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.

Safety of intramuscular COVID-19 vaccination in patients with haemophilia.

BACKGROUND: Guidelines recommend that patients with haemophilia should preferably receive vaccination subcutaneously. COVID-19 and other vaccines, however, are only licenced for intramuscular application. AIMS: To assess the safety of intramuscular COVID-19 vaccination in patients living with haemophilia. METHODS: Part A of this prospective observational study enrolled consecutive patients with haemophilia A (HA) and B (HB) of all ages and severities and assessed injection site bleeding and other complications within 30 days of vaccination. Part B enrolled patients providing informed consent for detailed data collection including medication and prophylaxis around the time of vaccination. Logistic regression was performed to assess potential risk factors for bleeding. RESULTS: Four hundred and sixty-one patients were enrolled into part A. The primary endpoint injection site bleeding occurred in seven patients (1.5%, 95% confidence interval .7-3.1%). Comprehensive analysis of 214 patients (404 vaccinations, part B) revealed that 97% of patients with severe haemophilia had prophylaxis before vaccination, either as part of their routine prophylaxis or using additional doses. 56% and 30% of patients with moderate and mild haemophilia, respectively, received prophylaxis before vaccination. Among the seven bleeds recorded, three occurred when intramuscular vaccination was done without prophylaxis (odds ratio 12). CONCLUSIONS: This is the first prospective study reporting on the safety of intramuscular vaccination in haemophilia. The rate of injection site bleeding was low in mild haemophilia, and in moderate and severe haemophilia if patients received factor prophylaxis.

The value of radiosynoviorthesis for treatment of chronic synovitis in hemophilic joint disease.

Chronic synovitis is contributing to the development of arthropathy in hemophilia A and B. In most patients with severe and moderate hemophilia, during lifetime, joint damage progresses despite early prophylaxis and intense treatment with coagulation factor concentrates. Recurrent hemorrhages into the joints and subclinical bleeding lead to chronic inflammation of the synovium, neoangiogenesis and remodeling, sustaining a vicious circle of bleeding-remodeling-bleeding and progression of osteochondral damage. Imaging techniques including ultrasound and MRI are able to early visualize synovitis and osteochondral changes. Early detection and sustained therapy of synovitis are important preconditions to prevent further deterioration of joint status. Chronic synovitis requires intensified substitution of coagulation factors and concomitant analgetic, antiphlogistic and physical therapy. The value of early radiosynoviorthesis (RSO) as effective method to control ongoing synovitis is discussed here. RSO is recommended as first choice therapy in case of persistant chronic synovitis, recorded in both national and international guidelines.

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.

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.

Consensus Recommendations for Intramuscular COVID-19 Vaccination in Patients with Hemophilia.

BACKGROUND: Currently available coronavirus disease 2019 (COVID-19) vaccines are approved for intramuscular injection and efficacy may not be ensured when given subcutaneously. For years, subcutaneous vaccination was recommended in patients with hemophilia to avoid intramuscular bleeds. Therefore, recommendations for the application of COVID-19 vaccines are needed. METHODS: The Delphi methodology was used to develop consensus recommendations. An initial list of recommendations was prepared by a steering committee and evaluated by 39 hemophilia experts. Consensus was defined as ≥75% agreement and strong consensus as ≥95% agreement, and agreement as a score ≥7 on a scale of 1 to 9. After four rounds, a final list of statements was compiled. RECOMMENDATIONS: Consensus was achieved that COVID-19 vaccines licensed only for intramuscular injection should be administered intramuscularly in hemophilia patients. Prophylactic factor replacement, given on the day of vaccination with a maximum interval between prophylaxis and vaccination of 24 hours (factor VIII and conventional factor IX concentrates) or 48 hours (half-life extended factor IX), should be provided in patients with moderate or severe hemophilia. Strong consensus was achieved that patients with mild hemophilia and residual factor activity greater than 10% with mild bleeding phenotype or patients on emicizumab usually do not need factor replacement before vaccination. Swelling, erythema, and hyperthermia after vaccination are not always signs of bleeding but should prompt consultation of a hemophilia care center. In case of injection-site hematoma, patients should receive replacement therapy until symptoms disappear. CONCLUSIONS: Consensus was achieved on recommendations for intramuscular COVID-19 vaccination after replacement therapy for hemophilia patients depending on disease severity.

Prevalence of Obesity in Young Patients with Severe Haemophilia and Its Potential Impact on Factor VIII Consumption in Germany.

Similar to the general population, overweight and obesity have increasingly become a medical and economic burden also in patients with haemophilia in industrialized nations. In this study in seven German haemophilia centres, we identified a prevalence of overweight and obesity of 25.2% among 254 young patients <30 years (median: 13 years; range: 0-30 years) with severe haemophilia A and without a history of inhibitors. The median FVIII dosage based on bodyweight was significantly higher in normal weight compared with overweight or obese patients (96.9 vs. 72.9 IU/kg/week, respectively; p < 0.0001). This suggests that an individualized dosing regime which might be based on FVIII pharmacokinetics, physical activity and pre-existing haemophilic arthropathy is applied rather than dosing by bodyweight only. The bleeding rates observed in obese (median: 1; range: 0-17) versus normal weight patients (median: 2; range: 0-28) did not differ significantly (p = 0.057). Lower bleeding rates might be due to reduced activity or expected higher FVIII plasma levels in overweight patients. Due to the increasing prevalence of overweight/obesity in patients with haemophilia an interdisciplinary approach for individualized haemophilia treatment and weight loss programmes might be helpful for optimal and economical treatment for this group of patients.