In 2017, all people with severe hemophilia B in Ireland switched to recombinant factor IX Fc fusion protein concentrate (rFIXFc) prophylaxis. Patient‐reported outcomes (PROs) and health‐related ...quality of life (HRQoL) are important to evaluate with new treatments.
To assess HRQoL in people with severe hemophilia B and their experience after switching to rFIXFc prophylaxis.
Participants completed a Patient Reported Outcomes Burden and Experience (PROBE) questionnaire on initiation and following two years of rFIXFc prophylaxis. The PROBE questionnaire has four domains: demographics, general health, haemophilia‐specific, and European Quality of Life 5‐Dimensions (EQ‐5D‐5L) questionnaire.
Twenty‐three participants completed the questionnaire at both time points. The number of activities where chronic pain occurred and interfered with the activity was reduced by 25% and 33%, respectively (P< .001), following two years of rFIXFc prophylaxis. There was a 9% decrease in chronic pain during the second year of rFIXFc prophylaxis compared to baseline, but the rate remained high, at 74%. A 25% reduction in the number of affected activities of daily living (ADLs) was reported following 2 years of rFIXFc prophylaxis (P= .007). The most common health problems were arthritis, hypertension, anxiety/depression, and gingivitis. The median EQ‐5D‐5L score was similar following two years of rFIXFc prophylaxis, 0.76 (range, −0.01 to 0.95), compared to 0.77 (range, 0.36‐1) at baseline.
This study of real‐world patient experience using PROs demonstrates a reduction in chronic pain and improvement in ADLs in participants after switching to rFIXFc prophylaxis. It provides important insights into patient‐identified health care needs and living with severe hemophilia B.
This retrospective survey of haemophilia A patients from multiple treatment centres in Ireland assessed the development of inhibitors following a switch in the prescribed treatment from recombinant ...factor VIII (rFVIII) produced by Chinese hamster ovary (CHO) cells (rFVIII-CHO) to rFVIII produced by baby hamster kidney (BHK) cells (rFVIII-BHK). Ninety-four patients participated in the survey. Most patients (89.4%) had severe haemophilia. One of 77 (1.3%) patients with no inhibitor history developed an inhibitor. This was a patient with moderate haemophilia. A who developed a transient, low-titre (1 BU) de novo inhibitor following surgery. Recurrent inhibitors were detected in three of 17 patients with an inhibitor history during the 20-month post-switch study period. All patients continued on rFVIII-BHK therapy, and all tested negative for inhibitors at the time of their last inhibitor assay during the observation period. These results are consistent with the low levels of inhibitor formation demonstrated in phase III studies of previously treated patients receiving BHK-produced rFVIII and support the low risk of inhibitor formation following a change from rFVIII-CHO to rFVIII-BHK.
Aim
This study aimed to examine physical activity (PA), physical fitness and cardiometabolic risk amongst people with moderate and severe haemophilia (PwMSH).
Methods
The following domains were ...examined: PA (accelerometry); functional aerobic capacity (6‐Minute Walk Test); grip strength (dynamometry); balance (One Leg Stand Test); body composition (anthropometry and bioimpedance analysis); blood pressure; arterial stiffness; and cardiometabolic disorders.
Results
A total of 53 PwMSH (44 years) and 33 controls (43 years; p = .679) were recruited. Compared to controls, PwMSH were significantly less active in moderate and vigorous PA parameters (all p < .05), and less physically fit indicated by 6‐Minute Walk distance (p < .0005), grip strength (p = .040) and balance (p < .0005). PwMSH had higher rates of abdominal adiposity compared to controls measured by waist circumference indices (all p < .05). Resting blood pressure and arterial stiffness were not significantly different (p = .797 and .818, respectively). With respect to overall PA, World Health Organisation recommended targets for adults were achieved by the majority of both groups (haemophilia: 72.9% vs. controls: 90.0%; p = .069). Importantly, the number of PwMSH who achieved guideline recommended PA via longer, sustained bouts of moderate–vigorous PA was significantly lower compared to controls (18.8% vs. 56.7%; p = .001). Lastly, clinically diagnosed hypertension, insulin resistance and hyperlipidaemia were more prevalent amongst PwMSH compared to controls.
Conclusion
Low levels of PA and physical fitness, and significant rates of abdominal adiposity and hypertension may collectively influence the risk and severity of various cardiometabolic and/or musculoskeletal health issues amongst ageing PwMSH. Personalised multi‐disciplinary health interventions involving PA, dietary and health psychology input for PwMSH warrant future investigation.
Introduction
Recombinant factor IX fusion protein concentrate (rFIXFc) is increasingly used for prophylaxis in people with haemophilia B (PWHB), but experience in the perioperative setting is ...limited.
Aims
To evaluate real‐world perioperative factor usage, bleeding and complications in PWHB (≥18 years) who received rFIXFc for surgical haemostasis and to describe the treatment regimens used.
Methods
Single centre, retrospective review of all PWHB who underwent a major or minor surgical procedure between June 2017 and July 2020 and received rFIXFc perioperatively for maintenance of surgical haemostasis.
Results
A total of 56 PWHB (45 male and 11 female), including people with mild (n = 32), moderate (n = 4) and severe (n = 20) haemophilia B, underwent 11 major and 131 minor procedures with rFIXFc for surgical haemostasis. Haemostasis was rated as excellent (9/11) or good (2/11) in all major procedures. Median total rFIXFc consumption for orthopaedic surgeries was 972 IU/kg (range 812–1031 IU/kg) and for other major (non‐orthopaedic) surgeries was 323 IU/kg (range 167–760 IU/kg). The median number of perioperative rFIXFc infusions was 19 (range 17–26) for orthopaedic surgery and 7 (range 5–17) for other major surgeries. The number of infusions in the postoperative period was determined by procedure and patient factors. Complications included bowel ileus and wound infection. Most minor procedures were managed with single infusion of rFIXFc, with no bleeding complications in 95% of minor procedures. There were no thromboembolic events or inhibitor formation.
Conclusion
This unique data provides real‐world evidence that rFIXFc is safe and effective in achieving haemostasis in PWHB undergoing surgery.
Introduction
In 2017, all people with severe haemophilia B (PWSHB) in Ireland switched from standard half‐life (SHL) recombinant FIX (rFIX) to rFIX Fc fusion protein (rFIXFc) prophylaxis.
Aims
To ...evaluate prophylaxis regimens, bleeding rates and factor usage for two years of rFIXFc prophylaxis in a real‐world setting.
Methods
Data collected retrospectively from electronic diaries and medical records of PWSHB for a two‐year period on rFIXFc prophylaxis were compared with paired baseline data on SHL rFIX treatment.
Results
28 PWSHB (≥18 years) were enrolled, and at switchover 79% were receiving prophylaxis and 21% episodic treatment with SHL rFIX. At 24 months following switchover, all remained on rFIXFc prophylaxis with reduced infusion frequency; median dose per infusion once weekly (55 IU/kg, 20/28), every 10 days (63 IU/kg, 2/28) or every 14 days (98 IU/kg, 6/28). Median annualised bleed rate improved significantly on rFIXFc prophylaxis (2.0 versus 3.3 on SHL FIX) (p = 0.01). Median FIX trough level with once‐weekly infusions was 0.09 IU/ml (0.06–0.14 IU/ml). Management of bleeding episodes was similar with rFIXFc and SHL rFIX; one infusion was sufficient to treat 74% and 77% of bleeds, respectively, with similar total median treatment per bleeding episode. Factor consumption reduced by 28% with rFIXFc prophylaxis (57 IU/kg/week, range 40–86 IU/kg/week) compared with SHL rFIX (79 IU/kg/week, range 44–210 IU/kg/week) (p = 0.002).
Conclusion
This study provides important insights into real‐world experience of switching to rFIXFc prophylaxis in an adult population, demonstrating high rates of prophylaxis, with reduced infusion frequency, bleeding and FIX consumption.
Previous studies have reported marked interindividual variation in factor VIII (FVIII) clearance in patients with hemophilia (PWH) and proposed a number of factors that influence this heterogeneity.
...To investigate the importance of the clearance rates of endogenous von Willebrand factor (VWF) compared with those of other FVIII half-life modifiers in adult PWH.
The half-life of recombinant FVIII was determined in a cohort of 61 adult PWH. A range of reported modifiers of FVIII clearance was assessed (including plasma VWF:antigen and VWF propeptide levels; VWF-FVIII binding capacity; ABO blood group; and nonneutralizing anti-FVIII antibodies). The FVIII-binding region of the VWF gene was sequenced. Finally, the effects of variation in FVIII half-life on clinical phenotype were investigated.
We demonstrated that heterogeneity in the clearance of endogenous plasma VWF is a key determinant of variable FVIII half-life in PWH. Both ABO blood group and age significantly impact FVIII clearance. The effect of ABO blood group on FVIII half-life in PWH is modulated entirely through its effect on the clearance rates of endogenous VWF. In contrast, the age-related effect on FVIII clearance is, at least in part, VWF independent. In contrast to previous studies, no major effects of variation in VWF-FVIII binding affinity on FVIII clearance were observed. Although high-titer immunoglobulin G antibodies (≥1:80) were observed in 26% of PWH, these did not impact FVIII half-life. Importantly, the annual FVIII usage (IU/kg/y) was significantly (p = .0035) increased in patients with an FVIII half-life of <12 hours.
Our data demonstrate that heterogeneity in the half-life of FVIII concentrates in patients with hemophilia A is primarily attributable to variability in the clearance of endogenous VWF.
•The half-life of factor VIII (FVIII) in patients with hemophilia (PWH) is influenced by plasma levels of von Willebrand factor (VWF):antigen, ABO blood group, and age.•Heterogeneity in the clearance of endogenous plasma VWF is a key determinant of variable FVIII half-life in PWH.•The effect of ABO blood group on FVIII half-life in PWH is modulated through its effect on the clearance rates of endogenous VWF.•The effects of age on FVIII clearance in PWH are, at least in part, VWF independent.
Objectives
To establish the prevalence of pain and functional disability in Irish adults with moderate and severe haemophilia, and to examine demographic and lifestyle influences.
Methods
Males ...≥18 years with moderate or severe haemophilia participated. Pain and function were examined using the PROBE questionnaire.
Results
Of 49 participants median age 44 (IQR 32, 52) years, most had severe haemophilia (Factor VIII = 30; Factor IX = 13) and were on regular prophylaxis (88%). Those with moderate haemophilia (Factor VIII = 5; Factor IX = 1) treated on demand (12%). Acute (72%) and chronic pain (71%), functional difficulties (58%), and analgesic requirements (92%) were prevalent. Age was significantly associated with more advanced haemophilic arthropathy (p = .002), chronic pain (p = .029) and functional difficulties (p = .036). Adults who reported chronic pain commenced prophylaxis significantly later in life 32 (20, 51) vs. 8 (1, 23) years; p = .004. Physical activity was significantly lower in those with functional difficulties (p < .05). A disparity between self‐perceived ‘target joints’ and clinically defined target joints was also identified (76% vs. 23%).
Conclusion
Haemophilic arthropathy, pain and functional disability were prevalent amongst Irish adults with moderate and severe haemophilia. Age‐dependent lifestyle, analgesic and treatment influences on pain and function warrant further investigation.
Introduction:
Standard factor VIII (FVIII) prophylaxis aims to minimise bleeding episodes in people with haemophilia A (PWHA) using a weight based dosing strategy. However, it is well recognised that ...FVIII half-life (FVIII t1/2) varies markedly between individual PWHA. Consequently, some PWHA continue to experience repeated bleeding episodes even after commencing standard dose prophylaxis therapy. In essence, these patients ‘bleed their way’ to eventually reaching their required optimal FVIII prophylactic regimen. Given that even a small number of joint bleeds have been shown to represent a risk factor for hemophilic arthropathy, there is a clear unmet need for the development of personalised treatment approaches for PWHA that include consideration of individual FVIII pharmacokinetics (PK) to guide prophylaxis dosing. With the introduction of limited plasma FVIII sampling and Bayesian analysis, evaluation of FVIII pharmacokinetics (PK) are now possible in routine clinical practice. However, real life clinical experience to date has been limited to small cohorts of PWHA. Critically, the influence of PK in modulating clinical phenotype has not been systematically studied. As part of the Irish Personalised Approach to the Treatment of Haemophilia (iPATH) study, we integrated extensive clinical data and individual PK profiles to investigate modulators of FVIII PK, the role of limited versus extended sampling FVIII PK and the impact of PK on FVIII prophylaxis and clinical phenotype.
Methods:
Written informed consent was obtained prior to recruitment to the iPATH study. All PK samples were obtained following administration of a single rFVIII product (antihemophilic factor recombinant; ADVATE®, Shire, Lexington, MA, USA) and using myPKFiT™ software (Shire, Lexington, MA, USA). Utilising limited sampling (2 timed FVIII:C levels, taken at 3‒6 and 24‒32 hours post rFVIII administration) and Bayesian analysis, PK curves were constructed using myPKFiT™. For each individual the FVIII t1/2, Von Willebrand Factor antigen (VWF:Ag), blood group, weight, age at PK and Haemophilia Joint Health Score (HJHS) was recorded. rFVIII prescribed over the preceding 5 years was analysed; all patients used antihemophilic factor (recombinant) throughout this time period. Mann-Whitney analyses were used for non-parametric comparisons and correlations were performed using the Pearson test on Prism 7.0c for Mac OSX.
Results:
Complete PK profiles were available for 53 patients with FVIII deficiency recruited to the iPATH study (3 moderate, 50 severe FVIII deficiency). FVIII t1/2 varied considerably, ranging from 7.7‒20.1 hours (median=11.4 hours). Patients with blood group O had a significantly shorter FVIII t1/2 (n=31, median=10.9 hours) than non-O patients (n=22, median=12.2 hours, p=0.014). Both increased age (r2=0.2932, p<0.0001) and higher plasma VWF:Ag levels (r2=0.3, p<0.0001) at time of PK were associated with a significantly longer FVIII t1/2. HJHS significantly increased with age (r2=0.494, p<0.0001) but no significant correlation between FVIII t1/2 and HJHS was observed, likely reflecting the multifactorial nature of arthropathy in PWHA.
In a subset of 10 PWHA we compared the FVIII t1/2 results generated from extended (10 point) to those from limited sampling (2 point) PK. Each limited sampling study included a 24 hour time point as well as either a 3, 4 or 6 hour sample. The 10 point results significantly correlated with limited sampling results using either the 3/24 hour (r2=0.9801, p<0.0001), 4/24 hour (r2=0.9762, p<0.0001) or 6/24 hour sampling combination (r2=0.9693, p<0.0001), underscoring the clinical utility of limited PK sampling.
Prior to the introduction of routine PK-guided dosing in 2018, prescribed rFVIII dose was altered according to bleed rate at clinical review. Analysing the prescribed rFVIII dose over the past 5 years, a clear relationship to rFVIII t1/2 was identified (r2=0.3517, p<0.0001), suggesting that bleeding events in PWHA guided them towards their PK dose.
Conclusions:
This study highlights the accuracy of simplified vs extended sampling for generation of PK profiles on antihemophilic factor (recombinant) using myPKFiT™. Bleed rate adjusted prophylaxis was found to correlate with FVIII t1/2 in an Irish population of PWHA, suggesting that early evaluation of PK and implementation of PK guided dosing of prophylaxis may be of benefit in minimising bleeds in PWHA.
Lavin:Shire: Honoraria, Research Funding, Speakers Bureau. Reipert:Shire: Employment, Equity Ownership. Pipe:Shire: Consultancy, Research Funding; HEMA Biologics: Consultancy; Pfizer: Consultancy; Nove Nordisk: Consultancy; Bioverativ: Consultancy; CSL Behring: Consultancy; Genentech: Consultancy; Ainylam: Consultancy; F. Hoffmann-La Roche Ltd: Consultancy; Apcintex: Consultancy; Catalyst Biosciences: Consultancy; Spark Therapeutics: Consultancy; Freeline: Consultancy; Bayer: Consultancy; uniQure: Consultancy; Biomarin: Consultancy; R2 Diagnostics: Research Funding; Siemens: Research Funding. Turecek:Shire: Employment, Equity Ownership. O'Donnell:Bayer: Research Funding, Speakers Bureau; Novo Nordisk: Research Funding, Speakers Bureau; Leo Pharma: Speakers Bureau; Octapharma: Speakers Bureau; CSL Behring: Consultancy; Daiichi Sankyo: Consultancy; Pfizer: Consultancy, Research Funding; Baxter: Research Funding, Speakers Bureau; Shire: Research Funding, Speakers Bureau.
Glanzmann thrombasthenia (GT) is an autosomal recessive bleeding disorder caused by a defect in platelet integrin αIIbβ3. Given the rarity of the condition (1/1,000,000), assessment and diagnosis ...should be undertaken in a specialist centre. We report the case of a 34 year old woman with severe menorrhagia and a childhood diagnosis from another centre of Von Willebrand Disease. She had an extensive bleeding history, with epistaxis, menorrhagia and postoperative bleeding requiring multiple previous transfusions. Repeat haemostatic workup in our centre revealed normal Von Willebrand levels but abnormal platelet aggregation consistent with Glanzmann thrombasthenia. Antibody screening detected both anti-HLA and anti-αIIbβ3 antibodies, complicating subsequent haemostatic management. This case highlights the importance of diagnostic accuracy, the potential negative sequelae of misdiagnosis and subsequent therapeutic interventions.
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