Method comparison between hematopoietic progenitor cell and CD34+ cell counts in hematopoietic stem cell collection.

BACKGROUND: The reference method for hematopoietic stem cell enumeration is flow cytometric CD34+ cell analysis. We evaluated using the hematopoietic progenitor cell (HPC) count on the Sysmex hematology analyzer to safely replace some flow cytometric measurements performed in peripheral blood samples to guide apheresis timing. STUDY DESIGN AND METHODS: We compared HPC and CD34+ cell counts in 133 preharvest peripheral blood samples and 124 apheresis products. RESULTS: Pre-apheresis HPC counts ≥24 × 106/L in healthy donors and ≥36 × 106/L in lymphoma patients predicted adequate mobilization with 100% specificity and positive predictive value, saving 79% and 63% of flow cytometry analyses, respectively. Due to a positive bias (mean bias 50.26; 95% CI 36.24-64.29), a higher threshold was needed in multiple myeloma patients (HPC ≥ $$ \ge $$ 132 × 106/L), saving only 24% of flow cytometry analyses. CONCLUSION: When the HPC count is above the corresponding threshold, apheresis could be safely initiated without waiting for the flow cytometry result, thereby reducing time-to-decision. Lower HPC values, however, require confirmation by flow cytometry.

Reliability and construct validity of the ACTIVLIM-Hemo and Haemophilia Activities List (HAL) questionnaires in individuals with haemophilia.

OBJECTIVE: The objective of this study is to assess the reliability and construct validity of ACTIVLIM-Hemo, a newly developed Rasch-built questionnaire designed to evaluate activity limitations in people with haemophilia (PwH), in comparison with the Haemophilia Activities List (HAL), which was developed using Classical Test Theory. METHODS: A total of 130 participants with haemophilia A or B were included. They underwent various assessments, including joint health scoring (HJHS), functional tests (TUG and 2MWT) and completed questionnaires such as the BPI, IPAQ, HAL and ACTIVLIM-Hemo. Reliability indices and the minimum detectable change (MDC95) were determined for ACTIVLIM-Hemo and for HAL. Construct validity was evaluated through correlations and multiple linear regression, considering demographic and clinical factors. RESULTS: Both ACTIVLIM-Hemo (Person Separation Index = 0.92) and HAL (Cronbach's α = 0.98) demonstrated high reliability. The MDC95 for ACTIVLIM-Hemo represented 11.6% of its measurement range, while for HAL, it amounted to 18/100 score points. Activity limitations measured by both instruments were significantly correlated with demographic and clinical factors. Joint health (HJHS), pain severity (BPI) and walking performance (2MWT) emerged as the main predictors of activity limitations, explaining 75% of the variance in ACTIVLIM-Hemo and 60% in HAL. CONCLUSION: ACTIVLIM-Hemo stands as a reliable and valid instrument for assessing activity limitations in PwH. Both instruments exhibited significant correlations with demographic and clinical factors, but ACTIVLIM-Hemo displayed a more homogeneous construct. Given its linear scale and lower MDC95 and better targeting, ACTIVLIM-Hemo shows promise as a patient-centric instrument for assessing responsiveness to treatment during individual follow-up.

Risk-based and individualised management of bleeding and thrombotic events in adults with primary immune thrombocytopenia (ITP).

Although bleeding is one of the main symptoms of primary immune thrombocytopenia (ITP), risk factors for bleeding have yet to be fully established. Low platelet count (PC; <20-30 × 109 /L) is generally indicative of increased risk of bleeding. However, PC and bleeding events cannot be fully correlated; many other patient- and disease-related factors are thought to contribute to increased bleeding risk. Furthermore, even though ITP patients have thrombocytopenia and are at increased risk of bleeding, ITP also carries higher risk of thrombotic events. Factors like older age and certain ITP treatments are associated with increased thrombotic risk. Women's health in ITP requires particular attention concerning haemorrhagic and thrombotic complications. Management of bleeding/thrombotic risk, and eventually antithrombotic therapies in ITP patients, should be based on individual risk profiles, using a tailored, patient-centric approach. Currently, evidence-based recommendations and validated tools are lacking to support decision-making and help clinicians weigh risk of bleeding against thrombosis. Moreover, evidence is lacking about optimal PC for achieving haemostasis in invasive procedures settings. Further research is needed to fully define risk factors for each event, enabling development of comprehensive risk stratification approaches. This review discusses risk-based and individualised management of bleeding and thrombosis risk in adults with primary ITP.

Apixaban for the Treatment of Venous Thromboembolism Associated with Cancer.

BACKGROUND: Recent guidelines recommend consideration of the use of oral edoxaban or rivaroxaban for the treatment of venous thromboembolism in patients with cancer. However, the benefit of these oral agents is limited by the increased risk of bleeding associated with their use. METHODS: This was a multinational, randomized, investigator-initiated, open-label, noninferiority trial with blinded central outcome adjudication. We randomly assigned consecutive patients with cancer who had symptomatic or incidental acute proximal deep-vein thrombosis or pulmonary embolism to receive oral apixaban (at a dose of 10 mg twice daily for the first 7 days, followed by 5 mg twice daily) or subcutaneous dalteparin (at a dose of 200 IU per kilogram of body weight once daily for the first month, followed by 150 IU per kilogram once daily). The treatments were administered for 6 months. The primary outcome was objectively confirmed recurrent venous thromboembolism during the trial period. The principal safety outcome was major bleeding. RESULTS: Recurrent venous thromboembolism occurred in 32 of 576 patients (5.6%) in the apixaban group and in 46 of 579 patients (7.9%) in the dalteparin group (hazard ratio, 0.63; 95% confidence interval [CI], 0.37 to 1.07; P<0.001 for noninferiority). Major bleeding occurred in 22 patients (3.8%) in the apixaban group and in 23 patients (4.0%) in the dalteparin group (hazard ratio, 0.82; 95% CI, 0.40 to 1.69; P = 0.60). CONCLUSIONS: Oral apixaban was noninferior to subcutaneous dalteparin for the treatment of cancer-associated venous thromboembolism without an increased risk of major bleeding. (Funded by the Bristol-Myers Squibb-Pfizer Alliance; Caravaggio ClinicalTrials.gov number, NCT03045406.).

Building a haemophilia-specific navigator in Epic® Electronic Health Records: Single-centre preliminary experience.

INTRODUCTION: With the increasing complexity of haemophilia care and the advent of numerous therapeutic innovations, there is an unmet need for documentation and data collection tools tailored to people with haemophilia (PwH). To date, no fully integrated haemophilia-specific electronic health record (EHR) has been described in the literature. AIM: To evaluate the feasibility of integrating a haemophilia-specific navigator into the Epic EHR. METHODS: Based on clinical experience and registry datasets, we identified key variables describing both PwH and carriers of haemophilia. These were then incorporated into a REDCap database, which served as a starting point for the development of a comprehensive haemophilia flowsheet. We built a dedicated haemophilia navigator within Epic that includes a flowsheet featuring up to 212 variables, as well as customised note templates and patient lists integrating data from the haemophilia flowsheet. RESULTS: It was feasible to develop a haemophilia navigator within Epic over the course of 12 months. The navigator's flowsheet enables systematic and comprehensive clinical assessment of PwH and carriers, while customised patient lists provide a quick summary of each patient's profile to the haemophilia treatment centre staff and highlight issues that require an intervention. In our clinical practice, patients actively participated in the new documentation process and responded positively to the navigator. CONCLUSION: Adapting EHRs to the needs of PwH and carriers promotes holistic care for this population and provides an opportunity for patient empowerment. Such haemophilia-specific EHRs are expected to promote standardisation of care and facilitate the collection of registry data on a national and international level.

Psychophysical assessment of pain in adults with moderate and severe haemophilia: A cross-sectional study.

BACKGROUND: Joint pain is the hallmark of haemophilia; therefore it seems clinically rather a musculoskeletal than a bleeding disorder. Although joint pain in people with haemophilia (PwH) is a complex and multidimensional problem, pain assessment remains primarily focused on the structural evaluation of their joints. Whereas, only few data are available on the potential implication of psychophysical and psychological factors. OBJECTIVE: This study aimed to perform a psychophysical pain assessment including quantitative sensory testing (QST) and an evaluation of psychological factors in a large sample of PwH, to get insight into the individuals' pain system. METHODS: Ninety-nine adults (36.9 ± 13.5 years) with moderate/severe haemophilia A/B and 46 healthy controls filled in self-reported pain and psychological questionnaires and underwent a QST evaluation including static and dynamic tests. Static tests focused on the determination of thermal detection and pain thresholds and mechanical pressure pain thresholds. Dynamic tests evaluated pain facilitation and the efficacy of endogenous pain inhibition. Besides comparing PwH and healthy controls, between-subgroup differences were studied in PwH based on their pain distribution. RESULTS: The study revealed increased thermal and mechanical pain sensitivity and the presence of unhelpful psychological factors such as anxiety/depression in PwH. Among the subgroups, especially PwH with widespread pain showed altered somatosensory functioning. Enhanced pain facilitation and impaired efficacy of endogenous pain inhibition in PwH could not be observed. CONCLUSION: Altered somatosensory functioning and unhelpful psychological factors, appear to play an important role in the pathophysiology of pain in PwH, especially in PwH with widespread pain.

ACTIVLIM-Hemo: A new self-reported, unidimensional and linear measure of activity limitations in persons with haemophilia.

INTRODUCTION: To assess activity limitations in people with haemophilia (PwH), the self-reported Haemophilia Activity List (HAL) is widely employed, despite several methodological limitations impacting the interpretation of categorical scores. Modern psychometric approaches avoid these limitations by using a probabilistic model, such as the Rasch model. The ACTIVLIM is a Rasch-built measurement of activity limitations previously validated in several clinical conditions like neuromuscular disorders. AIMS: This study sought to develop the ACTIVLIM-Hemo, meaning an ACTIVLIM scale version specifically adapted to assess daily activity limitations in adult PwH. METHODS: Daily activities were assessed as "impossible," "difficult" or "easy" by 114 PwH (median age of 44 years) with 63 of them reassessed after 12 days. The Rasch Rating Scale model was used to identify activities delineating a unidimensional and linear scale unbiased by demographic and clinical status. Concurrent validity was determined through correlation with the HAL sub-scores and sum score. RESULTS: The ACTIVLIM-Hemo included 22 pertinent activities, with difficulties independent of demographic and clinical conditions, allowing a reliable measure of activity limitations (PSI = .92) expressed on a linear and unidimensional scale in PwH (7%-100 % range, ceiling effect of 1/114) with excellent test-retest reliability (ICC = .978). Spearman rank correlations between ACTIVLIM-Hemo and HAL sub-scores ranged between .623 and .869. CONCLUSIONS: The ACTIVLIM-Hemo is an easy-to-administer, valid and reliable alternative to HAL in assessing activity limitations in PwH. Its invariant scale can be used across conditions and time to compare the functional status of PwH over a wide measurement range.

Pain interferes with daily activities, emotions and sleep in adults with severe, moderate and mild haemophilia: A national cross-sectional survey.

INTRODUCTION: Pain is a major issue in people with haemophilia (PwH). Few studies comprehensively assessed pain in PwH using a biopsychosocial framework and studies in mild PwH are lacking. AIM: To assess pain prevalence, pain interference and their relationship with health-related quality of life (HR-QoL) in male adults with haemophilia. METHODS: A survey was initiated by the Belgian national member organisation. Pain in the last 24 h, pain severity (BPI-PS) and pain interference (BPI-PI) scores were obtained with the Brief Pain Inventory short-form (BPI). HR-QoL was evaluated with the EQ-5D-3L, giving the health utility index (EQ-HUI). Associations between EQ-HUI, BPI-PS and BPI-PI were analysed using Pearson's correlation test. A multiple regression analysed the relationship between HR-QoL and BPI-PS, with age and haemophilia severity as confounding factors. RESULTS: Within 185 respondents (97, 31 and 57 respectively severe, moderate and mild PwH), 67% (118/177) reported pain. In severe, moderate and mild PwH, respectively 86% (79/92), 71% (22/31) and 32% (17/54) reported pain. Median [IQR] BPI-PS, BPI-PI and EQ-HUI scores were respectively 1.5 [.0; 4.0], 1.6 [.0; 3.6] and .81 [.69; 1.00]. PwH reported pain interference with general activity (56% (99/176)), psychosocial factors such as mood (53% (93/175)), and sleep (51% (90/177)). Moderate correlations were found between EQ-HUI, BPI-PS and BPI-PI. After adjusting for age and haemophilia severity, BPI-PS explained 14% of HR-QoL variance. CONCLUSIONS: Pain is a major issue amongst PwH, including people with mild haemophilia. Pain interferes with activities, emotions, sleep and HR-QoL, arguing for a comprehensive biopsychosocial approach of pain.

Discordance between joint pain and imagery severity in the ankle joint and contributors of lower limb activity limitations in adults with haemophilia: A cross-sectional study.

INTRODUCTION: People with haemophilia (PwH) suffer from knee and ankle joint pain, but the association with structural damage remains underexplored. They report activity limitations but it is unclear which factors contribute to lower limb activity limitations (LL-AL). AIMS: This study aimed (i) to analyse the association between ankle joint pain and structure and (ii) explore the contribution of haemophilia-related, individual and psychological factors to LL-AL in PwH. METHODS: This study included 104 moderate/severe PwH. Ankle pain intensity was assessed with a numeric rating scale and pain sensitivity with algometry (pressure pain threshold (PPTA )). Ankle structure was assessed with MRI (IPSG-MRI) and ultrasound (HEAD-US), joint health with the Haemophilia Joint Health Score (HJHS). The HAL-LOWCOM subscore evaluated LL-AL. A Spearman correlation analysed the correlation between ankle pain and structure. The contribution of haemophilia-related factors (joint health, overall pain (Brief Pain Inventory-Pain Severity (BPI-PS)), functional status (2-Minute-Walking-Distance, Timed Up and Go); individual factors (age, BMI) and psychological factors (fear and avoidance beliefs over physical activity (FABQ-PA) and work (FABQ-Work), anxiety and depression) to LL-AL was explored using a regression analysis. RESULTS: Only low correlations were found between ankle pain intensity and structure (IPSG-MRI, HEAD-US). PPTA was unrelated to structure. Altogether, HJHS, overall pain (BPI-PS), FABQ-Work and age explained 69% of HAL-LOWCOM variance, with 65% explained by the combination of HJHS and BPI-PS. CONCLUSION: No meaningful associations were found between ankle pain and structural damage, suggesting that other factors may contribute to PwH's ankle pain. In contrast, mainly haemophilia-related factors explained LL-AL variance.

Joint status, pain and quality of life in elderly people with haemophilia: A case-control study.

INTRODUCTION: Elderly people with haemophilia (PwH) develop haemophilic arthropathy, pain, and reduced health-related quality of life (HR-QoL). The condition of elderly mild haemophilia patients have rarely been evaluated. This study aimed to compare joint status, pain, and HR-QoL between elderly with mild, moderate/severe haemophilia and healthy elderlies. METHODS: Knee/ankle abnormalities were assessed by ultrasound (HEAD-US) and physical examination (HJHS 2.1). Pain severity and pain interference were investigated using the Brief Pain Inventory. Pressure pain thresholds (PPTs) were obtained at knees/ankles and forehead. Functional limitations were evaluated using the 2-Minute-Walking-Test, Timed-Up-and-Go and HAL. The EQ-5D-5L questionnaire evaluated HR-QoL. Healthy controls (HCs) and elderly individuals with moderate/severe and mild haemophilia were compared using Kruskal-Wallis and Mann-Whitney U tests. RESULTS: From the 46 elderly PwH approached, 40 individuals (≥60 years) with haemophilia A/B (17 moderate/severe; 23 mild) and 20 age-matched HCs were recruited. Moderate/severe PwH displayed worse joint status, lower PPTs, and poorer HR-QoL than mild PwH and HCs (p-value = .010-<.001). HEAD-US abnormalities were observed in 100% of knees and 94% of ankles in moderate/severe PwH, versus 50% of knees and 61% of ankles in mild PwH. Pain was reported by 80% and 57% of moderate/severe and mild PwH, respectively. Low PPTs, functional limitations, and poor HR-QoL scores were likewise observed in some mild PwH, yet without significantly differing from HCs. CONCLUSION: This study highlights poor joint/functional status, pain, and HR-QoL outcomes in elderly with moderate/severe haemophilia. A few mild haemophilia subjects presented joint abnormalities, pain, functional limitations, and poor HR-QoL, without significantly differing from HCs. HIGHLIGHTS: Elderly individuals with mild haemophilia have not yet been extensively studied, whereas moderate/severe haemophilia individuals have proven to suffer from haemophilic arthropathy, pain, and poor health-related quality of life (HR-QoL). Using a case-control design, joint status, pain, and HR-QoL outcomes were examined in elderly haemophilia individuals and compared with those of healthy controls (HCs). Elderly moderate/severe haemophilia individuals exhibited worse joint status, increased joint pain sensitivity, and reduced HR-QoL compared with both mild haemophilia subjects and HCs. A subset of mild haemophilia subjects exhibited poor joint status, pain, and HR-QoL outcomes, without any differences noted when compared with HCs.

Bridging the gap: Survey highlights challenges and solutions in outreach and identification of people with inherited bleeding disorders.

INTRODUCTION: Inherited bleeding disorders (IBD) are genetic conditions that affect blood clotting, leading to complications such as prolonged or spontaneous bleeding into muscles or joints. Early identification and treatment are crucial to prevent complications and improve outcomes. However, effective patient outreach and identification programs for IBD face significant challenges globally. AIM: This study aimed to identify successful patient outreach initiatives for IBD, barriers encountered during implementation, and approaches used to overcome them. METHODS: The World Federation of Haemophilia (WFH) conducted a survey of its national member organizations and other patient associations, totalling 153 organizations, to identify common strategies, barriers to their implementation, and solutions for outreach and the identification of people with IBD. The survey consisted of both closed-ended and open-ended questions, and the data were analysed using descriptive statistics and thematic analysis. RESULTS: Common challenges included resource and sustainability-related aspects such as financial constraints, limited lab equipment for diagnosis, and inadequate government commitment. Significant barriers also encompassed physical/geographical challenges like difficulty accessing remote areas, and inadequate logistical support and transportation. Seven themes emerged to enhance patient outreach: resource mobilization; awareness-raising and advocacy; knowledge and capacity building; collaboration and partnership; decentralization of services; improved logistical support and infrastructure; utilization of technology and innovation; and financial aid and incentives. CONCLUSION: Multistakeholder collaboration, coupled with secured government commitment, is crucial for improving global outreach, diagnosis rates, and access to care for individuals with IBD. Customized outreach programs should consider regional contexts, financial constraints, and prioritize innovation.

Pain coping behaviour strategies in people with haemophilia: A systematic literature review.

INTRODUCTION: Despite the fact that joint bleeds (haemarthrosis) frequently occur in people with haemophilia (PwH) with invalidating arthropathies as result, the clinical pain experience has received only limited attention. A sudden increase in pain intensity can be linked to a bleed, but in most cases, no acute bleed is confirmed. Nevertheless, a patient's perception of an acute bleed as cause of the pain might impact the patients' behaviour in response to pain. It is therefore essential to gain more insight into pain coping strategies seen in PwH. AIM: This systematic review aims to identify the range of pain coping behaviour strategies used among PwH and the factors associated with pain coping behaviour. METHODS: This review was reported according to the Preferred Reporting Items for Systematic reviews and Meta-analyses guidelines (PRISMA). PubMed and Web of Science were systematically screened for relevant literature using keyword combinations related to adult PwH, pain and pain coping behaviour strategies. Risk of bias was assessed with the modified Newcastle-Ottowa Scale. RESULTS: Eleven full text articles (nine cross-sectional and two comparative studies) consisting of 1832 PwH met the inclusion criteria. Due to the heterogeneity of the study samples, quality of evaluation instruments and varying risk of bias, it was difficult to draw conclusions regarding the used pain coping behaviour strategies and associated factors. CONCLUSION: Literature on pain coping behaviour strategies and associated factors in PwH is still scarce and describes heterogenous results. Validated haemophilia-specific instruments are warranted to inventory pain coping behaviour in a standardized way.

Gaining more insight into ankle pain in haemophilia: A study exploring pain, structural and functional evaluation of the ankle joint.

INTRODUCTION: Ankle arthropathy is highly prevalent among people with haemophilia (PwH), even with prophylaxis, and leads to pain and disability. Mechanisms and consequences of painful symptoms related to ankle arthropathy have not been extensively studied. METHODS: A consecutive sample of 30 adult PwH was included (60 ankles). Ankle structure was assessed with magnetic resonance imaging (IPSG-MRI) and ultrasound (HEAD-US). The HJHS 2.1 assessed function of ankles and knees. Physical functioning was assessed with the Timed Up and Go test, the 2-Minute Walking Test and activity limitations with the HAL questionnaire. Health-related quality of life was evaluated using the EQ-5D-5L questionnaire. Overall pain severity was examined using the Brief Pain Inventory questionnaire and ankle pain intensity with a visual analogue scale. Pressure pain thresholds with an algometer assessed pain sensitivity. Spearman correlations were used to calculate interrelations between joint structure, function and pain. RESULTS: Twenty-five PwH (83%) reported ≥1 painful joint, with 67% reporting the ankle as most painful joint. MRI-confirmed abnormalities were seen in 76% of talocrural and 55% of subtalar joints. HEAD-US abnormalities were seen in 93% of the ankles. A large variation was seen in pain sensitivity at the ankle. While moderate to high correlations were observed between ankle structure and HJHS, no meaningful correlations were found between MRI-scores and pain intensity or sensitivity. CONCLUSIONS: Structural joint damage is present in many ankles but is not related to pain in PwH. Further studies should consider somatosensory nervous system dysfunction in PwH as contributing factor to painful ankle arthropathy.

Antithrombotic Therapy Duration after Patent Foramen Ovale Closure for Stroke Prevention: Impact on Long-Term Outcome.

Background: The optimal duration of antithrombotic therapy (ATT) after patent foramen ovale (PFO) closure remains under debate. This study sought to compare the clinical outcome of patients receiving antithrombotic agents for a short (6 months) versus extended (>6 months) period after the procedure. Methods: This was a retrospective cohort study using a propensity score matching analysis on 259 consecutive patients (131 males, 43 ± 10 years) undergoing PFO closure due to cryptogenic stroke, with complete follow-up (median duration of 10 [4-13] years). The outcome was compared between patients receiving short-term (Group short, N = 88) versus extended ATT (Group long, N = 171). Results: The PFO closure device was successfully implanted in all cases, with 3% of minor complications. After propensity score matching, there were no differences between Groups short and long in the rate of stroke (0.3 vs. 0.4% patient-year, p=1.00), bleeding (2 vs. 2% patient-year, p=0.17), and device thrombosis (0.3 vs. 0.1% patient-year; p=0.60). Univariate analysis showed that short-term ATT was not associated with an increased risk of recurrent stroke (HR: 1.271 [95% CI: 0.247-6.551], p=0.775) or prosthesis thrombus (HR: 0.50 [95% CI: 0.070-3.548], p=0.72). Kaplan-Meier analysis revealed similar overall survival in Group short and long (100 vs. 99 ± 1%, respectively; p=0.25). Conclusions: Short-term (6 months) ATT after PFO closure did not impair the clinical outcome, with a preserved low rate of recurrent stroke (0.3% patient-year) and device thrombosis (0.2% patient-year) at 10-year follow-up.

Feasibility and outcomes of low-dose and low-frequency prophylaxis with recombinant extended half-life products (Fc-rFVIII and Fc-rFIX) in Ivorian children with hemophilia: Two-year experience in the setting of World Federation of Haemophilia humanitarian aid programme.

INTRODUCTION: In sub-Saharan Africa, access to clotting factor concentrates (CFCs) is often extremely limited and published data on people with haemophilia on prophylaxis are almost not existent. AIMS AND METHODS: To assess the feasibility, barriers and outcomes of a low-dose and low-frequency prophylaxis with extended half-life (EHL) recombinant Fc fusion FVIII and FIX in Ivorian children on a two-year period in the setting of the World Federation of Hemophilia's (WFH) humanitarian aid programme. RESULTS: Twenty-five boys with haemophilia were included. Mean (SD) age at inclusion was 5.6 (2.5) years. The median [range] follow-up duration was 17 [11-24] months. Regimen of prophylaxis was 20 IU kg-1 1×/week in haemophilia A and every 10 days in haemophilia B. We observed a maximal reduction by 87.6% of the annual spontaneous joint bleeding rate and a slight decrease in the total HJHS scores (p = .047). Adherence problems related to parents' low education level and shortage in CFCs were the main issues to carry out the programme. Inhibitors occurred in 12.5%. CONCLUSION: This study confirms the feasibility and efficacy of low-dose and low-frequency prophylaxis in young Ivorian children with haemophilia treated with EHL CFCs donated through the WFH humanitarian aid programme. This work also highlights the crucial role of adherence and the need for appropriate education to achieve prophylaxis. Finally, it reminds the paramount objective of achieving self-sufficient, sustainable and available haemophilia replacement therapy for all worldwide.

Patient perspectives regarding gene therapy in haemophilia: Interviews from the PAVING study.

INTRODUCTION: Exploring patient perceptions regarding gene therapies may provide insights about their acceptability to patients. OBJECTIVE: To investigate opinions of people with haemophilia (PWH) regarding gene therapies. Moreover, this study aimed to identify patient-relevant attributes (treatment features) that influence PWH's treatment choices. METHODS: Semi-structured individual interviews were conducted with Belgian PWH, types A and B. A predefined interview guide included information sections and open, attribute ranking and case questions. Qualitative data were organized using NVivo 12 and analysed following framework analysis. Sum totals of scores obtained in the ranking exercise were calculated per attribute. RESULTS: In total, 20 PWH participated in the interviews. Most participants demonstrated a positive attitude towards gene therapy and were very willing (40%; n = 8) or willing (35%; n = 7) to receive this treatment. The following five attributes were identified as most important to PWH in making their choice: annual bleeding rate, factor level, uncertainty of long-term risks, impact on daily life, and probability that prophylaxis can be stopped. While participants were concerned about the uncertainty regarding long-term safety, most participants were less concerned about uncertainty regarding long-term efficacy. CONCLUSIONS: This qualitative study showed that most PWH have a positive attitude towards gene therapy and that besides efficacy, safety and the related uncertainties, also impact on daily life is important to patients. The identified patient-relevant attributes may be used by regulators, health technology assessment bodies and payers in their evaluation of gene therapies for haemophilia. Moreover, they may inform clinical trial design, pay-for-performance schemes and real-world evidence studies.

Patient preferences for gene therapy in haemophilia: Results from the PAVING threshold technique survey.

OBJECTIVES: The aim of the Patient preferences to Assess Value IN Gene therapies (PAVING) study was to investigate trade-offs that adult Belgian people with haemophilia (PWH) A and B are willing to make when choosing between prophylactic factor replacement therapy (PFRT) and gene therapy. METHODS: The threshold technique was used to quantify the minimum acceptable benefit (MAB) of a switch from PFRT to gene therapy in terms of 'Annual bleeding rate' (ABR), 'Chance to stop prophylaxis' (STOP), and 'Quality of life' (QOL). The design was supported by stakeholder involvement and included an educational tool on gene therapy. Threshold intervals were analysed using interval regression models in Stata 16. RESULTS: A total of 117 PWH completed the survey. Mean thresholds were identified for all benefits, but substantial preference heterogeneity was observed; especially for the STOP thresholds, where the distribution of preferences was bimodal. Time spent on the educational tool and residence were found to impact MAB thresholds. The most accepted (88% of PWH) gene therapy profile investigated in this study comprised of zero bleeds per year (vs. six for PFRT), 90% chance to stop prophylaxis, no impact on QoL, and 10 years of follow-up on side effects (vs. 30 for PFRT). CONCLUSIONS: Results from this study proved the value of educating patients on novel treatments. Moreover, preference heterogeneity for novel treatments was confirmed in this study. In gene therapy decision-making, preference heterogeneity and the impact of patient education on acceptance should be considered.

Management of COVID-19 Coagulopathy in a Patient with Severe Haemophilia A.

A 54-year-old man with a long history of severe haemophilia A treated prophylactically with efmoroctocog alpha (3,000 IU twice weekly) was diagnosed with COVID-19 infection. He had multiple risk factors for COVID-19 severity including obesity, diabetes mellitus and hypertension. He required prolonged intensive care unit (ICU) stay due to the severity of respiratory failure until his death on day 24. During his ICU stay, he received a continuous infusion of efmoroctocog alpha in order to maintain factor VIII activity between 80 and 100%, together with therapeutic doses of low-molecular-weight heparin targeting anti-Xa activity above 0.5 IU/mol. He tolerated numerous invasive procedures without bleeding. At post-mortem examination, there was no evidence for thrombosis or haemorrhage in the different organs.

Low rate of subclinical venous thrombosis in patients with haemophilia undergoing major orthopaedic surgery in the absence of pharmacological thromboprophylaxis.

BACKGROUND: Deep venous thrombosis (DVT) is a common postoperative complication in patients undergoing major orthopaedic surgery of the lower limbs, such as total hip or knee replacement (THR, TKR). Routine pharmacological thromboprophylaxis with low-molecular-weight heparin (LMWH) or a direct oral anticoagulant agent is strongly recommended in this setting. THR and TKR as well as ankle arthrodesis are frequently performed in people with haemophilia (PWH) and chronic haemophilic arthropathy. Pharmacological thromboprophylaxis in this population remains controversial. METHODS: We report the results of a single-centre prospective study initiated in 2002 evaluating by systematic Doppler ultrasound the incidence of subclinical DVT in consecutive PWH referred for major orthopaedic surgery and not receiving pharmacological thromboprophylaxis. RESULTS: We included 46 different PWH (39 Haemophilia A, 7 Haemophilia B, 27 severe, 15 moderate and 4 mild forms) undergoing 67 orthopaedic procedures. Most (89.5%) were performed with continuous infusion of clotting factor concentrates. Rehabilitation was usually started on day 1 post-op. No clinical DVT or pulmonary embolism was suspected. In total, there were 5 cases (3 severe, 1 moderate HA and 1 moderate HB) of subclinical DVT which were all distal. Two patients were treated with a short course (10-14 days) of LMWH. The overall incidence of DVT was 7.5%. CONCLUSIONS: These data provide imaging-based evidence that the risk of DVT following major orthopaedic surgery among PWH is low. Identified DVTs were distal and resolved spontaneously in most cases. Systematic pharmacological thromboprophylaxis in this specific population is probably for most patients not required.

Can we compare haemophilia carriers with clotting factor deficiency to male patients with mild haemophilia?

INTRODUCTION: Certain haemophilia carriers demonstrate an increased bleeding tendency, mainly related to clotting factor deficiency. No study has so far formally compared the bleeding phenotype of women and girls with mild FVIII or FIX deficiency and associated management with that of male patients affected by mild haemophilia A and B. MATERIAL AND METHODS: We retrospectively evaluated 44 women and girls with mild FVIII or FIX deficiency (FVIII or FIX 0.05-0.5 IU/mL) and 77 male patients with mild haemophilia A or B and compared them with respect to clotting factor level, age at and trigger for diagnosis, as well as treatment modalities. RESULTS: After excluding gender-related haemorrhagic symptoms, haemophilia carriers with plasma factor levels in the mild haemophilia range and male patients affected by mild haemophilia present a comparable haemorrhagic profile, mainly characterized by mucocutaneous and postinjury bleeding. Haemophilia carriers with clotting factor deficiency, however, distinguish themselves in terms of later age at diagnosis, higher mean factor levels and trigger for diagnosis. CONCLUSIONS: Women and girls with mild FVIII or FIX deficiency should be considered as mild haemophilia patients and have access to care and management inspired from male haemophilia patients while integrating differences and specificities. Larger international studies comparing the clinical presentation and treatment modalities of mild clotting FVIII and FIX deficiencies in both haemophilia males and females should be encouraged.