Received: 6 July 2018 | Revised: 30 August 2018 | Accepted: 29 January 2019

DOI: 10.1111/hae.13711

ORIGINAL ARTICLE
Musculoskeletal

An exploratory comparison of single intra‐articular injection

of platelet‐rich plasma vs hyaluronic acid in treatment of
haemophilic arthropathy of the knee

Tsung‐Ying Li1,2,3 | Yung‐Tsan Wu1,2 | Liang‐Cheng Chen1,2 | Shin‐Nan Cheng3,4 |

Ru‐Yu Pan3,5 | Yeu‐Chin Chen3,6

1
Department of Physical Medicine and
Rehabilitation, Tri‐Service General Hospital, Introduction: Intra‐articular platelet‐rich plasma (PRP) injection therapy has been ex‐
Neihu District, Taipei, Taiwan tensively applied in clinical practice to treat musculoskeletal disorders such as osteo‐
2
Department of Physical Medicine and
arthritis, but the treatment for haemophilic arthropathy is rarely reported.
Rehabilitation, School of Medicine, National
Defense Medical Center, Taipei, Taiwan Aims: This study aimed to compare the efficacy of intra‐articular PRP vs hyaluronic
3
Haemophilia Care and Research Center, Tri‐ acid (HA) injections in treating haemophilic arthropathy of knee joints.
Service General Hospital, National Defense
Medical Center, Taipei, Taiwan
Patients: Twenty‐two haemophilia patients (mean age, 41.1 ± 1.7 [range, 20‐50] years)
4
Department of Paediatrics, Tung’s Taichung with painful haemophilic arthropathy of the knee were enrolled for this open‐label
Metrohabor Hospital, Taichung, Taiwan and observer‐blind study.
5
Department of Orthopaedics, Tri‐Service
Methods: Eleven patients were treated with a single intra‐articular injection of PRP
General Hospital, National Defense Medical
Center, Taipei, Taiwan and the other 11 received five consecutively weekly intra‐articular injections of HA.
6
Division of Haematology/Oncology, Tri‐ Outcome assessment included pain by visual analogue scale (VAS), Western Ontario
Service General Hospital, National Defense
Medical Center, Taipei, Taiwan and McMaster Universities Osteoarthritis Index (WOMAC) Chinese Version and syn‐
ovial change determined by ultrasonography.
Correspondence
Yeu‐Chin Chen, Haemophilia Care and Results: Platelet‐rich plasma and HA intra‐articular injection showed statistically sig‐
Research Center, Tri‐Service General nificant reduction in VAS, WOMAC total score and hyperaemia score from baseline
Hospital, National Defense Medical Center,
Taipei, Taiwan. to 6‐month post‐treatment. Inter‐group comparison showed statistically significant
Email: yeuchin99@gmail.com difference in the change in VAS score, WOMAC pain score, physical function score

Funding information and total score at 6 months, wherein PRP group showed sustained beneficial effect
Tri‐Service General Hospital, Grant/Award than HA group at 6 months.
Number: TSGH-C103-116
Conclusion: Our study demonstrates that, in comparison with five weekly injections
of HA, a single PRP injection resulted in better improvement in pain relief and knee
joint function, and greater reduction in synovial hyperaemia for up to 6 months. Our
results suggest that PRP may be practical and effective for haemophilic knee ar‐
thropathy, and further investigation is warranted.

KEYWORDS
haemophilic arthropathy, hyaluronic acid, intra‐articular injection, platelet‐rich plasma

484 | © 2019 John Wiley & Sons Ltd wileyonlinelibrary.com/journal/hae Haemophilia. 2019;25:484–492.
LI et al.
1 | I NTRO D U C TI O N
Severe haemophilia is characterized by frequent and lifelong bleed‐
ing episodes such as joint and muscle bleeding.1 Repeated joint
bleeding leads to alteration to peri‐articular environment and dis‐
ruption to homoeostasis, resulting in chronic synovitis, cartilage
damage and bony destruction, which are associated with the de‐
velopment of haemophilic arthropathy including pain, reduced
range of motion (ROM), muscle atrophy, functional impairment and
2
poor quality of life. Haemophilic arthropathy is a multifactorial
event. Evidence suggests that iron from lysed red blood cells and
pro‐inflammatory cytokines such as interleukin (IL)‐1, IL‐6 and tu‐
mour necrosis factor alpha (TNF‐α) released from white blood cells
could lead to chronic proliferative synovitis, hypervascularity and
3
progressive arthropathy. The management of chronic haemophilic
arthropathy can be challenging and is clearly consequential to the
life quality of patients.
The currently available drugs for the treatment of haemophilic
arthropathy, including analgesics, corticosteroids, nonsteroidal and
steroidal anti‐inflammatory drugs and intra‐articular injection of hy‐
aluronic acid (HA), predominantly provide symptomatic relief of pain
and inflammation. They have little to no effect on the degenerative
changes in the articular cartilage. There are also other treatment op‐
tions such as synoviorthesis, osteotomy and arthroscopy. Although
knee arthroplasty is effective for end‐stage haemophilic arthropa‐
4
thy, it is best kept as the last option after all else has failed, as it
is the most invasive management of all the treatment options and
revision surgery may be required in many patients 10‐15 years later.
Young patients are at a higher risk of revision surgery due to their
5
higher activity level as compared to elderly patients. Consecutive
surgery is more difficult and requires longer recovery time.
In terms of intra‐articular therapy, HA has been used for over two
decades to treat haemophilic arthropathy. In 1994, Fernandez‐Palazzi
6
et al first used intra‐articular HA injections for haemophiliacs with ar‐
thropathy and reported its beneficial effects in 2002. Recently, Carulli
et al7 reported that 27 haemophilia patients, with a mean follow‐up
period of 7 years, had excellent results in pain relief and functional
improvement of the knee after treatment with HA injections. HA is
a polyanionic, unbranched glycosaminoglycan polymer, the viscosity
and negative charge that attracts water of which provide protection on
cartilage surface.8 HA viscosupplementation is an approach to restore
the HA content within the joint. The treatment has been approved by
the FDA9 and is recommended by the Osteoarthritis Research Society
International (OARSI) for non‐severe osteoarthritis.10
Intra‐articular platelet‐rich plasma (PRP) injection is an easy
and minimally invasive therapy that provides a natural concen‐
trate of autologous growth factors from the blood.11,12 This
regenerative therapy has been increasingly applied in clinical
practice to treat musculoskeletal disorders such as tendon injury
13
and osteoarthritis. Growth factors in PRP, including platelet‐
derived growth factor, insulin‐like growth factor, vascular en‐
dothelial growth factor and transforming growth factor beta‐1,
are suggested to be the major anabolic components. Adhesive
| 485
proteins such as fibrinogen, fibronectin, vitronectin and throm‐
bospondin‐1, also play important roles in cell migration and
matrix remodelling. Although the therapeutic outcomes of PRP
intra‐articular injections in different connective tissues had vary‐
ing results, PRP is nonetheless considered useful in healing and
functional improvement of the injured connective tissues. There
were some advantages of PRP injection therapy for osteoarthritis
compared to other modalities including less frequent dosing re‐
quirement with one to three injections, and more effective pain
relief and functional improvement.14,15 However, this strategy is
infrequently applied in the treatment of haemophilic arthropa‐
thy. Only one study previously evaluated the use of PRP injec‐
tions for arthropathy treatment in haemophilia patients. Teyssler
et al16 reported that PRP could reduce the pain in chronic ankle
synovitis in haemophiliacs, although their study had some limita‐
tions including small sample size (n = 6), short term follow‐up and
absence of a control group. There was no serious side effect of
PRP, but Campbell et al17 reported that the use of multiple PRP
injections in osteoarthritic patients may increase the risk of local
adverse reactions such as infection and joint swelling.
Moreover, there are evidence showing that HA and PRP have
different mechanisms in the treatment of arthropathy. In vitro co‐
culture of synovium and cartilage comparing HA and PRP treatment
suggested that HA and PRP ameliorate inflammation differently, as
demonstrated in the different expressions of cytokines and matrix
metalloproteinases.18 PRP has also been shown to upregulate HA
production in synovial fibroblast in vitro.19 Hence, finding a benefi‐
cial effect of PRP in the treatment of haemophilic arthropathy sug‐
gests PRP to be a potential alternative therapy that may be useful to
patients who had bad response to HA treatment.
The aim of the present study was to investigate and compare the
efficacy, safety and duration of benefit of a single intra‐articular PRP
injection vs five weekly intra‐articular injections of HA for patients
with haemophilic arthropathy of the knee.
2 | M ATE R I A L S A N D M E TH O DS
2.1 | Patients
This single‐centre, non‐randomized, open‐label trial (NCT02601170,
ClinicalTrials.gov) was approved by the institutional ethics commit‐
tee, and all enrolled patients provided written‐informed consents.
From June 2014 to May 2016, 24 adult haemophilia patients, who
had persistent painful haemophilic arthropathy of the knee (visual
analogue score [VAS] ≥3) despite medication for at least 6 months
prior to the enrolment, were included in the study. Only patients
over 20 years of age (legal age of adulthood in Taiwan) were included.
The exclusion criteria were as follows: presence of joint infections,
surgery on the joint in the preceding 12 months, intra‐articular cor‐
ticosteroid or HA injection within the past 6 months, treatment with
systemic steroids, history of rheumatoid arthritis or gouty arthropa‐
thy, history of chicken or egg allergy, presence of neoplasm, use of
nonsteroidal anti‐inflammatory drugs within the 5 days before blood
486 | LI et al.

collection for preparing PRP, platelet count <100 000/mm3, acute
haemarthrosis, paresis and recent trauma. Based on the above cri‐
teria, two patients were excluded, including one patient with plate‐
let count <100 000/mm3 and the other patient was younger than
20 years old. A total of 22 patients were enrolled in the study. Since
not all patients were able to commit to five consecutively weekly
intra‐articular injections of HA due to work or school, we adopted
matched sampling method based on practical and logistical consid‐
erations, and stratified the 22 patients into two groups: patients
who could commit to HA treatment were allocated to the HA group,
otherwise patients were allocated to the PRP group. To compensate
for this non‐probabilistic method, we compared the baseline de‐
mographics between the two groups to ensure comparability. We
collected clinical information including age, body mass index (BMI),
haemophilia type, disease severity, inhibitor titre and the average
number of joint bleeds per month.
events during the study period were recorded in a diary by the
patients.
2.3 | PRP preparation method
A single 10‐mL of peripheral venous blood was collected from
each patient in the PRP group prior to factor replacement.
Subsequently, centrifugation was performed at 3400 rotations
per minute (1907 g) for 15 minutes to concentrate the platelets,
which provided 2.5 mL of PRP. A 0.5 mL aliquot was sent to the
laboratory for complete blood count testing, and the remaining
2 mL was used for intra‐articular injection. Complete blood count
analysis was performed on the whole blood and PRP samples.
This preparation method increased the number of platelets per
millilitre by a mean of 2.7 ± 0.4 times and the number of leuco‐
cytes by a mean of 1.2 ± 0.4 times that of the peripheral whole
blood.

2.2 | Intervention
2.4 | Evaluation
Before starting the treatment, a baseline ultrasound evaluation was
performed. Patients in the PRP group received a single intra‐artic‐
2.4.1 | Assessment of pain and ROM
ular injection of 2 mL PRP (RegentKit‐THT‐1, RegenLab SA, Mont‐
sur‐Lausanne, Switzerland) and patients in the HA group received The pain intensity of the knee was evaluated subjectively using
5 weekly intra‐articular injections of 2.5 mL hyaluronate sodium the VAS (0‐10, 10 cm line). ROM of the knee was measured in de‐
(ARTZDispo, Seikagaku Corporation, Tokyo, Japan). Treatment fre‐ grees using a goniometer according to the American Academy of
quency and volume were based on the manufacturer's instructions Orthopaedic Surgeons guidelines. All the ROM measurements were
for knee arthropathy. Intra‐articular injection was conducted with performed by the same examiner who was blinded to the patient
gloved hands, under septic condition disinfected with betadine and group.
ethanol, by the Physical Medicine and Rehabilitation physician at
the haemophilia centre. Ultrasonographic guidance was not used for
treatment. TA B L E 1 Baseline demographic characteristics of study patients
Before each intra‐articular injection, patients received an in‐
travenous injection of 25 IU/kg of factor VIII concentrate (Advate, Characteristic PRP (n = 11) HA (n = 11) P value

Shire, Dublin, Ireland, UK) replacement therapy for protection Age, y ± SE 41.3 ± 2.3 38.8 ± 2.4 0.47
against haemarthrosis. After each injection, the joint was rested for BH, cm ± SE 170.4 ± 2.3 170.0 ± 1.8 0.90
20 minutes and compression was applied with an elastic bandage BW, kg ± SE 69.5 ± 4.7 73.4 ± 4.8 0.57
to minimize any injection‐induced bleeding. All outcome measure‐ 2
BMI, kg/m ± SE 23.9 ± 1.4 25.4 ± 1.7 0.49
ments were performed initially at baseline and subsequently at 1, Haemophilia severity
2, 3 and 6 months after the last injection in each group. The pri‐
A, severe 9 9
mary outcome measure was reduction in pain intensity measured
A, moderate 1 1
by the VAS, ranging from 0 (no pain) to 10 (extremely severe pain).
B, severe 1 1
Secondary clinical outcomes included the Western Ontario and
HIV 1 2 0.53
McMaster Universities Osteoarthritis Index (WOMAC), assessment
Inhibitor 2 0 0.14
of synovial thickness using ultrasonography, assessment of hyper‐
aemia using power Doppler, ROM and quality of life assessed by Injected knee 11 11

Short Form 36 (SF‐36). Right/left 4/7 4/7

After treatment, the patients resumed their previous prophy‐ Pettersson score ± SE
laxis treatment, and self‐administered extra clotting factor by Injected knee 9.6 ± 0.3 9.0 ± 0.7 0.51
themselves for perceived knee joint bleeds based on their own Ipsilateral ankle 7.0 ± 1.6 4.9 ± 1.4 0.40
judgement if required. During the study period, the use of nonste‐ Ipsilateral hip 0±0 0.8 ± 0.8 0.75
roidal anti‐inflammatory medication was prohibited. Only investi‐
BH, body height; BMI, body mass index; BW, body weight; HA, hyalu‐
gator‐prescribed acetaminophen was permitted for additional pain ronic acid; HIV, human immunodeficiency virus; PRP, platelet‐rich
relief. The use of analgesics, joint bleeding episodes and adverse plasma; SE, standard error.
LI et al. | 487

and medial aspects of the anterior suprapatellar recess were

2.4.2 | Ultrasonography
Ultrasonography assessment was performed according to a
standard technique using Terason t3000 machines (Teratech™,
Burlington, MA, USA) with a 5‐12 MHz linear transducer. The
probe scanned the joint in the longitudinal view with the knee
in full extension. The synovial thickness and hyperaemia were
evaluated from the lateral, middle and medial aspects of the an‐
terior suprapatellar recess. 20,21 Power Doppler assessment of
the selected synovial sites was performed. The Power Doppler
gain was adjusted to a level just below the disappearance of ar‐
tefacts under the bony cortex. 21,22 The intensity of blood flow in
the synovium was scored on a semiquantitative scale from 0‐3
(grade 0, no intra‐articular colour signal; grade 1, up to 3 colour
signals or 2 single and 1 confluent signal in the intra‐articular
area; grade 2, greater than grade 1 to <50% of the intra‐articu‐
lar area filled with colour signals; grade 3, ≥50% of the intra‐ar‐
23
ticular area filled with colour signals). The averages of synovial
thicknesses and the scores of hyperaemia in the lateral, middle
calculated.
2.4.3 | Radiological evaluation
Anteroposterior and lateral plain radiographs of the knees were ac‐
quired and scored according to the Pettersson classification24 by the
designated orthopaedic specialist at our haemophilia centre.
2.4.4 | SF‐36
The SF‐36 is a generic measure of health status and has gained
popularity as a measure of outcome in a wide variety of patient
groups and surveys. 25 The SF‐36 is a 36‐item assessment tool that
measures eight general health concepts, including the physical func‐
tioning, role limitation due to physical health problems, bodily pain,
general health, vitality, social functioning, role limitation due to
emotional problems, and mental health. The SF‐36 is filled out, with
scores ranging from 0 to 100, taking into consideration the person's

TA B L E 2 Outcome measures of PRP & HA‐injected knees at baseline and 6‐mo follow‐up

RM-
Group Baseline 1 mo 2 mo 3 mo 6 mo ANOVA

VAS PRP 5.0 ± 0.6 2.5 ± 0.8*** 2.4 ± 0.8*** 2.5 ± 0.8*** 2.6 ± 0.7*** F = 17.76,
P < 0.01
HA 4.1 ± 0.5 1.8 ± 0.5*** 1.6 ± 0.5*** 2.3 ± 0.6* 3.4 ± 0.5 F = 13.33,
P < 0.01
SF‐36 PRP 56.7 ± 5.3 62.8 ± 4.6 63.5 ± 4.1 61.7 ± 4.7 65.1 ± 3.7 NS
HA 54.7 ± 4.9 58.5 ± 5.0 63.5 ± 3.6 63.3 ± 3.1 58.3 ± 4.7 NS
WOMAC PRP 38.3 ± 3.4 28.7 ± 3.7** 27.3 ± 3.3** 29.9 ± 3.9* 29.4 ± 3.7* F = 4.78,
P < 0.01
HA 33.4 ± 5.5 19.1 ± 3.9** 21.3 ± 3.7* 27.1 ± 4.7 35.8 ± 5.0 F = 9.27,
P < 0.01
ROM (degree) PRP 92.3 ± 8.5 99.5 ± 7.6 102.3 ± 7.9 101.4 ± 7.8 100.9 ± 8.5 NS
HA 90.9 ± 8.3 91.8 ± 8.1 91.8 ± 8.1 91.8 ± 8.1 91.8 ± 8.1 NS
Hemarthrosis PRP 0.5 ± 0.2 0.4 ± 0.2 0±0 0.6 ± 0.3 0.4 ± 0.3 NS
HA 0.7 ± 0.2 0.4 ± 0.1 0.3 ± 0.1 0.3 ± 0.2 0.6 ± 0.2 NS
Hyperaemia (score) PRP 1.0 ± 0.3 0.9 ± 0.3 0.3 ± 0.2** 0.4 ± 0.2* 0.3 ± 0.1* F = 4.16,
P < 0.05
HA 0.9 ± 0.2 0.4 ± 0.1** 0.2 ± 0.1** 0.2 ± 0.1* 0.3 ± 0.1* F = 5.63,
P < 0.05
Thickness of synovium PRP 8.0 ± 1.3 7.1 ± 1.0 7.0 ± 1.3 7.2 ± 1.2 6.9 ± 1.0 NS
(mm) HA 6.9 ± 1.0 6.5 ± 1.2 6.1 ± 1.1 6.0 ± 1.1 6.0 ± 1.1 NS

A significant difference was found between two groups in VAS score, WOMAC and hyperaemia between baseline and from one to 6 mo of follow‐up.
Score expressed as mean ± standard error. Hemarthrosis is defined as the number of knee bleeds in last 1 mo; Thickness of synovium is defined as the
average synovial thickness in lateral, middle, and medial aspects of suprapatellar pouch; Hyperaemia is defined as the average score of Power Doppler
assessment in lateral, middle, and medial suprapatellar recess synovium.
NS, not significant; RM‐ANOVA, repeated‐measure analysis of variance; ROM, range of Motion; SF‐36, Short Form‐36; VAS, Visual Analogue Scale;
WOMAC, Western Ontario and McMaster Universities Osteoarthritis Index.
a
Significant difference compared to baseline,
*P < 0.05,
**P < 0.01,
***P < 0.001.
488 | LI et al.

condition in the last 1 month; higher scores indicated better health‐

related quality of life.
2.4.5 | WOMAC
The WOMAC was developed in the early 1980s as a disease‐specific
measure for lower limb arthritis and arthropathy26; it consists of the
following 24 items: 5 pertaining to pain perception, 2 to stiffness
and 17 to physical function. We used 100 mm Visual Analog Chinese
version. For each item, the possible range of scores is therefore
0‐100. Items are summed for each subscale, resulting in ranges as
follows: pain = 0‐500, stiffness = 0‐200, physical function = 0‐1700.
Individual scores were then summed to form a raw score ranging
from 0 (best) to 2400 (worst). Finally, WOMAC total score normal‐
ized between 0 (best) and 100 (worst).
2.5 | Statistical methods
Continuous variables are expressed as mean values and standard devia‐
tions, and compared using the Mann‐Whitney U test. Categorical varia‐
bles are expressed as frequencies and percentage values and compared
using the Chi‐square test or Fisher's exact test. The repeated measures
analysis of variance (RM‐ANOVA) was used to analyse the differences
between the baseline and various follow‐up measures. A P‐value of
<0.05 was considered statistically significant. Statistical analysis was
conducted using IBM SPSS Statistics (version 22.0, Armonk, NY, USA).
3 | R E S U LT S
3.1 | Patients
This study included 22 patients with a mean age of 40.1 ± 1.7 (range,
20‐50) years. Of these, 20 had haemophilia A and 2 had haemophilia
B. All patients had severe haemophilia with the exception of two who
had moderate haemophilia. The patients were assigned to two treat‐
ment groups with intra‐articular injection of either PRP or HA. There
was no significant difference in baseline characteristics in terms of
age, BMI, history of inhibitor titre and Pettersson score (Table 1).
No significant adverse events or injection‐related haemarthroses
were observed in all patients. The series of changes from baseline
levels of the VAS, SF‐36, WOMAC, ROM, number of haemarthroses,
hyperaemia and synovial thickness to those assessed at 1, 2, 3 and
6 months are shown in Table 2.
3.3 | HA group
A significant reduction in VAS from haemophilic arthropathy of the
knee lasting for 6 months was observed (F = 13.33, P < 0.01). Also,
the WOMAC score significantly improved over the 6‐month period
after injection (F = 9.27, P < 0.01) and a significant improvement
in synovial hyperaemia was noted (F = 5.63, P < 0.05). There was
no significant change in the synovial thickness, number of hemar‐
throses, SF‐36 and ROM.
3.4 | PRP vs HA
Both treatments were found to be effective in reducing pain and
improving functional status of the knee. Figures 1 and 2 show the
comparison of VAS and WOMAC score change before and after
intra‐articular PRP or HA injection treatment. No significant differ‐
ence between PRP and HA groups in VAS, SF‐36 score, WOMAC
score, ROM, number of hemarthroses, hyperaemia and thick‐
ness of synovium at baseline was found. The VAS, WOMAC total
score, pain and physical function scores in PRP group were signif‐
icantly lower than those seen in HA group at 6 months (P < 0.05)
(Table 3). However, the comparative analysis showed no significant
inter‐group difference at the other follow‐up time points in the other
clinical scores that were evaluated.
4 | D I S CU S S I O N
To our best knowledge, this is the first prospective study to demon‐
strate the efficacy and safety of intra‐articular PRP injections in the
treatment of haemophilic arthropathy of the knee. In patients with
chronic knee joint pain, our study shows that treatment with intra‐
articular PRP injection could reduce pain, improve hyperaemia and
enhance knee joint function. In comparison with HA, PRP appeared
to have better efficacy in terms of pain reduction and functional

3.2 | PRP group

A significant reduction in VAS due to haemophilic arthropathy of
the knee lasting for 6 months was observed (F = 17.76, P < 0.01).
Likewise, the WOMAC score was significantly improved over the
6‐month period after injection (F = 4.78, P < 0.01) and a significant
F I G U R E 1 Mean of change from baseline in VAS between PRP
improvement in synovial hyperaemia was also achieved (F = 4.16,
and HA groups (mean ± standard error). PRP group had significant
P < 0.05). No significant changes in the SF‐36, synovial thickness, improvement compared with HA group at the 6‐mo follow‐up. VAS,
ROM and number of haemarthroses were observed. Visual Analogue Scale. *P < 0.05
LI et al.
F I G U R E 2 Mean of change from baseline in WOMAC between
PRP and HA groups (mean ± standard error). PRP group had
significant improvement compared with HA group at the 6‐mo
follow‐up. WOMAC, Western Ontario and McMaster Universities
Osteoarthritis Index. *P < 0.05
improvement at 6 months. The degree of improvement in VAS and
WOMAC scores in PRP group was significantly greater than those
seen in HA group at 6 months. This is similar to the observation in
Campbell's study where significant improvements in osteoarthritis
patients who received intra‐articular PRP injection compared to
other interventions at 6 months.17 While it should be acknowledged
that osteoarthritis and haemophilic arthropathy are different de‐
generative joint diseases, since PRP treatment has been often used
to treat osteoarthritis, and seldom for haemophilic arthropathy, we
used knowledge learned from previous osteoarthritis studies to
carefully assess our data.
Haemophilic arthropathy is a multifactorial event with evi‐
dence to suggest that iron along with cytokines, such as IL‐1 and
TNF‐α, may play major roles in chronic proliferative synovitis, hy‐
pervascularity, cartilage damage and bone destruction. 3,27 PRP,
an autologous derivative of whole blood, contains high concen‐
trations of growth factors that enhance the healing of tendons,
ligaments, muscles, cartilages and bones. Through the effects of
various growth factors, PRP has been shown to have positive ef‐
fects on chondrocyte proliferation and differentiation, 28 stimula‐
tion of synovial fibroblast to synthesize HA,19 and in increasing the
anti‐inflammatory and decreasing the pro‐inflammatory mediators
such as IL‐129 and TNF‐α. 30 These pieces of evidence suggest that
intra‐articular PRP injection might be beneficial in the treatment of
haemophilic arthropathy.
In general, PRP is defined as a volume of autologous plasma that
contains a platelet concentration above the basal level in whole
blood. PRP has been shown to be potentially beneficial in tissue re‐
generation, with many applications in different fields of medicine,
particularly in the musculoskeletal system.31 However, there is a lack
of standardization in the PRP collection method. The optimal con‐
centrations and regimen of PRP, which includes platelets, leucocytes
and growth factors, remain a topic of investigation that warrants fu‐
ture studies. Kon et al32 reported that physically active osteoarthritis
| 489
patients aged 50 years or younger with a lower degree of cartilage
degeneration achieved better results with PRP injections. Patel et
al33 reported that a single dose of PRP is as effective as two injec‐
tions to alleviate symptoms in early knee osteoarthritis; however,
deterioration of symptoms was observed after 6 months. In contrast
to the aforementioned osteoarthritis studies in which the effect of
PRP was most prominent in early stage of the disease, we found that
PRP remains to be a potentially effective treatment in pain relief,
reduction in synovial hyperaemia and restoration of joint function in
our cohort with high Pettersson score (mean: 9.4; median: 10), which
suggests advanced stage of haemophilic arthropathy.
Our study showed that a single intra‐articular PRP injection was
effective in treating haemophilic arthropathy of the knee joint for a
period of at least 6 months in haemophilia patients with an average
age of about 40 years old. More specifically, PRP showed beneficial
effects in pain reduction, joint function and synovial vasculature.
PRP treatment was found to provide sustained joint pain relief, as
only 1/11 patients returned to baseline level in VAS at 6 months,
whereas in the HA group, 4/11 patients returned to or exceeded
baseline level. Interestingly, PRP treatment was found to have en‐
tirely relieved minor pain for 6 months, whereas such sustained ef‐
fect was not observed in the HA group, as shown in the PRP group in
which 4/11 patients had a baseline VAS of 3 and a 6‐month VAS of
0. In contrast, 7/11 patients in the HA group had a baseline VAS of
3, achieved various improvement (VAS between 0 and 2) at 1 month,
and deteriorated by 6 months (VAS between 2 and 3). For patients
that had higher baseline VAS, varying degrees of pain‐relieving ef‐
fect was found in the PRP group (VAS [6‐month – baseline] between 0 and
5), whereas the effect was more consistent in the HA group (VAS
[6‐month – baseline] between 2 and 3). These suggest that HA and PRP
could be working through different antinociceptive mechanisms.
The change in WOMAC total score was found to be different
between PRP and HA groups at 6 months, and the differences orig‐
inated from the pain score and the physical function score, but not
stiffness score. WOMAC pain score was congruent to the VAS score,
wherein improvement in pain was observed in both groups, but was
only sustained in the PRP group through to 6 months. Similar pattern
was observed in physical function score. While no difference be‐
tween PRP and HA group in stiffness score was found, both groups
demonstrated improvement from baseline. Consistent and stable re‐
duction in stiffness was observed in PRP group. It should be noted
that, while not statistically significant, improvement in both stiffness
and physical function was greater in the HA group at 1 month, but
diminished earlier than PRP group. HA turnover time in a normal
joint was estimated to be <40 hours,34 suggesting that the therapeu‐
tic effects of intra‐articular injection of HA had other mechanisms of
action besides joint lubrication, namely reducing chondrocyte apop‐
tosis, increasing chondrocyte proliferation, upregulating proteogly‐
can and glycosaminoglycan synthesis, downregulating degradative
enzyme, inhibiting catabolic cytokine suppression and analgesic ef‐
fect via receptor interaction.35 Similarly, PRP is suggested to have
the effects of chondrocyte proliferation, proteoglycan deposition,
type II collagen deposition, chondrogenic differentiation, apoptosis
490 | LI et al.

TA B L E 3 The outcome variables (VAS and WOMAC) before and after treatment in both groups

PRP group (n = 11) HA group (n = 11)

Mean ± SE Mean difference ± SE Mean ± SE Mean difference ± SE P valuea

VAS baseline 5.0 ± 0.6 4.1 ± 0.5

Month 1 2.5 ± 0.8 −2.5 ± 0.5 1.8 ± 0.5 −2.3 ± 0.4 0.898
Month 2 2.4 ± 0.8 −2.6 ± 0.5 1.6 ± 0.5 −2.5 ± 0.5 0.699
Month 3 2.5 ± 0.8 −2.5 ± 0.4 2.3 ± 0.6 −1.7 ± 0.4 0.243
Month 6 2.6 ± 0.7 −2.5 ± 0.4 3.4 ± 0.5 −0.7 ± 0.5 0.016
WOMAC
Total score baseline 38.3 ± 3.4 33.4 ± 5.5
Month 1 28.7 ± 3.7 −9.7 ± 2.9 19.1 ± 3.9 −14.3 ± 4.4 0.606
Month 2 27.3 ± 3.3 −11.1 ± 3.0 21.3 ± 3.7 −12.1 ± 4.7 0.699
Month 3 29.9 ± 3.9 −8.5 ± 3.7 27.1 ± 4.7 −6.3 ± 4.6 0.748
Month 6 29.4 ± 3.7 −9.0 ± 3.7 35.8 ± 5.0 2.4 ± 3.1 0.047
Pain baseline 180.2 ± 16.4 126.3 ± 22.6
Month 1 125.2 ± 16.4 −55.0 ± 19.0 69.8 ± 16.4 −56.5 ± 15.5 0.898
Month 2 132.8 ± 26.7 −47.4 ± 24.2 96.6 ± 17.7 −29.6 ± 23.3 0.519
Month 3 146.3 ± 33.2 −33.9 ± 33.6 122.4 ± 27.0 −3.9 ± 18.2 0.300
Month 6 131.5 ± 27.7 −48.7 ± 31.5 155.5 ± 26.2 29.3 ± 16.5 0.047
Stiffness baseline 105.5 ± 21.7 97.3 ± 19.0
Month 1 69.1 ± 19.0 −36.5 ± 15.8 50.7 ± 13.4 −46.5 ± 19.1 0.797
Month 2 71.6 ± 19.1 −33.9 ± 22.7 59.8 ± 12.5 −37.5 ± 19.9 0.949
Month 3 73.7 ± 16.1 −31.8 ± 18.2 73.2 ± 15.1 −24.0 ± 15.3 0.797
Month 6 71.4 ± 19.8 −34.2 ± 18.3 89.5 ± 13.1 −7.8 ± 14.3 0.151
PF baseline 632.5 ± 57.0 568.5 ± 93.6
Month 1 493.4 ± 58.9 −139.0 ± 50.0 336.9 ± 69.3 −231.5 ± 69.6 0.300
Month 2 450.4 ± 46.2 −182.1 ± 49.6 354.2 ± 64.4 −214.3 ± 74.8 0.847
Month 3 496.0 ± 55.0 −136.5 ± 58.8 447.7 ± 86.6 −120.7 ± 87.1 0.949
Month 6 501.5 ± 49.1 −130.9 ± 58.5 620.9 ± 91.8 52.5 ± 49.2 0.028

PF, physical function; SE, standard error; VAS, Visual analog scale; WOMAC, Western Ontario and McMaster Universities Osteoarthritis Index.
a
Mann‐Whitney U Test (mean difference).

inhibition, inhibiting and catabolic cytokine suppression.36 Although
based on basic science evidence, PRP and HA seem to share some
therapeutic effects, data from our study suggest that in treating
haemophilic arthropathy, HA had a greater immediate efficacy that
could not be sustained for longer than 6 months, a finding that is
congruent to previous OA studies, whereas PRP had a relatively
smaller but persisting beneficial effect, suggesting possible tissue
reconstruction. These results provide evidence that PRP may halt
the progression of haemophilic arthropathy, and present PRP as a
disease‐modifying agent that repair joint structure through its pro‐
posed regenerative properties, although specific mechanisms re‐
main to be clarified.
Synovial vascular changes in haemophilia are associated with
increased bleeding and joint deterioration.37 In this study, synovial
hypervascularity was significantly improved after PRP injection and
the response was sustained for at least 6 months. This supports
our speculation that tissue reconstruction was involved in PRP
treatment, and hence may have the effect of blocking the vicious
cycle of haemarthrosis‐synovitis‐haemarthrosis, although this needs
to be verified in further study. Similar effect was found in the HA
group, and no significant difference was found between PRP and
HA groups.
Interestingly, we did not observe any significant changes in SF‐36
score, which is an indicator of quality of life. One possible reason is
that patients enrolled in this study had been under comprehensive
care (including treatment for knee arthropathy) at our haemophilia
centre and had learned to cope and overcome various challenges in
life. Hence their quality of life was not strongly hindered by knee
arthropathy. Furthermore, it should be added that both HA and PRP
groups showed overall trends of sustained improvement of quality
of life after injection. However, 10/11 patients in the PRP group
showed improvement in SF‐36 score at 6 months, whereas only
6/11 patients in the HA group showed improvement. The change
was not statistically significant due to the small sample size and large
LI et al.
variance, but the trends of reduced disability were observed in both
groups, and whether there is a difference in improvement in quality
of life between PRP and HA intra‐articular injection warrants further
investigation.
In economic perspective, the cost of PRP can vary from 0.2 to 2
times that of HA treatment, depending on whether the hospital lab‐
oratory can prepare PRP with or without a commercial kit. In patient
safety perspective, severe side effects associated with PRP injection
are rare.38 Local symptoms including pain and swelling at the injec‐
tion site are the most common adverse events. Allergic reactions are
also rare due to the autologous nature. The most significant com‐
plication is intra‐articular infection that can be prevented by using
strict aseptic precautions. No major complications in both HA and
PRP groups were noted in our study.
Limitations in this study include small sample size, short follow‐
up period, absence of a randomized double‐blind study design, and
using an active comparator instead of a negative control. A larger
sample size in a randomized, double‐blind controlled trial may help
further verify the efficacy of intra‐articular PRP injection over HA
injection for haemophilic arthropathy of the knee. However, such a
study may be challenging to conduct in Taiwan and would require
cooperative effort by multiple institutions, given the relatively
small numbers of haemophilia patients in most haemophilia cen‐
tres across the country. The short follow‐up period of 6 months is
another limitation of the present study, which was due primarily
to institutional budget constraints. Longer time of follow‐up may
be able to better assess the durability of PRP or HA treatment for
haemophilic arthropathy. Due to the severe and early degenerative
nature of haemophilic joints, this study chose HA as an active com‐
parator instead of a negative control, such as a single intra‐articular
injection of normal saline, to prevent joint deterioration. However,
it should also be added that patients in the HA group could be at
risks of injection‐related adverse effects due to the more frequent
five injections compared to those in the PRP group, which all re‐
ceived a single injection, but no such effects were observed in our
study.
In conclusion, our exploratory investigation suggests that single
PRP injections may be safe and effective in treating haemophilic ar‐
thropathy of the knee for up to 6 months. The treatment not only
reduced pain and improved knee function to a greater degree than
HA injections, but also reduced synovial hyperaemia. We therefore
propose that PRP therapy may be useful in the treatment of haemo‐
philic arthropathy of the knee and may also provide a good option
for temporary management to delay total knee arthroplasty. Further
investigation using rigorous research methodology is warranted to
establish the benefit of PRP on haemophilic arthropathy and stan‐
dardize PRP preparation and dosing regimens.
AC K N OW L E D G E M E N T S
This study was supported by a research grant, TSGH‐C103‐116
from the Tri‐Service General Hospital. The authors extend their
thanks to Dr. Vivek R. Sharma, research scientist and medical
| 491
director, adult haemophilia program, division of medical oncology/
haematology, University of Louisville, School of Medicine for his
thoughtful review of this manuscript, and Nurses Hsiao‐Chung
Lee and Ya‐Wen Chen for their excellent care of our haemophilia
patients and coordination of this study.
D I S C LO S U R E S
Li TY, Cheng SN and Chen YC each received a research grant from
Shire pharmaceutical company. The authors stated that they had no
interests which might be perceived as posing a conflict or bias.
AU T H O R C O N T R I B U T I O N
Li performed the study and wrote the paper. Wu performed the
study and analysed the data. Chen LC and Cheng revised the
paper critically. Pan performed the orthopaedic evaluation of the
patients. Chen YC designed the research study and revised the
paper.
ORCID
Tsung‐Ying Li https://orcid.org/0000-0002-7683-6010
REFERENCES
1. Stephensen D, Tait RC, Brodie N, et al. Changing patterns of
bleeding in patients with severe haemophilia A. Haemophilia.
2009;15:1210‐1214.
2. Krasuska M, Riva S, Fava L, von Mackensen S, Bullinger M. Linking
quality‐of‐life measures using the International Classification
of Functioning, Disability and Health and the International
Classification of Functioning, Disability and Health‐Children
and Youth Version in chronic health conditions: the exam‐
ple of young people with haemophilia. Am J Phys Med Rehabil.
2012;91:S74‐S83.
3. Lafeber FP, Miossec P, Valentino LA. Physiopathology of haemo‐
philic arthropathy. Haemophilia. 2008;14(Suppl 4):3‐9.
4. Rodriguez‐Merchan EC. Total knee replacement in haemophilic ar‐
thropathy. J Bone Joint Surg Br. 2007;89:186‐188.
5. Kurtz SM, Lau E, Ong K, Zhao K, Kelly M, Bozic KJ. Future young
patient demand for primary and revision joint replacement: na‐
tional projections from 2010 to 2030. Clin Orthop Relat Res.
2009;467:2606‐2612.
6. Fernandez‐Palazzi F, Viso R, Boadas A, Ruiz‐Saez A, Caviglia H, De
Bosch NB. Intra‐articular hyaluronic acid in the treatment of hae‐
mophilic chronic arthropathy. Haemophilia. 2002;8:375‐381.
7. Carulli C, Matassi F, Civinini R, Morfini M, Tani M, Innocenti M.
Intra‐articular injections of hyaluronic acid induce positive clinical
effects in knees of patients affected by haemophilic arthropathy.
Knee. 2013;20:36‐39.
8. Andia I, Abate M. Knee osteoarthritis: hyaluronic acid, plate‐
let‐rich plasma or both in association? Expert Opin Biol Ther.
2014;14(5):635‐649.
9. Sun S, Chou Y, Hsu C, Chen W. Hyaluronic acid as a treatment for
ankle osteoarthritis. Curr Rev Musculoskelet Med. 2009;2(2):78‐82.
10. Hunter DJ, Lo GH. The management of osteoarthritis: an overview
and call to appropriate conservative treatment. Med Clin North Am.
2009;93(1):127‐143.
492 | LI et al.
11. Pietrzak WS, Eppley BL. Platelet rich plasma: biology and new tech‐
nology. J Craniofac Surg. 2005;16:1043‐1054.
12. Caviglia H, Landro ME, Daffunchio C, et al. Platelet rich plasma
for chronic synovitis treatment in patients with haemophilia.
Haemophilia. 2017;23(4):613‐619.
13. Foster TE, Puskas BL, Mandelbaum BR, Gerhardt MB, Rodeo SA.
Platelet‐rich plasma: from basic science to clinical applications. Am
J Sports Med. 2009;37:2259‐2272.
14. Laudy AB, Bakker EW, Rekers M, Moen MH. Efficacy of platelet‐
rich plasma injections in osteoarthritis of the knee: a systematic
review and meta‐analysis. Br J Sports Med. 2015;49:657‐672.
15. Dai WL, Zhou AG, Zhang H, Zhang J. Efficacy of platelet‐rich plasma
in the treatment of knee osteoarthritis: a meta‐analysis of random‐
ized controlled trials. Arthroscopy. 2017;33:659‐670.e1.
16. Teyssler P, Kolostova K, Bobek V. The impact of platelet‐rich
plasma on chronic synovitis in haemophilia. Acta Orthop Belg.
2014;80:11‐17.
17. Campbell KA, Saltzman BM, Mascarenhas R, et al. Does intra‐ar‐
ticular platelet‐rich plasma injection provide clinically superior
outcomes compared with other therapies in the treatment of knee
osteoarthritis? A systematic review of overlapping meta‐analyses.
Arthroscopy. 2015;31:2213‐2221.
18. Sundman EA, Cole BJ, Karas V, et al. The anti‐inflammatory and ma‐
trix restorative mechanisms of platelet‐rich plasma in osteoarthritis.
Am J Sports Med. 2013;42(1):35‐41.
19. Anitua E, Sanchez M, Nurden AT, et al. Platelet‐released growth
factors enhance the secretion of hyaluronic acid and induce he‐
patocyte growth factor production by synovial fibroblasts from
arthritic patients. Rheumatology. 2007;46(12):1769‐1772.
20. Acharya SS, Schloss R, Dyke JP, et al. Power Doppler sonography in
the diagnosis of haemophilic synovitis–a promising tool. J Thromb
Haemost. 2008;6:2055‐2061.
21. Melchiorre D, Linari S, Innocenti M, et al. Ultrasound detects joint
damage and bleeding in haemophilic arthropathy: a proposal of a
score. Haemophilia. 2011;17:112‐117.
22. Chen YC, Chen LC, Cheng SN, Pan RY, Chang ST, Li TY. Haemophilic
arthropathy of shoulder joints: clinical, radiographic, and ultraso‐
nographic characteristics of seventy patients. J Bone Joint Surg Am.
2013;95:e43.
23. Backhaus M, Ohrndorf S, Kellner H, et al. Evaluation of a novel 7‐
joint ultrasound score in daily rheumatologic practice: a pilot proj‐
ect. Arthritis Rheum. 2009;61:1194‐1201.
24. Pettersson H, Ahlberg A, Nilsson IM. A radiologic classification of
haemophilic arthropathy. Clin Orthop Relat Res. 1980;153‐159.
25. Brazier JE, Harper R, Jones NM, et al. Validating the SF‐36 health
survey questionnaire: new outcome measure for primary care. BMJ.
1992;305:160‐164.
26. Martin DP, Engelberg R, Agel J, Swiontkowski MF. Comparison of
the musculoskeletal function assessment questionnaire with the
short form‐36, the Western Ontario and McMaster universities
osteoarthritis index, and the sickness impact profile health‐status
measures. J Bone Joint Surg Am. 1997;79:1323‐1335.
27. Roosendaal G, Vianen ME, Wenting MJ, et al. Iron deposits and cat‐
abolic properties of synovial tissue from patients with haemophilia.
J Bone Joint Surg Br. 1998;80:540‐545.
28. Schmidt MB, Chen EH, Lynch SE. A review of the effects of insulin‐
like growth factor and platelet derived growth factor on in vivo car‐
tilage healing and repair. Osteoarthritis Cartilage. 2006;14:403‐412.
29. van Buul GM, Koevoet WL, Kops N, et al. Platelet‐rich plasma re‐
leasate inhibits inflammatory processes in osteoarthritic chondro‐
cytes. Am J Sports Med. 2011;39:2362‐2370.
30. Woodell‐May J, Matuska A, Oyster M, Welch Z, O'Shaughnessey K,
Hoeppner J. Autologous protein solution inhibits MMP‐13 produc‐
tion by IL‐1beta and TNFalpha‐stimulated human articular chondro‐
cytes. J Orthop Res. 2011;29:1320‐1326.
31. Meheux CJ, McCulloch PC, Lintner DM, Varner KE, Harris JD.
Efficacy of intra‐articular platelet‐rich plasma injections in knee os‐
teoarthritis: a systematic review. Arthroscopy. 2015;32(3):495‐505.
32. Kon E, Mandelbaum B, Buda R, et al. Platelet‐rich plasma intra‐ar‐
ticular injection versus hyaluronic acid viscosupplementation as
treatments for cartilage pathology: from early degeneration to os‐
teoarthritis. Arthroscopy. 2011;27:1490‐1501.
33. Patel S, Dhillon MS, Aggarwal S, Marwaha N, Jain A. Treatment with
platelet‐rich plasma is more effective than placebo for knee osteo‐
arthritis: a prospective, double‐blind, randomized trial. Am J Sports
Med. 2013;41:356‐364.
34. Coleman PJ, Scott D, Ray J, Mason RM, Levick JR. Hyaluronan se‐
cretion into the synovial cavity of rabbit knees and comparison with
albumin turnover. J Physiol. 1997;503(Pt 3):645‐656.
35. Altman RD, Manjoo A, Fierlinger A, Niazi F, Nicholls M. The mech‐
anism of action for hyaluronic acid treatment in the osteoarthritic
knee: a systematic review. BMC Musculoskelet Disord. 2015;16:321.
36. Smyth NA, Murawski CD, Fortier LA, Cole BJ, Kennedy JG. Platelet‐
rich plasma in the pathologic processes of cartilage: review of basic
science evidence. Arthroscopy. 2013;29(8):1399‐1409.
37. Bhat V, Olmer M, Joshi S, et al. Vascular remodeling under‐
lies rebleeding in haemophilic arthropathy. Am J Hematol.
2015;90:1027‐1035.
38. Ornetti P, Nourissat G, Berenbaum F, et al. Does platelet‐rich
plasma have a role in the treatment of osteoarthritis? Joint, Bone,
Spine. 2016;83:31‐36.
How to cite this article: Li T‐Y, Wu Y‐T, Chen L‐C, Cheng S‐N,
Pan R‐Y, Chen Y‐C. An exploratory comparison of single
intra‐articular injection of platelet‐rich plasma vs hyaluronic
acid in treatment of haemophilic arthropathy of the knee.
Haemophilia. 2019;25:484–492. https://doi.org/10.1111/
hae.13711