study ,education ,Child ,Retrospective Studies ,education.field_of_study ,factor IX ,business.industry ,Infant ,Retrospective cohort study ,Hematology ,medicine.disease ,3. Good health ,nervous system diseases ,Regimen ,factor VIII ,Child, Preschool ,Female ,business ,Intracranial Hemorrhages ,030215 immunology ,Cohort study - Abstract
The discussion of prophylactic therapy in haemophilia is largely focused on joint outcomes. The impact of prophylactic therapy on intracranial haemorrhage (ICH) is less known. This study aimed to analyse ICH in children with haemophilia, with a focus on different prophylaxis regimens and sequelae of ICH. We conducted a multicentre retrospective and prospective study that included 33 haemophilia centres from 20 countries. Inclusion criteria were children and adolescents born between 1993 and 2014, with severe haemophilia A or B without inhibitors. Participants were categorized by prophylaxis regimen: full, partial or none, based on dose and dose frequency of regular infusions. The cohort study included 1515 children: 29 cases of ICH over 8038 patient years were reported. The incidence of ICH in the prophylaxis group, 0·00033 cases of ICH/patient year, was significantly lower compared to the no prophylaxis group, 0·017 cases of ICH/patient year (RR 50·06; P < 0·001) and the partial prophylaxis group, 0·0050 cases of ICH/patient year (RR 14·92; P = 0·007). In the on-demand-group, 8% (2/24) children with ICH died and 33% had long-term sequelae, including intellectual and behavioural problems, paresis and epilepsy. Children on regular, frequent prophylaxis have a low risk of ICH compared to those using non-frequent or no prophylaxis.
- Published
- 2017
25. Pain and pain management in haemophilia
- Author
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Anne Duffy, Cedric Hermans, Günter Auerswald, Massimo Morfini, Víctor Jiménez-Yuste, Thierry Lambert, Rolf Ljung, Gerry Dolan, Silva Zupančić Šalek, UCL - SSS/IREC/CARD - Pôle de recherche cardiovasculaire, and UCL - (SLuc) Service d'hématologie
- Subjects
Haemophilia ,medicine.medical_specialty ,Analgesic ,haemophilia ,Pain ,Chronic pain ,Review Article ,030204 cardiovascular system & hematology ,03 medical and health sciences ,0302 clinical medicine ,Quality of life ,bleed ,Intervention (counseling) ,medicine ,Humans ,Pain Management ,Adverse effect ,business.industry ,acute pain ,Hematology ,General Medicine ,Bleed ,medicine.disease ,Arthralgia ,pain management ,quality of life ,Joint pain ,Quality of Life ,Physical therapy ,medicine.symptom ,chronic pain ,business ,Acute pain ,030215 immunology - Abstract
Joint pain is common in haemophilia and may be acute or chronic. Effective pain management in haemophilia is essential to reduce the burden that pain imposes on patients. However, the choice of appropriate pain-relieving measures is challenging, as there is a complex interplay of factors affecting pain perception. This can manifest as differences in patients’ experiences and response to pain, which require an individualized approach to pain management. Prophylaxis with factor replacement reduces the likelihood of bleeds and bleed-related pain, whereas on-demand therapy ensures rapid bleed resolution and pain relief. Although use of replacement or bypassing therapy is often the first intervention for pain, additional pain relief strategies may be required. There is an array of analgesic options, but consideration should be paid to the adverse effects of each class. Nevertheless, a combination of medications that act at different points in the pain pathway may be beneficial. Nonpharmacological measures may also help patients and include active coping strategies; rest, ice, compression, and elevation; complementary therapies; and physiotherapy. Joint aspiration may also reduce acute joint pain, and joint steroid injections may alleviate chronic pain. In the longer term, increasing use of prophylaxis or performing surgery may be necessary to reduce the burden of pain caused by the degenerative effects of repeated bleeds. Whichever treatment option is chosen, it is important to monitor pain and adjust patient management accordingly. Beyond specific pain management approaches, ongoing collaboration between multidisciplinary teams, which should include physiotherapists and pain specialists, may improve outcomes for patients.
- Published
- 2016
26. Targeted re-sequencing of F8, F9 and VWF: Characterization of Ion Torrent data and clinical implications for mutation screening
- Author
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Rosanna Nilsson, Christer Halldén, Rolf Ljung, Christina Lind-Halldén, Eric Manderstedt, and Jan Astermark
- Subjects
0301 basic medicine ,DNA Mutational Analysis ,Gene Identification and Analysis ,Artificial Gene Amplification and Extension ,030204 cardiovascular system & hematology ,Cardiovascular Medicine ,medicine.disease_cause ,Polymerase Chain Reaction ,Factor IX ,Database and Informatics Methods ,0302 clinical medicine ,Gene Frequency ,INDEL Mutation ,Medicine and Health Sciences ,Biologiska vetenskaper ,Genetics ,Mutation ,Multidisciplinary ,High-Throughput Nucleotide Sequencing ,Nonsense Mutation ,Hematology ,Biological Sciences ,Reference Standards ,Phenotype ,Cardiovascular Diseases ,Medicine ,Research Article ,Substitution Mutation ,Pseudogene ,Science ,Biology ,Research and Analysis Methods ,03 medical and health sciences ,von Willebrand Factor ,medicine ,Humans ,Point Mutation ,Allele ,Indel ,Molecular Biology Techniques ,Allele frequency ,Gene ,Mutation Detection ,Blood Coagulation ,Molecular Biology ,Alleles ,Factor VIII ,Coagulation Disorders ,Biology and Life Sciences ,Ion semiconductor sequencing ,030104 developmental biology ,Biological Databases ,Genetic Loci ,Mutation Databases - Abstract
Mutations are not identified in ~5% of hemophilia A and 10-35% of type 1 VWD patients. The bleeding tendency also varies among patients carrying the same causative mutation, potentially indicating variants in additional genes modifying the phenotype that cannot be identified by routine single-gene analysis. The F8, F9 and VWF genes were analyzed in parallel using an AmpliSeq strategy and Ion Torrent sequencing. Targeting all exonic positions showed an average read depth of >2000X and coverage close to 100% in 24 male patients with known disease-causing mutations. Discrimination between reference alleles and alternative/indel alleles was adequate at a 25% frequency threshold. In F8, F9 and VWF there was an absolute majority of all reference alleles at allele frequencies >95% and the average alternative allele and indel frequencies never reached above 10% and 15%, respectively. In VWF, 4-5 regions showed lower reference allele frequencies; in two regions covered by the pseudogene close to the 25% cut-off for reference alleles. All known mutations, including indels, gross deletions and substitutions, were identified. Additional VWF variants were identified in three hemophilia patients. The presence of additional mutations in 2 out of 16 (12%) randomly selected hemophilia patients indicates a potential mutational contribution that may affect the disease phenotype and counseling in these patients. Parallel identification of disease-causing mutations in all three genes not only confirms the deficiency, but differentiates phenotypic overlaps and allows for correct genetic counseling.
- Published
- 2019
27. Timing of inhibitor development in more than 1000 previously untreated patients with severe hemophilia A
- Author
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Manuel Carcao, Christoph Male, Gili Kenet, Karin Kurnik, Elena Santagostino, Rolf Ljung, Krista Fischer, H. Marijke van den Berg, Chris Königs, Hervé Chambost, PedNet Haemophilia Research Foundation, Partenaires INRAE, University Medical Center [Utrecht], Royal Hospital for Sick Children, Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Service de pédiatrie, d'hématologie et d'oncologie [Hôpital de La Timone - APHM], Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Israeli Ministry of Health, University of Munich Medical Center, Goethe University Hospital, Medizinische Universität Wien = Medical University of Vienna, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), and Lund University [Lund]
- Subjects
0301 basic medicine ,congenital, hereditary, and neonatal diseases and abnormalities ,medicine.medical_specialty ,Letter ,Time Factors ,Immunology ,Kaplan-Meier Estimate ,Severe hemophilia A ,Hemophilia A ,Gastroenterology ,Biochemistry ,Severity of Illness Index ,03 medical and health sciences ,0302 clinical medicine ,Isoantibodies ,hemic and lymphatic diseases ,Internal medicine ,Severity of illness ,medicine ,Humans ,ComputingMilieux_MISCELLANEOUS ,Hematology ,Blood Coagulation Factor Inhibitors ,business.industry ,Incidence ,[SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology ,Cell Biology ,Inhibitory antibodies ,Prognosis ,3. Good health ,030104 developmental biology ,business ,Complication ,Biomarkers ,030215 immunology - Abstract
TO THE EDITOR: Inhibitory antibodies (inhibitors) against factor VIII (FVIII) develop in 25% to 35% of previously untreated patients (PUPs) with severe hemophilia A (SHA). It is the most serious complication of classic hemophilia treatment.[1][1][⇓][2]-[3][3] Most inhibitors develop during the
- Published
- 2019
28. Pulmonary Embolism in Children with Asymptomatic Proximal Deep Vein Thromboembolism: Single-Center Experience from Sweden
- Author
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Rolf Ljung and Bader Allahyani
- Subjects
medicine.medical_specialty ,business.industry ,Deep vein ,Immunology ,Cell Biology ,Hematology ,medicine.disease ,Single Center ,Biochemistry ,Asymptomatic ,Surgery ,Pulmonary embolism ,medicine.anatomical_structure ,medicine ,medicine.symptom ,business - Abstract
Introduction: Pulmonary embolism (PE) is rare in childhood but a potentially fatal condition in the venous thromboembolism spectrum. However, the incidence of PE in children has been steadily increasing, which can be multifactorial. Adults data suggested that the finding of asymptomatic proximal DVT on routine ultrasonography is associated with increased mortality. Data on pulmonary embolism in children are scarce. Objective: To evaluate the relationship between asymptomatic proximal deep vein thrombosis detected in children presented with Pulmonary embolism. Methods: We conducted a retrospective chart review of all consecutive ICD 9 codes of Pulmonary Embolism (PE) in children over 10 years (January 1, 2000, to December 31, 2010) in Skåne university hospital in Sweden, using an electronic diagnosis hospital database. Eligible subjects were children aged 1-18 years presenting with PE diagnosed with imaging, and having undergone complete lower extremities radiological screening workup for DVT and lacking symptoms of acute lower extremity DVT. Data regarding subject demographics and medical history, risk stratification, low risk, massive or submissive PE, location of the proximal DVT, imaging method, presence of congenital vascular anomaly, time from symptom onset to diagnosis of the pulmonary embolism. Coagulation studies at primary investigation including at least plasma concentrations of protein C, protein S, antithrombin, resistance to activated protein C, and the genotypes FVG1691A and FIIG20210A. Also, plasma values for coagulation factors, VIII, cardiolipin antibodies, management, duration of anticoagulant, and the outcome were analyzed. Results: A total of 20 children enrolled. Age range 10-18 years (mean 15.8), 18 (90%) were female. Time from symptom onset to diagnosis of the PE: mean 4.8 days (range 1-28). All were low risk, and 6 (30%) associated with asymptomatic proximal DVT. The most common acquired risk factor was OCP/hormonal therapy was in 11 (55%). Minor thrombophilia in 5 (25%) of the cohort. All received anticoagulation therapy for 6 months, non-received pharmacologic thrombolysis. No bleeding, recurrence, nor thrombosis related mortality in 4 years follow uptime. Conclusion: PE is rare in children, and it is associated with asymptomatic proximal DVT is not uncommon. Our finding demonstrated the prevalence of PE associated with asymptomatic proximal DVT is 30%. This finding highlighted the importance of anticoagulant therapy for all patients with incidental proximal DVT. Figure Disclosures No relevant conflicts of interest to declare.
- Published
- 2020
29. Origin of mutation in sporadic cases of severe haemophilia A in Sweden
- Author
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Anna Letelier, Eric Manderstedt, Annika Mårtensson, Stina Ivarsson, Rolf Ljung, and Christer Halldén
- Subjects
0301 basic medicine ,Genetics ,Pediatrics ,medicine.medical_specialty ,Haemophilia A ,Haplotype ,Newly diagnosed ,030204 cardiovascular system & hematology ,Biology ,medicine.disease ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,hemic and lymphatic diseases ,Mutation (genetic algorithm) ,medicine ,Severe haemophilia A ,Genetics (clinical) - Abstract
Many newly diagnosed Swedish severe haemophilia A (HA) patients are sporadic cases. Some genotypically non-carrier mothers have gone on to have two descendants with the same mutation, presumably due to mosaicism.
- Published
- 2016
30. WITHDRAWN: Primary prophylaxis in haemophilia care: Guideline update 2016
- Author
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Krista Fischer and Rolf Ljung
- Subjects
medicine.medical_specialty ,business.industry ,MEDLINE ,Molecular Medicine ,Medicine ,Cell Biology ,Hematology ,Guideline ,business ,Intensive care medicine ,Haemophilia ,medicine.disease ,Molecular Biology - Published
- 2020
31. Inhibitors in haemophilia A and B: Management of bleeds, inhibitor eradication and strategies for difficult‐to‐treat patients
- Author
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Elena Santagostino, Anne Duffy, Massimo Morfini, Thierry Lambert, Rolf Ljung, Cedric Hermans, Víctor Jiménez-Yuste, Silva Zupančić-Šalek, Gary Benson, Guenter Auerswald, Gerry Dolan, UAM. Departamento de Medicina, Instituto de Investigación Sanitaria Hospital Universitario de La Paz (IdiPAZ), UCL - SSS/IREC/CARD - Pôle de recherche cardiovasculaire, UCL - (SLuc) Service d'hématologie, and UCL - (SLuc) Centre de malformations vasculaires congénitales
- Subjects
Quality of life ,medicine.medical_specialty ,Medicina ,Premedication ,Haemophilia A ,Drug Resistance ,Hemorrhage ,Review Article ,Haemophilia ,Hemophilia A ,Hemophilia B ,Factor IX ,03 medical and health sciences ,0302 clinical medicine ,Isoantibodies ,Internal medicine ,Arthropathy ,medicine ,Immune Tolerance ,Humans ,Intensive care medicine ,Review Articles ,paediatric haematology ,Emicizumab ,Hematology ,Factor VIII ,Blood Coagulation Factor Inhibitors ,business.industry ,Disease Management ,General Medicine ,medicine.disease ,Increased risk ,Treatment Outcome ,quality of life ,coagulation disorders ,Desensitization, Immunologic ,030220 oncology & carcinogenesis ,Coagulation disorders ,Paediatric haematology ,business ,030215 immunology ,medicine.drug - Abstract
The standard therapy for patients with haemophilia is prophylactic treatment with replacement factor VIII (FVIII) or factor IX (FIX). Patients who develop inhibitors against FVIII/FIX face an increased risk of bleeding, and the likelihood of early development of progressive arthropathy, alongside higher treatment‐related costs. Bypassing agents can be used to prevent and control bleeding, as well as the recently licensed prophylaxis, emicizumab, but their efficacy is less predictable than that of factor replacement therapy. Antibody eradication, by way of immune tolerance induction (ITI), is still the preferred management strategy for treating patients with inhibitors. This approach is successful in most patients, but some are difficult to tolerise and/or are unresponsive to ITI, and they represent the most complicated patients to treat. However, there are limited clinical data and guidelines available to help guide physicians in formulating the next treatment steps in these patients. This review summarises currently available treatment options for patients with inhibitors, focussing on ITI regimens and those ITI strategies that may be used in difficult‐to‐treat patients. Some alternative, non‐ITI approaches for inhibitor management, are also proposed, Supported by a grant from Novo Nordisk Health Care AG, in compliance with international guidelines for good publication practice.
- Published
- 2018
32. Practical aspects of extended half-life products for the treatment of haemophilia
- Author
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Gerry Dolan, Cedric Hermans, Gary Benson, Víctor Jiménez-Yuste, Massimo Morfini, Silva Zupančić-Šalek, Thierry Lambert, Elena Santagostino, and Rolf Ljung
- Subjects
medicine.medical_specialty ,congenital, hereditary, and neonatal diseases and abnormalities ,practical considerations ,Laboratory monitoring ,Haemophilia A ,haemophilia ,Review ,030204 cardiovascular system & hematology ,Haemophilia ,03 medical and health sciences ,0302 clinical medicine ,Quality of life ,Internal medicine ,hemic and lymphatic diseases ,Arthropathy ,Medicine ,Haemophilia B ,Intensive care medicine ,Factor IX ,Hematology ,extended half-life products ,factor IX ,business.industry ,medicine.disease ,factor VIII ,prophylaxis ,business ,030215 immunology ,medicine.drug - Abstract
Haemophilia A and haemophilia B are congenital X-linked bleeding disorders caused by deficiency of coagulation factor VIII (FVIII) and IX (FIX), respectively. The preferred treatment option for patients with haemophilia is replacement therapy. For patients with severe disease, prophylactic replacement of coagulation factor is the treatment of choice; this has been shown to reduce arthropathy significantly, reduce the frequency of bleeds and improve patients’ quality of life. Prophylaxis with standard recombinant factor requires regular intravenous infusion at least two (FIX) to three (FVIII) times a week. Recombinant FVIII and FIX products with an extended half-life are in development, or have been recently licensed. With reported mean half-life extensions of 1.5–1.8 times that of standard products for FVIII and 3–5 times that of standard products for FIX, these products have the potential to address many of the unmet needs of patients currently treated with standard factor concentrates. For example, they may encourage patients to switch from on-demand treatment to prophylaxis and improve the quality of life of patients receiving prophylaxis. Indeed, extended half-life products have the potential to reduce the burden of frequent intravenous injections, reducing the need for central venous lines in children, promote adherence, improve outcomes, potentially allow for more active lifestyles and, depending on the dosing regimen, increase factor trough levels. Members of the Zürich Haemophilia Forum convened for their 19th meeting to discuss the practicalities of incorporating new treatments into the management of people with haemophilia. This review of extended half-life products considers their introduction in haemophilia treatment, including the appropriate dose and schedule of infusions, laboratory monitoring, patient selection, safety considerations, and the economic aspects of care.
- Published
- 2018
33. How I manage patients with inherited haemophilia A and B and factor inhibitors
- Author
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Rolf Ljung
- Subjects
Adult ,congenital, hereditary, and neonatal diseases and abnormalities ,medicine.medical_specialty ,Haemophilia A ,Hemorrhage ,030204 cardiovascular system & hematology ,Haemophilia ,Hemophilia A ,Hemophilia B ,Risk Assessment ,Severity of Illness Index ,Factor IX ,03 medical and health sciences ,0302 clinical medicine ,Isoantibodies ,hemic and lymphatic diseases ,medicine ,Humans ,Intensive care medicine ,Child ,Factor VIII ,Blood Coagulation Factor Inhibitors ,business.industry ,Age Factors ,Disease Management ,Hematology ,Bleed ,medicine.disease ,business ,Complication ,030215 immunology - Abstract
Development of inhibitors to coagulation factor VIII or IX is still the most challenging complication in haemophilia care. 'Bypassing agents' may be used to treat a bleed but the eradication of the inhibitor by immune tolerance induction (ITI) is the main objective in the treatment of a patient with haemophilia who has developed neutralizing antibodies. Several options exist for ITI and the patient may be at 'good' or 'bad risk' for successful outcome with different regimens. This paper offers a review of current regimens to be considered in the treatment of a bleed in a patient with an inhibitor but the main focus is the aspects of different choices in the management of the child or the adult with severe or mild forms of haemophilia A or B, who has developed an inhibitor. There are also some final outlooks on new and emerging treatment possibilities.
- Published
- 2017
34. The current status of prophylactic replacement therapy in children and adults with haemophilia
- Author
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Nadine Gretenkort and Rolf Ljung
- Subjects
Adult ,Pediatrics ,medicine.medical_specialty ,Premedication ,Haemophilia A ,Hemorrhage ,Hemophilia A ,Haemophilia ,Hemophilia B ,law.invention ,Factor IX ,Randomized controlled trial ,law ,medicine ,Humans ,Haemophilia B ,In patient ,Child ,Clotting factor ,Factor VIII ,business.industry ,Age Factors ,Hematology ,Bleed ,medicine.disease ,Observational study ,business - Abstract
Initiating prophylactic treatment at an early age is considered to be the optimal form of therapy for a child with haemophilia A or B. The pioneering long term experiences of prophylactic treatment from Sweden and The Netherlands demonstrated the benefit of prophylaxis in retrospective and observational studies. Decades later, these benefits were confirmed in a randomized controlled study in USA. We review the current status of prophylactic replacement therapy of haemophilia in children, adolescents, adults and the elderly. Prophylaxis should begin at an early age and there are arguments for continuing it into adulthood. The dose of prophylaxis is dependent on the goal of treatment, economic resources and venous access and should be tailored individually. Starting the first exposures to clotting factor concentrates as prophylactic treatment, instead of on-demand in response to a bleed, may decrease the frequency of inhibitors in patients with haemophilia A. Novel longer-acting products are being introduced that could be helpful for patients with difficult venous access and enable higher trough levels.
- Published
- 2015
35. Definitions in hemophilia: communication from the SSC of the ISTH
- Author
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H. M. van den Berg, Victor S. Blanchette, Marilyn J. Manco-Johnson, A. Srivastava, Nigel S. Key, and Rolf Ljung
- Subjects
medicine.medical_specialty ,Coagulants ,business.industry ,Disease progression ,Treatment outcome ,MEDLINE ,Hematology ,Hemophilia A ,Hemophilia B ,Severity of Illness Index ,Treatment Outcome ,Text mining ,Predictive Value of Tests ,Terminology as Topic ,Predictive value of tests ,Hemarthrosis ,Severity of illness ,Disease Progression ,medicine ,Humans ,business ,Intensive care medicine - Published
- 2014
36. Diagnosis and care of patients with mild haemophilia: practical recommendations for clinical management
- Author
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Gary, Benson, Günter, Auerswald, Gerry, Dolan, Anne, Duffy, Cedric, Hermans, Rolf, Ljung, Massimo, Morfini, and Silva Zupančić, Šalek
- Subjects
Blood Coagulation Factor Inhibitors ,hemic and lymphatic diseases ,Humans ,Guidelines as Topic ,Review ,Hemophilia A ,Blood Coagulation Factors - Abstract
Mild haemophilia is defined by factor levels between 0.05 and 0.40 IU/mL and is characterised by traumatic bleeds. Major issues associated with mild haemophilia are that it may not present for many years after birth, and that awareness, even within families, may be low. Methodological problems exist in diagnosis, such as inconsistencies in results obtained from different assays used to measure factor levels in mild haemophilia. Advances in genetic testing provide insight into diagnosis as well as the likelihood of inhibitor development, which is not uncommon in patients with mild or moderate haemophilia and can increase morbidity. The management of patients with mild haemophilia is a challenge. This review includes suggestions around formulating treatment plans for these patients, encompassing the full spectrum from clinical care of the newly diagnosed neonate to that of the ageing patient with multiple comorbidities. Management strategies consider not only the vast differences in these patients’ needs, but also risks of inhibitor development and approaches to optimally engage patients.
- Published
- 2017
37. The care of a child with a newly diagnosed immune thrombocytopenia
- Author
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Rolf Ljung
- Subjects
Pediatrics ,medicine.medical_specialty ,Purpura, Thrombocytopenic, Idiopathic ,business.industry ,General Medicine ,Newly diagnosed ,030204 cardiovascular system & hematology ,Thrombocytopenia ,Immune thrombocytopenia ,03 medical and health sciences ,0302 clinical medicine ,030220 oncology & carcinogenesis ,Pediatrics, Perinatology and Child Health ,medicine ,Humans ,business ,Child - Published
- 2017
38. Outcome measures for adult and pediatric hemophilia patients with inhibitors
- Author
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Rolf Ljung, Thierry Lambert, Günter Auerswald, Anne Duffy, Mehdi Osooli, Silva Zupančić Šalek, Gerry Dolan, Gary Benson, Víctor Jiménez-Yuste, Cedric Hermans, and Massimo Morfini
- Subjects
Adult ,medicine.medical_specialty ,Adolescent ,media_common.quotation_subject ,Population ,030204 cardiovascular system & hematology ,Outcome assessment ,Haemophilia ,Hemophilia A ,Hemophilia B ,Factor IX ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Quality of life (healthcare) ,Cost of Illness ,Isoantibodies ,Medicine ,Humans ,Quality (business) ,education ,Intensive care medicine ,Child ,media_common ,Aged ,education.field_of_study ,Factor VIII ,Blood Coagulation Factor Inhibitors ,business.industry ,Outcome measures ,Age Factors ,Hematology ,General Medicine ,Bleed ,Middle Aged ,Social engagement ,medicine.disease ,Recombinant Proteins ,Patient Outcome Assessment ,Child, Preschool ,Physical therapy ,business ,030215 immunology - Abstract
Recent advancements in almost all aspects of hemophilia treatment have vastly improved patient care and management, and new and emerging treatments hold the promise of further progress. However, there remains a scarcity of data on long-term outcomes in hemophilia, particularly among those patients with inhibitors, for whom no validated outcome assessment tools are currently available. At the 15th Zurich Haemophilia Forum, an expert panel reviewed the most important outcome measures in inhibitor patients and considered the challenges associated with assessing outcomes in this population. A framework for outcome assessment in inhibitor patients incorporates traditional hemophilia outcome measures, such as bleed frequency and mortality, alongside measures of health, functioning, disability, social participation, quality of life, and economic considerations. It is important to remember that inhibitor patients differ in their clinical needs, perspectives, and priorities according to age, inhibitor status, degree of joint disease, and activity levels; as a result, the relative importance of different outcome measures will change throughout an inhibitor patient's life. Challenges inherent in measuring long-term outcomes in inhibitor patients include the small number of known patients, the subjective nature of many outcome assessment tools, and the risk of overburdening patients with repeated requests to complete questionnaires or participate in studies. Therefore, there is an urgent need to reach consensus on the most important and appropriate assessment tools for measuring outcomes in this population. These tools should ideally be standardized, easily applied, and internationally applicable in order to collect and generate quality outcome data.
- Published
- 2017
39. Switching treatments in haemophilia: is there a risk of inhibitor development?
- Author
-
Gary Benson, Eduardo Remor, Gerry Dolan, Massimo Morfini, Víctor Jiménez-Yuste, Guenter Auerswald, Rolf Ljung, Elena Santagostino, Thierry Lambert, and Silva Zupančić Šalek
- Subjects
Risk ,medicine.medical_specialty ,Evidence-based practice ,Haemophilia A ,MEDLINE ,haemophilia ,Haemophilia ,Hemophilia A ,Drug Substitution ,Isoantibodies ,inhibitors ,medicine ,Humans ,product switching ,Elective surgery ,Intensive care medicine ,Review Articles ,Factor VIII ,business.industry ,Hematology ,General Medicine ,medicine.disease ,Recombinant Proteins ,Surgery ,Increased risk ,business - Abstract
Patients with haemophilia A (and their physicians) may be reluctant to switch factor VIII (FVIII) concentrates, often due to concerns about increasing the risk of inhibitors; this reluctance to switch may contribute to patients missing the clinical benefits provided by the arrival of new factor VIII products. This topic was explored at the Eleventh Zurich Haemophilia Forum. Clinical scenarios for which product switching may be cause for concern were discussed; when there is a clinical need, there are no absolute contraindications to switching, but some patients (e.g. previously untreated patients and those undergoing elective surgery) may require more careful consideration. Both patient and physician surveys indicate that the reluctance to switch, and the fear of inhibitor development, does not appear to be evidence based. The evaluation of more recent data did not support previous studies suggesting that particular products (e.g. recombinant vs. plasma-derived and full length vs. B-domain modified) may be associated with increased risk. In addition, data from three national product switches showed that switching was not associated with increased inhibitor risk, but highlighted the need for regular inhibitor testing and for a centralised, unbiased database of inhibitor incidence. To conclude, current evidence does not suggest that switching products significantly influences inhibitor development.
- Published
- 2014
40. Perinatal aspects of haemophilia
- Author
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Rolf Ljung, Laura Banov, and Marina Economou
- Subjects
Adult ,Pediatrics ,medicine.medical_specialty ,Intracranial haemorrhage ,Genetic counseling ,medicine.medical_treatment ,Genetic Counseling ,Hemorrhage ,Disease ,Hemophilia A ,Haemophilia ,Preimplantation genetic diagnosis ,Hemophilia B ,Pregnancy ,Humans ,Medicine ,Caesarean section ,business.industry ,Pregnancy Complications, Hematologic ,Infant, Newborn ,Hematology ,General Medicine ,Delivery, Obstetric ,medicine.disease ,Perinatal Care ,Female ,business ,Blood sampling - Abstract
Haemophilia is an X-linked recessive genetic disease of haemostasis. Women carriers may present with a bleeding tendency similar to milder forms of the disease. Haemophilic newborns present risk factors and patterns of bleeding that are challenging. Identification of carriers and genetic counselling before conception is considered optimal to help decide on available conception options and during pregnancy to help minimise bleeding risks for both carrier mother and affected baby. Preimplantation genetic diagnosis is attractive to many couples at risk of having a child with haemophilia and relevant technology is becoming more available although it has both practical and ethical limitations. Pregnancy in carriers should be managed by a multidisciplinary team in a comprehensive treatment centre. The optimal mode of delivery for carriers expecting a baby known to have or being at risk of haemophilia is an issue of great debate. The general consensus among authors is avoidance of instrumental delivery, foetal scalp electrodes and blood sampling in pregnancies at risk of carrying an affected foetus, as well as early recourse to Caesarean section as guided by obstetric indications. Intracranial haemorrhage, although infrequent, is one the most devastating types of bleeding in haemophilic newborns and can occur regardless of the mode of delivery or the severity of haemophilia. Early screening is proposed for all infants with severe or moderate haemophilia who have had traumatic delivery and/or have evidence of extracranial haemorrhage. Women with postpartum haemorrhage should have a bleeding work-up.
- Published
- 2014
41. Immune Tolerance Induction for FIX Inhibitors Using Combined B and T Cell Immune Modulation Therapy in Severe Hemophilia B
- Author
-
Paul E. Monahan, G. Allen, Rolf Ljung, Pia Petrini, Susanna Ranta, Annika Mårtensson, Yasmina L. Abajas, S. Horneff, Brenda Nielsen, and Johannes Oldenburg
- Subjects
medicine.medical_specialty ,business.operation ,business.industry ,Immunology ,Cell Biology ,Hematology ,Octapharma ,Biochemistry ,Titer ,Regimen ,Prednisone ,Internal medicine ,Concomitant ,medicine ,Rituximab ,Complication ,business ,medicine.drug ,Factor IX - Abstract
Introduction Development of an inhibitor to Factor IX is a potentially life-threatening complication that occurs in 2-4% of severe hemophilia B patients. Attempt to eradicate these neutralizing alloantibodies with immune tolerance induction (ITI) regimens using prolonged repeated exposure to FIX fails to induce tolerance in ~70% of cases, and is limited by severe complications including FIX hypersensitivity and nephrotic syndrome. Cases of FIX ITI with immunosuppressive drugs have been reported infrequently. In light of increased understanding of the role of active T lymphocyte regulation of clotting factor-directed B lymphocyte-mediated humoral immunity, an approach combining immune modulating agents and frequent FIX infusions was reported by Beutel, et al (Haemostaseologie, 2009; 2014). We report a multi-institutional retrospective experience with combination immune modulation therapy (CIT), including B cell suppression with anti-CD20 monoclonal antibody Rituximab and T cell modulation using mycophenylate mofetil (MMF) with FIX ITI in 11 males with severe congenital hemophilia B. Methods The originally published regimen of Beutel, et al involves a 50 day course including FIX 100 IU/kg twice daily, rituximab 375 mg/m2 x 4 doses, mycophenolate (MMF) 300 mg/m2/dose daily, dexamethasone 6 mg/m2/dose pulses and IVIG 1 g/kg x 6 doses. Following individual Institutional Review Board approval, data on 11 patients was contributed by the INPH investigators and via outreach internationally and collected retrospectively using a uniform data collection form. Cases were included in the CIT series if the combination of FIX, rituximab and MMF was used. Approaches varied in the concomitant use of IVIG and pulse corticosteroids (dexamethasone or prednisone). Results CIT was the first immune tolerance therapy for 9/11 patients. Patients were 14-222 months of age at time of CIT, with a median time from inhibitor diagnosis to CIT 20 (range 0-207) months. Median historical peak inhibitor titer prior to initiation of CIT was 3.2 (range 1-42) BU/ml. Inhibitor titers at the initiation of CIT ranged from undetectable to 7 BU/ml. Eighty-onepercent of patients had a history of FIX hypersensitivity reaction. Prior to initiation of therapy, 27% of the patients underwent FIX desensitization during the initial course. The patients received FIX BID (9/11 patients) or QD (2/11 patients), 4 doses of rituximab 375 mg/m2, MMF for a minimum of 49 days (varying duration from 49-1247 days). IVIG was infused in 10/11 patients, with most receiving 3-7 doses during each course of CIT. 6/11 patients received between 2-10 courses of pulse corticosteroids during a CIT course. Each course of CIT achieved disappearance of the titer of FIX inhibitor at a median time of 1 month (range 1-41 months) Hypersensitivity reactions did not limit the courses of CIT, but did recur with inhibitor recurrence in 1 patient. Recurrence occurred in 6/11 patients at a median time of 11 months from time of CIT, in some cases soon after documented B cell recovery with a median inhibitor titer of 1.8 (range 0.7-7) BU/ml. In cases of recurrence, a negative inhibitor titer was achieved again in 1 patient by increasing FIX dose and in 4 patients who received additional courses of CIT. Repeat recurrence was seen in these patients following repeat CIT, although at low titer with a median of 1 BU/ml (range 1-4), allowing ongoing management with FIX in 3 of the 4. Overall, patients have had a median follow-up of 61 months following CIT, 9/11 patients are currently managed with factor IX for prophylaxis and bleeding, while 2/11 use bypassing agents. The most common complication was hospitalization for central venous catheter-related bacterial infection that occurred from < 1 to > 12 months after the use of rituximab in 3/11 patients. Nephrotic syndrome occurred in 3/11 patients. In each case, nephrotic syndrome responded to corticosteroids or re-initiation of CIT and FIX could be resumed. Conclusions FIX ITI with CIT targeting both B and T cells in hemophilia B is an effective means of achieving a negative inhibitor titer with tolerable safety in this series, allowing return to use of FIX for hemostasis and prophylaxis in most patients. Although recurrence is common and longer follow up is needed, when compared to the experience with using FIX alone, outcomes appear to be improved using CIT with FIX ITI as an initial approach. Disclosures Abajas: Bayer: Honoraria; CSL Limited: Honoraria. Allen:Shire: Employment, Equity Ownership. Oldenburg:Pfizer: Honoraria, Research Funding; Biogen: Honoraria, Research Funding; CSL Behring: Honoraria, Research Funding; Grifols: Honoraria, Research Funding; Octapharma: Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Research Funding; Shire: Honoraria, Research Funding; Chugai: Honoraria, Research Funding; Biotest: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Swedish Orphan Biovitrum: Honoraria, Research Funding; Novo Nordisk: Honoraria, Research Funding.
- Published
- 2018
42. Venous Thromboembolism in Children 0-18 Years — a Regional Population-Based Study from Sweden
- Author
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Bader Allahyani and Rolf Ljung
- Subjects
medicine.medical_specialty ,business.industry ,Immunology ,Antithrombin III deficiency ,Cell Biology ,Hematology ,medicine.disease ,Thrombophilia ,Biochemistry ,Venous thrombosis ,Protein C deficiency ,Internal medicine ,medicine ,Factor V Leiden ,cardiovascular diseases ,Protein S deficiency ,Risk factor ,business ,Blood coagulation test - Abstract
Introduction: Venous thromboembolism (VTE) is a rare complication in childhood. Pediatric VTE is an important and increasingly frequent clinical challenge likely due to increased detection and advanced medical interventions leading to improved survival of previously fatal conditions. Objective: The principal aim of this population based study was to describe the incidence, age distribution, type/location of VTE, and acquired and genetic pro-thrombotic risk factors of VTE and recurrence of VTE in children 0-18 years. Material and Methods: The Regional Ethical Review Board in Lund approved the study. We conducted a retrospective regional study of all consecutive ICD-10 codes of VTE in children 0-18 years over a 15-year period (January 1, 2000, to December 31, 2015) in a regional catchment area of southern Sweden using an electronic diagnosis registry. Eligible subjects were defined as children under the age of 18 who presented with VTE and had imaging evidence of thrombosis. Of the 174 patients diagnosed with VTEs, 164 fulfilled the study group criteria. Data regarding subject demographics and medical history (central venous catheter, cancer, congenital heart disease, history of VTE, current infection, etc.), location of VTE and imaging method (upper, lower extremities, pulmonary embolism, renal, cardiac, cerebral sinus venous thrombosis (CSVT), etc.), coagulation studies at primary investigation which included in all cases evaluation of at least plasma concentrations of protein C, protein S, antithrombin, resistance to activated protein C and the genotypes FV-G1691A and FII-G20210A. In addition, plasma values for coagulation factors VIII and XI, D-dimer, PK-INR, and cardiolipin antibodies were analyzed. Results: The incidence of VTE in children in the investigated region of Sweden was found to be 0.8 per 10,000 children. Of the study group with confirmed VTE (n=164), 73/164 (45%) were males and 91/164(55%) females, with bimodal age distribution at diagnosis, 25 (15%) < 1 month, 139 (85%) >1 month-18 years. Of the children, 143/164 (87%) had DVT (deep venous thrombosis), 21/164 (13%) had PE (pulmonary embolism) and 5/164 (3%) had both DVT and PE. Of 143 patients with DVT, 50 (30%) had lower extremity DVT, 46 (28%) had upper extremity DVT and 34 (20.7%) CSVT and the remaining 13 various locations. 79/164 (59%) had acquired potential risk factors, 11/164 (11%) had genetic risk factors, 34/164 (21%) had both genetic and acquired risk factors, and 22/164 (13%) had no identified risk factors. The most frequent acquired risk factors in the cohort were the use of hormonal therapy (34%), concomitant malignancy (21%), infection at the time of thrombosis (19%) or a CVL (central venous line) (15%). Genetic thrombophilia risk factors were found in 45/164 (27.5%), the most common were Factor V Leiden (FVL) in heterozygous form in 35 (21%), FII mutation (heterozygous) in 4 (2%) and double heterozygosity for FVL and FII mutation found in 2 (1%). Plasma deficiency of Protein S was found in 5, Protein C deficiency in 6 and Antithrombin deficiency in 1 patient (who had 3 episodes of VTE). Recurrent VTE was documented in 9 (5%), of which 5 had a congenital pro-thrombotic disorder (i.e. FVL mutation (n=3), antithrombin deficiency (n=1) and a protein S deficiency (n=1). Two out of the nine with recurrent VTE had neither a genetic nor an acquired identified risk factor. Six out of a total of 45 (13.3%) with genetic risk factors had a recurrent VTE. No common acquired pro-thrombotic risk factor was found in the group with recurrent VTE. Conclusion: The incidence, age-distribution, locations and underlying disorders agree with published findings in pediatric populations. In our study, 87% of the children with VTE had either an identifiable acquired or genetic risk factor or a combination of both. Of those with a genetic risk factor, 13% had a recurrent VTE during the study period which indicates an even higher cumulative risk during childhood which emphasizes the need to consider prophylaxis in situations with increased risk of VTE. However, of those with recurrent VTE, no frequent acquired risk factor was identified. Disclosures No relevant conflicts of interest to declare.
- Published
- 2018
43. 99.3% of Inhibitors in Severe Hemophilia a Develop before Exposure Day 75. Time to Change Definition of Previously Treated Patients; Data from 1038 Patients with Severe Hemophilia a of the Pednet Registry
- Author
-
Elena Santagostino, Carmen Escuriola, Manuela Carvalho, Nadine Gretenkort-Andersson, Anne Rafowicz, Helen Platokouki, Manuel Carcao, Susanna Ranta, Beatrice Nolan, Christoph Koenigs, Torben Stamm Mikkelsen, Claudio Molinari, Rolf Ljung, Michael D. Williams, Liz Chalmers, Krista Fischer, Marijke Van den Berg, Ana Rosa Cid, Rainer Kobelt, Hervé Chambost, Christoph Male, Gili Kenet, Georges E. Rivard, Carmen Altisent, Teresa Álvarez-Roman, Ri Liesner, Karin Kurnik, Christel Van Geet, Martina Buehrlen, Ségolène Claeyssens, Johannes Oldenburg, and Anne Mäkipernaa
- Subjects
0303 health sciences ,business.operation ,Immunology ,Cell Biology ,Hematology ,Octapharma ,Severe hemophilia A ,Inhibitory antibodies ,Biochemistry ,Shire ,3. Good health ,Management ,Clinical study ,03 medical and health sciences ,0302 clinical medicine ,Safety risk ,Political science ,Honorarium ,Previously treated ,business ,030304 developmental biology ,030215 immunology - Abstract
Introduction.In patients with hemophilia treated with factor VIII products, the development of inhibitory antibodies poses the largest safety risk. Especially during the first 50 exposure days (EDs), up to 37% of patients with severe hemophilia A have been reported to develop an inhibitor. To study neo-immunogenicity of products and new treatment strategies, patients have been distinguished into previously untreated (PUPs) and previously treated patients (PTPs); the latter defined as patients treated for more than 150 EDs. The number of 150 EDs was established in the eighties during a time when most patients received on-demand treatment and testing for inhibitors was not frequently performed. More recent studies on inhibitor incidence in PUPs with severe hemophilia A report that 50% of inhibitors develop within 14-15 EDs, however the cut-off number of EDs for a PUP to become a PTP is not well defined. The aim of this study was to define the number of EDs for PUPs to become PTPs based on long-term follow-up of patients with severe hemophilia A Methods.All patients with severe hemophilia A born after January 1, 2000, treated for at least 1 ED and followed prospectively until inhibitor development or the number of EDs at last follow-up, were included. The number of EDs at inhibitor development is the last exposure day before the first positive titer was reported. An inhibitor was defined as positive when at least two positive inhibitor titers were measured. Positivity was defined according to the cut-off level in each individual center's laboratory. Results.Of 1,038 PUPs with severe hemophilia A, 930 (89.6%) were followed until 75 EDs, 429 until 500 EDs and 212 until 1000 EDs. In total, 300 inhibitors developed, of which 298 (99.3%) within the first 75 EDs. Thereafter only two inhibitors developed, both low titer: after 249 and 264 EDs. Conclusion.Almost all inhibitors develop during the first 75 EDs. Patients with severe hemophilia A can be defined as PTP after 75 instead of 150 exposure days. A change of definition of PTP will increase the number of severe hemophilia A patients eligible for new therapies. Disclosures Santagostino: Bioverativ: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Shire: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Kedrion: Membership on an entity's Board of Directors or advisory committees; Sobi: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; CSL Behring: Membership on an entity's Board of Directors or advisory committees; Grifols: Membership on an entity's Board of Directors or advisory committees; Octapharma: Membership on an entity's Board of Directors or advisory committees. Male:SOBI: Speakers Bureau; Shire: Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Octapharma: Speakers Bureau; Novo Nordisk: Speakers Bureau; Biotest: Speakers Bureau; Bayer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CSL Behring: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Oldenburg:Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Octapharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Biogen Idec: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Chugai: Honoraria, Membership on an entity's Board of Directors or advisory committees; Grifols: Honoraria, Membership on an entity's Board of Directors or advisory committees; Biotest: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL Behring: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Swedish Orphan Biovitrum: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Liesner:Baxalta: Consultancy, Research Funding; Novo Nordisk: Research Funding, Speakers Bureau; Sobi: Speakers Bureau; Bayer: Consultancy, Research Funding; Roche: Research Funding; Octapharma: Consultancy, Other: Clinical study investigator for NuProtect Study (Octapharma sponsored), Research Funding, Speakers Bureau. Carcao:Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Octapharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Grifols: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL-Behring: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; LFB: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bioverativ/Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Biotest: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Nolan:CSL Behring: Research Funding; Sobi: Research Funding; Bayer: Research Funding. Álvarez-Roman:Shire: Consultancy; NovoNordisk: Consultancy; SOBI: Consultancy. Koenigs:Gilead: Research Funding; CSL Behring: Consultancy, Research Funding; Pfizer: Research Funding, Speakers Bureau; Bayer: Consultancy, Research Funding, Speakers Bureau; Intersero: Research Funding; Bioverativ: Consultancy; Roche/Chugai: Consultancy; EU (IMI, FP7): Research Funding; Sobi: Consultancy, Research Funding, Speakers Bureau; Shire: Consultancy, Research Funding; Novo Nordisk: Consultancy, Speakers Bureau; Biotest: Research Funding, Speakers Bureau; Jansen: Research Funding.
- Published
- 2018
44. Intermediate-dose versus high-dose prophylaxis for severe hemophilia: comparing outcome and costs since the 1970s
- Author
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H. Marijke van den Berg, Margareta Holmström, Rolf Ljung, Pia Petrini, Krista Fischer, Katarina Steen Carlsson, and Erik Berntorp
- Subjects
Adult ,Male ,medicine.medical_specialty ,Pediatrics ,Time Factors ,Adolescent ,Clinical Trials and Observations ,Immunology ,Hemophilia A ,Biochemistry ,Factor IX ,Young Adult ,Hemophilias ,Quality of life ,Internal medicine ,medicine ,Humans ,Prospective Studies ,Young adult ,Child ,Prospective cohort study ,Netherlands ,Retrospective Studies ,Sweden ,Factor VIII ,Hematology ,Dose-Response Relationship, Drug ,Coagulants ,business.industry ,Infant ,Retrospective cohort study ,Cell Biology ,Confidence interval ,Treatment Outcome ,Child, Preschool ,Quality of Life ,Female ,business ,medicine.drug - Abstract
Prophylactic treatment in severe hemophilia is very effective but is limited by cost issues. The implementation of 2 different prophylactic regimens in The Netherlands and Sweden since the 1970s may be considered a natural experiment. We compared the costs and outcomes of Dutch intermediate- and Swedish high-dose prophylactic regimens for patients with severe hemophilia (factor VIII/IX1 IU/dL) born between 1970 and 1994, using prospective standardized outcome assessment and retrospective collection of cost data. Seventy-eight Dutch and 50 Swedish patients, median age 24 years (range, 14-37 years), were included. Intermediate-dose prophylaxis used less factor concentrate (median: Netherlands, 2100 IU/kg per year [interquartile range (IQR), 1400-2900 IU/kg per year] vs Sweden, 4000 IU/kg per year [IQR, 3000-4900 IU/kg per year]); (P.01). Clinical outcome was slightly inferior for the intermediate-dose regimen (P.01) for 5-year bleeding (median, 1.3 [IQR, 0.8-2.7] vs 0 [IQR, 0.0-2.0] joint bleeds/y) and joint health (Haemophilia Joint Health Score10 of 144 points in 46% vs 11% of participants), although social participation and quality of life were similar. Annual total costs were 66% higher for high-dose prophylaxis (mean, 180 [95% confidence interval, 163 - 196] × US$1000 for Dutch vs 298 [95% confidence interval, 271-325]) × US$1000 for Swedish patients; (P.01). At group level, the incremental benefits of high-dose prophylaxis appear limited. At the patient level, prophylaxis should be tailored individually, and many patients may do well receiving lower doses of concentrate without compromising safety.
- Published
- 2013
45. Immune tolerance induction in patients with severe hemophilia with inhibitors: expert panel views and recommendations for clinical practice
- Author
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Thierry Lambert, Silva Zupančić Šalek, Ivo Elezovic, Rolf Ljung, Massimo Morfini, Gary Benson, Günter Auerswald, and Eduardo Remor
- Subjects
medicine.medical_specialty ,Hematology ,medicine.diagnostic_test ,business.industry ,MEDLINE ,General Medicine ,030204 cardiovascular system & hematology ,Bethesda unit ,Haemophilia ,medicine.disease ,3. Good health ,Surgery ,Immune tolerance ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Medicine ,Observational study ,business ,Intensive care medicine ,030215 immunology ,Genetic testing ,Factor IX ,medicine.drug - Abstract
For hemophilia patients with inhibitors, immune tolerance induction (ITI) may help to restore clinical response to factor (F) VIII or FIX concentrates. Several ITI regimens and protocols exist; however, despite 30 yr of progressive investigation, the ITI evidence base relies mainly on observational data. Expert opinion, experience, and interpretation of the available evidence are therefore valuable to support clinical decision-making. At the Sixth Zurich Haemophilia Forum, an expert panel considered recent data and consensus to distill key practice points relating to ITI. The panel supported current recommendations that, where feasible, ITI should be offered early to children and adults (ideally ≤ 5 yr of inhibitor detection) when inhibitor titers are
- Published
- 2012
46. Tuesday, 26 July 2011
- Author
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Annika Mårtensson and Rolf Ljung
- Subjects
Pregnancy ,Pediatrics ,medicine.medical_specialty ,Amniotic fluid ,medicine.diagnostic_test ,business.industry ,media_common.quotation_subject ,Incidence (epidemiology) ,Chorionic villus sampling ,Prenatal diagnosis ,Hematology ,Haemophilia ,medicine.disease ,hemic and lymphatic diseases ,medicine ,Girl ,Sibling ,business ,reproductive and urinary physiology ,media_common - Abstract
Aims: To study the number, outcome and reasons for prenatal diagnosis (PND) and how it has affected the incidence of haemophilia, the number of siblings and the number of potential carriers in the families. Study Group: Women in SWE, compromising over 95% of total, who underwent PND of haemophilia during the years 1970-2010. A total of 46 women were identified who together underwent 79 PND procedures. Method: Structured personal interview and registry of laboratory analysis. So far, 27 women have been interviewed. Preliminary Results: 19/79 PND had been performed by analysis of foetal blood, 55/79 by genetic analysis of chorionic villi sampling and 5/79 by analysis of amniotic fluid. A total of 24 foetuses were found to be affected with haemophilia and 13/24 were aborted. The 24 foetuses affected with haemophilia were carried by 20 women. Twelve of these 20 women chose to end their pregnancy because of the findings. The preliminary results suggest that the drop in incidence of haemophilia due to PND in the 1990s no longer exists since almost half of the women today use PND to prepare themselves and their families psychologically to have a child with haemophilia and not to terminate the pregnancy. Furthermore, there seem to be more women becoming mothers since the improvement of care, thus giving birth to more children, both boys and girls, the latter being possible carriers. Conclusions: PND of haemophilia is still requested, but the number of affected foetuses aborted has diminished. Furthermore, the number of siblings seems to have increased, so the number of future carriers will also increase. (Less)
- Published
- 2011
47. Prophylaxis for severe haemophilia: clinical challenges in the absence as well as in the presence of inhibitors
- Author
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Victor S. Blanchette, Rolf Ljung, Krista Fischer, and Leonard A. Valentino
- Subjects
Male ,medicine.medical_specialty ,Pediatrics ,Adolescent ,Disease ,Hemophilia A ,Haemophilia ,Drug Administration Schedule ,law.invention ,Cohort Studies ,Factor IX ,Randomized controlled trial ,Quality of life ,law ,Hemarthrosis ,Arthropathy ,medicine ,Humans ,Child ,Genetics (clinical) ,Randomized Controlled Trials as Topic ,Clotting factor ,Factor VIII ,business.industry ,Hematology ,General Medicine ,medicine.disease ,Surgery ,Treatment Outcome ,Quality of Life ,Patient Compliance ,Observational study ,business ,Cohort study - Abstract
Prophylaxis is defined as the regular administration of clotting factor concentrates to prevent bleeding. Extensive data from observational studies and a recent randomized controlled trial (have established that early prophylactic treatment prevents bleeds and arthropathy in boys with severe haemophilia. The initiation of prophylaxis in young children remains challenging. To prevent arthropathy, prophylaxis should be started early, before the onset of joint damage. Alternative strategies of starting include starting before the age of 2 years, or starting before the third joint bleed. Dose and frequency vary between the original Swedish regime of 20-40 IU kg(-1) three times per week and lower dosed and step up regimes starting with 50 IU kg(-1) once weekly and rapidly increasing dose and frequency in case of bleeds. In the second decade, most patients on prophylaxis learn self-infusion. Self-management warrants confirmation of adequate knowledge of the disease. Increasing self-management concurring with major physical and psychological changes may cause reduced adherence. The challenge is to promote adherence and continue to prevent bleeds during this important period of rapid growth. The third decade of life often represents a change in lifestyle. Patients may get a job and periods of physical activity may be more confined. About two thirds of patients experiment with discontinuing prophylaxis in their early twenties, and 20-30% with mild bleeding patterns switch to on-demand treatment for prolonged periods or even permanently. The challenge is to optimize efficiency by individualizing prophylactic dose and frequency according to lifestyle and bleeding pattern. Inhibitors may develop in up to 30% of patients with severe haemophilia. Especially those with high titre inhibitors are at increased risk of developing target joints and severe arthropathy. The use of prophylactic treatment with bypassing agents in inhibitor patients is increasing. Early studies report in a significant reduction of bleeds, including intracranial bleeds, and improvement in quality of life. Data on results of primary prophylaxis in patients with inhibitors to prevent arthropathy are not yet available.
- Published
- 2008
48. Haemophilia in the first years of life
- Author
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H. Chambost, A.-M. Stain, Rolf Ljung, and Donna DiMichele
- Subjects
Male ,Catheterization, Central Venous ,Pediatrics ,medicine.medical_specialty ,Haemophilia A ,MEDLINE ,Hemophilia A ,Haemophilia ,Factor IX ,Risk Factors ,Hemarthrosis ,Health care ,medicine ,Humans ,Haemophilia B ,Genetic Testing ,Genetics (clinical) ,Genetic testing ,Factor VIII ,medicine.diagnostic_test ,business.industry ,Infant, Newborn ,Infant ,Thrombosis ,Hematology ,General Medicine ,medicine.disease ,Circumcision, Male ,Child, Preschool ,business ,Intracranial Hemorrhages ,Developed country - Abstract
Surgery in infants and young children with haemophilia, when preceded by accurate diagnosis and accompanied by safe and effective factor prophylaxis, is not associated with a significant risk of haemorrhage. Haemophilic newborns undergoing circumcision or major surgery prior to diagnosis and in the absence of appropriate haemostatic prophylaxis remain as a concern. Inhibitor development has replaced haemorrhage as the major surgical complication in the developed world, largely because of the intensity of treatment used to secure haemostasis. For that reason only, essential surgery should be performed. Intracranial haemorrhage (ICH) during the neonatal period affects 3.5-4.0% of all haemophilia boys in countries with a good standard of health care, which is considerably (40-80 times) higher than expected in the normal population. Because of the high frequency of sporadic cases, ICH in the neonatal period can only be partially prevented by improved carrier diagnosis and counselling. Infections and thrombosis are the major serious complications of central venous lines. Large differences are seen in the frequency of these complications, the most plausible explanations are probably related to the protocol used for device care, the quality of education and the compliance of the users, an issue addressed in an on-going study.
- Published
- 2008
49. Management of carriers and babies with haemophilia
- Author
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S A Lavery, A M Street, and Rolf Ljung
- Subjects
Adult ,Male ,Heterozygote ,congenital, hereditary, and neonatal diseases and abnormalities ,Pediatrics ,medicine.medical_specialty ,Adolescent ,Genetic counseling ,Haemophilia A ,Genetic Counseling ,Prenatal diagnosis ,Hemophilia A ,Haemophilia ,Factor IX ,Pregnancy ,Risk Factors ,hemic and lymphatic diseases ,medicine ,Humans ,Haemophilia B ,Genetic Testing ,Family history ,Child ,Genetics (clinical) ,Genetic testing ,Factor VIII ,medicine.diagnostic_test ,business.industry ,Pregnancy Complications, Hematologic ,Infant, Newborn ,Infant ,Hematology ,General Medicine ,medicine.disease ,Phenotype ,Child, Preschool ,Female ,business ,Intracranial Hemorrhages - Abstract
Although up to 30% of babies born with haemophilia do not have a family history of the disorder, the remaining 70% are born in families where haemophilia has been diagnosed. It has been estimated that for each male with haemophilia, there are five potential female carriers. Such women will benefit from knowledge of both their genetic (mutation present or not) and phenotype (level of plasma factor activity) status. Genetic counselling services to provide information and testing, together with plasma factor measurement, should be offered where available to all women at risk of being carriers. It is critical that women know their plasma factor measurement as they may have mild haemophilia (factor 5-30%, reference range 50-150%) which requires management at times of medical and surgical procedures and following trauma. Close liaison between adult and paediatric haemophilia centres and obstetric-gynaecology units is important to ensure that clinical carers identify and address carriers' needs. Genetic testing should be performed only after a potential carrier has been counselled and supported to receive such information. There is no coercion to accept such testing. An advantage of genetic testing is to then discuss pre-implantation genetic diagnosis which is an ex-vitro form of prenatal diagnosis. This can assist couples at risk of having a child with haemophilia who wish to reduce their anxieties about reproduction. Approximately 4% of boys with haemophilia, born in countries with good maternal care, will have intracranial haemorrhage in the neonatal period. There are no high-level evidence-based guidelines for the management of delivery or of the newborn with haemophilia. Obstetricians or other birth attendants need to be advised of the possibility of delivery of a boy with haemophilia and seek support from a haemophilia specialist during the pregnancy. The mother can then be monitored and plans for delivery be developed between her medical consultants and discussed with her. It is always preferable for a carrier to know of her genetic and phenotypic status before becoming pregnant so that she is informed as to her options and requirements for safe delivery.
- Published
- 2008
50. Secondary prophylaxis with recombinant activated factor VII improves health-related quality of life of haemophilia patients with inhibitors
- Author
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H. R. Roberts, Liselotte S. Ebbesen, Rolf Ljung, Barbara A. Konkle, W. K. Hoots, G. Auerswald, James Weatherall, and J.-M. Ferran
- Subjects
Adult ,medicine.medical_specialty ,Pediatrics ,Adolescent ,Visual analogue scale ,Factor VIIa ,Hemophilia A ,Haemophilia ,Hemophilia B ,Acquired immunodeficiency syndrome (AIDS) ,Quality of life ,Internal medicine ,Hemarthrosis ,Outcome Assessment, Health Care ,medicine ,Humans ,Prospective Studies ,Child ,Prospective cohort study ,Genetics (clinical) ,Hematology ,Coagulants ,business.industry ,Secondary prophylaxis ,General Medicine ,medicine.disease ,Recombinant Proteins ,humanities ,Quality-adjusted life year ,Child, Preschool ,Quality of Life ,Quality-Adjusted Life Years ,business - Abstract
Haemophilia patients with inhibitors characteristically have impaired joint function and reduced health-related quality of life (HRQoL). This analysis examined whether secondary prophylaxis with recombinant activated factor VII (rFVIIa) improves HRQoL vs. conventional on-demand therapy in patients with haemophilia with inhibitors and frequent bleeds. After a 3-month preprophylaxis period, 22 patients received daily rFVIIa prophylaxis (90 or 270 microg kg(-1)) for 3 months, followed by 3 months' postprophylaxis. Days of hospitalization, absence from school/work and mobility aids requirements were recorded. HRQoL was assessed by EuroQoL (EQ-5D) questionnaire, visual analogue scale (VAS), derived Time to Trade-Off (TTO) scores and Quality Adjusted Life Years (QALYs). rFVIIa prophylaxis significantly (P < 0.0001) reduced bleeding frequency vs. prior on-demand therapy. Hospitalization (5.9% vs. 13.5%; P = 0.0026) and absenteeism from school/work (16.7% vs. 38.7%; P = 0.0127) decreased during prophylaxis; these effects tended to be maintained during postprophylaxis. HRQoL (evaluated by EQ-5D) tended to improve during and after rFVIIa prophylaxis. Notably, pain decreased and mobility increased in 40.9% and 27.3% of patients, respectively, at the end of the postprophylaxis period vs. preprophylaxis. Median VAS score increased from 66 to 73 (P = 0.048), and TTO scores suggested better HRQoL (0.62 vs. 0.76; P = 0.054) during postprophylaxis than preprophylaxis. Small to moderate changes in effect sizes were reported for VAS and TTO scores. Median QALYs were 0.68 (VAS) and 0.73 (TTO). Reductions in bleeding frequency with secondary rFVIIa prophylaxis were associated with improved HRQoL vs. on-demand therapy.
- Published
- 2008
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