Effects of Individualized Exercise Intervention Combined With Manual Therapy on Musculoskeletal System, Cardiopulmonary Endurance and Quality of Life in Severe Hemophilia Patients With Polyarthropathy
Phase: NA
Conditions: Severe Hemophilia
Sponsor: Far Eastern Memorial Hospital

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Far Eastern Memorial Hospital 
Human subject research study protocol 
I. 
Title 
Effects of individualized exercise intervention combined with manual therapy on the 
musculoskeletal system, cardiorespiratory endurance and quality of life in severe 
hemophilia patients with polyarthropathy. 
II. 
Principal Investigator 
Wan-Jung Kao / Title: Physical Therapist  
III. 
Co-Investigator 
Hui-Hsun Tien, Ting-Wei Chi / Title: Physical Therapist  
IV. 
Background 
Hemophilia is clinically characterized by acute bleeding, more than 80% of which 
occur in specific joints (commonly occurring in ankle joints, knee joints and elbow 
joints, followed by hip joints, shoulder joints and wrist joints) and muscles (iliopsoas 
and gastrocnemius). Joint bleeding worsens joint damage in hemophilia patients, 
increasing the risk of chronic synovitis and hemophilic arthropathy in the long term. 
Improper treatment of intramuscular bleeding cause muscle contracture, especially 
in muscles that cross joints (such as calf muscles and psoas muscles), bleeding sites 
in these muscles are related to neurovascular damage and require immediate 
treatment to prevent permanent damage and loss of function [1]. 
For hemophilia patients with chronic synovitis who cannot take routine prophylaxis, 
the World Federation of Hemophilia recommends non-surgical treatment, including 
short-term prophylaxis for 6-8 weeks to control bleeding, selective COX-2 inhibitors, 
or physical therapy improves muscle strength and joint function to reduce pain and 
inflammation [6]. In addition, past studies have also recommended that patients 
with hemophilia receive physical therapy evaluation and intervention to improve 
muscle strength, balance, cardiorespiratory fitness, reduce the risk of falls, and 
improve quality of life [7]. 
A complete assessment of acute joint bleeding and physical therapy based on the 
clinical status of the case is necessary [3]. Past studies have shown that 
individualized exercise significantly improve muscle strength, upper and lower limb 
mobility [10], so individualized physical therapy should develop treatment plans and 
content based on the individual's abilities and goals [6]. 
Many literatures have discussed the safety and effectiveness of different physical 
therapy interventions for hemophilia patients and found that exercise therapy, 
manual therapy, electrotherapy and hydrotherapy, etc. improve muscle strength and 

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joint mobility [6][10][11]. Coupled with appropriate physical therapy, it can also 
strengthen muscles, increase joint stability, avoid joint contracture, and reduce the 
possibility of re-bleeding [2][4][7][8]. Past literature has recommended that exercise 
therapy should be provided to patients with hemophilia. However, there is currently 
no consensus on the type, severity, and frequency of safe exercise programs, 
especially for hemophilia patients with polyarthropathy [12][13]. In addition, manual 
therapy is another effective physical therapy intervention to increase biomechanical 
extensibility and joint function by mobilizing and stretching joints and soft tissues 
(including muscles and nerves). Although the use of manual therapy for patients with 
hemophilia is increasing, most studies focus on exploring the mobility of single joint 
[12][13], and the number of studies on manual therapy for multiple joints in the past 
literature is limited. As hemophilia patients' life expectancy increases, workforce 
participation, overall functioning, and independent activity daily living have become 
current issues and challenges. Therefore, much more evidence-based research is 
needed on manual therapy and exercise programs in hemophilia patients with 
polyarthropathy. Therefore, this study intends to investigate the impact and 
effectiveness of individualized physical therapy based on case conditions (severe 
hemophilia with polyarthropathy) [3]. It is hoped to try to combine different physical 
therapy techniques (manual therapy and exercise intervention) to improve pain, 
muscle strength, joint health, cardiopulmonary endurance, and thereby enhance the 
overall quality of life [5][7][8][9]. 
V. 
Purpose  
Whether the use of individualized physical therapy combined with manual therapy 
and exercise intervention effectively improve joint status, muscle strength, pain, 
cardiopulmonary endurance, etc. for severe hemophilia patients with 
polyarthropathy, and at the same time prevent the possibility of recurrence of 
bleeding. 
 
VI. 
Methods  
A. Selection criteria and number of people. 
1. Number of subjects: It is expected that 10 subjects. 
2. Inclusion criteria: 
  a. Over 20 years old and diagnosed with severe hemophilia   
  b. Those who receive prophylaxis regularly 
  c. There are more than 2 target joints (arthrosis) 
3. Exclusion criteria: 
  a. Unable to sign the informed consent form 
  b. Any neurological disease or major musculoskeletal system disease (such  

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as fracture) one year ago 
c. Have had more than 3 (excluding 3) joint replacement surgeries (different joints) 
d. Unable to walk due to hemophilic arthropathy or any other disease 
e. Major bleeding events that pose risks or hinder research 
f. Unable to follow instructions due to cognitive impairment 
4. Recruitment methods: through the Rehabilitation Department of Far Eastern 
Memorial Hospital, the Hemophilia Center and relevant hemophilia associations. 
Recruitment is open and a promotional leaflet has been given. 
5. Method of consent of research subjects: After the assessment and confirmation  
of inclusion and before the start of the research, fully inform the experiment content. 
and process, and ask the subjects to sign the human subject clinical trial consent 
form. 
B. Design  
1. Research conduct method 
a. The physical therapists of the research team will evaluate whether they meet the 
 inclusion criteria to recruit subjects who meet the conditions of this trial. 
b. Fully inform the experiment content and process, and ask the subjects to sign the 
subject informed consent form. 
c. Study location: Rehabilitation department 
d. The execution content is as follows: 
      (i) Manual treatment: including fascia release, progressive passive stretching, joint 
mobilization, etc., and adjustments will be made according to the subject's 
current condition. 
(ii) Exercise therapy: including upper and lower limbs muscle strengthening, trunk 
(spine) exercise, and adjustments based on the subject's current condition. 
 
Upper extremity 
strengthening 
! 
Shoulder external rotation (with theraband): 10 
repetitions per set 
Position the upper arm and forearm at a 90-degree 
angle, holding the theraband with both hands. Rotate 
outward while keeping the upper arms close to the sides 
of the body throughout the movement. 
! 
Shoulder flexion (with theraband): 10 repetitions per set 
Hold the theraband in one hand, extend the arm upward 
to lift it straight, and then slowly lower it back down. 
! 
Shoulder abduction (with sandbag or theraband): 10 
repetitions per set 
Hold a sandbag or theraband in one hand, and slowly lift 

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the arm outward to the side until it is parallel to the 
floor. 
! 
Elbow flexion / extension (with theraband): 10 
repetitions per set 
While seated, pull the theraband with one hand, 
performing elbow flexion and extension movements. 
Lower extremity 
strengthening 
! 
Hip & knee 
flexion/extension 
(with 
sandbag): 
10 
repetitions per set 
Stand with both hands supporting a stable table or chair. 
Attach a sandbag to one leg, perform hip and knee flexion, 
and then slowly extend the leg backward. 
! 
Hip abduction (with theraband): 10 repetitions per set 
Lie on your side with a theraband secured around both 
feet for resistance. Perform hip abduction by lifting the 
top leg outward against the resistance. 
! 
Ankle dorsiflexion/plantarflexion (with theraband): 10 
repetitions per set 
While seated, attach a theraband to one ankle for 
resistance. Perform ankle dorsiflexion (lifting the foot 
upward) and plantarflexion (pointing the foot downward). 
! 
Ankle eversion/inversion (with theraband): 10 repetitions 
per set 
While seated, attach a theraband to one ankle for 
resistance. Perform ankle eversion (turning the foot 
outward) and inversion (turning the foot inward). 
Trunk(spine) 
exercise 
! 
Pelvic tilting: 10 repetitions per set 
Lie flat on your back with your knees bent and feet flat on 
the bed. Inhale as you tilt your pelvis forward, creating a 
hollow in the lower back; exhale as you tilt your pelvis 

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backward, pressing your lower back flat against the bed. 
! 
Thoracic spine rotation: 10 repetitions per set 
Lie on your side, and rotate the shoulder joint backward 
and outward as far as possible. This movement can be 
coordinated with breathing. 
! 
Abdominal core training: 10 repetitions per set 
While seated, lift your feet off the ground with both knees 
bent.  
! 
Dynamic neuromuscular stabilization: 10 repetitions per 
set 
Lie flat on your back with your hips and knees at a 
90-degree angle. If it’s difficult to maintain this position, 
use a ball or chair for support. Slowly inhale, allowing 
your abdomen to expand. Exhale slowly, trying to 
maintain the abdominal expansion without letting it 
collapse. 
 
(iii) Exercise prescription settings: 
(1) Frequency: 10 times/time, 1~2 times/day, 3~5 days/week. 
(2) The time is 10 minutes, and the time can be gradually increased depending on 
the situation. 
(3) The intensity is adjusted in time according to the patient's condition: the 
sandbag can be gradually increased from 0.5 kg, and the elastic band can be 
gradually increased starting from the lightest resistance coefficient (from light 
to dark according to the color). 
e. Intervention schedule: Once a week for three months (about 12 weeks), 30 minutes 
of traditional physical therapy plus 30 minutes of individualized physical therapy 
intervention, about 1 hour.  
f. Questionnaires and scales were conducted before intervention, at the 6th week after 
intervention (mid-term intervention) and at the 12th week (end of intervention) to 
evaluate changes in joint status, pain, cardiopulmonary endurance, functional level, 
and quality of life.  
g. The patient daily note includes exercise duration and content, intensity, manual 

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therapy techniques, bleeding, and remark on special situations. 
  (i) Exercise duration and content, intensity, and manual therapy techniques: 
Gradually increase according to the current situation and ability, as mentioned 
above. 
(ii) Bleeding: It can be determined by the range of motion of the joint, the severity of 
the pain, and the appearance of redness, swelling and heat. 
(iii) Notes on special circumstances: If there are any special things in this study, 
please note them down. 
h. Subjects will be given NT$500 each in the 6th and 12th weeks respectively, for a total 
of NT$1,000 in traffic allowance. 
2. Subject follow-up or necessary rehabilitation plan: 
During the study period, subjects will come to the treatment room for individualized 
physical therapy once a week, and safety status will be tracked regularly. 
After the study is completed, if necessary (depending on subject’s opinion and 
therapist’s judgment), rehabilitation plan will be arranged based on the actual 
situation. 
3. Treatment effect evaluation and statistical analysis methods: 
This study employed the non-parametric statistical software SPSS version 20.0, with a 
significance level set at p<0.05. Descriptive statistics were used to describe the 
characteristics and distribution of the basic data variables. Furthermore, the Wilcoxon 
signed-rank test was utilized to examine differences in joint condition, muscle strength, 
pain, and cardiopulmonary endurance before intervention, and at 6 and 12 weeks 
post-intervention. The statistical analysis included comparisons between pre-test and 
mid-test, as well as pre-test and post-test, to mitigate the risk of incomplete data due to 
participants dropping out before completing the final test. Additionally, sample size 
calculations were performed using G*Power. The effect size was based on the visual 
analogue scale measuring perceived pain in patients with hemophilic knee joint disease, 
set at d = −1.30 [20]. With an alpha level of 0.05 and a power value of 0.95, the 
required sample size was determined to be 9 participants. To account for potential 
sample attrition, a 10% increase in sample size was applied, resulting in a projected 
total sample size of 10 hemophilia patients [12]. 
 
4. Questionnaires or other research-related scales: 
This study utilized the following scales and questionnaires to assess changes in joint 
condition, pain, cardiopulmonary endurance, functional level, and quality of life in 
patients before intervention, and at 6 and 12 weeks post-intervention, in order to 
confirm treatment efficacy: 
a. Hemophilia Joint Health Score (HJHS): This scale is designed to monitor joint 

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    changes over time in hemophilia patients. It evaluates the swelling of the elbow, knee, 
and ankle joints, duration of persistent swelling, muscle atrophy, presence of 
crepitus during movement, reduction in range of motion, joint pain level, muscle 
strength, and overall gait performance. Validity: The scale has high evidence of both 
convergent validity and discriminant construct validity for detecting joint damage in 
adults with hemophilia, making it suitable for this population. Reliability: The scale 
demonstrates excellent reliability, with test-retest (ICC=0.89) and inter-observer 
(ICC=0.83) values.[14] The scale was assessed and completed by physical therapists. 
b. Visual Analog Scale (VAS): This scale evaluates pain in target joints of 
hemophilia patients, converting the results into scores to provide a clearer 
understanding of overall pain experience. Reliability: The scale exhibits high 
reliability with an ICC of 0.97 (95% CI 0.96 to 0.98). Research indicates that it is a 
reliable and valid instrument. [15] 
c. 6-Minute Walk Test (6MWT): This test assesses the overall cardiopulmonary 
endurance of patients. Reliability: The reliability is good, with test-retest values 
ranging from 0.88 to 0.94. Validity: It has moderate convergent validity, with a 
correlation of 0.71 to 0.82 with treadmill performance. [16] The assessment and 
completion of this scale are performed by physical therapists. 
d. Hemophilia Activity List (HAL): This scale evaluates functional activities in 
hemophilia patients across seven domains: lower limb function, upper limb function, 
transportation, self-care, household tasks, leisure activities and exercise, and 
modification or use of assistive devices. Validity: The HAL demonstrates good 
construct and convergent validity. Reliability: It shows good internal consistency, 
with a Cronbach's alpha ranging from 0.61 to 0.96. [17] This scale is completed by 
the patients themselves. 
e. EQ-5D-5L: This scale assesses patients' quality of life, including mobility, self-care, 
usual activities, pain or discomfort, and anxiety or depression. Validity: It exhibits 
satisfactory construct validity for measuring quality of life in hemophilia patients. 
Research indicates that this scale has both good reliability and validity. [18] [19] The 
scale is completed by the patients themselves. 
f. Patient Diary Card: This card assesses patient status, including basic information 
and daily living activities, and records the content of each treatment session. The 
documentation is completed by physical therapists. 
VII. Handling of Research Materials: 
A. Collection and processing of paper, electronic data / samples during the study: 
      The principal investigator is responsible for explaining the experimental procedures 
and distributing consent forms. The principal investigator also oversees the 
execution of exercise and manual therapy, while the co-investigator handles clinical 

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assessments and data statistics and analysis. All data is collected and processed by 
the research team. Paper records are securely locked in the principal investigator’s 
personal filing cabinet, and electronic data is temporarily consolidated and stored 
on a personal computer. 
B. Post-study processing, storage, and retention of paper and electronic data / samples: 
      To ensure the appropriate handling and security of the data, the research team will 
utilize a lockable filing cabinet to store paper records securely. Electronic data, once 
consolidated, will be saved on a personal computer. Upon completion of the study, 
all research data will be retained for five years. After this period, the principal 
investigator will be responsible for the destruction of electronic data to ensure 
privacy. Additionally, paper records containing personal information will be 
destroyed by incineration through a process managed by Far Eastern Memorial 
Hospital, to mitigate the risk of data leakage. 
VIII. Protection of subjects' rights 
A. Potential physical, psychological, and social harm and mitigation measures: 
Although the likelihood is low, this study may still cause physical discomfort such 
as muscle soreness or joint bleeding due to the testing procedures. Therefore, prior 
to testing, participants will be asked if they regularly receive prophylaxis. If any 
discomfort occurs during the testing, the procedure will be immediately halted, 
and appropriate management will be taken. Should the discomfort occur three 
times, the subject will be withdrawn from the study ahead of schedule. During the 
testing period, professionals will assist in enhancing the safety of the subjects. 
B. Conditions and mechanisms for study suspension / termination or early 
withdrawal: 
Since rehabilitation outcomes may vary among individuals, the therapist will 
continuously monitor the subject's condition throughout the intervention period. 
Additionally, subjects may withdraw their consent to participate in the study at any 
time, and this decision will not affect the therapist's future medical care of the 
subject. Subjects need not worry about the impact of withdrawal on subsequent 
rehabilitation treatment (this will be explicitly stated in the consent form), thereby 
minimizing any psychological pressure or burden. 
C. Subject compensation: 
Subjects will receive transportation expenses of 500 TWD each at the 6th and 12th 
weeks, totaling 1000 TWD. 
IX.  Outcomes 
A. Expected results and major benefits: 

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  This study aims to investigate the therapeutic benefits of individualized physical 
  therapy approach, combined with manual therapy and exercise interventions, for 
  severe hemophilia patients with polyarthropathy. Based on previous research, 
  manual therapy and exercise intervention have been shown to effectively improve 
  musculoskeletal conditions. It is anticipated that this study will also enhance 
  subjects' pain management, muscle strength, joint health, and cardiopulmonary 
  endurance, ultimately improving overall quality of life. 
B. Ownership and utilization of results: 
  Upon completion of the research, the results will be owned by Far Eastern 
  Memorial Hospital. 
X.  Funding requirements and sources: 
The funding for this study will be sourced from an internal project grant provided by Far 
Eastern Memorial Hospital. 
XI.  Conflicts of interest: 
This trial is not sponsored by any manufacturers and does not have any commercial 
interests. 
XII.  References or domestic and international literature: 
1. 
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(2020). WFH Guidelines for the Management of Hemophilia, 3rd edition. Haemophilia 
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Strike K, Mulder K, Michael R. (2016). Exercise for haemophilia. Cochrane Database 
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3. Johnny Mahlangu et al. WFH Guidelines for the Management of Hemophilia, 3rd 
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Donoso-Úbeda E, Meroño-Gallut J, López-Pina JA, Cuesta-Barriuso R. (2020). Effect 
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Scaturro et al. (2022). Effectiveness of rehabilitation on pain and function in people 
affected by hemophilia. Medicine. 100:50, 1. doi: 10.1097/MD.0000000000027863. 
6. Adolfo Llinás et al. WFH Guidelines for the Management of Hemophilia, 3rd edition. 
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