Comprehensive laboratory assessment of lonoctocog alfa versus octocog alfa in severe haemophilia A.

INTRODUCTION: Lonoctocog alfa is a single-chain factor VIII (FVIII) molecule with high binding affinity to von-Willebrand-factor. While it is well known that its plasma activity is underestimated by one-stage clotting assays (OSCA), there is a lack of knowledge on the post-infusion performance of lonoctocog alfa in global coagulation assays or its potential impact on the haemostatic balance in vivo. AIM: To characterize lonoctocog alfa versus octocog alfa in pre- and post-infusion samples obtained from patients undergoing repeated investigation of incremental recovery (IR). METHODS: Eighteen patients with severe haemophilia A (lonoctocog alfa: 10, octocog alfa: 8) were included. A panel of factor-specific and global coagulation assays was applied, comprising a FVIII OSCA, two FVIII chromogenic substrate assays (CSA), rotational thrombelastography and thrombin generation (TG). Potential activation of coagulation was assessed by measuring plasma thrombin markers and levels of activated protein C. RESULTS: Comparable IRs were found for lonoctocog alfa and octocog alfa (2.36 [IU/dL]/[IU/kg] vs. 2.55 [IU/dL]/[IU/kg], respectively). Lonoctocog alfa activities were found to be underestimated by the FVIII OSCA while also the two FVIII CSAs showed statistically significant assay discrepancies on lonoctocog alfa. Effects of both FVIII products on rotational thrombelastography were less distinct than those on TG parameters. No elevated pre- or significantly shifting post-infusion plasma levels of coagulation biomarkers were detected. CONCLUSION: Lonoctocog alfa and octocog alfa showed comparable recovery and safety in vivo as well as similar impacts on TG in vitro. Observed assay discrepancies on lonoctocog alfa demonstrated variability of results also between different FVIII CSAs.

Determination of body composition by dual x-ray absorptiometry in persons with haemophilia.

BACKGROUND: There is limited research on body composition in persons with haemophilia (PwH). The literature describes an increased body fat distribution and decreased lean mass in PwH compared to healthy controls using bioimpedance analysis. Using dual x-ray absorptiometry (DXA), which is known to be the most accurate method, this investigation aims to postulate reference data for body composition parameters within haemophilia severity phenotypes and age groups. METHODS: Persons underwent whole body DXA screening using Horizon. Body fat percentage, estimated visceral adipose tissue (VAT), appendicular fat and lean mass, and lean and fat mass in relation to body height were assessed. Haemophilia severity and five age groups were distinguished. RESULTS: Two hundred and one persons with mild (n = 44), moderate (n = 41), or severe (n = 116) haemophilia A/B (median age 40 [28-55; 1.IQ-3.IQ] years) were analysed. The median body fat percentage was 28.7% [25.5%-33.9%] and median estimated VAT was 657 g [403-954 g] with no significant difference between severity phenotypes (p = .474; p = .781). Persons with severe haemophilia had less lean mass compared to moderate and mild haemophilia (p = .013; p = .034). Total and appendicular fat is increased in older PwH (aged ≥40 years) compared to younger PwH (aged ≤29 years; p < .05). Lean mass did not differ between age groups. CONCLUSION: This study provides valuable reference data for body composition parameters in PwH. Persons with severe haemophilia show significantly less lean mass compared to persons with moderate or mild haemophilia. Body fat percentage and VAT did not differ between severity phenotypes, but increased with age.

Physical activity and factor VIII levels in patients with haemophilia: A real-world prospective observational study.

INTRODUCTION: Regular physical activity (PA) is recommended for patients with haemophilia (PwH). For PwH it is crucial to ensure a sufficient factor level to prevent PA-induced bleedings. However, there is a gap in the literature dealing with specific factor levels, which are needed when performing specific types of PA. AIM: To provide data on factor VIII (FVIII) levels at the start of PA performed by PwH. METHODS: In this prospective 12-month real-world observational study, 23 PwH recorded every PA they performed and the FVIII levels at the start of the PA using a pharmacokinetic application. PA types were clustered according to the collision and injury risk into three categories (Cat I = low, Cat II = medium, Cat III = high risk). Haemophilia Joint Health Scores (HJHS) were performed at baseline, after 6 and 12 months. RESULTS: 795 PA sessions of Cat I, 193 of Cat II, and 23 of Cat III were documented. FVIII levels at the start of PA were different between categories (Cat I: 29.8 ± 32.1%, Cat II: 38.3 ± 33.4%, Cat III: 86.6 ± 29.2%). Out of all PA sessions, 145 (14%) were performed at a factor level of ≤3%. Three PA-induced bleeding occurred. Baseline HJHS was 14.5 ± 13.6 points and did not change throughout the study. CONCLUSION: This study provides real-life data on FVIII levels at the start of 1011 PA sessions. PwH are mainly active in low-risk sports with higher FVIII levels observed in Cat II and III, respectively. Only three PA-induced bleeding occurred, even though several PA were started with low FVIII levels.

Changes of static and dynamic spine alignment in patients with severe haemophilia.

INTRODUCTION: Haemophilic arthropathy results in a restricted range of motion and pain that often affects gait. The effect of these gait changes on spinal posture has not been studied. AIM: To evaluate whether the altered joint situation in patients with haemophilia (PwH) leads to compensatory mechanisms evident in the trunk and spine, considering static and dynamic conditions. METHODS: PwH and healthy controls (20-65 years) were examined using rasterstereography in a controlled cohort study. Analysis was performed in static and dynamic conditions in regard to gait phases. Joint status was determined using the Haemophilia Joint Health Score (HJHS). RESULTS: Static measurements showed no group differences in PwH (n = 40) compared to healthy controls (n = 40) except pelvic torsion (median [25%-quartile;75%-quartile]: -1.9[-3.2;.9]° vs. .5[-1.1;1.9]°; P = .007). In contrast, under dynamic conditions PwH showed significantly higher trunk inclination and lower apex lumbar lordosis in all gait phases. Additionally, pelvic torsion was increased in mid stance and terminal swing. Considering joint status, PwH had a higher global HJHS (23.5[13.0;30.0] vs. 3.0[1.0;5.0]; P<.001). A significant moderate correlation was shown between the HJHS mobility score and spine parameters (r = .228-.588; P<.05). CONCLUSION: Degenerative joint changes in PwH lead to altered spine posture during gait. A reason could be the reduced mobility in the affected joint. Changes in spinal and pelvic posture lead to higher structural burdens; therefore, clinicians should focus on posture of spinal column during gait in daily treatment.

Quality of electronic treatment records and adherence to prophylaxis in haemophilia and von Willebrand disease: Systematic assessments from an electronic diary.

INTRODUCTION: HaemoassistTM 2 is an electronic system designed for people with bleeding disorders and their physicians to record prophylactic infusions and treatment of bleeds. It aims to improve adherence by permitting reminders and accuracy of documentation by facilitating real-time reporting. AIM: To assess documentation quality and adherence to prophylactic regimens in patients with haemophilia A, haemophilia B or von Willebrand disease who are using HaemoassistTM 2. METHODS: Ten centres enrolled consecutive patients, who had been using HaemoassistTM 2 for ≥ 3 months (Cohort 1, 'quality of documentation'). Of these, patients who had a specified prophylactic regimen in HaemoassistTM 2 for ≥ 3 months were eligible for inclusion in Cohort 2 ('adherence to prophylaxis'). RESULTS: Cohort 1 comprised 796 patients (71% with severe haemophilia A; median 20.5 months of HaemoassistTM 2 use). The most common method of documentation for patients was using the mobile app; the median time between infusion and documentation was 4 hours using the app, compared with 85 hours using a web portal on a stationery device. The median total annualised number of infusions was consistent in the first and last 3 months of documentation (128; IQR: 70-184 and 120; IQR 64-176, respectively). Cohort 2 comprised 202 patients (79% severe haemophilia A; median of 13 months on prophylactic regimen in HaemoassistTM 2). The rate of adherence to prophylaxis was 83%; median deviation between planned and actual infusion time was ± 2 hours. CONCLUSION: HaemoassistTM 2 was used consistently over prolonged periods of time and allowed for precise analysis of adherence to prophylaxis.

Value and risk of laparoscopic surgery in hemophiliacs-experiences from a tertiary referral center for hemorrhagic diatheses.

PURPOSE: Laparoscopic surgery (LS) is gaining popularity worldwide because of benefits like faster recovery, earlier hospital discharge, and better cosmetic results. In hemophiliacs, surgery in general harbors an increased risk for severe complications. Whether LS or conventional surgery (CS) should be recommended in these patients is controversial and therefore the issue of our present study. METHODS: We performed a retrospective matched-pair analysis including laparoscopically operated non-hemophiliacs (LONH), laparoscopically operated hemophiliacs (LOH), and conventionally operated hemophiliacs (COH) concerning duration of surgery, drainages, hospital stay, complications, factor use (VIII, IX, and X), and blood values. Mann-Whitney U test was used (significance level P = 0.05). RESULTS: No significant differences were found in duration of surgery and drains in laparoscopically or conventionally operated hemophiliacs versus matched pairs. Complication rate did not differ among the different groups. Concerning the total duration of hospital stay (t-DHOS) and the postoperative duration of hospital stay (p-DHOS), there was no statistical difference between LOH versus matched LONH. However, in COH versus matched LOH, a longer time was required for preparation and recovery (t-DHOS, P = 0.04; p-DHOS, P < 0.001). Also, the median factor supply perioperatively including the day of surgery did not differ between laparoscopically versus conventionally operated hemophiliacs. CONCLUSIONS: Our study underscores the safety and benefits of laparoscopic procedures in hemophiliacs by showing a significantly shorter hospital stay for these patients resulting in reduced therapeutic costs and a faster mobilization. Still, the surgical and perioperative management of hemophiliacs continues to be a challenge requiring an experienced interdisciplinary team.

Patient perspective on living with mild hemophilia in Germany: results from a nationwide survey.

Introduction: The disease burden and bleeding risk of patients with mild hemophilia may be underestimated. Their health-related quality of life (QoL) may be negatively impacted by insufficient treatment and bleed-related joint damage connected to a potentially delayed diagnosis. Aim: This study aims to gain information on the care reality and QoL of patients aged ≥12 years with mild hemophilia in Germany. Methods: An anonymous cross-sectional patient survey using standardized questionnaires was conducted in a validated electronic patient-reported outcome system. Medical specialists, hemophilia centers, patient organizations, and support groups across Germany invited the patients. Results: A total of 43 patients (35 patients with hemophilia A, 5 patients with hemophilia B, and 3 patients for whom the information was missing) with a median age of 33 years were analyzed. The median age at diagnosis was 6.0 years (interquartile range [IQR] 2.0-15.0), and the median factor activity was 14.0% (IQR 12.0-25.0). Nearly 85% of the patients received factor concentrates in the past, and the most common reasons for the treatment were surgery or joint bleeding (each 65.6%). Half of the patients who provided feedback experienced complications during bleeding episodes. Prophylactic treatment with factor concentrates was rare (10.3%). The patients had minor problems regarding their health status. Conclusion: Bleeding complications and joint bleeding, in particular, may be highly underestimated in patients with mild hemophilia, highlighting a medical need in this population. Patients with a potential benefit from prophylaxis need to be identified. Mild hemophilia has a negative impact on patients' QoL. Hemophilia centers satisfied the patients' needs. Further research is needed to address the current lack of awareness and improve adequate treatment in the future.

Perioperative Management for Port Catheter Procedures in Pediatric Patients with Severe Hemophilia and Inhibitors.

BACKGROUND: The objective of this systematic study was to assess the perioperative management and outcome of surgery in pediatric patients with hemophilia A/B and inhibitors compared to nonhemophilic pediatric patients. METHODS: The surgical outcome of 69 port catheter operations in patients with hemophilia who developed inhibitory antibodies against the administered factor was compared to 51 procedures in the control group. In the patients with hemophilia and inhibitors, a standardized protocol for recombinant activated factor VII was used to prevent perioperative bleeding. RESULTS: Hemophilic pediatric patients with inhibitors showed no significant differences in perioperative management (blood transfusion: p = 0.067, duration of surgery: p = 0.69; p = 0.824) in comparison to patients without hemophilia. The length of hospital stay was significantly longer in pediatric patients with hemophilia and inhibitors (20 days vs. 4 days for insertion; 12 days vs. 1 day for explantation). Moreover, no statistically significant difference was found for secondary bleeding (three patients with hemophilia vs. none in the control group; p = 0.11) or surgical complications (five hemophilia patients vs. none with grade I complication; one hemophilia patient vs. none with grade II complications; p = 0.067). CONCLUSION: This study has demonstrated that port catheter insertion and removal is safe in these patients. Moreover, it shows the importance of a coordinated approach with a multidisciplinary team.

Urological surgery in patients with hemorrhagic bleeding disorders Hemophilia A, Hemophilia B, von Willebrand disease: a retrospective study with matched pairs analysis.

PURPOSE: To determine retrospectively the perioperative management and outcome of transurethral prostate/bladder surgery (TURP, TURB) and transrectal prostate biopsy in hemophiliacs. METHODS: Thirty-seven hemophilic patients underwent TURP (12 patients), TURB (13 patients), or transrectal prostate biopsy (12 patients) with proactive hemostaseological management (i.e., factor supply, close meshed hemostaseological analysis). Thirty-seven non-hemophiliac patients served as matched pairs who matched for age, gender, accompanying diseases, and the type of surgical procedure. The resulting pairs were analyzed for duration of surgery, hospital stay, and complications. RESULTS: Average TURP length in hemophiliacs was 77.92 min, in the matched pairs group TURP 67.08 min (p = 0.487). Mean TURB length in hemophiliacs was 43.46 min versus 35.38 min in controls (p = 0.678). More important, the length of hospital stay was significant longer in the hemophiliacs undergoing TURP compared to non-hemophiliac control group (12.08 days vs. 5.83 days; p < 0.001). In TURB patients, similar results were found (11.15 days hemophiliacs vs. 6.15 controls; p = 0.018). Regarding complications (bleeding, hemorrhage, readmission), no significant difference between the groups was obtained. CONCLUSION: Urological interventions in hemophiliac patients with factor supply have the same risk for postoperative complications as in non-hemophiliacs. The only significant difference between hemophiliacs and non-hemophiliacs was the length of hospital stay.

Osteoporosis Remains Constant in Patients with Hemophilia-Long-Term Course in Consideration of Comorbidities.

INTRODUCTION: Patients with hemophilia (PWHs) suffer from an increased risk of osteoporosis. Multiple hemophilia and hemophilic arthropathy associated factors correlate with a low bone mineral density (BMD) in PWHs. The aim of this study was to assess the long-term development of BMD in PWH as well as to analyze potentially influencing factors. METHODS: A total of 33 adult PWHs were evaluated in a retrospective study. General medical history, specific-hemophilia-associated comorbidities, joint status using the Gilbert score, calcium level, and vitamin D level as well as at least two results of bone density measurements with a minimum range of 10 years per patient were taken into account. RESULTS: The BMD did not change significantly from one point of measurement to the other. A total of 7 (21.2%) cases of osteoporosis and 16 (48.5%) cases of osteopenia were identified. The two following significant correlations could be revealed: the higher the patients' body mass index, the higher their BMD (r = 0.41; p = 0.022). Moreover, a high Gilbert score came along with a low BMD (r = -0.546; p = 0.003). CONCLUSION: Even if PWHs frequently suffer from a reduced BMD, our data suggest that their BMD remains constant on a low level in the course of time. A risk factor of osteoporosis often found in PWHs is a vitamin D deficiency and joint destruction. Therefore, a standardized screening of PWHs on BMD reduction by collecting vitamin D blood level and assessing joint status seems appropriate.

Clinical experience of switching patients with severe hemophilia to rVIII-SingleChain or rIX-FP.

OBJECTIVE: Prophylaxis treatment is the current standard of care for patients with severe hemophilia. Factor concentrates with improved pharmacokinetics have offered more options for individualizing treatment. The treatment focus may be on increased protection, aiming for higher trough factor levels or longer dosing intervals to reduce the burden of hemophilia. Both aspects can have long-term effects on joint health. Products, such as rVIII­SingleChain and rIX-FP have been developed to reduce the treatment burden for patients with hemophilia and optimize prophylactic efficacy. The objective of this report is to provide a summary of the clinical experience of different Hemophilia Treatment Centers in managing the switch to rVIII-SingleChain or rIX-FP in patients with hemophilia. METHODS: This report summarizes a selection of patient cases presented at the 3rd Alliance for Coagulation Academy Meeting in October 2020. The cases from the participating centers provide examples of the clinical experience in managing patients' switch to rVIII-SingleChain and rIX­FP, including which types of patients are suitable for switching, and practical steps in managing a switch. RESULTS: It is important to take into consideration the physical and social fulfillment of the patient when deciding to switch to rVIII-SingleChain or rIX-FP. The physician plays an important role in the motivation of patients as they understand not only the patient's needs but the potential benefits of the new treatment. CONCLUSION: The selected patient cases reported here demonstrate that patients may wish to switch factor products for a variety of reasons; therefore, it is critical to understand why patients switch and what they expect from switching.

Antidrug antibodies against the polyethylene glycol moiety inhibit the procoagulant activity of therapeutic polyethylene glycolated factor VIII.

BACKGROUND: The standard therapy for patients with hemophilia A (HA) is the replacement with factor VIII (FVIII) therapeutics. To overcome the limitation of short half-life of wild-type FVIII protein, polyethylene glycol (PEG) can be coupled to therapeutic FVIII to improve pharmacokinetics. OBJECTIVES: We aimed to characterize antibodies developed against a FVIII therapeutic PEGylated with a 40-kDa PEG (40PEG-BDDFVIII) in 2 patients with mild HA. METHODS: An inhouse bead-based immunoassay was developed to characterize and confirm the specificity of the detected antibodies. The neutralizing nature of the antibodies toward PEGylated therapeutics was determined by a modified Nijmegen-Bethesda assay. RESULTS: Two out of 46 patients treated with 40PEG-BDDFVIII developed inhibitory antibodies toward the drug. Switching to a non-PEGylated FVIII successfully increased the FVIII activity in both patients. In patient 1, antibodies were raised against FVIII and PEG. Anti-FVIII antibodies were of the immunoglobulin (Ig)G isotype, whereas anti-PEG antibodies were of IgG, IgM, and IgA isotypes. In patient 2, antibodies of IgG and IgA isotypes were directed only against the PEG moiety. Competitive assays confirmed the specificity of the antibodies against PEG. The applied Nijmegen-Bethesda assay revealed that patients' anti-PEG antibodies and AGP3, an antibody against the backbone of PEG, can inhibit all currently available PEGylated therapeutics but to different degrees. No inhibitory FVIII antibodies were detected. CONCLUSION: Antibodies against the PEG moiety of 40PEG-BDDFVIII abolished the efficacy of the drug. This is the first report on real-world experiences with the development of neutralizing anti-PEG antibodies after treatment with PEGylated FVIII therapeutics in mild HA.

Extracorporeal Treatment for the Acute und Long-Term Outcome of Patients with Life-Threatening Acquired Hemophilia.

OBJECTIVES: In acquired hemophilia (AH), autoantibodies (inhibitors) impede blood coagulation factors leading to severe bleedings. Cornerstones of a successful treatment are the control of bleeding and an eradication of autoantibodies. The present study is an update of our previous documentation of the treatment of high-titer AH patients with severe life-threatening bleeding undergoing the modified Bonn-Malmö-Protocol (MBMP). METHODS: 64 AH patients were treated by a standard combination protocol (MBMP) consisting of antibody depletion through immunoadsorption, i.v. immunoglobulin, immunosuppression, and high-dose FVIII substitution. They underwent a long-term follow-up. RESULTS: Primary study endpoints loss of detection of the activity of the inhibitor and FVIII recovery ? 5% were reached in a median time of 3 days (95% CI: 2.6-3.4 days), the median time of FVIII substitution was 13 days (95% CI 10.6-15.3 days), and the median time of immunoadsorption was 16 days (95% CI 13-18.9 days). In 5 patients the AH occurred as paraneoplastic syndrome, and partial remission was achieved. Relapses without bleeding event occurred only in second-line MBMP. Those responded excellently to short time treatment. Overall patients remained in remission over a median follow-up time of 8 years. Conclusion: Except for paraneoplastic AH, MBMP-treated patients have a remarkable prognosis which is confirmed by long-term follow-up with a complete response rate of 93% (53/57) in the first year post MBMP and 100% during long-term follow-up. These outcome in life-threatening AH is unique and until now not achievable via other treatment schedules. In life-threatening bleedings physicians should take into account MBMP as a first line treatment.

Matching-Adjusted Indirect Comparison of Efficacy and Consumption of rVIII-SingleChain Versus Two Recombinant FVIII Products Used for Prophylactic Treatment of Adults/Adolescents with Severe Haemophilia A.

INTRODUCTION: Given the relatively small number of patients with haemophilia A, head-to-head comparisons between recombinant FVIII (rFVIII) products are difficult to conduct. This study compared the efficacy and consumption of rVIII-SingleChain (lonoctocog alfa, AFSTYLA®) with rAHF-PFM (octocog alfa, Advate®) and rFVIIIFc (efmoroctocog alfa, Elocta®), for the prophylaxis and treatment of bleeding episodes in previously treated adolescents/adults with severe haemophilia A, through a matching-adjusted indirect comparison (MAIC). METHODS: A systematic literature review identified published clinical trials for rAHF-PFM and rFVIIIFc. Individual patient data for rVIII-SingleChain were used to match baseline patient characteristics to those from published trials, using an approach similar to propensity score weighting. After matching, annualized bleeding rates (ABR), percentage of patients with zero bleeds, and rFVIII consumption were compared across trial populations. RESULTS: Published data were identified from two rAHF-PFM trials and one rFVIIIFc trial. rVIII-SingleChain had similar ABR (risk ratio [RR]: 0.74 [0.16; 3.48]; RR: 1.18 [0.85; 1.65]) and percentage of patients with zero bleeds (odds ratio [OR]: 1.34 [0.56; 3.22]; OR: 0.78 [0.47; 1.31]) versus rAHF-PFM and rFVIIIFc, respectively. Annual rVIII-SingleChain consumption was significantly lower than rAHF-PFM (mean difference: - 1507.66 IU/kg/year [- 2011.71; - 1003.61]) and equivalent to rFVIIIFc (RR: 0.96 [0.62; 1.49]). CONCLUSION: Although limited to published information for comparator trials, these results suggest that with an annualized rFVIII consumption comparable to rFVIIIFc, but significantly lower than rAHF-PFM, routine prophylaxis with rVIII-SingleChain is able to maintain a similar ABR and percentage of patients with zero bleeds, attesting to the long-acting nature of rVIII-SingleChain.

It is difficult to directly compare different recombinant FVIII products in head-to-head studies because there are few patients with haemophilia A. This study aimed to indirectly compare the efficacy and consumption of different recombinant FVIII products in the prophylactic treatment of haemophilia A using published clinical data. A proven method for performing indirect comparisons of products is referred to as a matching-adjusted indirect comparison. Using this approach, we were able to compare rVIII-SingleChain with two other recombinant FVIII products (rAHF-PFM and rFVIIIFc). Our results suggest that annual FVIII consumption with rVIII-SingleChain is comparable to rFVIIIFc, but is significantly lower than rAHF-PFM, while maintaining a similar bleeding rate. These results highlight the long-acting nature of the product.

Extended Half-Life Factor VIII/Factor IX Products: Assay Discrepancies and Implications for Hemophilia Management.

Due to structural differences between extended half-life (EHL) factor VIII (FVIII) or FIX products and equivalent plasma wild-type molecules used for assay calibration, reagent-dependent discrepancies during monitoring of FVIII- and FIX-replacement therapies with EHL products have been described. To assess the performance of available one-stage clotting and chromogenic substrate assays on the Siemens Atellica COAG 360 analyzer, an in vitro study using spiked plasma samples was performed. The described results confirm previously described findings and allowed allocation of each EHL product to an appropriate assay. In addition, corresponding EHL product-specific analytes were defined within the order entry system of the University Hospital Bonn. The requirement of product-specific FVIII and FIX assays complicates patient monitoring and demonstrates the need for both continuous education and communication between treating physicians and the coagulation laboratory.

Body Mass Index Best Predicts Recovery of Recombinant Factor VIII in Underweight to Obese Patients with Severe Haemophilia A.

BACKGROUND: Factor VIII (FVIII) products are usually dosed according to body weight (BW). This may lead to under- or over-dosing in underweight or obese patients, respectively. OBJECTIVE: This article evaluates the pharmacokinetics (PK) of recombinant FVIII concentrate, particularly recovery, in relation to body mass index (BMI) and other body composition descriptors. MATERIALS AND METHODS: Thirty-five previously treated adults with severe haemophilia A from five BMI categories (underweight, normal, overweight, obese class I and II/III) were included. PK was evaluated after 50 IU per kilogram of BW single-dose recombinant FVIII (turoctocog alfa). The body composition variable was based on measurements of weight, height, bioimpedance analysis, and dual-energy X-ray absorptiometry. A dosing model was derived to achieve similar peak FVIII activity levels across BMI categories. RESULTS: A statistically significant positive association between BMI and C30min, IR30min, and AUC0-inf was observed; CL and Vss showed a significant negative association with BMI; t½ was independent of BMI and other parameters. The dosing model introduced a correction factor 'M' for each BMI category, based on linear regression analysis of C30min against BMI, which ranged from 0.55 for underweight to 0.39 for obese class II/III. This model achieved similar peak FVIII activity levels across BMI categories, estimating an average dose adjustment of +243.3 IU (underweight) to -1,489.6 IU (obese class II/III) to achieve similar C30min. CONCLUSION: BMI appears to be the best predictor of recombinant FVIII recovery; however, PK endpoints were also dependent on other body composition variables. The model demonstrated that dosing can be adjusted for individual BMI to achieve better FVIII predictability across BMI categories.

The role of variant alleles of the mannose-binding lectin in the inhibitor development in severe hemophilia A.

INTRODUCTION: The administration of FVIII leads to inhibitors in up to 30% of patients with hemophilia A (HA), the most severe treatment complication. FVIII-mannosylation fosters the presentation of FVIII to CD4+-T-lymphocytes. Mannose as primary ligand for the mannose-binding lectin (MBL) activates the lectin pathway of complement. MBL2 single nucleotide polymorphisms (SNPs) lead to low peripheral MBL concentrations that may hamper the removal of mannosylated FVIII. OBJECTIVE: Investigation of the association between the inhibitor development in hemophilia A and MBL2-SNPs. METHODS: In a case-control study the MBL2-SNPs in exon 1 at codons 52, 54 and 57 (C, B, D-Alleles respectively) were determined in 237 patients with severe hemophilia A with and without inhibitors to FVIII (119 vs 118). The association of MBL2-SNPs and the -308 G>A TNF-α-polymorphism with the presence of inhibitors were determined. RESULTS: In the inhibitor group higher frequencies of the B allele (codon 54) (OR: 1.77, P < 0.05) were present. Summarising the MBL2 SNPs (alleles B, C and D) as 0, the 0/0 type occurred only in the inhibitor group (frequencies: 0.08 vs 0, P = 0.003). Based on the genetic background a functional immune response phenotype was determined. 11.8% of patients with inhibitors were of the low MBL/high TNF-α phenotype vs 0.03% of the non-inhibitor patients (OR: 3.71). CONCLUSION: Data suggest an association of MBL2-SNPs alone or combined with the 308-TNF-α polymorphism in the inhibitor development. Investigations of components of all three complement pathways are required to comprehend their individual and overall contribution to the inhibitor development in HA.

Antiviral therapy for hepatitis C virus recurrence after liver transplantation in HIV-infected patients: outcome in the Bonn cohort.

Recurrent hepatitis C is a major cause of mortality in HIV/hepatitis C virus (HCV)-co-infected patients after orthotopic liver transplantation. We report sustained viral clearance in all four transplanted HIV/HCV-positive patients treated with pegylated interferon/ribavirin. Early therapy after HCV recurrence, tailoring treatment duration to the individual decline in HCV-RNA and the management of side effects are key factors for improved efficacy. At experienced centres interferon treatment is a valuable option for recurrent hepatitis C in HIV-positive patients.

Falling and fall risk in adult patients with severe haemophilia.

The objective of this study was to define fall rates and to identify possible fall risk factors in adult patients with severe haemophilia. PATIENTS, MATERIAL, METHODS: 147 patients with severe haemophilia A and B were evaluated using a standardized test battery consisting of demographic, medical and clinical variables and fall evaluation. RESULTS: 41 (27.9 %) patients reported a fall in the past 12 months, 22 (53.7 %) of them more than once. Young age, subjective gait insecurity and a higher number of artificial joints seem to be risk factors for falling. CONCLUSION: Falls seem to be a common phenomenon in patients with severe haemophilia. Fall risk screening and fall prevention should be implemented into daily practice.