Clin Orthop Relat Res (2022) 00:1-10

DOI 10.1097/CORR.0000000000002264

Clinical Research

No Benefit to Platelet-rich Plasma Over Placebo Injections in

Terms of Pain or Function in Patients with Hemophilic Knee
Arthritis: A Randomized Trial
Weifeng Duan MD1, Xinlin Su MD, PhD1, Ziqiang Yu MD, PhD2,3, Miao Jiang MD, PhD2,3, Lingying Zhao BS2,3,
Peter V. Giannoudis MD4,5, Jiong Jiong Guo MD, PhD1,2

Received: 21 January 2022 / Revised: 18 April 2022 / Accepted: 11 May 2022 / Published online: 31 May 2022
Copyright © 2022 by the Association of Bone and Joint Surgeons

Abstract
Background Hemophilic knee arthritis is one of the most
common presenting symptoms of hemophilia, and its man-
agement continues to be challenging to practitioners.
Preliminary research has suggested that platelet-rich plasma
(PRP) may have short-term efficacy in the treatment of hemo-
philic knee arthritis, but evidence for this treatment is limited.
Questions/purposes What is the effectiveness of PRP
compared with placebo in (1) reducing pain and improving

The institution of one or more of the authors (JJG) has received, during the study period, funding from the National Key Research and
Development Program of China (grant number 2022YFE0199900) and Clinical Application-oriented Medical Innovation Foundation (grant
number 2021-NCRC-CXJJ-PY-09) from National Clinical Research Center for Orthopedics, Sports Medicine & Rehabilitation and Jiangsu
China-Israel Industrial Technical Research Institute Foundation.
Each author certifies that there are no funding or commercial associations (consultancies, stock ownership, equity interest, patent/licensing
arrangements, etc.) that might pose a conflict of interest in connection with the submitted article related to the author or any immediate
family members.
All ICMJE Conflict of Interest Forms for authors and Clinical Orthopaedics and Related Research® editors and board members are on file with
the publication and can be viewed on request.
Ethical approval for this study was obtained from the First Affiliated Hospital of Soochow University, Suzhou, People’s Republic of China
(number 2017-279).
This work was performed at the First Affiliated Hospital of Soochow University, Suzhou, People’s Republic of China.

The first two authors contributed equally to this article.

1
Department of Orthopedics and Sports Medicine, The First Affiliated Hospital of Soochow University, Suzhou, People’s Republic of China
2
Department of Hematology, National Clinical Research Center for Hematologic Disease, The First Affiliated Hospital of Soochow University,
Suzhou, People’s Republic of China
3
Jiangsu Institute of Hematology, Key Laboratory of Thrombosis and Hemostasis of Ministry of Health of the People’s Republic of China,
Suzhou, People’s Republic of China
4
Academic Department of Trauma and Orthopaedics, School of Medicine, University of Leeds, Leeds General Infirmary, Leeds, UK
5
National Institute for Health Research, Leeds Biomedical Research Centre, Chapel Allerton Hospital, Leeds, UK

J. J. Guo ✉, 188 Shizi Street, Suzhou 215006, People’s Republic of China, Email: guojiongjiong@suda.edu.cn

Copyright © 2022 by the Association of Bone and Joint Surgeons. Unauthorized reproduction of this article is prohibited.
 2 Duan et al.
knee joint function (as measured by WOMAC, VAS, and
Hemophilia Joint Health Score [HJHS]) and (2) improving
quality of life (as measured by SF-36 scores) in patients with
hemophilic knee arthritis through 24 months of follow-up?
Methods This was a prospective, parallel-group, double-
blinded, single-center, placebo-controlled randomized
clinical trial that included participants from a tertiary care
center starting January 1, 2019, with follow-up completed
on November 30, 2021. Participants were older than 18
years and had hemophilic knee arthritis confirmed by MRI,
and they were randomly allocated to interventions in a 1:1
ratio. The investigators were not informed of the random-
ization sequence generated by the computer. Patient groups
were comparable with respect to age, gender, BMI, he-
mophilia type, and disease severity at baseline. Physicians
delivered three sessions (one per week) of a standard
intraarticular injection of PRP (n = 95) or placebo (n = 95).
The rate of successful blinding was balanced across the
groups, which was assessed by asking participants which
injection they thought they had received. The primary
outcome was the WOMAC score (range 0 to 96; higher
scores indicate more pain and worse function; minimum
clinically important difference, 6.4 points) over 24 months.
Among the 190 patients assigned to PRP or saline injec-
tions (mean age 31 6 7 years), 100% (190) of patients were
men). There was no between-group difference in the pro-
portion of patients who completed the trial; 97% (92 of 95)
of patients in the PRP group and 94% (89 of 95) of patients
in the placebo group completed the trial. The most common
adverse events were injection site discomfort 8% (8 of 95)
in the PRP group and 4% (4 of 95) in the placebo group. An
intention-to-treat analysis was planned, but there was no
crossover between groups. All patients were included in the
analyses. With 95 patients in each group, the study was
powered a priori at 90% to detect a difference in WOMAC
score of 6.4 points, which was considered a clinically im-
portant difference.
Results There were no clinically important differences in the
mean WOMAC, VAS pain, HJHS, SF-36, and MRI scores
between groups at any timepoint. Intraarticular PRP did not
ameliorate function, symptoms, and quality of life in patients
with hemophilic knee arthritis. At 24 months of follow-up,
the mean difference between the PRP and placebo groups in
the WOMAC score was -1 (95% CI -5 to 2; p = 0.42). The
mean difference in the VAS pain score was -0.3 (95% CI -0.8
to 0.2; p = 0.19), in the HJHS was -0.6 (95% CI -1.4 to 0.1;
p = 0.10), in the SF-36 physical component summary was
0 (95% CI -2 to 3; p = 0.87), and in the SF-36 mental
component summary was -1 (95% CI -3 to 2; p = 0.64). The
mean differences in the MRI scores of soft tissue and
osteochondral subscore were 0.1 (95% CI -0.3 to 0.5; p =
0.59) and -0.3 (95% CI -0.7 to 0.1; p = 0.19), respectively.
Conclusion Among patients with hemophilic knee ar-
thritis, three intraarticular PRP injections, compared with
Copyright © 2022 by the Association of Bone and Joint Surgeons. Unauthorized reproduction of this article is prohibited.
Clinical Orthopaedics and Related Research®
placebo injections, did not improve hemophilic knee
symptoms, function, and quality of life over 24 months.
The results of this study do not support the use of PRP
injections in patients who have hemophilic knee arthritis.
Level of Evidence Level I, therapeutic study.
Introduction
Patients with severe Factor VIII or IX deficiency (hemo-
philia Type A or B) usually experience spontaneous joint
bleeding [3, 28]. Recurrent episodes of intraarticular
hemorrhage often lead to hemophilic arthritis [29].
Preliminary laboratory research has suggested that platelet-
rich plasma (PRP), which is derived from peripheral blood
with a concentrate of platelets and a natural concentration
of autologous growth factors, may promote healing in
several tissue types [1]. Some early animal research has
suggested that PRP may have a role in the treatment of
hemophilic knee arthritis by inhibiting the development of
synovitis and cartilage matrix loss in the affected
joints [33].
Investigation of PRP for hemophilic knee arthritis in
humans is limited to three small case series and one open‐
label trial [5, 20, 22, 32], which were generally supportive
of its use, but biases that tend to accrue in those study
designs (in particular, selection bias and assessment bias)
will tend to result in overestimation of the apparent benefits
of treatment. Others have pointed out the substantial gaps
in what we know about this topic and have called for well-
designed research to address those gaps [30]. To our
knowledge, no randomized trials have compared PRP with
placebo in patients with hemophilic knee arthritis, and
without those, it is impossible to know whether this treat-
ment will improve patients’ function or reduce their levels
of pain.
Consequently, we performed a randomized clinical trial
to assess the efficacy of PRP injections in hemophilic knee
arthritis, in which we asked: What is the effectiveness of
PRP compared with placebo in (1) reducing pain and im-
proving knee joint function (as measured by WOMAC,
VAS, and Hemophilia Joint Health Score [HJHS]) and (2)
improving quality of life (as measured by SF-36 scores) in
patients with hemophilic knee arthritis through 24 months
of follow-up?
Patients and Methods
Study Overview and Trial Design
This prospective, parallel-group, double-blinded, single-
center, placebo-controlled randomized clinical trial was
conducted at the National Clinical Research Center for
 Volume 00, Number 00
Hematological Disorders of China. Enrollment began on
January 1, 2019, and the last patient’s 24-month follow-up
occurred on November 30, 2021. A checklist of minimum
reporting requirements for clinical studies of PRP [25] is
available (Supplementary Table 1; http://links.lww.
com/CORR/A821).
Study Participants
Patients with hemophilic knee arthritis were recruited
among inpatients and outpatients of our center. The study
was conducted in the comprehensive hemophilia treatment
center of a national clinical research institution. Patients
who were interested in participating in the study were in-
vited to call a coordinator at the hemophilia treatment
center, who scheduled screening. The patient screening
was performed in the outpatient department, where two
experienced physicians (ZY, JJG) evaluated patients’ eli-
gibility for enrollment in this study through history taking,
imaging examination, and laboratory tests. Patients were
included in this study only if they met all the inclusion
criteria. Inclusion criteria were patients with a diagnosis of
Type A or B hemophilia, patients who were 18 years or
older, those who had radiographic and clinical evidence of
hemophilic knee arthritis, those with no previous intra-
articular injections or surgeries in the target knee before the
procedure, and those who were able to understand and
agree with informed consent.
Patients were excluded if they were had coagulation
factor inhibitors (had an inhibitor titer $ 0.6 Bethesda
units [BUs] using the Nijmegen modification of the
Bethesda assay on at least two consecutive tests [4]),
inflammatory disease or a condition that would affect the
joint, platelet count < 100310^9/L, a history of gouty
arthropathy or rheumatoid arthritis, treatment with sys-
temic steroids, or use of NSAIDs within 5 days before
blood collection for PRP. Patients were also excluded if
they had recurrent joint bleeding during the 24-month
follow-up period.
Allocation to Treatment
After baseline data collection, participants were randomly
allocated by a 1:1 ratio. The independent statistician
provided a computer-generated randomization sequence
concealed to the investigators. Participants were ran-
domly assigned to receive a PRP injection (n = 95) or
placebo injection (n = 95). Participants and researchers
were blinded to the data before trial completion. Written
and oral informed consent was obtained from all
participants by the research assistant during a face-to-face
inclusion visit.
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PRP in Hemophilic Knee Arthritis 3
Baseline Data
A total of 714 adults with hemophilic knee arthritis were
assessed for eligibility; of these, 27% (190 patients) were
enrolled in the trial. There was no difference between
groups in terms of loss to follow-up; 97% (92 of 95) of
patients in the PRP group and 94% (89 of 95; p = 0.31) of
patients in the placebo group completed the trial (Fig. 1).
The mean patient age was 31 6 7 years. All patients were
men because of the genetic sex linkage of hemophilia.
Overall, 158 patients had severe hemophilia and 32 had
moderate hemophilia, classified based on residual co-
agulant activity in blood. Patient groups were homoge-
neous with respect to age, gender, BMI, hemophilia type,
and disease severity at baseline (Table 1).
The platelet count in the PRP after centrifugation was
higher than that in the whole blood by approximately 3.5
times (751.25 3 10^9/L versus 213.42310^9/L) in the PRP
group. The leukocyte count in the PRP was lower compared
with that in the whole blood (0.36310^9/L versus
5.39310^9/L). The concentration of tumor necrosis factor
[TNF]-a and interleukin [IL]-1b in peripheral blood de-
clined after PRP injection in the treatment group; however,
there was no difference between the two groups
(Supplementary Fig. 1; http://links.lww.com/CORR/A822).
Throughout the study, patient’s NSAID use was regis-
tered. There was no difference between the groups
(Supplementary Table 2; http://links.lww.com/CORR/A823).
Intervention and Masking
The two groups were given either three weekly intra-
articular injections of PRP or three weekly intraarticular
injections of saline. All included patients received pro-
phylactic administration of Factor VIII or Factor IX con-
centrate two to three times per week as is standard practice
for patients with severe Type A or B hemophilia. A study
nurse prepared the intervention in a separate room
according to the randomization result. Before the injection,
the syringe was appropriately covered to prevent patients
and physicians from discovering the contents of the sy-
ringe. The patients, physicians, and coordinating re-
searcher were blinded to the allocation of the intervention.
The success of blinding was assessed by asking partici-
pants which injection they thought they received; this was
then recorded accordingly. The proportion of successful
blinding was balanced across the groups (Supplementary
Table 3; http://links.lww.com/CORR/A824).
Blood was drawn from the arm of participants in both
groups to ensure participant blinding. The nurse disposed
of blood from participants in the placebo group in a sepa-
rate location. The nurse extracted 50 mL of peripheral
venous blood from each participant’s medial cubital vein.
 4 Duan et al. Clinical Orthopaedics and Related Research®

Fig. 1. This flowchart shows recruitment, randomization, and follow-up of patients in the
trial.

Then, 5 mL of blood was sent to the laboratory for cell
counting and cytokine (TNF-a and IL-1b) analysis, and the
remaining blood was put into tubes containing 5 mL 3.8%
sodium citrate. Two centrifugations were performed with a
hematology centrifuge. The first centrifugation was per-
formed at 3200 rpm for 5 minutes, and the second centri-
fugation was performed at 3300 rpm for 3 minutes. After
centrifugation, the tubes were gently agitated to ensure all
visible platelet aggregates detached from the separating gel
and tube wall, and approximately 5 mL was gently with-
drawn into a syringe. We sent 1 mL of the plasma to the
laboratory for platelet and leukocyte counting analyses
using a hematology analyzer (MEK-6400, Nihon), and the
remaining plasma was used for treatment. According to
MARSPILL Classification [31], the PRP in this study
would be classified as M (H), A (A-), R (RBC-p), S (SP-2),
P (PL[3-5]), I (G-), L (Lc-P), L- (A-) .
Venous blood samples were collected using vacutainer
tubes and centrifuged at 2000 rpm for 10 minutes to sep-
arate the serum. The serum was placed into sterile
Eppendorf tubes and stored in a refrigerator at -80°C for
laboratory analysis. The concentration of TNF-a and IL-1b
in serum was measured in the laboratory by using com-
mercial ELISA kits (Absin Bioscience Inc), and a

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 Volume 00, Number 00 PRP in Hemophilic Knee Arthritis 5

Table 1. Baseline characteristics of the study populationa

Characteristic PRP group (n = 95) Placebo groupb (n = 95) p value
Age in years 30 6 7 31 6 6 0.61
Men 100 (95) 100 (95)
Weight in kg 70 6 10 69 6 9 0.55
Height in m 1.71 6 0.08 1.72 6 0.09 0.81
BMI in kg/m2 24 6 2 23 6 2 0.21
Left laterality 38 (36) 42 (40) 0.55
Hemophilia type 0.40
A 96 (91) 97 (92)
B 4 (4) 3 (3)
Hemophilia severityc 0.70
Moderate 16 (15) 18 (17)
Severe 84 (80) 82 (78)
Infected with HBV/HCV/HIV, n 3/10/4 4/7/0
WOMAC score
Pain 863 863 0.83
Stiffness 362 362 0.58
Function 32 6 7 34 6 8 0.20
Total 43 6 10 45 6 14 0.33
VAS score 5.4 6 1.3 5.5 6 1.3 0.74
HJHS 10.1 6 2.8 10.5 6 2.4 0.37
SF-36
Physical component summary 34 6 9 35 6 8 0.68
Mental component summary score 51 6 7 52 6 9 0.71
IPSG - MRI score
Soft tissue subscore 4.2 6 1.2 4.0 6 1.3 0.37
Osteochondral subscore 2.8 6 1.5 3.0 6 1.4 0.35
Data presented as mean 6 SD or % (n unless indicated otherwise).
a
Categorical percentages may not add up to 100 owing to rounding.
b
Placebo indicates intraarticular injection of saline three times, once per week.
c
The classification is based on plasma procoagulant levels, with levels < 0.01 IU/mL (< 1% of normal) factor defined as severe, 0.01 to 0.05 IU/mL
(1% to 5% of normal) as moderate, and > 0.05 to 0.40 IU/mL (5% to 40% of normal) as mild; HBV = hepatitis B virus; HCV = hepatitis c virus.

microplate reader (BioTek) was used for detection. The
results are shown as mean values (pg/mL) with a standard
curve on a linear logarithm.
Procedures
passive extension and flexion of the target knee were per-
formed to distribute PRP or saline throughout the joint
cavities. Afterward, patients rested in the supine position
for 5 minutes. They were also recommended to avoid
putting weight on the target knee for the subsequent 24
hours.

Intraarticular injection in the target knee was performed by

the same physician using anatomic landmarks (injections
were given lateral to the patellar ligament at the level of the
joint line). Each joint was injected with 4 mL of PRP or
isopycnic saline three times, once for 3 consecutive weeks.
On the day of the intraarticular injection, all patients re-
ceived an intravenous injection of clotting factor substi-
tutes (30 IU/kg) in case of postinjection bleeding. The
injection site was covered with a bandage without com-
pression. Immediately after injection, three repetitions of
Follow-up
All clinical and MRI assessments were conducted by as-
sessors blinded to treatment allocation. Two experienced
physicians (ZY, JJG) evaluated the clinical outcomes of
each patient at baseline and 1 month, 3 months, 6 months,
12 months, and 24 months after injection. All patients
underwent an MRI examination before PRP injection and
24 months after injection.

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 6 Duan et al.
Primary and Secondary Study Outcomes
The primary outcome was the WOMAC total score during
the 24-month follow-up period. The WOMAC is used
widely in studies of arthritis and includes five items for pain,
two items for stiffness, and 17 items for assessing functional
limitations. Each question is scored from 0 to 4, with lower
scores indicating less pain and better functional status [24].
Secondary outcomes were the WOMAC total score at
1 month, 3 months, 6 months, and 12 months (other time-
points than the primary outcome). We assessed pain using
the VAS [16] (range indicated on a standard 10-cm line:
0 cm [no pain] to 10 cm [worst pain]). Joint health was
assessed using the Hemophilia Joint Health Score (HJHS)
[13] (range 0-20 points; higher scores indicate a worse joint
condition). The HJHS evaluates six joints (bilateral elbows,
knees, and ankles) and originally included a global gait
analysis; only the knee score was evaluated in the present
study. Health-related quality of life was assessed using the
SF-36 [19] (range 0-100 points; higher scores indicate
higher quality of life) at 1 month, 3 months, 6 months,
12 months, and 24 months of follow-up and MRI findings,
which were scored according to the additive International
Prophylaxis Study Group (IPSG) MRI score [18] (range
0-17; higher scores indicate more symptoms) at the 24-
month follow-up interval. The MRI score includes a soft
tissue subscore (scoring of effusion/hemarthrosis, synovial
hypertrophy, and hemosiderin deposition) and an osteo-
chondral subscore (scoring of surface erosions, subchondral
cysts, and cartilage degradation). The minimum clinically
important differences (MCIDs) were unknown for these
scores in patients with hemophilic knee arthritis. We spec-
ified 1.5 cm as the MCID on a 10-cm VAS pain score based
on available research [15]. We recorded all adverse events
reported by the patient or observed by the investigator.
Adverse Events
Adverse events were collected via patient self-report dur-
ing data collection and by asking the nurse after each in-
jection. No patients experienced severe adverse effects
such as wound infection, septic arthritis, fever, long-term
pain, or bleeding. In the PRP group, 8% (8 of 95) of patients
reported mild pain after injection that lasted within 48
hours; these patients did not undergo treatment. Four per-
cent (4 of 95) of patients in the placebo group described
mild pain that resolved within 2 days.
Sample Size
The study’s statistical power was designed to detect an
MCID of 6.4 points [12] for the primary outcome of the
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Clinical Orthopaedics and Related Research®
WOMAC score (range 0-96) during the 24-month follow-
up period. In patients with hemophilic knee arthritis, there
is no formal consensus on the MCID for the WOMAC
score. In patients with knee osteoarthritis who had com-
parable disease-specific patient-reported outcome
measures, a 6% to 14% change in the used scale was
considered an MCID. Within this range, we specified an
MCID of 6.4 points.
According to a pilot research study [20], WOMAC total
scores in patients with hemophilic knee arthritis were ap-
proximately normally distributed with an SD of 12.3.
With a 5% two-sided significance level, 90% power, 20%
dropout rate, and a predicted SD of 12.3, 95 patients per
group were required (190 in total). Patient recruitment
terminated in all groups when the required minimum
number of patients was attained.
Ethical Approval
This study was designed in accordance with the
Declaration of Helsinki and was approved by the National
Research Ethics Committee (2017-279) on February 27,
2017. After detailed preclinical preparation, the study was
registered at the Chinese Clinical Trial Registry (number
ChiCTR1800018120), and the study followed the World
Health Organization’s guidelines.
Statistical Analysis
An intention-to-treat analysis was planned, but there was
no crossover between groups. All patients were included in
the analyses. The means and SDs of continuous variables
were calculated and compared using Mann-Whitney U
tests. Categorical data are reported as frequencies and were
compared using either the chi-square or the Fisher exact
test. We used the Kolmogorov-Smirnov method to test
normality. We used a repeated-measures general linear
model (GLM) with a Sidak test for multiple comparisons to
analyze the differences in all clinical scores and objective
measurements at the various follow-up intervals.
Additionally, a GLM was performed as a multivariate
analysis to determine the effect of therapy on the evolution
of all clinical scores and objective measurements across
time. We used ANOVA to determine between-group dif-
ferences in continuous, normally distributed, and homo-
scedastic data; alternatively, we used the Mann Whitney
test. We compared whole peripheral blood and purified
PRP using a paired-samples t-test. Multivariable imputa-
tion by chained equations was used to impute missing data
for the sensitivity analysis of the primary and secondary
outcomes. For all tests, a two-sided p value # 0.05 was
considered statistically significant. All statistical analyses
 Volume 00, Number 00 PRP in Hemophilic Knee Arthritis 7

Table 2. Primary and secondary outcomes among the PRP and saline groups at different follow-up intervals
Outcome PRP group (n = 95) Placebo groupa (n = 95) Mean difference (95％CI) p value
WOMAC total score
1 month 43 6 13 43 6 12 0 (-3 to 4) 0.97
3 months 41 6 12 42 6 13 -1 (-4 to 3) 0.71
6 months 40 6 13 40 6 13 0 (-4 to 4) 0.91
12 months 39 6 12 41 6 12 -1 (-5 to 2) 0.41
24 months 40 6 10 41 6 13 -1 (-5 to 2) 0.42
VAS score
1 month 4.5 6 1.3 5.3 6 1.5 -0.8 (-1.2 to -0.4) < 0.001
3 months 4.3 6 1.4 5.2 6 1.4 -0.8 (-1.3 to -0.4) < 0.001
6 months 4.3 6 1.5 5.16 1.3 -0.8 (-1.2 to -0.4) < 0.001
12 months 4.3 6 1.6 5.0 6 1.4 -0.7 (-1.1 to -0.3) 0.001
24 months 4.3 6 1.7 4.6 6 1.5 -0.3 (-0.8 to 0.2) 0.19
Hemophilia Joint Health Score
1 month 9.6 6 2.8 10.2 6 2.4 -0.6 (-1.4 to 0.1) 0.11
3 months 9.6 6 2.8 10.1 6 2.3 -0.5 (-1.2 to 0.3 ) 0.23
6 months 9.6 6 2.8 10.1 6 2.5 -0.5 (-1.3 to 0.3) 0.20
12 months 9.5 6 2.8 10.2 6 2.5 -0.6 (-1.4 to 0.1) 0.11
24 months 9.5 6 2.7 10.1 6 2.3 -0.6 (-1.4 to 0.1) 0.10
SF-36 physical component summary
1 month 35 6 9 35 6 8 0 (-2 to 3) 0.92
3 months 35 6 9 35 6 8 0 (-3 to 2) 0.98
6 months 34 6 9 35 6 8 -1 (-3 to 1) 0.43
12 months 34 6 9 35 6 8 -1 (-3 to 2) 0.53
24 months 34 6 9 34 6 8 0 (-2 to 3) 0.87
SF-36 mental component summary
1 months 51 6 7 52 6 9 -1 (-3 to 1) 0.36
3 months 52 6 7 52 6 9 0 (-3 to 2) 0.71
6 months 52 6 7 52 6 9 0 (-3 to 2) 0.68
12 months 52 6 7 52 6 9 0 (-3 to 2) 0.72
24 months 53 6 7 53 6 9 -1 (-3 to 2) 0.64
International Prophylaxis Study Group MRI score
Soft tissue subscore 4.3 6 1.2 4.2 6 1.4 0.1 (-0.3 to 0.5) 0.59
Osteochondral subscore 3.3 6 1.5 3.6 6 1.4 -0.3 (-0.7 to 0.1) 0.19
Data are presented as the mean 6 SD; we specified 1.5 cm as the MCID on a 10-cm VAS pain score based on available research [15].
a
Placebo indicates intraarticular injection of saline three times, once per week.

were performed using IBM SPSS for Windows, version
26 (IBM).
Results
Pain and Function
With the numbers available, there were no differences
between the groups in terms of knee pain and function at
any timepoint (Table 2). There was no difference in the
WOMAC total score between the PRP group and the
placebo group at 24 months after treatment (mean differ-
ence -1 [95% CI 5 to 2]; p = 0.42). Between baseline and
24-month follow-up, the mean WOMAC score improved
by 3 points in the PRP group compared with 4 points in the
placebo group (Fig. 2A). The sensitivity analysis had no
substantial impact on the results (Supplementary Table 4;
http://links.lww.com/CORR/A825). In a post hoc analysis,
there was no between-group difference in PRP versus
placebo for the WOMAC total score over 24 months (mean
difference -1 [95% CI -5 to 1]; p = 0.15) (Supplementary
Table 5; http://links.lww.com/CORR/A826). There were
no differences in the WOMAC score between the PRP

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 8 Duan et al. Clinical Orthopaedics and Related Research®

Fig. 2. A-B These graphs show changes in the (A) WOMAC score from baseline to 24 months and (B) WOMAC score at all timepoints
in a study of the effect of PRP injections versus placebo on patients with hemophilia who have arthritis of the knee. The baseline
WOMAC total score for individual participants is connected using blue lines for the PRP group and orange lines for the placebo
(intraarticular injection of saline) group. Changes from baseline to 24 months are represented by vertical lines, with downward lines
indicating improvement in the knee and upward lines indicating deterioration. Box plots show the summary of baseline, 24 months,
and changes by group. The horizontal lines in the boxplots from bottom to top show the 25th, 50th (median), and 75th percentiles.
The dot in the boxplot indicates the mean. The whiskers indicate the highest and lowest values no further than 1.5 times the
interquartile range. Dots outside the boxplot indicate outliers outside the whisker range.

group and the placebo group at the 1-month, 3-month, 6-
month, and 12-month timepoints (Fig. 2B). There were no
clinically important differences in the VAS; the small dif-
ferences observed early favored PRP (Supplementary Fig.
2A; http://links.lww.com/CORR/A827), but since they
were less than 1.5 cm on the 10-cm scale, they likely were
imperceptible or unimportant to patients based on pub-
lished MCID values [15]. These small differences were
observed at the 1-month, 3-month, 6-month, and 12-month
timepoints (mean difference -0.8 [95% CI -1.2 to -0.4]; p <
0.001, -0.8 [95% CI -1.3 to -0.4]; p < 0.001, -0.8 [95% CI
-1.2 to -0.4]; p < 0.001, and -0.7 [95% CI -1.1 to -0.3]; p =
0.001, respectively). There was no difference in VAS
scores at 24 months (mean difference -0.3 [95% CI -0.8 to
0.2]; p = 0.19) (Table 2). There were no differences in the
HJHS between groups at any time point (Supplementary
Fig. 2B; http://links.lww.com/CORR/A827). The mean
difference between groups in the HJHS was -0.6 (95% CI
-1.4 to 0.1; p = 0.10) at 24 months of follow-up.
Quality of Life and MRI Findings
MRI score (Supplementary Fig. 2E-F; http://links.lww.
com/CORR/A827).
Discussion
Platelet-rich plasma is seeing wider use because of its pu-
tative regenerative properties, with an ever-growing range
of indications across multiple disciplines, even though its
effectiveness is debatable, and its mechanism of action is
unidentified. Given the shortage of existing RCT trials and
the absence of placebo comparisons, the effectiveness of
PRP in hemophilic knee arthritis to this point has not been
well evaluated. In our randomized trial, we found no dif-
ferences in WOMAC scores, HJHS, or SF-36 scores fa-
voring PRP at any timepoint, and the small, early
differences observed in VAS pain levels were below the
MCID of 1.5 cm on a 10-cm scale for that outcomes tool
[15]; in fact, even the upper bound of the 95% confidence
intervals on the VAS scale were below the MCID. Based
on these findings, we recommend against the use of PRP in
patients with hemophilic knee arthritis.

No between-group differences were found in SF-36 physical

component summary and mental component summary
scores at any follow-up timepoint (Supplementary Fig. 2C-
D; http://links.lww.com/CORR/A827). There were no
between-group differences in MRI findings such as de-
creased synovial proliferation, diminished joint effusion, or
cartilage repair; specifically, no between-group differences
were found in soft tissues (mean difference 0.1 [95% CI -0.3
to 0.5]; p = 0.59) or osteochondral defects (mean difference
-0.3 [95% CI -0.7 to 0.1]; p = 0.19) according to the IPSG
Limitations
This study has several limitations. First, the population
recruited was from a single center. However, since critical-
illness insurance started to cover excessive medical costs
for hemophilia in China in 2017, all included patients re-
ceived prophylactic treatments for that condition. Second,
there was a high prevalence of blood-transmitted diseases
before the implementation of viral inactivating procedures

Copyright © 2022 by the Association of Bone and Joint Surgeons. Unauthorized reproduction of this article is prohibited.
 Volume 00, Number 00
and viral screening before 2000. In this series, four patients
had HIV and 17 had hepatitis C virus, which may have
influenced the results. However, these patients were evenly
distributed between the two groups. Third, the follow-up
period might not have been long enough. However, we
suspect that if a benefit of PRP is not observed either
clinically or on MRI inspection of the knee by 2 years after
treatment, it is unlikely to appear later.
Discussion of Key Findings
In this randomized trial comparing PRP to placebo, we
found no benefit to PRP in terms of WOMAC scores (which
measure pain and function), no benefit in terms of quality-of-
life scores (SF-36), no benefit on a disease-specific scoring
system (HJHS), no benefit on MRI examination, and no
clinically important benefit in terms of knee pain. This is at
odds with some preliminary studies on this topic, which
reported a positive effect of PRP therapy [5, 20, 22, 32]. We
note that these were short-term studies, and none of them
used randomization for treatment allocation. Those meth-
odological shortcomings typically result in overestimation
of treatment effects, and it is not unusual for randomized
trials to report smaller effect sizes (or no effect) when case
series appear to suggest treatment benefits. That was the case
here. Based on our findings, we recommend against the use
of PRP for this indication until or unless future randomized
trials identify a clinically important benefit of this treatment.
This is especially important considering the risks of serial
injections in patients with hemophilia.
Three injections of PRP were performed in the present
trial. Previous clinical and experimental research has posited
that multiple injections may be superior to a single injection of
PRP [6, 14], and so we used three injections to give PRP the
best chance to demonstrate a benefit. The concept of dose-
dependent improvement in the chondroprotective effect with
PRP was suggested in a guinea pig model of early knee os-
teoarthritis [6]. Despite this, we found no clinically important
reduction in pain in favor of PRP. The statistical differences in
VAS scores were small (all less than 1.5 cm on the 10-cm
VAS pain scale), even at the extremes of the 95% confidence
intervals; extensive prior research suggests that patients will
not perceive those statistical changes as clinically important
[21], and they may not perceive those differences at all.
In addition to evaluating clinical manifestations, MRI
examination was used in this study to assess pathologic
changes to joint cartilage and synovium before and after
treatment. We found no visible changes favoring PRP on
MRI. Although a poor consistency between MRI findings
and the real extent of joint damage was found by Dobón
et al. [10], MRI is still a useful noninvasive approach to
assess pathologic changes in joint cartilage and synovium
[11], and we would expect some favorable, discernable
Copyright © 2022 by the Association of Bone and Joint Surgeons. Unauthorized reproduction of this article is prohibited.
PRP in Hemophilic Knee Arthritis 9
change in patients treated with PRP if PRP is having a
structural effect on the tissues in these joints. None was
observed here.
Other short-term clinical studies found that PRP injec-
tions did not improve symptoms or function in patients with
ankle arthritis [26] or chronic Achilles tendinopathy [17]
either. In a prospective study [2], three intraarticular injec-
tions at weekly intervals of PRP did not result in improve-
ments in symptoms or joint structure at 12 months among
patients with knee osteoarthritis. However, another recent
study [7] found a better functional outcome of knee arthritis
after three PRP injections. Concentrations of growth factors
and cytokines vary depending on the donor’s age, health,
and gender. The formulations, dose, and timing of PRP
application may influence its efficacy, if it has any [9], and
differences in those parameters may explain some of the
between-study differences that have been observed. Cole
et al. [8] found that patients with milder radiographic signs of
arthrosis (Kellgren Lawrence Grade 1) respond better to
intraarticular therapy than patients with more advanced ar-
throsis (Kellgren Lawrence Grades 2 or 3). According to
Park et al. [27], the potential differences in the PRP sepa-
ration methods, the follow-up period, and the degree of the
osteoarthritis may affect results. As for patients with he-
mophilia, the first bleeding episode can lead to irreversible
joint injury, and so prophylactic administration cannot en-
tirely prevent bleeding episodes and the progression of joint
destruction, leading to the progression of hemophilic ar-
thropathy in early childhood [23]. In our study, all patients
were adults who already had arthritis, which might decrease
the likelihood that PRP will have a therapeutic benefit; of
course, the other explanation of our findings is that PRP has
no benefit in patients with hemophilic arthropathy.
Conclusion
Among patients with hemophilic knee arthritis, three
intraarticular PRP injections, compared with placebo in-
jections, did not meaningfully improve hemophilic knee
symptoms, function, or imaging findings over 24 months.
The results of this study do not support the use of PRP
injections in patients with hemophilic knee arthritis.
Acknowledgments We thank the 714 hemophilia patients who vol-
unteered to participate in the trial, their families, and the many nurses,
surgeons, physicians, and research staff members who helped to make the
trial a success. We dedicate this article to the memory of Ms Lingfen Zhou,
the mother of J. J. Guo MD, who made important contributions to the
development and realization of this project.
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