Neonatal circumcision in severe haemophilia: a survey of paediatric haematologists at United States Hemophilia Treatment Centers

Neonatal circumcision in patients with severe haemophilia has not been well studied. We performed a survey of paediatric haematologists from Hemophilia Treatment Centers (HTC) across the United States to better understand the attitudes toward and management of neonatal circumcision in haemophilia patients. Response rate to our survey was 40% (n = 64/159). Thirty‐eight percent of respondents (n = 24) said that they would allow this procedure in the newborn period but in many cases this was against medical advice. The most reported concern regarding neonatal circumcision in haemophilia patients was the risk of development of an inhibitor (n = 25; 39%) followed by the concern for bleeding (n = 22; 34%) and issues related to vascular access in the neonate (n = 11; 17%). All respondents recommended at least one preprocedure dose of factor replacement. Twenty‐two percent (n = 14) of respondents did not use more than one dose of factor replacement but 32% (n = 21) used 1–2 postoperative doses. The remainder of paediatric haematologists surveyed recommended between 3–5 (16%; n = 10) and 6–10 (3%, n = 2) additional days postoperatively. There was wide variation in both techniques of circumcision as well as adjuvant haemostatic agents used. Only 22% of respondents said that they had an established protocol for management of circumcision in the newborn haemophilia patient. These survey results highlight the need for evidence‐based guidelines regarding the optimal management of circumcision in neonates with severe haemophilia.     

Oral surgery‐associated postoperative bleeding in haemophilia patients – a tertiary centre's two decade experience

Our goal in this research was to evaluate potential and targeted therapy, correlated with haemophilia severity and dental procedural risk, to reduce postoperative bleeding risk. Patients with haemophilia who were treated at the Oral and Maxillofacial Surgery Clinic at Sheba Medical Center between 1996 and 2012 comprised the study cohort. Data collected included disease history and severity, perioperative factor concentrate therapy, local haemostatic agent application, systemic tranexamic acid use and outcome. Bleeding was defined as excessive bleeding during or within 20 days following procedure. Dental procedures (n = 1968) of 125 patients were studied. Patients’ bleeding risk score was evaluated according to the severity of haemophilia with or without the presence of an inhibitor, presence of comorbid coagulopathy and the type of dental procedure. Thirty‐four patients undergoing a total of 880 high‐risk and 1088 low‐risk procedures suffered 40 postoperative bleeding events that necessitated further dental and/or haematological intervention. Among risk factors for delayed bleeding, the use of fibrin glue was significantly (P = 0.027) associated with the risk of postprocedural bleed probably as it was applied to high‐risk patients and procedures. Earlier treatment period (P = 0.055), postprocedure hospitalization (P = 0.039) and dental “high‐risk” procedures (P < 0.0001) also increased bleeding risk. Patients with haemophilia may be safely treated if meticulous haemostasis is applied, along with fibrin glue and systemic therapy as required. Factor transfusions are not mandatory and should be applied considering the procedure‐related risk and the patient's calculated haematological risk for bleeding.     

Long‐acting recombinant factor IX Fc fusion protein (rFIXFc) for perioperative management of subjects with haemophilia B in the phase 3 B‐LONG study

In the phase 3 B‐LONG (Recombinant Factor IX Fc Fusion Protein [rFIXFc] in Subjects With Haemophilia B) study, rFIXFc demonstrated a prolonged half‐life compared with recombinant factor IX (rFIX), and safety and efficacy for prophylaxis and treatment of bleeding in subjects with moderately‐severe to severe haemophilia B. In this B‐LONG sub‐analysis, rFIXFc was evaluated for efficacy in subjects requiring major surgery. Dosing was investigator‐determined. Assessments included dosing, consumption, bleeding, transfusions and haemostatic response. A population pharmacokinetics model of rFIXFc was used to predict FIX activity. Twelve subjects underwent 14 major surgeries (including 11 orthopaedic surgeries); most subjects (11/12) received rFIXFc prophylaxis before surgery (range, ~2 weeks–12 months). Investigators/surgeons rated haemostatic responses as excellent (n = 13) or good (n = 1). In most surgeries (85·7%), haemostasis from the pre‐surgical dose until the end of surgery was maintained with a single rFIXFc infusion. Blood loss was consistent with similar surgeries in subjects without haemophilia. The strong correlation (R² = 0·9586, P < 0·001) between observed and population pharmacokinetic model‐predicted FIX activity suggests surgery did not impact rFIXFc pharmacokinetics. No unique safety concerns or inhibitors were observed. In conclusion, rFIXFc was safe and efficacious, with prolonged dosing intervals and low consumption, when used perioperatively in haemophilia B. Surgery did not appear to alter rFIXFc pharmacokinetics.     

Obesity in haemophilia patients: effect on bleeding frequency,clotting factor concentrate usage,and haemostatic and fibrinolytic parameters

The prevalence of obesity in patients with haemophilia (PWH) is increasing. We investigated the effect of obesity on bleeding frequency and clotting factor concentrate (CFC) usage in PWH and assessed whether prothrombotic changes observed in obesity differ between controls and PWH. Number of bleeds and CFC usage were compared between obese (N = 51) and non‐obese (N = 46) haemophilia A patients. Markers of haemostasis and fibrinolysis were compared between PWH, and gender‐, age‐ and body mass index (BMI)‐matched non‐haemophilic controls (N = 91). Median number of bleeds/patient‐month was comparable between obese and non‐obese patients with severe haemophilia (P = 0.791). Obese patients with severe haemophilia used 1.4 times more CFC/patient‐month than non‐obese patients (P = 0.036). When adjusting for weight this difference disappeared (P = 0.451). von Willebrand factor plasma concentration (VWF:Ag), factor VIII activity and endogenous thrombin potential were higher in obese than in non‐obese controls. Obesity did not influence these markers in PWH. Plasminogen activator inhibitor type 1 levels were higher in obese vs. non‐obese PWH (P < 0.001), whereas levels were comparable between PWH and controls (P = 0.912). Plasmin‐α2‐antiplasmin complex (PAP) levels appeared to be lower in obese vs. non‐obese subjects, both within controls (P = 0.011) and PWH (P = 0.008). However, in PWH, PAP levels were higher than in controls (P < 0.001). Obesity is associated with an increase in net CFC usage in PWH, but has no effect on bleeding frequency. In addition, obesity attenuates hyperfibrinolysis in PWH. Future research investigating whether obese PWH need CFC treatment dosed on weight or whether a lower dosage would suffice to prevent and treat bleedings is needed.     

Clinical features and management of haemophilic pseudotumours: a single US centre experience over a 30‐year period

Given the rarity of haemophilic pseudotumours, consensus on management is lacking. We describe the clinical features and management of haemophilic pseudotumours by retrospectively reviewing the medical records of haemophilia patients with a diagnosis of pseudotumour seen at our Hemophilia Center from 1981 to 2011. We recorded the following data: type and severity of haemophilia, documented aetiological antecedent, localization of the pseudotumour, presenting symptoms, management and outcome. We identified 12 pseudotumours in 11 patients over a 30‐year period. Six patients had known inhibitors or a history of inhibitor. An aetiological antecedent leading to the development of pseudotumour was reported in nine cases. Localization of the pseudotumour was confined to soft tissue (n = 3) and bone (n = 8). Six of the 12 pseudotumours (50%) were not diagnosed at the time of initial presentation, with a delay ranging from 6 weeks to 6 years. In eight cases, surgical intervention (surgical drainage, n = 2; excision, n = 4; limb amputation, n = 2) was the initial treatment choice, with complete resolution in six cases. Conservative management with close monitoring occurred in three cases, with one case subsequently requiring surgical resection. We conclude that haemophilic pseudotumours still occur sporadically, and the diagnosis is frequently delayed. Surgical intervention is generally a safe and effective treatment, although conservative management may be appropriate in selected cases.     

Intracranial haemorrhage in children and adolescents with severe haemophilia A or B – the impact of prophylactic treatment

The discussion of prophylactic therapy in haemophilia is largely focused on joint outcomes. The impact of prophylactic therapy on intracranial haemorrhage (ICH) is less known. This study aimed to analyse ICH in children with haemophilia, with a focus on different prophylaxis regimens and sequelae of ICH. We conducted a multicentre retrospective and prospective study that included 33 haemophilia centres from 20 countries. Inclusion criteria were children and adolescents born between 1993 and 2014, with severe haemophilia A or B without inhibitors. Participants were categorized by prophylaxis regimen: full, partial or none, based on dose and dose frequency of regular infusions. The cohort study included 1515 children: 29 cases of ICH over 8038 patient years were reported. The incidence of ICH in the prophylaxis group, 0·00033 cases of ICH/patient year, was significantly lower compared to the no prophylaxis group, 0·017 cases of ICH/patient year (RR 50·06; P < 0·001) and the partial prophylaxis group, 0·0050 cases of ICH/patient year (RR 14·92; P = 0·007). In the on‐demand‐group, 8% (2/24) children with ICH died and 33% had long‐term sequelae, including intellectual and behavioural problems, paresis and epilepsy. Children on regular, frequent prophylaxis have a low risk of ICH compared to those using non‐frequent or no prophylaxis.     

Burden of illness and costs among paediatric haemophilia patients with and without central venous access devices treated in US hospitals

Introduction

Central venous access devices (CVADs) facilitate repeated or urgent treatments for paediatric haemophilia patients, but are associated with complications. This study examined the burden of illness, healthcare utilization and costs for CVADs in a real‐world hospital setting.

Materials and Methods

This study included haemophilia patients ages ≤18 years with discharges during 2006‐2014 in the US Premier Healthcare Database. Haemophilia was identified using ICD‐9 diagnosis codes and CVAD exposure using billing information. After matching haemophilia patients with and without CVADs on demographic and clinical characteristics, we compared infection, thrombosis, length of stay (LOS), inflation‐adjusted hospital cost (2014 $USD) and readmission outcomes using generalized estimating equation models adjusted for hospital teaching status.

Results

Among 4793 paediatric haemophilia patients treated at one of 548 hospitals, a total of 197 patients were identified with CVAD exposure. The matched sample included 310 haemophilia patients (155 CVAD and 155 non‐CVAD). CVAD cases had greater frequencies of all‐cause infections (29% vs 17%, P = .01) and thrombosis (6% vs 1%, P = .06), longer adjusted mean LOS (9.5 vs 4.7 days, P = .002), higher adjusted mean inpatient total hospitalization costs ($47200 vs $25389, P = .02) as well as more inpatient and outpatient visits at 30‐, 60‐ and 90‐days (P < .05 for all differences) compared with non‐CVAD patients.

Conclusion

Paediatric haemophilia patients with CVADs experienced greater infection rates, healthcare utilization and higher hospitalization costs compared with non‐CVAD patients. The results of this study may inform further research efforts to understand the costs and benefits of novel treatment alternatives for young haemophilia patients requiring CVADs.     

A pilot randomized control trial to evaluate the feasibility of an Internet‐based self‐management and transitional care program for youth with haemophilia

Adolescents with haemophilia must assume responsibility for their health and management of their disease. An online self‐management program was developed to support adolescents during this transition. To determine the feasibility of the program using a randomized control trial (RCT) design in terms of 1 accrual/attrition rates, 2 willingness to be randomized, 3 compliance with the program/outcome measures and 4 satisfaction. Adolescents, ages 13–18, were enrolled in a pilot RCT (NCT01477437) and randomized to either the intervention (8‐week program with telephone coaching) or the control arm (no access to the website, weekly telephone call as attention‐strategy). All participants completed pre/postoutcome measures. Twenty‐nine teens participated (intervention n = 16, control n = 13). Participants in the intervention arm spent an average of 50 min on the website per week and completed the modules in an average of 14 weeks (SD = 4.9). Attrition was higher in the control group compared to the intervention group (54% vs. 25%). 17/18 (94%) who completed the program also completed the poststudy measures. Teens on the intervention arm showed significant improvement in disease‐specific knowledge (P = 0.004), self‐efficacy (P = 0.007) and transition preparedness (P = 0.046). There was a statistically significant improvement in knowledge in the intervention group when compared to the control group (P = 0.01). Overall, the teens found the website to be informative, comprehensive and easy to use and were satisfied with the program. This pilot RCT study suggests benefit to the program and indicates an RCT design to be feasible with minor adjustments to the protocol.     

Prenatal diagnosis of haemophilia B: the Italian experience

This article describes prenatal diagnosis (PND) of haemophilia B (HB) within the framework of Italian haemophilia centres and genetics laboratories. The study details the experience from six haemophilia genetic centres (three in the North, one in the Centre and two in the South of Italy) and summarizes the different techniques used to perform PND of HB during the last 15 years. To date, the Italian HB database includes 373 characterized unrelated patients and their genetic information has permitted the identification of 274 carriers of childbearing age. This database represents the main instrument for timely and precise PND. Sixty‐six prenatal diagnoses were performed on 52 HB carriers whose average age at the time was 34 (ranging from 24 to 44 years). In 44 cases, genetic counselling for carrier status determination was performed before pregnancy, while eight were not studied prior to pregnancy. Foetal samples were obtained by chorionic villus sampling in 52 cases, by amniocentesis in 12 while two were diagnosed by analysis of free foetal DNA obtained from maternal peripheral blood. In 35 (53%) pregnancies the foetus was female. For 31 men (47%), haemophilia status was determined by analysis of previously determined informative markers or familial mutations (12 affected and 19 unaffected). There may be more than one laboratory involved in the PND diagnostic pathway (providing DNA extraction, karyotype analysis, gender determination, maternal contamination detection, molecular diagnosis and sequencing). Good communication between all the parties, coordinated by the haemophilia centre, is essential for a successful and rapid process.     

A cross‐sectional study of bleeding phenotype in haemophilia A carriers

Haemophilia A carriers have historically been thought to exhibit normal haemostasis. However, recent data demonstrates that, despite normal factor VIII (FVIII), haemophilia A carriers demonstrate an increased bleeding tendency. We tested the hypothesis that obligate haemophilia carriers exhibit an increase in clinically relevant bleeding. A cross‐sectional study was performed comparing haemophilia A carriers to normal women. Questionnaire assessment included a general bleeding questionnaire, condensed MCMDM‐1VWD bleeding assessment tool and Pictorial Bleeding Assessment Chart (PBAC). Laboratory assessment included complete blood count, prothrombin time, activated partial thromboplastin time, fibrinogen activity, FVIII activity (FVIII:C), von Willebrand factor antigen level, ristocetin cofactor, platelet function analyser‐100^TM and ABO blood type. Forty‐four haemophilia A carriers and 43 controls were included. Demographic features were similar. Laboratory results demonstrated a statistically significant difference only in FVIII:C (82·5 vs. 134%, P < 0·001). Carriers reported a higher number of bleeding events, and both condensed MCMDM‐1 VWD bleeding scores (5 vs. 1, P < 0·001) and PBAC scores (423 vs. 182·5, P = 0·018) were significantly higher in carriers. Haemophilia A carriers exhibit increased bleeding symptoms when compared to normal women. Further studies are necessary to fully understand the bleeding phenotype in this population and optimize clinical management.     

Oral health status in children and adolescents with haemophilia

This case‐controlled study aimed to evaluate the existing oral health status in children and adolescents with haemophilia. A total of 50 haemophilia patients and 50 matched controls aged seven to 16 years were recruited into the study. Clinical examination was carried out to determine dental caries experience, oral hygiene status and gingival condition in these two groups. Information regarding previous dental history, oral hygiene practices and dietary habits were also obtained. No significant difference was found in mean caries experience in primary and secondary dentitions (P = 0.86 and 0.32) and in Simplified Oral Hygiene Index (OHI‐S, P = 0.20) between both groups. However, a significantly higher proportion of haemophilia patients (24%) had better oral hygiene status as compared to the controls (2%, P = 0.004). Furthermore, there was a significant difference in Modified Gingival Index (MGI, P = 0.02) between the two groups with the study group having less gingival inflammation. A total of 88% (n = 44) of the haemophilia patients were registered and received dental treatment in specialist dental clinics. More than half (56%, n = 28) had frequent dental visits and only one‐third of the haemophilia patients had history of hospitalization due to oral problems. There was no significant difference in oral hygiene practices and dietary habits between both groups. In general, haemophilia children and adolescents in this study had similar caries experience, a significantly better oral hygiene status and gingival health as compared to healthy controls. The main reason for this is the multidisciplinary approach implemented by medical health‐care professionals as primary care provider and the dental team.     

Adherence to prophylaxis is associated with better outcomes in moderate and severe haemophilia: results of a patient survey

Severe haemophilia is associated with bleeding into joints and development of arthropathy. Prophylactic treatment with infusion of replacement clotting factor is known to prevent bleeding, preserve joint functioning and result in higher health‐related quality of life (HRQoL) than episodic treatment; however, adhering to standard prophylaxis schedules can be difficult, and little is known about the relationship between adherence to prophylactic treatment and outcomes. The aim of this study was to assess the relationship between self‐reported adherence to prophylaxis and health outcomes, including HRQoL and bleeding episodes. Adults with haemophilia (n = 55) and caregivers of children with haemophilia (n = 55) in Australia, Canada, and the United States completed an online questionnaire which included measures of HRQoL (SF‐12v2 for adults and SF‐10 for caregivers of children), self‐reported bleeding episodes, and the VERITAS‐Pro measure of adherence to prophylaxis in haemophilia. Regression analysis was used to test the association between VERITAS‐Pro total score and outcomes. Poorer adherence (higher VERITAS‐Pro scores) was associated with a greater number of self‐reported bleeding episodes in the past year among adults (p < 0.01), more days of work/school missed among paediatric patients (p < 0.01), and lower physical health status scores among paediatric patients (p < 0.05). This study highlights the benefits of adherence to prophylaxis among those with severe haemophilia and provides evidence for the utility of the VERITAS‐Pro by demonstrating a relationship between adherence and outcomes.     

Platelet activation and aggregation: the importance of thrombin activity—A laboratory model

This study introduces a new laboratory model of whole blood platelet aggregation stimulated by endogenously generated thrombin, and explores this aspect in haemophilia A in which impaired thrombin generation is a major hallmark. The method was established to measure platelet aggregation initiated by tissue factor evaluated by means of impedance aggregometry. Citrated whole blood from healthy volunteers and haemophilia A patients with the addition of inhibitors of the contact pathway and fibrin polymerization was evaluated. In healthy persons, a second wave of platelet aggregation was found to coincide with the thrombin burst and to be abolished by thrombin inhibitors. In this system, platelet aggregation in severe haemophilia A (n = 10) was found to be significantly decreased as compared with healthy individuals (912 ± 294 vs. 1917 ± 793 AU × min, P = 0.003), most probably due to the weak level of thrombin generation. For the first time, analysis of platelet aggregation as induced by endogenously generated thrombin was demonstrated. The new method makes it possible to explore the influence of the coagulation system on platelet function. In contrast to the general understanding, the data suggest that the impaired thrombin generation in haemophilia may affect platelet activation. Future studies will address whether our results may contribute to understanding differences in bleeding phenotypes and response to haemostatic substitution observed among patients.     

Comparison of ultrasound and magnetic resonance imaging for diagnosis and follow‐up of joint lesions in patients with haemophilia

Haematomas and recurrent haemarthroses are a common problem in haemophilia patients from early age. Early diagnosis is critical in preventing haemophilic arthritis, and recent years have seen excellent advances in musculoskeletal ultrasound as a diagnostic tool in soft tissue lesions. In this study, we compared the results of ultrasound imaging for the diagnosis of musculoskeletal injuries in haemophilia patients with scores obtained using magnetic resonance (MRI) scans. A total of 61 haemophilia patients aged 4–82 years were included in this study. Both knees and ankles of each patient were assessed using the Gilbert (clinical assessment) and Pettersson scores (X‐ray assessment). Patients with severe haemophilia (n = 30) were examined using ultrasound and MRI (Denver scoring system). Results obtained with ultrasound and MRI in severe patients were correlated using the Pearson test. In patients with severe haemophilia, normal joints were similarly assessed with MRI and ultrasound (κ = 1.000). By component of joint assessment, haemarthrosis was similarly diagnosed with both techniques in all joints (κ = 1.000). A good positive correlation was found between these techniques in detecting and locating synovial hyperplasia (κ = 0.839–1.000, knees and ankles respectively), and erosion of margins (κ = 0.850–1.000). The presence of bone cysts or cartilage loss was better detected with MRI (κ = 0.643–0.552 for knees and ankles, and κ = 0.643–0.462 respectively). Ultrasound is useful in detecting joint bleeds, synovial hyperplasia and joint erosions, with results comparable to those of MRI. A quick and affordable technique, ultrasound imaging may be useful for monitoring joint bleeds and structure normalization and maintenance in routine practice.     

Cardiovascular comorbidities are increased in US patients with haemophilia A: a retrospective database analysis

There is conflicting evidence in the literature on whether individuals with haemophilia in the USA have greater, reduced, or similar risks for cardiovascular disease as the general population. This study evaluated the prevalence of cardiovascular comorbidities among USA males with haemophilia A, relative to an unaffected general male population with similar characteristics. Males with haemophilia A and continuous insurance coverage were identified by ICD‐9‐CM code 286.0 (1 January 2007–31 December 2009) using the MarketScan^® Commercial and Medicare Research Databases. Individuals with haemophilia A were exact matched 1:3 with males without a diagnosis of haemophilia A. The prevalence of cardiovascular comorbidities identified by ICD‐9‐CM code was determined for matched cohorts. Of the study population, 2506 were grouped in the haemophilia A cohort and 7518 in the general cohort. Proportions of individuals with haemorrhagic stroke (2.0% vs. 0.5%, P < 0.001), ischemic stroke (4.7% vs. 2.7%, P < 0.001), coronary artery disease (10.7% vs. 5.8%, P < 0.001), myocardial infarction (0.8% vs. 0.3%, P = 0.003), hypertension (22.6% vs. 15.5%, P < 0.001), hyperlipidaemia (15.9% vs. 11.9%, P < 0.001), arterial thrombosis (12.1% vs. 5.9%, P < 0.001), and venous thrombosis (4.4% vs. 1.1%, P < 0.001) were significantly greater for the haemophilia A cohort. Results were consistent across most age groups, and comorbidities appeared at an earlier age in those with haemophilia A than in the general population. Among the USA haemophilia A population cardiovascular comorbidities are more prevalent and they appear earlier in life in comparison to the general male population, suggesting the need for earlier, enhanced screening for age‐related comorbidities in the haemophilia community.     

Improved joint health in subjects with severe haemophilia A treated prophylactically with recombinant factor VIII Fc fusion protein

Introduction

Joint arthropathy is the long‐term consequence of joint bleeding in people with severe haemophilia.

Aim

This study assessed change in joint health over time in subjects receiving recombinant factor VIII Fc fusion protein (rFVIIIFc) prophylaxis.

Methods

ALONG is the phase 3 pivotal study in which the benefit of rFVIIIFc as a prophylactic treatment for bleeding control was shown in previously treated severe haemophilia patients ≥12 years of age (arm 1: 25‐65 IU/kg every 3‐5 days, arm 2: 65 IU/kg weekly and arm 3: episodic). After completing ALONG, subjects had the option to enrol into the extension study (ASPIRE). This interim, post hoc analysis assessed changes in joint health over ~2.8 years in these patients.

Results

Forty‐seven subjects had modified Haemophilia Joint Health Score (mHJHS) data at A‐LONG baseline, ASPIRE baseline and ASPIRE Year 1 and Year 2. Compared with A‐LONG baseline (23.4), mean improvement at ASPIRE Year 2 was ?4.1 (95% confidence interval [CI], ?6.5, ?1.8; P = .001). Regardless of prestudy treatment regimen, subjects showed continuous improvement in mHJHS from A‐LONG baseline through ASPIRE Year 2 (prestudy prophylaxis: ?2.4, P = .09; prestudy episodic treatment: ?7.2, P = .003). Benefits were seen in subjects with target joints (?5.6, P = .005) as well as those with severe arthropathy (?8.8, P = .02). The mHJHS components with the greatest improvement at ASPIRE Year 2 were swelling (?1.4, P = .008), range of motion (?1.1, P = .03) and strength (?0.8, P = .04).

Conclusions

Prophylaxis with rFVIIIFc may improve joint health over time regardless of prestudy prophylaxis or episodic treatment regimens.     

A cross-sectional follow-up study of physical activity in adults with moderate and severe haemophilia

Aim

To conduct a cross-sectional follow-up assessment of physical activity (PA) in people with moderate and severe haemophilia (PwMSH) from the Irish Personalised Approach to the Treatment of Haemophilia (iPATH) study.

Methods

Between June–December 2021, participants’ PA was measured over one week using accelerometery, and was compared with their previously measured data from the original iPATH assessment. Self-awareness of PA and the impact of the Covid-19 pandemic on PA, pain, mobility and function were retrospectively examined using a survey.

Results

Of 30 participants who returned surveys [n = 19, severe (FVIII, <.01 IU/mL); n = 4, moderate (FVIII, .01–.05 IU/mL); n = 7, severe (FIX, <.01 IU/mL); age: 47 (36, 55) years], 28 completed accelerometery (follow-up time: 3 years). There were no significant differences in accelerometer PA (all p > .05), but achievement of World Health Organisation guidelines increased (67.9%–75.0%; p = .646). Increased self-awareness of PA was reported by 76.7%, and 66.7% reported desires to become more physically active. Compared to normal, most reported either no differences or lower levels of PA during lockdown restrictions. Self-reported PA increased for most when restrictions eased from April 2021 onwards. Beyond the pandemic, concerns included pain and access to exercise resources.

Conclusion

Self-reported PA throughout the pandemic was variable, whilst there were no significant differences in objectively measured PA between assessment periods, despite reports of increased self-awareness and desires to be physically active at follow-up. Further qualitative research is needed to design personalised PA and health interventions, capturing perspectives of patients, their families, and multi-disciplinary haemophilia healthcare providers.     

Prediction of the haemostatic effects of bypassing therapy using comprehensive coagulation assays in emicizumab prophylaxis-treated haemophilia A patients with inhibitors

In emicizumab prophylaxis, the concomitant therapy using bypassing agents (BPAs) is required for breakthrough bleeding and invasive procedures with attention to thrombotic complications. To predict coagulant effects of BPAs in emicizumab-treated patients with haemophilia A (PwHA) with inhibitor (PwHAwI), blood samples from emicizumab-treated PwHAwI (n = 8) and PwHA without inhibitor (n = 2) in phase 1/2 and HAVEN 1 study, spiked with activated prothrombin complex concentrates (aPCC) or recombinant factor VIIa (rFVIIa) ex vivo, and blood samples from emicizumab-treated PwHAwI-receiving BPAs were analysed by Ca²⁺-triggered rotational thromboelastometry (ROTEM) and ellagic acid/tissue factor-triggered clot waveform analysis (CWA). Spiked aPCC, corresponded to 10–100 U/kg, markedly shortened ROTEM parameters beyond the normal range, while spiked rFVIIa, corresponded to 90–270 μg/kg, shortened them within near-normal range. Each of the spiked BPA-improved adjusted maximum coagulation velocity of CWA to within or near the normal range. In blood samples at post-infusion of aPCC (44–73 U/kg) or rFVIIa (79–93 μg/kg), the parameters of both assays improved to approximately the normal range. Taken together, ex vivo results of spiking tests in ROTEM and CWA, except aPCC spiking test in ROTEM, were relatively consistent with in vivo ones, and could usefully predict the coagulant effects of concomitant bypassing therapy for emicizumab-treated PwHAwI.     

Joint health scores in a haemophilia A cohort from Pakistan with minimal or no access to factor VIII concentrate: correlation with thrombin generation and underlying mutation

Haemophilia A is associated with recurrent joint bleeding which leads to synovitis and debilitating arthropathy. Coagulation factor VIII level is an important determinant of bleed number and development of arthropathy . The aim of this study was to compare the haemophilia joint health score (HJHS) and Gilbert score with severity, age, thrombin generation (TG) and underlying mutation in a haemophilia A cohort which had minimal access to haemostatic replacement therapy. Ninety‐two haemophilia A individuals were recruited from Pakistan. Age, age at first bleed, target joints, haemophilic arthropathy joints, HJHS and Gilbert score were recorded. A strong correlation was found between HJHS and Gilbert score (r = 0.98), both were significantly higher in severe (n = 59) compared with non‐severe (n = 29) individuals before the age of 12 years (P ≤ 0.01) but not thereafter. When individuals were divided according to developmental age (<12 years, 12–16 years and >16 years), both HJHS and Gilbert score were significantly lower in the youngest group (P ≤ 0.001), there was no difference between 12–16 years and >16 years. In severe individuals there was no correlation between in vitro TG and joint score, whereas in non‐severe individuals there was a weak negative correlation. In the severe group, no significant difference was observed for either joint score according to the underlying mutation type (inversion, missense, nonsense, frameshift). In this cohort of haemophilia A individuals with minimal access to haemostatic treatment, haemophilic arthropathy correlated with severity and age; among severe individuals, joint health scores did not relate to either the underlying mutation or in vitro TG.     

Clinical,neuroimaging, and behavioural risk factors for neurocognitive impairment in Chinese patients with haemophilia: A multicentre study

Background

Few studies have evaluated the impact of subclinical microstructural changes and psychosocial factors on cognitive function in patients with haemophilia.

Objectives

To determine the prevalence and characteristics of cognitive impairment in patients with haemophilia, and identify associated risk factors.

Methods

We recruited haemophilia A or B patients who were aged ≥10 years old from three public hospitals in Hong Kong. A neurocognitive battery was administered to evaluate their attention, memory, processing speed and cognitive flexibility performances. They also underwent magnetic resonance imaging to identify cerebral microbleeds. Validated self-reported questionnaires were administered to assess their mental health status and adherence to prophylactic treatment. General linear modelling was used to investigate the association of neurocognitive outcomes with risks factors, adjusting for age and education attainment.

Results

Forty-two patients were recruited (median age 32.0 years; 78.6% haemophilia A; 80.9% moderate-to-severe disease). Six patients (14.3%) had developed cerebral microbleeds. A subgroup of patients demonstrated impairments in cognitive flexibility (30.9%) and motor processing speed (26.2%). Hemarthrosis in the previous year was associated with worse attention (Estimate = 7.62, 95% CI: 1.92–15.33; p = .049) and cognitive flexibility (Estimate = 8.64, 95% CI: 2.52–13.29; p = .043). Depressive (Estimate = 0.22, 95% CI: 0.10–0.55; p = .023) and anxiety (Estimate = 0.26, 95% CI: 0.19–0.41; p = .0069) symptoms were associated with inattentiveness. Among patients receiving prophylactic treatment (71.4%), medication adherence was positively correlated with cognitive flexibility (p = .037).

Conclusion

A substantial proportion of patients with haemophilia demonstrated cognitive impairment, particularly higher-order thinking skills. Screening for cognitive deficits should be incorporated into routine care. Future studies should evaluate the association of neurocognitive outcomes with occupational/vocational outcomes.