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Abstract
Introduction Haemophilic arthropathy, a serious complication of haemophilia, results from recurrent joint bleeding, causing progressive joint damage and severely impacting patient quality of life. Rehabilitation therapy (RT) effectively addresses declining physical function due to joint degradation, but pain during RT can hinder its success. Therefore, an effective pain-alleviating treatment method is required. The single-joint hybrid assistive limb (HAL-SJ), a powered exoskeleton, measures bioelectric potential during muscle contraction and provides motorised support, potentially alleviating pain.
Objective This study outlines our protocol for a randomised, prospective, single-blind (evaluator) trial aimed to investigate the effects of HAL-SJ on pain reduction during RT, kinesiophobia and other physical functions in patients with haemophilia.
Methods and analysis This two-group comparison intervention study will include 24 male patients aged 12–85 years diagnosed with a bleeding disorder necessitating RT for pain and physical function improvement. The primary outcome measures pain changes during the first and second RT session in patients receiving HAL-SJ-assisted RT compared with traditional RT without HAL-SJ. The secondary outcomes include kinesiophobia (Japanese version of the Tampa Scale for Kinesiophobia), standing position gait (zebris FDM-T treadmill), range of motion (manual goniometer) and body surface temperature (infrared thermography camera) during the study period of up to 3 months or until the end of 10 RTs. RT intensity remains below that required to move the affected joint against gravity, given HAL-SJ’s muscular support. The follow-up period extends to 1 month after the last RT. Intergroup study variables are compared by an unpaired t-test or Mann-Whitney test. Intragroup comparisons of secondary outcomes are analysed by a paired t-test or Wilcoxon signed-rank test.
Ethics and dissemination This study was approved by the accreditation committee of Nara Medical University Hospital. The study results will disseminate through publication in a peer-reviewed journal.
Trial registration number jRCTs052220076.
- Haemophilia, hybrid assistive limb
- rehabilitation therapy
- haemophilic arthropathy
- bleeding disorders
- single-joint limb
Data availability statement
Not applicable.
This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.
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- Haemophilia, hybrid assistive limb
- rehabilitation therapy
- haemophilic arthropathy
- bleeding disorders
- single-joint limb
Strengths and limitations of this study
This study is a randomised prospective, single-blind two-group comparison intervention study at a single facility.
This study will be the first to investigate the effectiveness of rehabilitation therapy (RT) using the powered exoskeleton single-joint hybrid assistive limb (HAL-SJ) in patients with diagnosed bleeding disorders.
HAL-SJ for bleeding disorders detects bioelectric potential during muscle contractions and assists with joint movement, possibly enabling RT to be performed with less pain and fear.
Due to the rarity of bleeding disorders, the sample size for this study will be small, and patient recruitment may be prolonged.
The level of pain and fear experienced by patients during movement may depend on the degree of joint degradation and severity of the joint deformity.
Introduction
Haemophilia is the most common congenital coagulation disorder caused by deficiencies of coagulation factors VIII or IX.1 2 Patients with haemophilia (PwH) have recurrent bleeding episodes from early childhood. Haemarthrosis is one of the primary symptoms of PwH. This condition involves leakage of blood into the joint cavity, causing inflammation that leads to severe pain, fear of haemorrhage and kinesiophobia, defined as the self-imposed limitation of physical movement due to the fear of pain.3 4 Repeated intra-articular haemorrhages result in chronic synovitis, which, in turn, can destroy articular cartilage and subchondral bone, leading to haemophilic arthropathy (HAT).5 HAT is frequently observed in the ankle, knee and elbow. As HAT progresses, destructive changes occur in the joints,6 7 and physical function reduces due to limited range of motion (ROM) in the joints and/or muscle weakness, drastically impeding the quality of life (QOL).8–10 Notably, the development of new therapeutic formulations and improvements in therapeutic methods have reduced the incidence of symptomatic bleeding among PwH.11 However, it is difficult to avoid haemorrhage for an entire lifetime, and although the degree of arthritis may vary, it affects nearly all PwH.
While there are reports that RT can effectively enhance physical function and alleviate chronic pain12–14 in individuals with HAT, there are no reports of pain assessment during RT. Conversely, a study of patients without haemophilia reported the association of a strong fear of pain with poor adherence to RT,15 suggesting that intense pain is detrimental to RT success. Kinesiophobia in PwH is well known; thus, it is plausible that minimising pain during rehabilitation in PwH may not only enhance adherence but also ameliorate kinesiophobia.
Recent advances in robotics technology have led to the development of exoskeleton devices that can support patients during RT. Previous studies have reported positive outcomes from using an exoskeleton device, called single-joint hybrid assistive limb (HAL-SJ), for RT following orthopaedic surgery.16 17 HAL-SJ detects the patient’s bioelectric potential when they attempt to contract a muscle and assists with completing the joint movement.18 19 This reduces the burden on the joint, lessening the pain in RT and ultimately improving the muscle strength and physical function.20 However, to our knowledge, no study has yet investigated HAL-SJ application to reduce pain and kinesiophobia in PwH, including those with HAT.
The study aims to investigate the effectiveness of HAL-SJ in reducing pain during the initial, often the most painful, period of RT in PwH. We hypothesise that the utilisation of HAL-SJ will reduce acute pain and alleviate kinesiophobia. The first and second RT sessions will be conducted with or without HAL-SJ immediately following haemorrhage, surgery or a chronic decline in physical function. Additionally, all patients will begin the HAL-SJ-assisted RT in the third session to confirm the effectiveness of the long-term use of HAL-SJ in reducing daily pain and fear of exercise and improving ROM, body surface temperature, standing posture and gait.
Methods and analysis
Trial design
This single-facility randomised prospective, single-blind two-group comparison intervention study will investigate the effectiveness of HAL-SJ-assisted RT in PwH. Since HAL-SJ is a device physically affixed to the patient’s body, it is not feasible to maintain blinding for both the subjects and the therapists. However, the evaluator will be blinded throughout the study. This study was approved by the Nara Medical University Certified Review Board (ID: nara0038) and registered in the Japan Registry of Clinical Trails (trial registration number: jRCTs052220076). This study began on 1 September 2022 and was scheduled to conclude on 31 October 2025. Due to the COVID-19 pandemic and associated restrictions on rehabilitation and surgical procedures, the actual date of patient enrolment commenced on 8 June 2023.
Patients
Male patients diagnosed with a bleeding disorder, mainly haemophilia A and B, will be recruited from the Rehabilitation Department of Nara Medical University Hospital in Japan (figure 1). Additionally, all patients participating in the study will undergo an examination by a rehabilitation specialist to confirm their eligibility for inclusion. Treatment will commence after the patient has given informed consent to participate in the study.
Study flowchart. HAL-SJ, single-joint hybrid assistive limb.
Inclusion criteria
This study will include male patients aged 12–85 years, diagnosed with a bleeding disorder at Nara Medical University Hospital and requiring RT to improve pain and physical function. All patients will be required to provide written informed consent. The determination of whether a patient meets the above selection criteria will be made during the medical examination by a rehabilitation specialist.
Exclusion criteria
The exclusion criteria will be as follows: (1) patients with severe joint deformities or skin sensitivities that prohibit using HAL-SJ; (2) patients who have undergone arthrodesis in the past (except for those who required RT at a different joint), those with fragile skin and possible skin damage due to electrode attachment, those with an implanted pacemaker or implantable cardioverter-defibrillator or those with a history of cardiovascular or respiratory diseases; (3) patients with moderate or severe involuntary movements, ataxia, postural instability or severe contractures/spasticity; (4) patients for whom haemophilia treatment was challenging (such as PwH with high or low responder inhibitors in whom high-dose clotting factor concentrates treatment failed in the past); and (5) patients who have difficulties understanding the explanations or instructions and those deemed unsuitable by physicians.
The study details and protocols will be explained to each patient verbally and in writing. The patients will be informed that they will be randomly assigned to study groups, with each group undergoing a different course of therapy.
Randomisation
Patient randomisation will be conducted at the case registration centre, before initiating the study, and based on the allocation results. Patients will be stratified according to the joint requiring RT (elbow, knee or ankle joint), as recorded during RT registration, and their condition and randomised using a stratified permuted block method. Additionally, the researchers will be blinded to the details of the randomisation allocation procedure to reduce predictability.
Intervention
HAL-SJ (HAL-FS01, Cyberdyne Inc., Japan) will be used during RT (figure 2). To assess the effectiveness of pain reduction using HAL-SJ, patients will be divided into two groups during the first and second RT sessions: one group will use HAL-SJ (HAL-SJ-wearing group), and the other will not (HAL-SJ-non-wearing group). From the third RT session onwards, all patients will undergo RT using HAL-SJ.
Rehabilitation treatment flowchart. RT, rehabilitation treatment; HAL, hybrid assistive limb; VAS, visual analogue scale; TSK-J, Japanese version of the Tampa Scale for Kinesiophobia.
During the first and second RT sessions, patients in the HAL-SJ-wearing group will undergo an initial RT session, including static stretching of the musculoskeletal system around the affected area and isometric contraction exercises of the affected area to the extent that such exercises do not cause pain. Next, the patients will perform five repetitions of active assistive and flexion-extension exercises for the affected joint using HAL-SJ. After completing the flexion-extension exercises with and without HAL-SJ, the patient’s pain will be assessed using a visual analogue scale (VAS). Lastly, the Japanese version of the Tampa Scale for Kinesiophobia (TSK-J) will be used after the first, second and last RT sessions to evaluate the effect of the RT session with and without HAL-SJ on kinesiophobia.
Patients who do not wear HAL-SJ during the first and second RT sessions will undergo static stretching of the musculoskeletal system around the affected area and isometric contraction exercises on the affected area to the extent that such exercises do not cause pain. Next, the patients will perform five repetitions of flexion-extension exercises via active assistive exercises. After a 5 min break, equivalent to the time required for the HAL-SJ-wearing group to attach the device, the second group will perform another round of five repetitions of flexion-extension exercises on the affected area via active assistive exercises. After each set of flexion-extension exercises, the patients’ pain will be assessed using a VAS. To assess the effect of the RT session on kinesiophobia, TSK-J will be used at the end of each RT session.
For patients requiring therapy on more than one joint, only the data of a single joint will be included, and the remaining joints will undergo RT after assessing the pain and kinesiophobia for the target joint. The intervention period for the primary outcome extends until the completion of the second RT, while for the secondary outcome, it spans up to 3 months or until the conclusion of 10 RTs. Subsequently, there is a follow-up period of 1 month following the last RT session.
The principal investigator and the sub-investigators will discontinue the HAL-SJ-assisted therapy if they determine that the clinical trial cannot continue. The date and reason for discontinuation and the patient’s progress will be recorded in the patient’s medical chart, case report and electronic medical chart. If the trial is discontinued due to illness, appropriate follow-up will be conducted until the patient regains baseline health.
Overview and setup of HAL-SJ
HAL-SJ is a wearable robot comprising a controller, proximal and distal attachments, and a power unit that generates torque to assist patients during joint flexion-extension exercises (figure 3). The single-joint type device includes a motor that assists during the exercise of a single joint only. The patient’s muscle contractions are monitored using attached electrodes to provide feedback to the device, and the electrodes are placed according to the SENIAM guidelines.21 The rehabilitation specialist and physical therapist set the flexion and extension angles, discretionary control mode (Basic, Auto Flx, Auto Ext or Calm), assist gain adjustment (0–100) and flexion-extension assist balance (0–100%) based on the patient’s condition. RT intensity remains below that required to move the affected joint against gravity since the HAL-SJ supports the patient’s muscular movements.
Lateral image of the single-joint hybrid assistive limb on the elbow (a), knee (b) and ankle joints (c).
Outcome measurements
A physical therapist with a master’s degree in musculoskeletal medicine and 7 years of clinical experience will assist with the RT and conduct all the patient evaluations. Besides diagnosis, severity, number of previous haemorrhage events, level of breakdown in the therapeutic target joint RT, HAT severity by X-ray (Pettersson scoring), medical history and complications, sociodemographic variables, such as patient age, height, weight, dominant hand, dominant foot and the assessment of fatigue and satisfaction with RT, will be recorded in the case report by the therapist. Additionally, a VAS will be used to assess the joint exercise pain and the TSK-J to evaluate kinesiophobia.
The primary study outcomes will be assessed by measuring the level of pain experienced during flexion-extension exercises of the affected area using a VAS after each RT session. Patients who wear HAL-SJ will have their pain measured twice: after performing five repetitions of flexion-extension exercises of the affected area without the device and after performing five repetitions of flexion-extension exercises using HAL-SJ. Furthermore, patients who do not wear HAL-SJ will have their pain measured after performing five repetitions of flexion-extension exercises and another five repetitions of the same exercises. The degree of change in pain will be compared between the two groups after the first and second RT sessions. Moreover, pain levels will be measured during the third and subsequent RT sessions as a secondary outcome.
The secondary outcome is the change in kinesiophobia, quantified using the TSK-J. Kinesiophobia will be assessed at registration and compared with the results after the second and final RT sessions. Additionally, pain, kinesiophobia, muscle strength, ROM, standing posture, gait parameters and body surface temperature will be assessed before and after each RT session.
The TSK-J will be used to measure kinesiophobia.22 23 The TSK-J is a 17-item questionnaire that employs a four-tier Likert scale, with total scores of 17–68 points; higher scores indicate higher levels of kinesiophobia. Specifically, scores exceeding 37 points indicate a high level of kinesiophobia, as described in a previous study.24
FDM-T treadmill on a zebris FDM-T treadmill (zebris Medical GmbH, Germany), with a built-in force sensor metric system, will be used to evaluate the patient’s standing posture and gait parameters. The reliability of spatiotemporal and kinematic gait parameters has been demonstrated in a previous study.25 Patients will stand on a force plate for 10 s to measure the centre of pressure (COP) trajectory for the standing posture. Additionally, patients will walk on the treadmill for 30 s at a comfortable pace set by the patient without therapeutic intervention from the evaluator to measure the COP trajectory for walking gait. Patients will be instructed to ‘walk normally’ at a comfortable speed. Static (standing) and walking parameters will be analysed using the zebris FDM software, version 1.10. The standing posture will be analysed using the COP path length (mm) and 95% confidence ellipse area (mm2). Additionally, gait will be analysed using the following: (1) COP anterior/posterior variability (mm), the SD of the intersection point in the anterior/posterior direction, with zero being equivalent to constant strides on the treadmill; (2) COP lateral variability (mm), the SD of the intersection point in the lateral direction, with zero being equivalent to a constant width between the legs; (3) COP lateral symmetry (mm), the left/right shift of the intersection point, with the zero position being equivalent to perfect symmetry; (4) single limb support line (mm), the longitudinal length of the movement of the COP during single-leg support, which is calculated as a numerical value on each side; and (5) velocity (km/h). Notably, COP refers to the intersection of the COP trajectories, with a positive value indicating a shift of the centre of gravity to the right and a negative value indicating a shift to the left. These parameters will be automatically calculated and generated using the FDM-T software and converted to absolute values for statistical analyses.
ROM of the affected joint and the opposite joint will be measured using a manual goniometer. Additionally, the passive ROM during flexion and extension of the joint undergoing RT will be measured using the range of joint motion indication and measurement methods proposed by the Japanese Orthopaedic Association and the Japanese Association of Rehabilitation Medicine. The elbow joint flexion and extension will be measured with patients in the upright sitting position with the forearm in a supine position, using the humerus as the basic axis and the radius as the moving axis. Moreover, the knee joint flexion and extension will be measured with patients in the supine position, using the femur as the basic axis and the fibula as the moving axis. Hip joint flexion will be conducted for knee flexion measurement, and ankle joint flexion and extension will be measured with patients in the supine position and the knee in flexion, using the vertical line along the sagittal plain towards the fibular axis as the basic axis and the sole of the foot as the moving axis.
The body surface temperature will be measured using the Teledyne FLIR infrared thermography camera (FLIR E54-EST; Teledyne FLIR LLC, USA). The clothing covering the affected and non-affected joints will be removed, and the patients will rest for 5 min before temperature measurement to minimise the effects of exercise or clothing on changes in body surface temperature. The measurements will be obtained in a room with uniform temperature and humidity without air conditioning, fan or sunlight. Moreover, the images will be analysed using Thermal Studio Pro (Teledyne FLIR LLC, USA) and ThermoHuman software (ThermoHuman, Madrid, Spain) to calculate the difference in the mean skin temperature for the regions of interest between the affected and non-affected joints.
Assessment of safety
The safety of the HAL-SJ-assisted RT for PwH will be assessed by comparing the frequency of haemorrhage during conventional RT performed with HAL-SJ with a historical control value.
Assessment of patient symptoms
The safety of the HAL-SJ-assisted RT has been reported in previous studies.16 17 26 However, no studies have reported its use for PwH, and the prevalence of new haemorrhage in the affected areas is unclear. Ultrasound, CT or MRI will be used to assess severe pain, redness/heat or increased surface temperature in the affected area to determine whether a haemorrhage has occurred. If severe haemorrhage is detected, the HAL-SJ-assisted RT will be discontinued. When the haemorrhage is resolved, conventional RT will be resumed without using HAL-SJ. Additionally, clinical examinations will be conducted daily if the patient has severe or moderate pain without haemorrhage. Moreover, the HAL-SJ-assisted RT will be continued if the patient recovers within 3 days but will be discontinued if the pain or haemorrhage persists for >3 days.
Sample size
Due to the small number of PwH, the number of patients eligible for registration is expected to be low. The number of patients who regularly visit the Nara Medical University Hospital and meet the inclusion criteria will be approximately 35, and it is estimated that consent would be obtained from 24 (70%). When statistical significance is set at p<0.05, a 1.15-point decrease in pain due to the use of HAL-SJ would be equivalent to a statistical power of 80%.
Criteria for discontinuation
The HAL-SJ-assisted RT will be discontinued if the principal investigator and sub-investigators determine that the clinical trial should not continue. The date and reason for discontinuation and the patient’s progress will be noted in the patient’s medical chart and case report. If the trial is paused due to illness, appropriate follow-up will be performed until the patient regains baseline health.
The reasons for discontinuation of the HAL-SJ-assisted RT include the patient’s request for withdrawal or withdrawal of consent, the discovery that the patient does not meet the inclusion criteria after trial registration, RT not being recommended due to haemorrhage or pain, worsening complications, patient illness, early hospital discharge or transfer preventing a full course of RT at the study hospital and the presiding physician determining that the trial cannot continue.
Statistical analyses
Categorical baseline data will be expressed as numbers and percentages and continuous variables as mean and SD or median and range. For all analyses, the significance level will be set at 5%. All statistical analyses will be performed using SPSS version 26.0 for Windows (SPSS Inc., Chicago, Il, USA). To assess homogeneity, the Shapiro-Wilk test will be conducted. To compare study variables between groups, either an unpaired t-test or a Mann-Whitney test will be employed. For secondary outcomes, intragroup comparisons will be analysed by either a paired t-test or Wilcoxon signed-rank test.
Primary outcomes
The difference in VAS scores will be calculated as the VAS score after the second set of flexion-extension exercises minus the VAS score after the first set of flexion-extension exercises. Additionally, the VAS score differences will be calculated for the first and second sessions for each patient, and the mean value will be used in the analyses. If there are only values from the first or second sessions, those values will be used as such. Moreover, the differences in VAS scores between the groups will be analysed using an unpaired t-test and the Mann-Whitney U-test with point estimation and an estimated CI of 95%. Additionally, a sensitivity analysis will be performed with linear models with values from the first and second sessions and randomisation factors adjusted as covariates to graphically assess the change in VAS score over time.
Secondary outcomes
The changes in each secondary outcome between the time of patient registration and immediately following the first and second RT sessions will be determined. Moreover, the number of sessions performed will be compared between the groups using a paired t-test and the Wilcoxon signed-rank test with point estimation and an estimated CI of 95%. Additionally, the differences between the groups will be analysed using an unpaired t-test and the Mann-Whitney U-test with point estimation and an estimated CI of 95%.
Analysis of safety
The safety of RT using HAL-SJ and specifically the frequency of at least one haemorrhagic event during RT will be determined. The cumulative number of haemorrhages will be recorded for each patient. Additionally, the differences in the number of haemorrhages between the groups will be analysed using an unpaired t-test and the Mann-Whitney U-test with point estimation and an estimated CI of 95%. Lastly, the incidence of haemorrhage in this study will be compared with that reported in previous studies regarding the non-HAL-SJ-assisted conventional RT.
Patient and public involvement statement
Patients and/or the public are not involved in the design, conduct, reporting, or dissemination plans of this research.
Data monitoring
Data monitoring will be conducted by a clinical research coordinator independent of competing interests within the institution.
Protocol amendments
If we require changes to the study protocol, we request the Accreditation Committee of Nara Medical University Hospital to make the corrections.
Disclosure of clinical research information
Before commencing this research, we registered the study protocol in the database (jRCT) maintained by the Ministry of Health, Labour and Welfare of Japan. The results of this research belong to the research group. We plan to report the results at academic conferences or as research papers. We also plan to grant public access to the full protocol, participant-level dataset and statistical code.
Ethics and dissemination
All patients will be provided with a full explanation of the study orally and in writing following the guidelines set out by the Declaration of Helsinki, and patient consent and signatures will be obtained. This study was approved by the Accreditation Committee of Nara Medical University Hospital (ID: nara0038).
Management of personally identifiable information
Data is anonymised and managed. The correspondence table is stored on an encrypted hard drive that can only be accessed from a specific PC. With regard to the handling and storage of materials, a record shall be made of the provision of the relevant samples and information. The principal investigator shall retain the relevant records prepared by the investigators, etc, for a period of 3 years from the date of the provision of the specimens and information. The principal investigator shall retain documents related to the conduct of the study, etc, and dispose them in an anonymised form 5 years after the publication of the research.
Discussion
In this study, we assumed the HAL-SJ-assisted RT could provide less-pain rehabilitation, achieve early goals for muscle strength and ROM and overcome kinesiophobia. The decline in physical function in PwH is due to mechanical impairment of the joints and psychological factors, such as kinesiophobia and fear of haemorrhage. Previous reports have shown that rehabilitation can improve physical function in PwH.11–13 Therefore, rehabilitation is recommended for PwH. However, PwH strongly fear pain, making the initiation and continuation of RT challenging. A report on RT with HAL-SJ after total knee replacement in non-haemophilic patients showed that the HAL-SJ-assisted exercise causes less pain during RT and has a higher therapeutic effect than conventional RT.26 27 Moreover, reducing kinesiophobia improves the QOL of PwH, according to a report.28 Based on this, we hypothesised that HAL-SJ might be an optimal rehabilitation method to improve QOL of PwH with latent fear of pain by improving their mechanical functions and alleviating their psychological fears, maximising the RT effect.
A limitation of this study is the small number of cases. Notably, the number of planned cases is based on the number that can be allocated at a single site during the study period. Advances in haemophilia treatment have reduced the number of cases requiring joint surgery and cases of bleeding. However, as the Joint Outcome Study has shown,8 patients with joint dysfunction will remain prevalent even in the future. This study offers a new treatment strategy for PwH, whose QOL is unlikely to improve with advances in coagulation agents.
Data availability statement
Not applicable.
Ethics statements
Patient consent for publication
Acknowledgments
We thank Naoki Matsumoto for assistance with the submission and NaokiOzu for instruction in statistical analysis. We thank Editage (https://www.editage.jp) for editing a draft of this manuscript.
References
Footnotes
YM and AS contributed equally.
Contributors Conceptualisation was done by the following authors: YM, AS, YI and MS. The design was prepared by as follows: AS, YI, DS and MS. Data analysis was conducted by these authors: YM, AS and KT. Data interpretation was done by all authors. The following authors did the manuscript drafting: YM, AS, YI, KT and AS. Final approval was given by as follows: KN, YT, AK and MS. All authors have reviewed the article and have approved the final manuscript.
Competing interests YM, AS, KT and MS: members of Medicinal Biology of Thrombosis and Hemostasis established by Nara Medical University and Chugai Pharmaceutical Co., Ltd. MS: patents for inventions relating to products of Chugai Pharmaceutical Co., Ltd. YI: grants or research support from Chugai Pharmaceutical Co., Ltd. and Olympus Co., Ltd. DS and AK: no conflict of interest. KT: grants or research support from Japan Blood Products Organisation, The Mother and Child Health Foundation and Novo Nordisk Pharma. KN: grants or research support from Chugai Pharmaceutical Co., Ltd.; Takeda Pharmaceutical Co., Ltd.; KM Biologics Co., Ltd.; Sanofi Co., Ltd; Novo Nordisk Pharma Co., Ltd; Bayer Co., Ltd.; AbbVie GK LLC; and Janssen Pharmaceutical K.K. Co., Ltd; honoraria or consultation fees from Chugai Pharmaceutical Co., Ltd.; Sanofi Co., Ltd; and CSL Behring. YT: grants from Chugai Pharmaceutical Co., Ltd. and Asahi Kasei Co., Ltd. MS: representative of Medicinal Biology of Thrombosis and Hemostasis collaborative research laboratory; research support from Chugai Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd. and CSL Behring; honoraria or consultation fees from Chugai Pharmaceutical Co., Ltd.; speaker’s bureau from Chugai Pharmaceutical Co., Ltd.; CSL Behring; Sanofi; Bayer; Novo Nordisk Pharma; Takeda Pharmaceutical Co., Ltd.; Pfizer; and Fujimoto Seiyaku Corp.
Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Provenance and peer review Not commissioned; externally peer reviewed.