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1.
  • Berntorp, Erik, et al. (author)
  • Liposuction in Dercum's disease.
  • 2006
  • In: Liposuction : Principles and Practice - Principles and Practice. - 9783540280422 - 9783540280439 ; , s. 516-518
  • Book chapter (peer-reviewed)
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2.
  • Berntorp, Erik, et al. (author)
  • Liposuction in Dercum’s disease
  • 2016. - 2
  • In: Liposuction: Principles and Practice. - Berlin, Heidelberg : Springer Berlin Heidelberg. - 9783662489031 - 9783662489017 ; , s. 657-660
  • Book chapter (peer-reviewed)abstract
    • Adiposis dolorosa or Dercum’s disease is associated with pain. The symptoms are very therapy resistant and may have a major impact on quality of life. The authors describe the diagnosis and classification as well as treatment including medications and surgery. Liposuction seems to be a logical treatment of the symptoms in Dercum’s disease, but according to the experience at the authors’ hospital, the improvement of pain has a rather short duration.
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3.
  • Berntorp, Erik, et al. (author)
  • Liposuction in Dercum's disease: impact on haemostatic factors associated with cardiovascular disease and insulin sensitivity.
  • 1998
  • In: Journal of Internal Medicine. - 1365-2796. ; 243:3, s. 197-201
  • Journal article (peer-reviewed)abstract
    • OBJECTIVE: To study the impact of adipose tissue removal by liposuction on factors associated with increased risk of cardiovascular atherosclerotic disease within the coagulation and fibrinolytic system and glucose metabolism. DESIGN, SETTING AND SUBJECTS: Liposuction was performed in 53 patients with Dercum's disease. The levels of fibrinogen, von Willebrand factor antigen (VWF:Ag) and plasminogen activator inhibitor type 1 activity (PAI-1) were measured preoperatively, and 2 weeks, 4 weeks and 3 months postoperatively. In a subsample of 10 patients, insulin sensitivity was determined before and 2-4 weeks after surgery using the 2-h euglycaemic hyperinsulinaemic clamp technique. The study was performed as a single-centre study. MAIN OUTCOME MEASURE: Fibrinogen, PAI-1 and VWF:Ag levels, and glucose uptake before and after removal of adipose tissue. RESULTS: Weight reduction was sustained throughout the follow-up period with a mean decrease from 90.7 to 86.6 kg (P < 0.0001). There was a slight increase in levels of coagulation factors 2 and 4 weeks postoperatively, probably in reaction to the surgical trauma. After 3 months the values had returned to preoperative levels except for PAI-1, which still showed a slight increase (P < 0.05). In the subsample of 10 patients, glucose uptake was improved (P < 0.05) from a short-term perspective after surgery. CONCLUSION: Surgical removal of adipose tissue, without change in lifestyle, does not seem to improve the levels of coagulation and fibrinolytic factors associated with cardiovascular atherosclerotic disease, whereas glucose takeup may be facilitated and insulin sensitivity increases from a short-term perspective.
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4.
  • Henricsson, Marianne, et al. (author)
  • Progression of retinopathy after improved metabolic control in type 2 diabetic patients. Relation to IGF-1 and hemostatic variables
  • 1999
  • In: Diabetes Care. - 1935-5548. ; 22:12, s. 1944-1949
  • Journal article (peer-reviewed)abstract
    • OBJECTIVE: To determine the impact of improved glycemic control on the development and progression of retinopathy after the institution of insulin therapy in patients with type 2 diabetes and to assess the relation to IGF-1 and hemostatic variables. RESEARCH DESIGN AND METHODS: In a prospective observational study, 45 type 2 diabetic patients were examined at baseline and 1, 3, 6, 12, and 24 months after change to insulin therapy. Retinopathy was graded on fundus photographs using the Wisconsin scale; HbA1c, IGF-1, and hemostatic variables were measured. RESULTS: During the observation period of 2 years, 23 patients progressed in the retinopathy scale; 8 progressed > or = 3 levels. After 2 years of insulin treatment, HbA1c and IGF-1 were significantly lower than at baseline, whereas the hemostatic variables had not changed significantly. Progression of retinopathy > or = 3 levels was related to the degree of HbA1c reduction, the duration of diabetes, a higher prothrombin fragment 1 + 2 levels (F1 + 2), but not to other hemostatic variables or IGF-1. The relative risk for progression > or = 3 levels was 2.6 when HbA1c had been reduced > or = 3 percent units (95% CI 1.1-6.1). CONCLUSIONS: The magnitude of improvement of HbA1c by the institution of insulin treatment over a 2-year period may be associated with progression of retinopathy in patients with type 2 diabetes.
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5.
  • Widell, Anders, et al. (author)
  • Antibody to a hepatitis C virus related protein among patients at high risk for hepatitis B
  • 1991
  • In: Scandinavian Journal of Infectious Diseases. - : Informa UK Limited. - 1651-1980 .- 0036-5548. ; 23:1, s. 19-24
  • Journal article (peer-reviewed)abstract
    • Anti-HCV prevalence in treated hemophiliacs, their heterosexual partners, intravenous drug addicts and homosexual men was studied. In hemophiliacs and many of the intravenous drug addicts, greater than or equal to 2 sera drawn 1-18 or 1-17 years apart were available. Anti-HCV testing was performed by ELISA (Ortho). Among patients with severe and moderate hemophilia A, 87% (98/112) were positive for anti-HCV at least once and among patients with severe and moderate hemophilia B, 83% (24/29) were positive for anti-HCV. Seroconversion to anti-HCV was observed in 21% of hemophilia patients. In hemophilia A, HCV infection generally occurred during the first years of life and in hemophilia B somewhat later. Loss of anti-HCV antibody was seen in 12% (17 patients). The rest, 54% (76 patients) were seropositive in first and last samples. All 12 tested spouses to anti-HCV positive men were anti-HCV negative. 80% of the drug addicts (137/172) were seropositive for anti-HCV. In those with greater than 1 serum tested, 8% were consistently negative and 68% consistently positive. 21% seroconverted to anti-HCV while 3% lost antibody. 10% (22/211) of homosexual men were anti-HCV positive. Intravenous transmission of HCV thus seemed highly efficient whereas sexual transmission was much less efficient.
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6.
  • Abshire, T. C., et al. (author)
  • Prophylaxis in severe forms of von Willebrand's disease: results from the von Willebrand Disease Prophylaxis Network (VWD PN)
  • 2013
  • In: Haemophilia. - : Wiley. - 1351-8216. ; 19:1, s. 76-81
  • Journal article (peer-reviewed)abstract
    • The bleeding patterns of severe von Willebrand's disease (VWD) adversely affect quality of life, and may be life threatening. There is a presumed role for prophylaxis with VWF-containing concentrates, but data are scarce. The von Willebrand Disease Prophylaxis Network (VWD PN) was formed to investigate the role of prophylaxis in clinically severe VWD that is not responsive to other treatment(s). Using a retrospective design, the effect of prophylaxis was studied. Availability of records to document, or reliably assess, the type and frequency of bleeding episodes prior to, and after, the initiation of prophylaxis was required. Annualized bleeding rates were calculated for the period prior to prophylaxis, during prophylaxis and by primary bleeding indication defined as the site accounting for more than half of all bleeding symptoms. The Wilcoxon signed-rank test of differences in the medians was used. Sixty-one subjects from 20 centres in 10 countries were enrolled. Data for 59 were used in the analysis. The median age at onset of prophylaxis was 22.4 years. Type 3 VWD accounted for the largest number (N = 34, 57.6%). Differences in bleeding rates within individuals during compared with before prophylaxis were significant for the total group (P < 0.0001), and for those with primary bleeding indications of epistaxis (P = 0.0005), joint bleeding (P = 0.002) and GI bleeding (P = 0.001). The effect of prophylaxis was similar among those age < 18 years and those >= 18. One person developed an inhibitor during treatment. We conclude that prophylactic treatment of VWD is efficacious.
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7.
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8.
  • Abshire, T, et al. (author)
  • Prophylaxis Escalation in Severe von Willebrand Disease: A Prospective Study from the von Willebrand Disease Prophylaxis Network.
  • 2015
  • In: Journal of Thrombosis and Haemostasis. - : Elsevier BV. - 1538-7933 .- 1538-7836. ; 13:9, s. 1585-1589
  • Journal article (peer-reviewed)abstract
    • Treatment of mucosal bleeding (epistaxis, gastrointestinal and menorrhagia) and joint bleeding remains problematic in clinically severe von Willebrand Disease (VWD). Patients are often unresponsive to treatment (e.g. desmopressin or antifibrinolytic therapy) and may require von Willebrand (VW) factor replacement therapy. There are little data on the use of prophylaxis in VWD and none applied in a prospective, treatment escalation design.
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9.
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10.
  • Ahnström, Josefin, et al. (author)
  • A 6-year follow-up of dosing, coagulation factor levels and bleedings in relation to joint status in the prophylactic treatment of haemophilia
  • 2004
  • In: Haemophilia. - : Wiley. - 1351-8216 .- 1365-2516. ; 10:6, s. 689-697
  • Journal article (peer-reviewed)abstract
    • The primary aim of this study was to investigate the possible relationship between coagulation factor level and bleeding frequency during prophylactic treatment of haemophilia after stratification of the patients according to joint scores. The secondary aim was to obtain a systematic overview of the doses of coagulation factors prescribed for prophylaxis at the Malmo haemophilia treatment centre during a 6-year period. A retrospective survey of medical records for the years 1997-2002 and pharmacokinetic study results from the 1990s was complemented by collection of blood samples for coagulation factor assay when needed. Information on the dosing and plasma levels of factor VIII or factor IX, joint scores and incidence of bleedings (joint bleeds and 'other bleeds') was compiled. The patients were stratified by age (0-6, 7-12, 13-18, 19-36 and >36 years) and joint score (0, 1-6 and >6). Individual pharmacokinetic parameters of plasma coagulation factor activities (FVIII:C and FIX:C) were estimated. Trough levels during the treatment were calculated, as well as the number of hours per week of treatment during which plasma FVIII:C/FIX:C fell below a 1, 2 or 3% target level. Fifty-one patients with haemophilia A (two moderate, 49 severe) and 13 with haemophilia B (all severe) were included, yielding data for 364 patient-years of treatment. There was a wide range of dosing schedules, the most common ones being three times a week or every other day for FVIII and twice a week or every third day for FIX. The overall relationship between FVIII:C/FIX:C levels and incidence of joint bleeding was very weak, even after stratification of the patients according to joint score. There was no relationship between coagulation factor level and incidence of other bleeds. In this cohort of patients on high-dose prophylactic treatment, dosing was based more on clinical outcome in terms of bleeding frequency than on the aim to maintain a 1% target level of FVIII:C/FIX:C. Some patients did not bleed in spite of a trough level of <1% and others did in spite of trough levels >3%. The practical implication of our findings is that dosing in prophylactic treatment of haemophilia should be individualized. Thus, proposed standard regimens should be implemented only after careful clinical consideration, with a high readiness for re-assessment and individual dose tailoring.
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11.
  • Al-Shanqeeti, A, et al. (author)
  • Protein Z and protein Z-dependent protease inhibitor - Determinants of levels and risk of venous thrombosis
  • 2005
  • In: Thrombosis and Haemostasis. - 0340-6245. ; 93:3, s. 411-413
  • Journal article (peer-reviewed)abstract
    • To assess the potential roles of protein Z (PZ) and protein Z-dependent protease inhibitor (ZPI) in venous thrombosis, their plasma levels were measured in 426 individuals with venous thrombosis and 471 control individuals participating in the Leiden Thrombophilia Study. A relationship between the level of PZ or ZPI and venous thrombosis was not detected in the overall case-control study. PZ and ZPI circulate as a complex and their plasma levels are interdependent. Both PZ and ZPI are increased with oral contraceptive use and reduced with oral anticoagulant therapy.
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12.
  • Ar, Muhlis Cem, et al. (author)
  • Methods for individualising factor VIII dosing in prophylaxis
  • 2014
  • In: European Journal of Haematology. - : Wiley. - 1600-0609 .- 0902-4441. ; 93, s. 16-20
  • Research review (peer-reviewed)abstract
    • Haemophilia A is a sex-linked disorder characterised chiefly by recurrent, spontaneous joint and muscle bleedings resulting from deficiency of factor VIII (FVIII). Recurrent joint bleeds result in haemophilic arthropathy. Unless treated with factor replacement therapy, many patients with severe haemophilia become disabled. The first clinical evidence favouring prophylaxis originated from the studies in Sweden and the Netherlands in the 1960s. Later on, it was shown that prophylaxis could prevent arthropathy, if started early in life, or slow its progression in adults with established arthropathy. The optimal dosing of FVIII in long-term prophylaxis has still not been determined, and there is growing evidence that the dose and frequency of FVIII should be individualised. We conducted a systematic search of PubMed to identify all relevant articles on FVIII prophylaxis in severe haemophilia A. We focused on articles with detailed information about individualisation of prophylaxis. Long-term prophylaxis in haemophilia was introduced in Sweden in the late 1950s. However, standard prophylactic regimens may not be appropriate for all patients with severe haemophilia. Factors such as age, joint status, co-morbidities and differences in pharmacokinetics lead to interindividual variation in factor requirement. Dose tailoring of FVIII by clinical outcome was first described in 1994. Since then, several dose-finding studies questioned the necessity to maintain preinfusion levels of FVIII above 1%. Individualising prophylaxis by dose tailoring is now recommended. Each country should adopt policies for individualising prophylaxis in patients with severe haemophilia. This would lead to a better distribution of the available source of factor concentrates.
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13.
  • Arvanitakis, Alexandros, et al. (author)
  • A comparison of MyPKFiT and WAPPS-Hemo as dosing tools for optimizing prophylaxis in patients with severe haemophilia A treated with Octocog alfa
  • 2021
  • In: Haemophilia. - : Wiley. - 1351-8216 .- 1365-2516. ; 27:3, s. 417-424
  • Journal article (peer-reviewed)abstract
    • Introduction: MyPKFiT and the Web-Accessible Population Pharmacokinetic service—Hemophilia (WAPPS-Hemo) are web-based population-based applications developed for helping physicians individualize and optimize replacement therapy. Although MyPKFiT is intended for Octocog alfa and Rurioctocog alfa pegol use only, the WAPPS-Hemo is applicable to all factor VIII concentrates. Aim: To compare MyPKFiT and WAPPS-Hemo as dosing tools for optimizing treatment of patients with severe haemophilia A on regular prophylaxis with Octocog alfa in a real-world setting. Methods: Fourteen patients with severe haemophilia A (median age 30.8 years; range 20–71) were enrolled. The FVIII activity was measured twice after a regular dose of Octocog alfa by the chromogenic and the one-stage assays. PK analyses were performed using each tool and dosing estimations to reach trough levels of 1%, 3% or 5% after 48 h. Findings were calculated and compared. Results: The two PK algorithms yielded similar t½ independent of the type of FVIII assay used. However, there were significant differences in the time to reach 1%, 3% and 5%. The WAPPS-Hemo generated 10–12 h longer time to a trough of 1% and up to 4 h for the troughs of 3% and 5%. Accordingly, the doses estimated by WAPPS-Hemo for a daily regimen were between 28% and 100% of those proposed by MyPKFiT. Conclusions: MyPKFiT and WAPPS-Hemo provided similar half-life estimations for Octocog alfa independent of the FVIII assay used. The doses suggested by WAPPS-Hemo to reach specific troughs were overall lower, which may have implications for treatment optimization.
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14.
  • Arvanitakis, Alexandros, et al. (author)
  • Clinical outcome and adherence rate in Scandinavian patients with intermediate-intensity prophylaxis before and after the switch of standard half-life FVIII products to BAY 81–8973
  • 2022
  • In: Haemophilia. - : Wiley. - 1351-8216 .- 1365-2516. ; 28:2, s. 223-229
  • Journal article (peer-reviewed)abstract
    • Introduction: Treatment optimization in haemophilia A can be achieved by choice of FVIII product and knowledge of pharmacokinetics (PK), phenotype and adherence. A favourable PK profile of BAY 81–8973 (octocog alfa) (Kovaltry, Bayer AB) compared to other standard half-life (SHL) FVIII products has been suggested. Aim: To evaluate whether the switch to BAY 81–8973, using the same dosing schedule, impact factor consumption and bleed rates, taking arthropathy and adherence into account. Methods: Forty patients on prophylaxis with SHL (median age 40.5 years) attending the haemophilia treatment centres in Malmö and Oslo were enrolled. The annualised bleeding rate (ABR) and joint bleeding rate (AJBR) before and after the switch to BAY 81–8973 was calculated. PK analyses were performed with WAPPS-Hemo. Joint health status and treatment adherence were assessed. Results: The median ABR and AJBR was 0 before and after the switch, at both centres. The median yearly factor consumption was 3,345 IU/Kg/year in the entire study group corresponding to intermediate-intensity prophylaxis in most patients and with significantly more used in Malmö (3,862 IU/Kg/year), compared to Oslo (2,337 IU/Kg/year) (P.006). There was no correlation between arthropathy and bleeding. The median BAY 81–8973 t½ was 20 h (range 7.5–29 h), with significant correlation to VWF levels, and 13.4 h after exclusion of VWF outliers. Adherence to treatment was 97%. Conclusions: Concentrate switch, using mainly intermediate-intensity regimens with high adherence rates, preserves excellent prophylaxis outcome using standard half-life FVIII products, indicating the value of individualized prophylaxis and close follow-up.
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15.
  • Arvanitakis, Alexandros, et al. (author)
  • Impact of timing of prophylaxis commencement, F8 genotype and age on factor consumption and health-related quality of life in patients with severe haemophilia A
  • 2023
  • In: Haemophilia. - 1351-8216. ; 29:4, s. 1032-1038
  • Journal article (peer-reviewed)abstract
    • Introduction: The timing of prophylaxis and F8 genotype can impact treatment outcomes in adults with severe haemophilia A (HA). Aim: To investigate how F8 genotype, timing, and type of prophylaxis influence arthropathy, bleeding rates, factor consumption and health-related quality of life (HRQoL). Methods: Thirty-eight patients with severe HA were enrolled. Bleeding events were recorded retrospectively during median 12.5 months. F8 gene variants were classified as null or non-null. Joint health and HRQoL were assessed with HJHS and EQ-5D-5L, respectively. Results: The median age at prophylaxis start was 1.25 years in the primary prophylaxis group (N = 15, median age 26 years) and 31.5 years in the secondary group (N = 22, 45 years), respectively. There were significant differences in the medians of HJHS (4 vs. 20, p <.001), EQ-5D-5L index (0.9647 vs. 0.904, p =.022), EQ VAS (87 vs. 75, p =.01) and FVIII consumption (3883 vs. 2737 IU/kg/year, p =.02), between the primary and secondary groups, respectively. Median annualized bleeding rate (ABR) was 0 for both groups. Twenty-five null and thirteen non-null F8 gene variants were identified. In the secondary prophylaxis group, lower median FVIII consumption (1926 vs. 3370 IU/kg/year) was shown for non-null compared to null variants, respectively, with similar ABR and HJHS. Conclusion: Delayed prophylaxis start with intermediate dose intensity prevents bleeds but at a cost of more arthropathy and reduced HRQoL, compared to higher intensity primary prophylaxis. Non-null F8 genotype may allow lower factor consumption with similar HJHS and bleeding rates, compared to null genotype.
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16.
  • Astermark, Jan, et al. (author)
  • A randomized comparison of bypassing agents in hemophilia complicated by an inhibitor.
  • 2007
  • In: Blood. - : American Society of Hematology. - 1528-0020 .- 0006-4971. ; 109:Sep 21, s. 546-551
  • Journal article (peer-reviewed)abstract
    • The development of inhibitory antibodies to factor VIII is a serious complication of hemophilia. FEIBA (factor VIII inhibitor-bypassing activity), an activated prothrombin complex concentrate (aPCC), and NovoSeven, recombinant factor Vila (rFVIIa), are used as hemostatic bypassing agents in treating patients with inhibitors. The FENOC study was designed to test equivalence of the products in the treatment of ankle, knee, and elbow joint bleeding. A prospective, open-label, randomized, crossover, equivalency design was used. The parameters of interest were the percentage of patients who reported efficacy in response to FEIBA and the percentage that reported efficacy in response to NovoSeven. A difference in these percentages of no more than 15% was determined to be a clinically acceptable magnitude for equivalence of the 2 products. The primary outcome was evaluation 6 hours after treatment. Data for 96 bleeding episodes contributed by 48 participants were analyzed. The criterion for declaring the 2 products equivalent at 6 hours was not met; however, the confidence interval of the difference in percentages of efficacy reported for each product only slightly exceeded the 15% boundary (-11.4%-15.7%), P=.059. FEIBA and NovoSeven appear to exhibit a similar effect on joint bleeds, although the efficacy between products is rated differently by a substantial proportion of patients. This trial was registered at www.clinicaltrials.gov as #NCT00166309.
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17.
  • Astermark, Jan, et al. (author)
  • Anti- and procoagulant activities in factor VII-deficient subjects
  • 2001
  • In: Thrombosis Research. - 1879-2472. ; 101:6, s. 435-440
  • Journal article (peer-reviewed)abstract
    • The clinical feature in patients with congenital factor VII deficiency is in part dependent on the underlying genetic defect, but the mechanisms influencing the genotype-phenotype correlation remain to be fully elucidated. In addition, thromboembolic events have been reported. Compensatory mechanisms involving vitamin K-dependent factors have been suggested. We have measured anticoagulant activities in 25 factor VII-deficient subjects (factor VII activity < or =36%) and 23 age-matched controls and correlated these to the vitamin K-dependent procoagulant activities. Two of the patients had a history of thromboembolism. The factor VII-deficient patients were found to have a significantly lower protein C activity than the controls [0.84 U/ml (95% CI 0.78; 0.89) vs. 0.98 U/ml (95% CI 0.91; 1.05), P=.004]. In addition, the protein C activity was correlated to that of factor VII (r=.36; P=.014), factor IX (r=.45; P=.002) and factor X (r=.50; P=.0006), respectively. The level of prothrombin fragment 1+2 was correlated to the protein C (r=.40; P=.012) and to the factor VII activity (r=.42; P=.011). No differences between patients and controls were seen regarding total and free protein S, antithrombin, plasminogen activator inhibitor-1 (PAI-1) and tissue factor pathway inhibitor (TFPI). Seven of the patients were found to have the Factor V Leiden mutation, but none of them had experienced any thromboembolic event. The present data support the notion that compensatory hemostatic mechanisms might exist in that the protein C activity was found to be decreased in the factor VII-deficient subjects. Whether this could influence the clinical feature, including the risk of thromboembolic events in association with replacement therapy, remains to be evaluated.
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18.
  • Astermark, Jan, et al. (author)
  • Antibodies to factor VIIa in patients with haemophilia and high-responding inhibitors.
  • 2002
  • In: British Journal of Haematology. - : Wiley. - 0007-1048. ; 119:2, s. 342-347
  • Journal article (peer-reviewed)abstract
    • The haemostatic effect of by-passing agents such as activated prothrombin complex concentrates (aPCC) and recombinant factor VIIa is inadequate in some patients with severe haemophilia and high-responding inhibitors. Theoretically, this could be due to antibody reactivity to procoagulant proteins other than the deficient factor. To evaluate this hypothesis, immunoglobulin (Ig) fractions from six multi-transfused patients (three haemophilia A and three haemophilia B) were purified on protein A sepharose and then subjected to immunoaffinity chromatography on factor IX sepharose and factor VIIa sepharose. All three Ig fractions from the haemophilia B patients, but not commercially available Ig, contained antibodies that bound to both gels. None of the haemophilia A patients had antibodies to factor IX but all three had antibodies towards factor VIIa. The immunoaffinity purified antifactor IX and VIIa antibodies from the haemophilia B patients inhibited thrombin formation in vitro using Feiba(R) as active enzyme, but had no significant effect in the presence of NovoSeven(R). In contrast, no inhibitory effect was observed with the antifactor VIIa antibodies from the haemophilia A patients. Cross-reactivity to factor IX was seen for the antifactor VIIa antibodies from the patients with haemophilia B. Our findings show that antibody reactivity to other procoagulant factors such as factor VIIa exists in patients with high-responding inhibitors and that these antibodies may have an inhibitory potential that correlates to the amount of active enzyme present. The characterization of the antibody profile may facilitate an optimal treatment with by-passing agents in severe bleeding events.
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19.
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20.
  • Astermark, Jan, et al. (author)
  • Arandomized comparison of bypassing agents in hemophilia complicated by an inhibitor: the FEIBA NovoSeven Comparative (FENOC) Study.
  • 2009
  • In: Gematologiâ i Transfuziologiâ. - 0234-5730. ; 54:5, s. 35-35
  • Journal article (peer-reviewed)abstract
    • Arandomized comparison of bypassing agents in hemophilia complicated by an inhibitor: the FEIBA NovoSeven Comparative (FENOC) Study. J. Astermark(1), Sh. M. Donfield(2), D. M. DiMichele(3), A. Gringeri(4), S. A. Gilbert(2), J. Waters(2), E. Berntorp(1), for the FENOC Study Group. Department for Hematology and Coagulation Disorders, Malmo, University Hospital, Malmo, Sweden(1); Department of Biostatistics, Rho, Chapel Hill, NC2; Department of Pediatrics, Weill Medical College, Cornell University, New York, NY3; Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, University of Milan, Italy(4). The development of inhibitory antibodies to factor VIII is a serious complication of hemophilia. FEIBA (factor VIII inhibitorbypassing activity), an activated prothrombin complex concentrate (aPCC), and NovoSeven, recombinant factor Vila (rFVIIa), are used as hemostatic bypassing agents in treating patients with inhibitors. The FENOC study was designed to test equivalence of the products in the treatment of ankle, knee, and elbow joint bleeding. A prospective, open-label, randomized, crossover, equivalency design was used. The parameters of interest were the percentage of patients who reported efficacy in response to FEIBA and the percentage that reported efficacy in response to NovoSeven. A difference in these percentages of no more than 15% was determined to be a clinically acceptable magnitude for equivalence of the 2 products. The primary outcome was evaluation 6 hours after treatment. Data for 96 bleeding episodes contributed by 48 participants were analyzed. The criterion for declaring the 2 products equivalent at 6 hours was not met; however, the confidence interval of the difference in percentages of efficacy reported for each product only slightly exceeded the 15% boundary (11.4-15.7%); p = 0.059. FEIBA and NovoSeven appear to exhibit a similar effect on joint bleeds, although the efficacy between products is rated differently by a substantial proportion of patients. This trial was registered at www.clinicaltrials.gov.
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21.
  • Astermark, Jan, et al. (author)
  • Blödarsjuka med HIV. Långsammare infektionsförlopp hos yngre och vid större förbrukning av faktorkoncentrat
  • 1998
  • In: Läkartidningen. - 0023-7205. ; 95:1, s. 48-50
  • Journal article (peer-reviewed)abstract
    • HIV disease progression and the effect of replacement therapy with clotting factor concentrates (CFCs) were studied in 100 Swedish haemophiliacs, mean age at seroconversion 29 years (range, 4-72). On average 16 years after seroconversion, 67 per cent of the patients had CD4+ cell counts of < 200 x 10(6)/l, 50 per cent had developed AIDS, and 58 per cent had died. HIV disease progression was significantly slower in those aged less than 28 (median age) at seroconversion (P = 0.004). Moreover, mortality was inversely correlated to total annual CFC consumption after adjustment for age and HIV-related therapy, i.e., Pneumocystis carinii prophylaxis and antiretroviral drugs (P = 0.014), but unrelated to the purity of the CFCs used. After adjustment for age, annual CFC consumption and HIV-therapy, prophylactic replacement therapy was not associated with significantly better survival than on-demand treatment. It is concluded that in HIV-positive haemophiliacs replacement therapy may have a beneficial effect on the immune system, and that CFC purity and the regimen (prophylaxis vs on-demand) would seem to be factors of minor importance.
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24.
  • Astermark, Jan, et al. (author)
  • Low recurrence rate after deep calf-vein thrombosis with 6 weeks of oral anticoagulation
  • 1998
  • In: Journal of Internal Medicine. - : Wiley. - 1365-2796 .- 0954-6820. ; 244:1, s. 79-82
  • Journal article (peer-reviewed)abstract
    • OBJECTIVES: To evaluate the recurrence rate after deep calf-vein thrombosis treated with 6 weeks of oral anticoagulation. DESIGN AND SUBJECTS: A 2 year follow-up of 126 consecutive patients admitted to the Department of Internal Medicine with venographically verified deep calf-vein thrombosis. RESULTS: One hundred and twenty-six patients were treated with warfarin for 6 weeks, 18 of them having had a previous episode of venous thrombosis (DVT). Eleven patients (8.7%) suffered a recurrent thromboembolic episode within 2 years, four of which were within the first 3 months. Eight of those without a history of DVT had a recurrence (7.4%). Three of these were activated protein C (APC)-resistant, one was protein C-deficient and one had malignant melanoma. Eight patients (6.3%) reported minor haemorrhagic complications, but no major bleeding was seen. CONCLUSION: Our data support the use of a 6 week regimen of secondary oral prophylaxis after a first episode of deep calf-vein thrombosis in patients without a permanent risk factor. Whether individuals with inherited thrombophilia require prolonged treatment remains to be evaluated.
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25.
  • Astermark, Jan, et al. (author)
  • Major surgery seems not to influence HIV disease progression in haemophilia patients
  • 1998
  • In: British Journal of Haematology. - : Wiley. - 0007-1048. ; 103:1, s. 10-14
  • Journal article (peer-reviewed)abstract
    • The influence of major surgery on HIV disease progression and decline in CD4+ cell count was evaluated in 23 seropositive haemophilia patients. 24 HIV-infected patients served as non-operated controls. In addition, 32 age-matched seronegative subjects were included. The follow-up time was up to 5 years. During the course of the study, eight of the operated (35%) and 11 of the non-operated (48%) subjects developed HIV-related symptoms (P=0.267). The relative risk for developing HIV-related symptoms after surgery was 0.60 (95% CI 0.25; 1.48). A significant decline in CD4+ cell counts was observed in both the surgery (4.0 x 10(6)/l/month, 95% CI 2.0; 6.0 x 10(6), P=0.001) and the non-surgery (4.0 x 10(6)/l/month, 95% CI 2.0; 6.0 x 10(6), P=0.004) seropositive subgroup, but no difference between the two subgroups was seen (P=0.793). HIV (6.0 x 10(6)/l/month, 95% CI 2.1; 9.9 x 10(6), P=0.0005) but not surgery (-1.0 x 10(6)/l/ month, 95% CI -3.0; 0.96 x 10(6), P=0.647) was an independent predictor for the decline in CD34+ cell count. No interaction effect was observed between HIV infection and surgery (P=0.361). The annual amount of factor concentrate used for regular replacement therapy did not influence the decline in CD4+ cell count (P=0.492). We conclude that major surgery may be considered in symptom-free HIV-seropositive haemophilia patients, with CD4+ cell counts > or = 0.20 x 10(9)/l under similar premises as for seronegative subjects.
  •  
26.
  • Astermark, Jan, et al. (author)
  • Malmo International Brother Study (MIBS): an international survey of brother pairs with haemophilia
  • 1999
  • In: Vox Sanguinis. - 1423-0410. ; 77:Suppl. 1, s. 80-82
  • Journal article (peer-reviewed)abstract
    • Malmo International Brother Study (MIBS) was initiated in 1996 in order to set up an international registry of twins and non-twin brothers with haemophilia and to search for genetic and compound factors predisposing for inhibitor development. As of July, 1997, 178 brother pairs are registered (143 haemophilia A and 35 haemophilia B patients). Sixteen of these pairs are twins. In 48 of the brother pairs (27%) there is a history of inhibitors, in 25 of them involving only one of the brothers. Immune tolerance induction has been attempted in 13 brother pairs (27%) and in four pairs the inhibitor has been eradicated. Additional demographic data need to be collected and, if possible plasma, IgG and DNA samples will be taken from inhibitor patients to serve as a tool for basic inhibitor experiments.
  •  
27.
  • Astermark, Jan, et al. (author)
  • No effect of a new second-generation B-domain-deleted recombinant product on lymphocyte transformation in vitro: a study of plasma-derived and recombinant products
  • 1997
  • In: British Journal of Haematology. - : Wiley. - 0007-1048 .- 1365-2141. ; 99:2, s. 289-294
  • Journal article (peer-reviewed)abstract
    • Immunomodulatory effects of various factor VIII and factor IX clotting factor concentrates (CFCs) and of albumin were evaluated by a sensitive assay measuring the incorporation of 3H-thymidine in phytohaemagglutinin-stimulated lymphocytes in the presence of monodansylthiacadaverine. In contrast to previous findings by others, we found lymphocyte transformation to be inhibited by all plasma-derived factor VIII concentrates at concentrations of 0.02, 0.2 and 2.0 IU/ml, including those purified by monoclonal antibodies (P < 0.05). Kryobulin TIM3 had the most pronounced effect. In addition, three plasma-derived human albumin preparations exerted a similar inhibitory effect as the factor VIII concentrates, whereas the corresponding plasma-derived factor IX concentrates only manifested minor immunomodulatory effects. Of the recombinant preparations, only Recombinate exerted an inhibitory effect at 0.02 and 0.2 IU/ml, whereas both Kogenate and Recombinate decreased 3H-thymidine incorporation at 2.0 IU/ml (P = 0.01). No immunomodulatory effect at all was observed with r-VIII SQ, a new B-domain-deleted recombinant factor VIII preparation free from added albumin. The significance of this finding regarding immunological side-effects including inhibitor development remains to be evaluated, but this second-generation recombinant product opens up new and interesting perspectives yet to be explored.
  •  
28.
  •  
29.
  • Astermark, Jan, et al. (author)
  • Polymorphisms in the IL-10 but not in the IL-1{beta} and IL-4 genes are associated with inhibitor development in patients with hemophilia A.
  • 2006
  • In: Blood. - : American Society of Hematology. - 1528-0020 .- 0006-4971. ; 107:8, s. 3167-3172
  • Journal article (peer-reviewed)abstract
    • The aim of the Malmö International Brother Study (MIBS) is to evaluate host genetic factors associated with the development of inhibitory antibodies in patients with hemophilia. Factor VIII gene mutations and genetic polymorphisms of the IL1beta, IL4, and 100 genes, known to influence antibody production in autoimmune diseases, were analyzed in 164 patients (124 with severe, 26 with moderate, and 14 with mild disease) in 78 unrelated families with hemophilia A. Seventy-seven (47%) patients in 54 families had a history of inhibitors (57 high responding, 20 low responding). Inversions were found in 36 families (75 patients). There was no association between the development of inhibitor and the IL1beta Taql RFLP alleles in exon 5 or the -590 C/T single nucleotide polymorphism (SNP) in the promoter region of IL4. There was, however, a strong association between an allele with 134 bp in one of the CA repeat microsatellites, IL10G, located in the promoter region of the IL10 gene, and the development of inhibitor (odds ratio [OR], 4.4; 95% confidence interval [95% CI], 2.1-9.5; P < .001). The association was consistent in the subgroup of families with severe hemophilia and inversions. IL10 is the first gene located outside the causative factor VIII gene mutation to be associated with inhibitor development.
  •  
30.
  • Astermark, Jan, et al. (author)
  • Polymorphisms in the TNFA gene and the risk of inhibitor development in patients with hemophilia A.
  • 2006
  • In: Blood. - : American Society of Hematology. - 1528-0020 .- 0006-4971. ; 108:12, s. 3739-3745
  • Journal article (peer-reviewed)abstract
    • The HLA class I/II alleles and the tumor necrosis factor alpha (TNFA) locus are closely linked in the MHC complex. We have characterized the causative factor VIII mutation, HLA alleles as well as 4 polymorphisms (-827C > T, -308G > A, -238A > G, and 670A > G) in the TNFA gene in 164 patients (124 severe, 26 moderate, and 14 mild) in 78 families with hemophilia A enrolled in the Malmo International Brother Study (MIBS). Inhibitors were identified in 77.8% of patients with a single haplotype (Hap 2) and 72.7% of the patients with the TNFA -308 A/A genotype within this haplotype compared with 39.70/6 for TNFA -308 G/G patients and 46.9% for TNFA -308 G/A heterozygotes (OR 4.0; 95% CI, 1.4-11.5; P = .008). The association between the -308 A/A genotype and inhibitors was enhanced in subgroups of patients with severe hemophilia (OR 19.2; 95% CI 2.4-156.5; P < .001) and with inversions (n = 75; OR, 11.8; 95% CI, 1.3-105.1; P = .013). Associations were found for the HLA A26 and B44 alleles, but these were not consistent in the subgroup analysis. Our data imply that the TNFA -308G > A polymorphism within Hap 2 is a useful marker and potential modulator of the immune response to replacement therapy in patients with hemophilia.
  •  
31.
  • Astermark, Jan, et al. (author)
  • Primary prophylaxis in severe haemophilia should be started at an early age but can be individualized
  • 1999
  • In: British Journal of Haematology. - : Wiley. - 0007-1048. ; 105:4, s. 1109-1113
  • Journal article (peer-reviewed)abstract
    • The frequency of joint bleeds and orthopaedic joint scores were evaluated in 121 patients with severe haemophilia who had started prophylactic treatment with clotting factor concentrates at least once weekly before the age of 10. 75 of the patients started before the age of 3, 31 at the age of 3-5 and 15 at the age of 6-9. Each subgroup was evaluated separately. In addition, a regimen of one infusion weekly was compared with that of two (haemophilia B) or three (haemophilia A) infusions weekly in each patient. A significant decrease in the overall number of joint bleeds per year was found after shortening the infusion interval (P<0.005), but the individual bleeding pattern varied. In survival analysis of the first pathologic joint score event, those who started prophylaxis before the age of 3 had a better outcome overall than those starting at later ages (P=0.001). However, in subgroup analysis, no significant difference was seen in the annual number of joint bleeds and the development of arthropathy between those starting with, or shifting to, the more intensive regimen before the age of 3 and those that were put on this regimen at the age of 3-5. Age at start of prophylaxis was found to be an independent predictor for the development of arthropathy (P=0.0002), whereas dose and infusion interval at start were not. Our data emphasize the importance of starting replacement therapy during the first years of life. However, it seems that when beginning the regimen it can be individualized and adjusted according to the bleeding pattern. In this way, the need for a venous access system may be assessed on an individual basis.
  •  
32.
  • Astermark, Jan, et al. (author)
  • The B-Natural study—The outcome of immune tolerance induction therapy in patients with severe haemophilia B
  • 2021
  • In: Haemophilia. - : Wiley. - 1351-8216 .- 1365-2516. ; 27:5, s. 802-813
  • Journal article (peer-reviewed)abstract
    • Introduction: Inhibitors develop less frequently in haemophilia B (HB) than haemophilia A (HA). However, when present, the success of tolerization by immune tolerance induction (ITI) therapy is lower and the risk of complications higher. Aim: To evaluate the use and outcome of ITI in patients with HB and inhibitors. Methods: Subjects include singletons or siblings with a current/history of inhibitors enrolled in B-Natural—an observational study designed to increase understanding of clinical management of patients with HB. Patients were followed for 6 months and information on demographics, medical and social history, and treatment were recorded. Results: Twenty-nine patients with severe HB and inhibitors were enrolled in 24 centres. Twenty-two underwent one or more courses of ITI with or without immune suppression. Eight patients (36.4%) were successfully tolerized after the first course of ITI. One of these successes (12.5%) experienced allergic manifestations, whereas the corresponding number for the 10 treatment failures was five (50%). One of seven (14.2%) patients with large deletions and three of eight (37.5%) with nonsense mutations were tolerized at the first attempt, and all patients experiencing nephrosis either failed or were on-going. At study end, 11 (50%) were considered successfully tolerized after one or more ITI courses, three were unsuccessful, and eight were still undergoing treatment. Conclusion: Our data underscore the possibilities and difficulties of achieving tolerization in patients with HB with inhibitors. The type of mutation and complications appear to correlate with ITI outcome, but more accurate definitions of successful ITI are warranted.
  •  
33.
  • Astermark, Jan, et al. (author)
  • The Malmo International Brother Study (MIBS): further support for genetic predisposition to inhibitor development in hemophilia patients
  • 2001
  • In: Haemophilia. - : Wiley. - 1351-8216. ; 7:3, s. 267-272
  • Journal article (peer-reviewed)abstract
    • The issue of factors predisposing for inhibitor development in haemophilia patients is still largely unresolved. In an attempt to address this problem, we initiated a registry in 1996 of siblings with haemophilia and with or without a history of inhibitors. Four hundred and sixty families have accrued, of whom 388 suffer from haemophilia A and 72 haemophilia B. Twenty-five of the brother pairs are twins. The inhibitor incidence in all families with severe haemophilia A was 31.7%. The corresponding figure in the caucasian patients was 27.4%, whereas a higher incidence of inhibitors was reported in the black subjects (55.6%). Twins were reported in six of the 100 inhibitor families, for whom monozygocity was confirmed in three cases. In 32 families (32%), at least two brothers had a history of inhibitors. In 22 (69%) of these families, the inhibitor was also of the same type, i.e. either high- or low-responding. The overall concordance within the severe haemophilia A families was found to be 78.3% (195/249) compared to an expected figure of 68.0% and 58.0% using an inhibitor incidence of 20 and 30%, respectively (P < 0.0001). The corresponding figure for the twins was 88.2% (15/17). Moreover, the risk for inhibitor development in families with a previous inhibitor history was found to be 48% (95% confidence interval [CI] 35-62%), whereas the risk in families with no previous known inhibitor was only 15% (95% CI 11-21%) corresponding to a relative risk of 3.2 (95% CI 2.1-4.9). Immune-tolerance induction was reported in 24 families, of whom 13 siblings were successfully treated. Our data clearly support the concept that a genetic predisposition for inhibitor development exists. However, the markers of this predisposition remain to be elucidated and we believe that the MIBS registry will be useful for this purpose.
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34.
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35.
  • Astermark, Jan, et al. (author)
  • The polygenic nature of inhibitors in hemophilia A: results from the Hemophilia Inhibitor Genetics Study (HIGS) Combined Cohort.
  • 2013
  • In: Blood. - : American Society of Hematology. - 1528-0020 .- 0006-4971. ; 121:8, s. 1446-1454
  • Journal article (peer-reviewed)abstract
    • Studies of determinants of development of inhibitory antibodies to factor VIII in people with hemophilia A indicate a complex process involving multiple factors. The Hemophilia Inhibitor Genetics Study Combined Cohort was formed to extend understanding of the genetic background of risk. The study group contains 833 subjects from three independent cohorts: brother pairs and singletons with and without a history of inhibitors, as well as 104 brother pairs discordant for inhibitor status. Using an Illumina iSelect platform, 13,331 SNPs from 1,081 genes, primarily immune response and immune modifier genes, were typed. Each cohort was analyzed separately with results combined using a meta-analytic technique. After adjustment for potential confounders, 53 SNPs were significant predictors of inhibitor status using the criteria of odds ratios (OR) in the same direction in all cohorts, or allowing for a 20% interval around an OR of 1 in one of the three, and significant in at least two. Of the 53, 13 markers had meta p-values of <0.001. Eight of the 53 were significant predictors among the discordant pairs. Results support the complexity of the immune response, and encourage further research with the goal of understanding the pathways involved.
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36.
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37.
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38.
  • Berntorp, Erik, et al. (author)
  • A prospective registry of European haemophilia B patients receiving nonacog alfa, recombinant human factor IX, for usual use.
  • 2012
  • In: Haemophilia. - : Wiley. - 1351-8216. ; 18:4, s. 503-509
  • Journal article (peer-reviewed)abstract
    • Summary. Nonacog alfa, a recombinant factor IX (FIX) used for the treatment of haemophilia B, was approved in Europe in 1998. In accordance with European Medicines Agency requirements, a registry study was conducted from 2002 to 2009. A reformulated iso-osmotic version was approved for European use in 2007. This study was conducted to evaluate the safety of nonacog alfa in a usual care setting, and provide clinical trial and postmarketing surveillance data support. This open-label, non-interventional, prospective observational cohort study (registry) comprised 52 sites in nine European countries. Patients with haemophilia B receiving nonacog alfa in either formulation for prevention or treatment were followed on a usual care schedule. A total of 218 patients were enrolled, of whom 66 (30.3%) were <18 years of age. Haemophilia severity was evenly distributed, with baseline FIX activity of <1%, 1-5% and >5% in 33.3%, 36.6% and 30.1% of patients, respectively. One hundred thirty-eight patients received the original formulation alone; 80 switched to or received only the new formulation. There was a low incidence of events of special interest (ESIs), with less-than-expected therapeutic effect in five patients (2.2%), inhibitor development in two (0.9%), thrombosis in one (0.5%) and allergic events in eight (3.7%). These accounted for the majority of the 15 serious AEs reported in six patients. Six patients discontinued because of AEs, primarily related to hypersensitivity. Nonacog alfa was shown to be safe for the treatment of haemophilia B, with a low incidence of serious AEs and ESIs.
  •  
39.
  • Berntorp, Erik, et al. (author)
  • A retrospective study of Octaplex in the treatment of bleeding in patients with haemophilia A complicated by inhibitors.
  • 2010
  • In: Blood Coagulation and Fibrinolysis. - 1473-5733. ; 21, s. 577-583
  • Journal article (peer-reviewed)abstract
    • The nonactivated prothrombin complex concentrate (PCC) Octaplex (Octapharma PPGmbH, Vienna, Austria) has been used successfully for the treatment of congenital and acquired coagulation factor deficiencies and associated bleeding. The aims of this study were to assess retrospectively whether Octaplex is an effective treatment option for haemophilia A patients with high-titre inhibitors of factor VIII (FVIII) and to investigate the impact of Octaplex on thrombin generation in vitro and ex vivo. Retrospective data were collected from 15 haemophilia A patients with FVIII inhibitors who had been treated with Octaplex. Mild bleeds were treated for a median of 1 day with a median dose of 77 IU/kg and moderate bleeds for 3 days with 57 IU/kg. The physician's overall satisfaction with Octaplex, taking into account efficacy, safety and cost in comparison with other treatment options, was assessed for each bleed. The overall rating was good, very good or excellent for 29 of 41 (71%) bleeds. No adverse drug reactions were reported. In in-vitro studies of thrombin generation with normal plasma samples, experimental inhibition of FVIII activity prolonged the lag phase, diminished the peak thrombin concentration and decreased the area under the concentration-time curve, as expected. Marked improvement in thrombin generation parameters was achieved by adding 0.5-3 IU factor IX/ml PCC into the samples. The same held true when using plasma samples from haemophilia A patients with FVIII inhibitors. These results demonstrate that Octaplex overcomes inhibition of FVIII in in-vitro and ex-vivo assays of thrombin generation, and that Octaplex is an effective treatment option for haemophilia A patients with FVIII inhibitors.
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40.
  • Berntorp, Erik, et al. (author)
  • A systematic overview of the first pasteurised VWF/FVIII medicinal product, Haemate P/ Humate -P: history and clinical performance.
  • 2008
  • In: European Journal of Haematology. Supplementum. - : Wiley. - 0902-4506 .- 0902-4441 .- 1600-0609. ; 80:s70, s. 3-35
  • Research review (peer-reviewed)abstract
    • Patients with von Willebrand disease (VWD) and haemophilia A (HA) lack, to varying degrees, the von Willebrand factor (VWF) and coagulation factor VIII (FVIII) that are critical for normal haemostasis. These conditions in turn make patients prone to uncontrolled bleeding. Historically, patients with severe forms of VWD or HA were crippled before adulthood and their life expectancy was significantly reduced. Over the past decades, specific coagulation factor replacement therapies including Haemate P, have been developed to help patients achieve and maintain normal haemostasis. Haemate P is a human, plasma-derived VWF/FVIII medicinal product, which was first licensed in Germany in 1981 for the treatment of HA-associated bleeding. It has since then come to be accepted as the gold standard for both the treatment and prophylaxis of bleeding in VWD, especially in cases where desmopressin [1-deamino-8-D-arginine vasopressin (DDAVP)] has been ineffective. Haemate P was the first effectively virus-inactivated (pasteurisation: 60 degrees C for 10 h in aqueous solution) FVIII product, whereby the risk of potentially threatening infective complications of plasma-derived products was reduced. Haemate P was also shown to have a VWF multimer profile remarkably close to that of normal plasma. This bibliographic review presents previously unpublished clinical data of Haemate P, based upon internal clinical study reports of the proprietor, CSL Behring, in addition to data already presented in other publications. The data demonstrate a predictable and well-characterised pharmacokinetic profile, and a proven record of short- and long-term safety, while effectively correcting the haemostatic defects in VWD and HA. Recently available data have also shown Haemate P to be of haemostatic value in exceptional clinical circumstances including surgical interventions. By virtue of its plasma-derived combination of VWF and FVIII, in addition to its high VWF:FVIII content ratio (2.4:1), Haemate P is also associated with successful immune tolerance induction in those patients developing inhibitor antibodies. Although the theoretical risk of thromboembolic complications does exist while receiving Haemate P, as it does with any FVIII replacement therapy, the incidence of such complications has remained notably low. Given the robust data that have accumulated for the use of Haemate P, dosing recommendations are also described in this review; the recommendations are tailored to patient-specific contexts including baseline VWF and FVIII levels in plasma and the type of surgical intervention being undertaken. A wide variety of studies have also provided data on paediatric and geriatric populations, all of which have suggested that Haemate P can be safely and effectively used in a wide variety of clinical circumstances.
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41.
  • Berntorp, Erik, et al. (author)
  • Advancing personalized care in hemophilia A: ten years' experience with an advanced category antihemophilic factor prepared using a plasma/albumin-free method.
  • 2014
  • In: Biologics : targets & therapy. - 1177-5475. ; 8:Apr 5, s. 115-127
  • Research review (peer-reviewed)abstract
    • Detailed analysis of data from studies of recombinant antihemophilic factor produced using a plasma/albumin-free method (rAHF-PFM) in previously treated patients showed a substantial level of interpatient variation in pharmacokinetics (PKs), factor VIII dosing, and annualized bleed rate (ABR), suggesting that individual patient characteristics contributed to outcome. For example, plasma half-life (t1/2), recovery, and clearance appeared to differ between patients aged <6 years and 10-65 years. Prophylaxis resulted in lower ABRs than episodic treatment in both age groups; better adherence to the prophylactic regimen resulted in a lower ABR in patients aged 10-65 years. The weekly frequency of dosing and adherence to dosing were both significantly and inversely related to the rate of bleeding (young children, P<0.0001 for both all bleeds and joint bleeds; older patients, P<0.0001 for all bleeds and P<0.05 for joint bleeds), as was adherence to dosing frequency (P<0.0001 for all comparisons). A post-marketing randomized study of prophylaxis demonstrated that a PK-guided dosing regimen, based on an individual patient's rAHF-PFM PK (infusion interval, estimated t1/2, and recovery), was as effective as standard prophylaxis and that both prophylactic regimens were superior to episodic treatment with respect to ABR and quality of life measures. Thus, compared with standard prophylaxis, the PK-guided regimen achieved comparable efficacy with fewer weekly infusions. A two-compartment population PK model describes the PK data across the entire age range and forms the basis for future PK-guided therapy with rAHF-PFM. The model confirmed a shorter t1/2 and faster clearance of rAHF-PFM in children <6 years of age versus patients ≥10 years and predicted similar PK parameters with either a full or reduced blood sampling schedule, offering the potential for the use of PK-guided, individualized treatment in the routine clinical care setting.
  •  
42.
  • Berntorp, Erik, et al. (author)
  • An approach to study the viral safety of plasma-derived products in previously treated, non-infected patients
  • 2001
  • In: Haemophilia. - : Wiley. - 1351-8216 .- 1365-2516. ; 7:4, s. 360-363
  • Journal article (peer-reviewed)abstract
    • Using the polymerase chain reaction (PCR), we designed a study concept to evaluate the safety of plasma derivatives in previously treated patients who are non-infected by the specific viruses studied. Several product lots can be studied in a single patient, with a study period for each lot of 3 months. In the present study 19 patients were included for treatment with Baxter Hyland Immuno's PCR-screened factor VIII concentrate Immunate (n=7), factor IX concentrate Immunine (n=10), the by-passing agent FEIBA plus Immunine (n=1), and the protein C concentrate Ceprotin (n=1). PCR testing for hepatitis B, C or HIV genomic material in patient samples was done as well as serological testing. All patients remained negative for the tested markers. All seven Immunate patients completed three treatment periods with three different lots of the study drug. The median study period was 282 days and the median dose 115 000 units, with a median of 115 exposure days. Five of the 10 Immunine patients completed three treatment periods and four patients, two treatment periods. One Immunine patient was discontinued from the study for reasons unrelated to the study drug administration. The median study period was 305 days and the median total dose 82 200 units, with a median of 88 exposure days. Our study presents a new design to approach the evaluation of viral safety of new plasma derivatives in previously treated, non-infected patients (NIPs) and offers several advantages over the currently recommended studies using testing for serological markers of infection in previously untreated patients (PUPs).
  •  
43.
  • Berntorp, Erik, et al. (author)
  • Centraliserad vård grundläggande i vårdprogram för blödarsjuka
  • 1999
  • In: Läkartidningen. - 0023-7205. ; 96:15, s. 1849-1852
  • Journal article (peer-reviewed)abstract
    • Haemophilia is a rare and potentially life-threatening disease. In Sweden, with a population of approximately 8.5 million, about 350 people suffer from the more severe forms of haemophilia or von Willebrand disease. Meticulous management is important if the patients are to be spared chronic disability and serious treatment complications. The disease is lifelong and affects psychosocial aspects of life among patients and their families. With the help of a grant from the Swedish Board of Halth and Welfare, a care programme has been designed to guarantee Swedish haemophiliacs comparable and optimal care. The programme has been drawn up by representatives of the three haemophilia centres in Sweden (at University Hospital, Malmo, Sahlgrenska University Hospital, Gothenburg, and Karolinska Hospital, Stockholm) in co-operation with the World Federation of National Haemophilia Organisations. To ensure optimal individual application of the programme, individualised management strategies and patient information leaflets have been prepared.
  •  
44.
  • Berntorp, Erik, et al. (author)
  • Comorbidities and inhibitors in adult patients with haemophilia: issues, costs and management strategies.
  • 2015
  • In: European Journal of Haematology. - : Wiley. - 1600-0609 .- 0902-4441. ; 95, s. 1-15
  • Research review (peer-reviewed)abstract
    • Along with greater life expectancy in patients with haemophilia has been an increase in associated haemophilia-related (arthropathy, osteoporosis, viral infections) and age-related (cardiovascular disease, renal disease, cancer and others) comorbidities, many of which are only just emerging as the population ages. At present, experience in managing these comorbidities is limited. As the demographic shift continues, haemophilia care centres can expect to encounter more patients with greater levels of complexity. In the absence of evidence-based information to guide the management of adult patients with haemophilia, it is important that the scientific position be reviewed on a regular basis. To this end, several topics relevant to the clinical management of adult patients with haemophilia were examined in a symposium entitled Comorbidities and inhibitors in adult patients with haemophilia: issues, costs and management strategies held on 11 February 2015 in Helsinki, Finland, in conjunction with the 8th Annual Congress of the European Association for Haemophilia and Allied Disorders. This article is a summary of that event.
  •  
45.
  • Berntorp, Erik, et al. (author)
  • Consensus perspectives on prophylactic therapy for haemophilia: summary statement.
  • 2003
  • In: Haemophilia. - : Wiley. - 1351-8216. ; 9:Suppl 1, s. 41278-41278
  • Journal article (peer-reviewed)abstract
    • Participants in an international conference on prophylactic therapy for severe haemophilia developed a consensus summary of the findings and conclusions of the conference. In the consensus, participants agreed upon revised definitions for primary and secondary prophylaxis and also made recommendations concerning the need for an international system of pharmacovigilance. Considerations on starting prophylaxis, monitoring outcomes, and individualizing treatment regimens were discussed. Several research questions were identified as needing further investigation, including when to start and when to stop prophylaxis, optimal dosing and dose interval, and methods for assessment of long-term treatment effects. Such studies should include carefully defined cohorts, validated orthopaedic and quality-of-life assessment instruments, and cost-benefit analyses.
  •  
46.
  • Berntorp, Erik (author)
  • Differential response to bypassing agents complicates treatment in patients with haemophilia and inhibitors.
  • 2009
  • In: Haemophilia. - : Wiley. - 1351-8216 .- 1365-2516. ; 15, s. 41343-41343
  • Journal article (peer-reviewed)abstract
    • Summary. The bypassing agents factor eight inhibitor bypassing activity (FEIBA) anti-inhibitor coagulant complex and recombinant activated factor VII (rFVIIa) have been established as safe and effective therapies for treating bleeding episodes in haemophilia patients with inhibitors. However, the efficacy of each bypassing agent can vary, and neither agent is universally effective. The reasons for such variability have yet to be confirmed, but may involve patient-specific factors and the mechanisms of action (MOAs) and pharmacokinetic profiles of these two agents. This issue underscores the necessity of both products in the comprehensive care of patients with haemophilia and inhibitors. The objective of this review is to discuss the evidence of a differential haemostatic response to bypassing agents and the potential roles of MOA and patient-specific factors in contributing to the differences in response.
  •  
47.
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48.
  • Berntorp, Erik (author)
  • Erik von Willebrand.
  • 2007
  • In: Thrombosis Research. - : Elsevier BV. - 1879-2472 .- 0049-3848. ; 120, s. 3-4
  • Journal article (peer-reviewed)
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49.
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50.
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