Accepted Manuscript Use of Platelet Rich Plasma in Intra-Articular Knee Injections for Osteoarthritis: A Systematic Review Lawrence P. Lai, MD, MS, Todd P. Stitik, MD, Patrick M. Foye, MD, John S. Georgy, MD, MBA, Varun Patibanda, MD, Boqing Chen, MD, PhD PII:
S1934-1482(15)00074-X
DOI:
10.1016/j.pmrj.2015.02.003
Reference:
PMRJ 1428
To appear in:
PM&R
Received Date: 18 April 2014 Revised Date:
22 January 2015
Accepted Date: 10 February 2015
Please cite this article as: Lai LP, Stitik TP, Foye PM, Georgy JS, Patibanda V, Chen B, USE OF PLATELET RICH PLASMA IN INTRA-ARTICULAR KNEE INJECTIONS FOR OSTEOARTHRITIS: A SYSTEMATIC REVIEW, PM&R (2015), doi: 10.1016/j.pmrj.2015.02.003. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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USE OF PLATELET RICH PLASMA IN INTRAARTICULAR KNEE INJECTIONS FOR
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OSTEOARTHRITIS: A SYSTEMATIC REVIEW Authors
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Lawrence P. Lai, MD, MS1; Todd P. Stitik, MD1; Patrick M. Foye, MD1; John S. Georgy, MD, MBA2; Varun Patibanda, MD3; Boqing Chen, MD, PhD1
Affiliations:
1. Rutgers, New Jersey Medical School, Department of Physical Medicine and
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Rehabilitation, Newark, NJ.
2. Albert Einstein College of Medicine/Montefiore Medical Center, Department of Physical Medicine and Rehabilitation, Bronx, NY.
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3. American University of Antigua College of Medicine, New York, NY.
Correspondence: *
All correspondences and requests for reprints should be addressed to Lawrence P. Lai,
MD, MS. Rutgers, New Jersey Medical School, Newark, NJ.
Disclosures: None
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USE OF PLATELET RICH PLASMA IN INTRA-
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ARTICULAR KNEE INJECTIONS FOR
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OSTEOARTHRITIS: A SYSTEMATIC REVIEW
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ABSTRACT
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Objective: The aim of this study was to systematically synthesize the literature on
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the utilization of PRP for intra-articular injections of the knee and its efficacy in the
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treatment of knee OA.
Design: Systematic literature reviews were conducted in PubMed, EMBASE and
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CINAHL on October 30, 2013 using the keywords “platelet-rich plasma” and “knee” and
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“osteoarthritis”. Inclusion criteria included 1) studies with human subjects, 2)
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prospective clinical studies (including either clinical trials or observational studies), and
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3) full-text articles published in English. Exclusion criteria were: 1) animal studies, 2)
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retrospective studies; 3) patients with prior surgical intervention with total knee
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arthroplasty or reconstruction of the anterior cruciate ligaments, and 4) non-English
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articles.
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Results: A total of 319 abstracts and titles were reviewed (60 from PubMed, 250 from
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EMBASE and 9 from CINAHL). A total of 8 relevant journal articles were identified,
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all of which were published between 2010 and 2013. Half of the studies were
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prospective observational studies including only PRP treatment; the rest were prospective
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ACCEPTED MANUSCRIPT Lit Review comparative studies including both PRP and controls – two of them were randomized
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controlled trials. Of the 4 comparative studies, three compared PRP with HA, which was
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considered as a commonly used effective treatment for knee OA; the other one used
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saline injection (i.e., placebo) as the control. Although most of the analyses suffered
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small sample size and was thus inconclusive, the findings consistently indicated that PRP
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might have better outcomes in patients with lower degree of degeneration and younger
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patients.
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Conclusion: PRP intra-articular injections of the knee may be an effective alternative
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treatment for knee osteoarthritis. However, current studies are at best inconclusive
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regarding the efficacy of the PRP treatment. A large multicenter randomized trial study
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is needed to further assess the efficacy of PRP treatment for patients with knee
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osteoarthritis.
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Key Words:
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Platelet Rich Plasma; Intra-articular; Knee
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INTRODUCTION
Osteoarthritis (OA) is a prevalent disease, affecting approximately 27 million adults in the United States1. The prevalence increases with age, with 13.9% among
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adults 25 and older and 33.6% among those 65 and older2. The most common areas
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affected by OA are in the knees, which accounted for 41.2% of 847 OA cases in one
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study3. The Framingham cohort study showed that the prevalence of knee OA has been
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increasing for the past 20 years from 1974 to 1994,4 primarily due to increased physical
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activity and aging of the population.
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Knee OA is characterized by articular cartilage degeneration. Because the cartilage is avascular and the cells have a low mitotic activity, it has limited healing
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potential once injured, and eventually leads to irreversible damage. Knee OA is
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associated with pain and loss of mobility and can significantly impair quality of life. It is
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one of the top causes of disability in the United States5.
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The goals for the treatment of knee OA are relieving pain, improving function and quality of life and reducing disability. A variety of modalities have been used in the
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treatment of knee OA, including both conservative methods and surgical methods.
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Surgical options include arthroscopy, osteotomy, and arthroplasty. Although surgical
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treatments can be effective, they are associated with some serious complications such as
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infection, deep vein thrombosis, prosthesis loosening and are thus often reserved after
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failure of non-surgical or minimally invasive methods. Conservative methods include
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oral medications (such as anti-inflammatory agents), topical agents, therapeutic exercise ,
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braces, in-shoe orthotics, acupuncture, and injections including intra-articular
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corticosteroid and hyaluronic acid (HA) viscosupplementation injections. However,
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concerns. Their benefits are often limited to short term without impact on the natural
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history of the disease, and some may even have negative impact on knee structures6.
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Therefore, innovative methods are needed to more effectively treat knee OA, especially if
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the disease process itself can be altered.
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Recent development in biologic research has highlighted the importance of
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growth factors in maintenance of normal tissue structure and tissue lesion repair6,7.
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Platelet-rich plasma (PRP) is the concentrated platelets from centrifuged- spun whole
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blood8. This product contains a concentration of multiple growth factors that can be
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utilized for tissue regeneration. PRP was first used in the dental field in the healing
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process of implants and jaw reconstruction. It has now been widely explored in numerous
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medical specialties, including neurosurgery, ophthalmology, dermatology,
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otolaryngology, orthopedic surgery and sports medicine. Because PRP is relatively
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simple, potentially low-cost and minimally invasive, it has generated substantial interest
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in the treatment of knee OA in recent years. However, its clinical efficacy remains
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unclear.
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The aim of this study was to systematically synthesize the literature on the utilization of PRP for intra-articular injections of the knee and its efficacy in the
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treatment of knee OA.
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METHODS
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Systematic literature review Systematic literature reviews were conducted in PubMed, EMBASE and CINAHL on October, 30 2013, using the keywords “platelet-rich plasma” and “knee” and
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“osteoarthritis”. Two levels of screening were applied. At level 1, titles and abstracts
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were reviewed to exclude irrelevant studies; at level 2, full-text articles were reviewed to
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determine the relevance of the studies. In addition, the bibliographies of the articles were
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reviewed to identify additional relevant studies that had not been included in the level 1
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and 2 searches.
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Inclusion criteria included 1) studies with human subjects, 2) prospective clinical
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studies (including either clinical trials or observational studies), and 3) full-text articles
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published in English. Exclusion criteria were: 1) animal studies, 2) retrospective studies;
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3) patients with prior surgical intervention with total knee arthroplasty or reconstruction
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of the anterior cruciate ligaments, and 4) non-English articles.
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Literature synthesis
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Identified studies were reviewed systematically. The following information was
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extracted from each study: year and geographic locations, study design, treatment arms,
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major inclusion/exclusion criteria, PRP treatment, patient baseline characteristics, study
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duration, outcomes measures (function, pain, quality of life and others), and key findings.
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RESULTS
Description of included studies
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A total of 319 abstracts and titles were reviewed (60 from PubMed, 250 from EMBASE and 9 from CINAHL). A total of 8 relevant journal articles were identified,
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all of which were published between 2010 and 2013 (Table 1). Two studies (Kon et al.,
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2010 and Filardo et al., 2011) were kin studies presenting results at different follow-up
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times9,10. Half of the studies were prospective observational studies including only PRP
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treatment; the rest were prospective comparative studies including both PRP and controls
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– two of them were randomized controlled trials. Of the 4 comparative studies, three
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compared PRP with HA, which was considered as a commonly used effective treatment
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for knee OA; the other one used saline injection (i.e., placebo) as the control. Sample
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size for the PRP arm varied substantially, ranging from 14 knees to 115 knees; however,
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the majority (5 studies) had a sample size of 50 to 60 in the PRP groups. Three studies
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had 6 months follow up; 4 had 12 months; and 1 study had a 2-year follow up. Of the 8
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studies, 5 were conducted in Europe (4 in Italy and 1 in Slovakia), 1 in the US, 1 in India
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and 1 conducted jointly in the US and Italy.
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All studies included only adults and required patients to have symptomatic knee
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degeneration (Table 2). The mean/median age of the studies was relatively comparable
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(between 47 and 58 years) though the age range varied across studies. Mean body mass
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index (BMI) was also comparable across studies, ranging from 25 to 27. However,
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substantial differences were observed across these studies. Particularly, the degree of
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degeneration (mostly measured as Kellgren-Lawrence grade) and proportion of patients
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receiving prior surgical treatment varied considerably in the study populations.
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The administration of PRP also varied in terms of frequency and treatment
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intervals. The intervention ranged from single administration to three times in the
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treatment course. If multiple administrations were implemented, the interval ranged from
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one week to one month.
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With respect to outcomes assessed in these studies, all studies included function and pain measures (Table 3). Six studies also included quality of life outcomes. The
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most commonly used measurements included IKDC subjective scale, WOMAC, KOOS,
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pain VAS and EQ VAS. In addition, some studies also included IKDC objective
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assessment and ultrasound assessments.
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Outcomes associated with PRP
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Regardless of the outcome measures, all studies have consistently demonstrated the efficacy of PRP in improving function and quality of life and reducing pain among
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patients with knee OA (Table 3). The onset of treatment effects appeared fairly early in
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the treatment (within 2 months of treatment initiation)6,9,11,12,13. However, it seemed that
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the effects were only stable in the short term. In multiple studies, numerically worse
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outcomes were observed with longer follow up period. For example, some studies
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showed that WOMAC, pain VAS and EQ VAS were slightly worse at 6 months
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compared to the outcomes measured at 2 and 3 months6,7,9,11. Only two studies
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demonstrated that improved outcomes were maintained up to 12 months13,14. The only
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study with a follow up time beyond one year10 showed clearly worse outcomes at 2 years
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compared to those at 1 year, although the outcomes were still better compared at baseline.
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The median duration of clinical improvement was only 9 months10.
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The findings from the only placebo-controlled RCT demonstrated that PRP has superior efficacy in improving pain, stiffness and physical function compared to placebo
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ACCEPTED MANUSCRIPT Lit Review during a 6-month study11. The same study also suggested that frequency of PRP did not
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impact the treatment outcomes11. The studies comparing PRP vs. HA revealed mixed
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findings. While the two prospective observational studies6,7 showed that PRP was
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generally associated with better function and reduced pain compared to HA, the RCT12
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suggested no differences in outcomes between the two groups in the overall trial
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population.
Several studies also assessed the outcomes of PRP in patient subgroups. Although
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most of the analyses suffered small sample size and was thus inconclusive, the findings
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consistently indicated that PRP might have better outcomes in patients with lower degree
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of degeneration and younger patients 6,10,11,12.
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PRP formulations and WBCs
The authors of this review acknowledged the concentrations of PRP utilized in the
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studies. One study derived 200% concentration of whole blood values 14. Another study
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provided 6 billion platelets per injection 10. This variation can be attributed to a few
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factors- the first being the quantity of venipuncture sample. Kon et al in 2010 collected
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150 mL of whole blood where as Sampson et al collected 54 mL. The addition and type
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of anticoagulant also varied in each study. One study utilized 1ml of CPDA for each ml
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of whole blood collected where as another used 1mL if 0.106 M Sodium Citrate 7,11. The
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amount of centrifugations, the rpms, and the duration of each cycle differed within each
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study (Table 1). One studied centrifuged the whole blood thrice where as another study
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utilized just one cycle at 1500 rpm 9,11. Even more, certain studies chose to include white
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blood cells into the PRP at different concentrations where as one study elected to exclude
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them using leukocyte filters 7,11,12. Two studies failed to mention a concentration of
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WBCs utilized in their respective methods 6,10.
DISCUSSION
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PRP has been gaining popularity in the treatment of knee OA due to its simplicity, low cost and minimally invasive nature. While this innovative approach showed
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promising results in some preliminary clinical studies, no confirmative findings have
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been demonstrated in its efficacy. The current review systematically synthesized the
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clinical evidence on the impact of PRP on function, pain and quality of life among
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patients with knee OA. Overall, the clinical research with this regard is very limited.
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The existing studies suggest that PRP could be an effective treatment in the short term to
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improve patients’ function and quality of life and reduce pain. However, its long-term
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efficacy remains unclear. The only long-term study (2 years) suggests that the benefits of
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PRP are not sustainable10, which may limit the utility of this new treatment in the clinical
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use. In addition, the incremental value of PRP compared to the existing treatments,
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particularly HA, remains a question, as the only RCT12 did not reveal superiority of PRP.
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More evidence is indicated before PRP is widely adopted in the treatment of knee OA.
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Also, it’s important to acknowledge the variation in both platelet and leukocyte
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concentrations since they are the major forces behind the inflammatory responses after
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PRP administration. A systematic review of PRP literature revealed that only 1 of its 21
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reports included an analysis of WBCs, platelet, and RBC contents of their PRP
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formulations 15. Dragoo et al revealed that the synthetic capacities of chondrocytes were
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increased by 71% upon PRP administration but no prior study has been conducted on the
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varying concentrations of white blood cells were administered to patients. Some
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formulations in the study were leukocyte rich where as others were not. Some
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formulations also contained RBCs where as others did not. Ultimately, the study
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concluded that leukocyte rich PRP and PRP with RBCs were cytotoxic to synioviocytes
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but it failed to find a discernable pattern between WBC and RBC inclusion in different
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concentrations, PRP formulations and the overall efficacy.
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Similarly, the authors of this review found that only a few studies included
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information on WBC concentrations, whereas others did not (Table 1). This confounding
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variable, along with the variations in venipuncture sample, centrifuge cycles and
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duration, and the amount and type of anticoagulant, all play a role in obscuring a clear
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connection between PRP and its benefits. Therefore, future research must focus on
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reducing these variations in order to establish a direct and clear correlation between PRP
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and its benefits.
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The current review also sheds light on future research directions. First, the
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existing studies are limited by small sample size and their observational nature. In order
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to demonstrate the efficacy of PRP in knee OA, larger-scale multi-center RCTs are
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needed. Second, knee OA is a chronic disease and long-term outcomes should be an
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important consideration in evaluating new treatments. Hence, clinical trials with longer
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follow up are indicated. Third, the current findings suggest that PRP may have
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differential impacts across patient subgroups. In order to further assess the value of PRP,
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it is desirable to identify patients who can benefit most from this innovative treatment,
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particularly compared to the existing conservative treatments with proved efficacy.
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CONCLUSIONS
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OA for patients who do not adequately symptomatically respond to more traditional
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treatments. However, current studies are, at best, inconclusive regarding the efficacy of
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PRP treatment. Significant variations in administration schedule, platelet concentration,
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and inclusion or exclusion of WBCs and RBCs, make it difficult to draw definitive
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conclusions about PRP in general. A large multicenter randomized clinical trial
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employing a uniform method of administration schedule that stratifies subgroups with
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long-term follow up is needed to further assess the efficacy of PRP treatment for patients
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with knee osteoarthritis.
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ACKNOWLEDGEMENTS: The authors would like to thank Dr. Gautam
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Malhotra for reviewing the manuscript.
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1. R.C. Lawrence, D.T. Felson, C.G. Helmick, L.M. Arnold, H. Choi, R.A. Deyo et al. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part II. Arthritis Rheum, 58 (2008), pp. 26–35. 2. Centers for Disease Control and Prevention. Osteoarthritis. Accessed November 17, 2013, at:http://www.cdc.gov/arthritis/basics/osteoarthritis.htm. 3. Cushnaghan J, Dieppe P. Study of 500 patients with limb joint osteoarthritis. I. Analysis by age, sex, and distribution of symptomatic joint sites. Ann Rheum Dis. 1991 Jan;50(1):8-13. 4. U.S. Nguyen, Y. Zhang, Y. Zhu, J. Niu, B. Zhang, D.T. Felson. Increasing prevalence of knee pain and symptomatic knee osteoarthritis: survey and cohort data. Ann Intern Med, 155 (2011), pp. 725–732. 5. Centers for Disease Control and Prevention. Accessed November 29, 2013, at: http://www.cdc.gov/Features/dsAdultDisabilityCauses/. 6. Kon E, Mandelbaum B, Buda R, Filardo G, Delcogliano M, Timoncini A, Fornasari PM, Giannini S, Marcacci M. Platelet-rich plasma intra-articular injection versus hyaluronic acid viscosupplementation as treatments for cartilage pathology: from early degeneration to osteoarthritis. Arthroscopy. 2011 Nov;27(11):1490-501. 7. Spaková T, Rosocha J, Lacko M, Harvanová D, Gharaibeh A. Treatment of knee joint osteoarthritis with autologous platelet-rich plasma in comparison with hyaluronic acid. Am J Phys Med Rehabil. 2012 May;91(5):411-7. 8. Paoloni J, De Vos RJ, Hamilton B, Murrell GA, Orchard J. Platelet-rich plasma treatment for ligament and tendon injuries. Clin J Sport Med. 2011;21:37-45. 9. Kon E, Buda R, Filardo G, Di Martino A, Timoncini A, Cenacchi A, Fornasari PM, Giannini S, Marcacci M. Platelet-rich plasma: intra-articular knee injections produced favorable results on degenerative cartilage lesions. Knee Surg Sports Traumatol Arthrosc. 2010 Apr;18(4):472-9. 10. Filardo G, Kon E, Buda R, Timoncini A, Di Martino A, Cenacchi A, Fornasari PM, Giannini S, Marcacci M. Platelet-rich plasma intra-articular knee injections for the treatment of degenerative cartilage lesions and osteoarthritis. Knee Surg Sports Traumatol Arthrosc. 2011 Apr;19(4):528-35. 11. Patel S, Dhillon MS, Aggarwal S, Marwaha N, Jain A. Treatment with plateletrich plasma is more effective than placebo for knee osteoarthritis: a prospective, double-blind, randomized trial. Am J Sports Med. 2013 Feb;41(2):356-64. 12. Filardo G, Kon E, Di Martino A, Di Matteo B, Merli ML, Cenacchi A, Fornasari PM, Marcacci M. Platelet-rich plasma vs hyaluronic acid to treat knee degenerative pathology: study design and preliminary results of a randomized controlled trial. BMC Musculoskelet Disord. 2012 Nov 23;13:229. 13. Sampson S, Reed M, Silvers H, Meng M, Mandelbaum B. Injection of plateletrich plasma in patients with primary and secondary knee osteoarthritis: a pilot study. Am J Phys Med Rehabil. 2010 Dec;89(12):961-9.
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14. Gobbi A, Karnatzikos G, Mahajan V, Malchira S. Platelet-rich plasma treatment in symptomatic patients with knee osteoarthritis: preliminary results in a group of active patients. Sports Health. 2012 Mar;4(2):162-72. 15. Van buul GM, Koevoet WL, Kops N, et al. Platelet-rich plasma releasate inhibits inflammatory processes in osteoarthritic chondrocytes. Am J Sports Med. 2011;39(11):2362-70. 16. Braun HJ, Kim HJ, Chu CR, Dragoo JL. The effect of platelet-rich plasma formulations and blood products on human synoviocytes: implications for intraarticular injury and therapy. Am J Sports Med. 2014;42(5):1204-10.
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Kon et al 2011
Three treatment centers in Bologna, Italy and Santa Monica, CA, USA
Single arm prospective observational study
12 months Measurements were conducted at 2, 6, and 12 months
PRP (n=91 patients and 115 knees)
Three injections were administered 3 weeks apart; 1st unit: lab analysis 2nd unit: injected within 2 hours of initial draw 3rd-4th unit stored at (-30° C) – were thawed in dry thermostat at (37° C) for 30 minutes before application
Single arm prospective observational study
52 weeks Measurements were conducted at 2, 5, 11, 18 and 52 weeks
PRP (n=14)
Three injections were performed 4 weeks apart
Prospective comparative observational study
6 months Measurements were conducted at 2 and 6 months
PRP Formulations
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PRP treatment and image guidance
Initial venipuncture sample: 150 mL collected in 21 ml of sodium citrate Centrifugations: 2. (1st- 1,800 rpm for 15 minutes to separate erythrocytes, 2nd- 3,500 rpm for 10 minutes to concentrate platelets) Quantity of PRP used: 20mL total, 5ml units Concentration: total number of platelets per ml in PRP mean more than 6 million platelets given in every injection Other: CaCl2 was added before the injection No data on WBCs were recorded Initial venipuncture sample: 54 mL mixed with 6ml of anticoagulant citrate
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Treatment arms
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Santa Monica, CA, USA
Duration of study
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Sampson et al 2010
Bologna, Italy
Study Design
PRP n=50; hyaluronic acid high molecular weight (HW HA) n=50; hyaluronic acid low molecular weight (LW HA) n=50
Three injections were administered 2 weeks apart 1st unit: lab analysis 2nd unit: injected within 2 hours of initial draw 3rd-4th unit stored at (-30° C) – were thawed in dry thermostat at (37° C) for 30 minutes before application
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Geographic location
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Table 1. Study
dextrose formula A.
Centrifugations: 1. (15 minutes at 1700g) Quantity of PRP used: 6 mL Concentration: Not specified Other: 0.6 mL of a 1000U/mL bovine thrombin suspension in 10% CaCl2 was added to PRP prior to injection No data on WBCs were recorded Initial venipuncture sample: 150 mL Centrifugations: 2. (1st- 1,480 rpm for 6 minutes to separate erythrocytes, 2nd- 3,400 rpm for 15 minutes to concentrate platelets) Quantity of PRP used: 20mL total, 5mL units Concentration: total number of platelets per ml in PRP mean more than 6 billion platelets given in every injection Other: CaCl2(Ca+2 = 0.22 mEq X dose) was added before the injection No data on WBCs were recorded
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Spakova et al 2012
Kosice, Slovakia
Single arm prospective observational study
Prospective comparative observational study
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Initial venipuncture sample: 150 mL Centrifugations: 2(1st- 1,800 rpm for 15 minutes to separate erythrocytes, 2nd- 3,500 rpm for 10 minutes to concentrate platelets) Quantity of PRP used: 20mL total, 5mL units Concentration: total number of platelets per ml in PRP mean more than 6 billion platelets given in every injection Other: CaCl2 was added before the injection No data on WBCs were recorded
Initial venipuncture sample: 8 mL Centrifugations: 1. (3,500 rpm for 9 minutes) Quantity of PRP used: 4 mL Concentration: 200% of whole blood values Other: Pretreatment blood analysis of patients showed an average platelet count of 261,000 platelets. After centrifugation of 8mlm platelet recovery of >95% and leukocyte recovery of 58% (mononuclear cell recovery, 93%) in 4 ml of PRP. 2-fold increase of platelets. No solution was added to activate PRP before injections. Initial venipuncture sample: 27 mL collected in 3 10-mL containers of 1mL if 0.106 M Sodium Citrate. Centrifugations: 3 (1st- 3,200 rpm for 15 minutes to separate erythrocytes/leukocytes/plasma, 2nd- 1,500 rpm for 10 minutes to separate leukocytes, 3rd- 3,200 rpm for 10 minutes was performed to obtain a two-part plasma: upper part consisting of platelet-poor plasma and the lower part consisting of PRP. The platelet-poor plasma was first discarded to avoid its mixing up with PRP. The tubes were shaken vigorously for 30 secs to suspend platelets. The buffy coat layer, consisting of platelets, was then gently aspirated into a syringe in a volume of 3mL of plasma and used for intraarticular injection within 30 minutes.
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PRP (n=90 patients, 114 knees)
2 years
Two injections with 1month intervals in between
12 months Measurements were conducted at 6 and 12 months
PRP (n=50)
6 months Measurements were conducted at 3 and 6 months
PRP n=60; HA n=60
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Single arm prospective observational study
Three injections were administered with weekly intervals.
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Bologna, Italy
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Filardo et al 2011
Three injections were administered 3 weeks apart; 1st unit: lab analysis 2nd unit: injected within 2 hours of initial draw 3rd-4th unit stored at (-30° C) – were thawed in dry thermostat at (37° C) for 30 minutes before application
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Quantity of PRP used: 3mL Concentration: 450% of whole blood values Other: Aliquot was removed to determine the intial platelet count. WBCs were incorporated in the PRP.
Bologna, Italy
Patel et al 2013
Chandigarh, India
Randomized active-controlled trial
12 months Measurements were conducted at 2, 6, and 12 months
PRP n=54 HA n=55
Three injections were administered with weekly intervals. 1st unit: lab analysis 2nd--4th unit: stored at (30° C) No data shows thawing temperature or duration before application
Double-blinded randomized controlled placebocontrolled trial
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Platelet count in the whole blood had a mean value of 150 ± 30 x 106 platelets/ml, and platelet count in PRP had a mean value of 680 ± 132 x 106 platelets/ml. The mean platelet density increased by 450% (4.5fold) in average when compared with the whole blood. Complete blood count after centrifugation increased white blood cell count concentration 3.6-fold. (6.4± 2.3 x 103/µl to 23.2± 7.6 x 103/ µl) and decreased the red blood cell concentration by 40% (3.8± 0.6 x 106/µl to 1.4± 0.9 x 106/ µl)
6 months Measurements were conducted at 6 weeks, 3 months and 6 months
PRP single injection n=52 knees; PRP 2 injections n=50 knees; saline n=46 knees
One group: single injection
Second group: two injections with 3 weeks apart
The centrifuge increased the concentration 3.6 fold Initial venipuncture sample: 150 mL Centrifugations: 2 (1st- 1,480 rpm for 6 minutes to separate erythrocytes, 2nd- 3,400 rpm for 15 minutes to concentrate platelets) Quantity of PRP used: 20 mL total, 5 mL units Concentration: Total number of platelets per mL in PRP represented a mean increase of 5 times compared with whole blood values. Platelet concentration the prescence of leukocytes was 1.2 times with respect to normal blood values. Other: WBCs were incorporated in the PRP. The centrifuge increased the WBC concentration 1.2 fold Initial venipuncture sample: 100 mL collected in a 100-mL bag with CPA-A1 (citrate phosphate dextrose and adenine) Centrifugations: 1 (1st- 1,500 rpm for 15 minutes to separate PRP and residual red blood cells with the buffy coat)
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Major inclusion/exclusion criteria
1. History of chronic (>=4 months) pain or swelling of the knee and imaging findings of degenerative changes in the joint. 2. Exclusion criteria were systemic disorders, such as diabetes, rheumatoid arthritis, major axial deviation (varus[5 , valgus[5 ), hematological diseases (coagulopathies), severe cardiovascular diseases, infections, immunodepression, patients in therapy with anticoagulants–antiaggregants, use of NSAIDs in the 5 days before blood donation, patients with Hb values of 3 months; d)Patients with stable knees, normal tibiofemoral alignment, or patellofemoral tracking. 2. Exclusion criteria include: a) Patients with blood diseases, systemic metabolic, immunodeficiency, hepatitis B or C, HIV-positive status, infection and septicemia, local infection; b) Patients with advanced and tricompartmental osteoarthritis, rheumatoid or polyarticular arthritis, symptomatic hip osteoarthritis, or symptomatic contralateral knee osteoarthritis; c) Significant joint swelling or clinical signs of acute inflammation (possible inflammation or infection); d) Varus-valgus malalignment above 5°, patellofemoral maltracking or untreated instability, and total or subtotal meniscectomy (> 2/3 excised); e) Pretreatment blood platelets value 25% below the reference value or alcoholism, smoking, drugs; f) Treatment with corticosteroids < 3 months or medication < 7 days that could interfere with platelet aggregation
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Age: 47.7 years 62% men Kellgren: 22% in 1, 38% in 2 and 40% in 3 Prior surgery: 50%
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1. History of chronic pain of the knee lasting at least 12 months and the radiologic signs of knee OA Grade 1, 2, and 3 according to Kellgren and Lawrence classification. All patients had previously been treated conservatively using analgesics and nonsteroidal anti-inflammatory drugs without success for at least 6 mos. 2. The exclusion criteria were thrombocytopenia (platelet count, G100 109/liter), anemia (hemoglobin, G10 g/dl), systemic disease, hematologic disease, history of tumor or active tumor or hematologic malignant disease, severe cardiovascular disease, infection, immunosuppressive status, active anticoagulant therapy, and application of intra-articular depot glucocorticoid injection or HA within 3 months before application of tested substance. Using anti-inflammatory drugs was not permitted from 5 days before the beginning of treatment to 7 days after the last treatment dose of
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52.5% men Age: mean 53 years BMI: mean 27.9 Kellgren: 3.3% in 1; 63.3% in 2; 33.3% in 3.
1. History of chronic (at least 4 months) pain or swelling of the knee and imaging findings (X-ray or MRI) of degenerative changes of the joint. 2. Exclusion criteria were systemic disorders such as diabetes, rheumatoid arthritis, major axial deviation (varus >5 degree , valgus >5 degree), hematological diseases (coagulopathy), severe cardiovascular diseases, infections, immunodepression, patients in therapy with anticoagulants or antiaggregants, the use of NSAIDs in the 5 days before blood donation and patients with Hb values of
S1934-1482(15)00074-X
DOI:
10.1016/j.pmrj.2015.02.003
Reference:
PMRJ 1428
To appear in:
PM&R
Received Date: 18 April 2014 Revised Date:
22 January 2015
Accepted Date: 10 February 2015
Please cite this article as: Lai LP, Stitik TP, Foye PM, Georgy JS, Patibanda V, Chen B, USE OF PLATELET RICH PLASMA IN INTRA-ARTICULAR KNEE INJECTIONS FOR OSTEOARTHRITIS: A SYSTEMATIC REVIEW, PM&R (2015), doi: 10.1016/j.pmrj.2015.02.003. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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USE OF PLATELET RICH PLASMA IN INTRAARTICULAR KNEE INJECTIONS FOR
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OSTEOARTHRITIS: A SYSTEMATIC REVIEW Authors
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Lawrence P. Lai, MD, MS1; Todd P. Stitik, MD1; Patrick M. Foye, MD1; John S. Georgy, MD, MBA2; Varun Patibanda, MD3; Boqing Chen, MD, PhD1
Affiliations:
1. Rutgers, New Jersey Medical School, Department of Physical Medicine and
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Rehabilitation, Newark, NJ.
2. Albert Einstein College of Medicine/Montefiore Medical Center, Department of Physical Medicine and Rehabilitation, Bronx, NY.
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3. American University of Antigua College of Medicine, New York, NY.
Correspondence: *
All correspondences and requests for reprints should be addressed to Lawrence P. Lai,
MD, MS. Rutgers, New Jersey Medical School, Newark, NJ.
Disclosures: None
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USE OF PLATELET RICH PLASMA IN INTRA-
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ARTICULAR KNEE INJECTIONS FOR
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OSTEOARTHRITIS: A SYSTEMATIC REVIEW
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ABSTRACT
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Objective: The aim of this study was to systematically synthesize the literature on
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the utilization of PRP for intra-articular injections of the knee and its efficacy in the
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treatment of knee OA.
Design: Systematic literature reviews were conducted in PubMed, EMBASE and
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CINAHL on October 30, 2013 using the keywords “platelet-rich plasma” and “knee” and
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“osteoarthritis”. Inclusion criteria included 1) studies with human subjects, 2)
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prospective clinical studies (including either clinical trials or observational studies), and
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3) full-text articles published in English. Exclusion criteria were: 1) animal studies, 2)
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retrospective studies; 3) patients with prior surgical intervention with total knee
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arthroplasty or reconstruction of the anterior cruciate ligaments, and 4) non-English
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articles.
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Results: A total of 319 abstracts and titles were reviewed (60 from PubMed, 250 from
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EMBASE and 9 from CINAHL). A total of 8 relevant journal articles were identified,
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all of which were published between 2010 and 2013. Half of the studies were
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prospective observational studies including only PRP treatment; the rest were prospective
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controlled trials. Of the 4 comparative studies, three compared PRP with HA, which was
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considered as a commonly used effective treatment for knee OA; the other one used
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saline injection (i.e., placebo) as the control. Although most of the analyses suffered
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small sample size and was thus inconclusive, the findings consistently indicated that PRP
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might have better outcomes in patients with lower degree of degeneration and younger
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patients.
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Conclusion: PRP intra-articular injections of the knee may be an effective alternative
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treatment for knee osteoarthritis. However, current studies are at best inconclusive
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regarding the efficacy of the PRP treatment. A large multicenter randomized trial study
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is needed to further assess the efficacy of PRP treatment for patients with knee
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osteoarthritis.
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Key Words:
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Platelet Rich Plasma; Intra-articular; Knee
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INTRODUCTION
Osteoarthritis (OA) is a prevalent disease, affecting approximately 27 million adults in the United States1. The prevalence increases with age, with 13.9% among
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adults 25 and older and 33.6% among those 65 and older2. The most common areas
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affected by OA are in the knees, which accounted for 41.2% of 847 OA cases in one
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study3. The Framingham cohort study showed that the prevalence of knee OA has been
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increasing for the past 20 years from 1974 to 1994,4 primarily due to increased physical
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activity and aging of the population.
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Knee OA is characterized by articular cartilage degeneration. Because the cartilage is avascular and the cells have a low mitotic activity, it has limited healing
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potential once injured, and eventually leads to irreversible damage. Knee OA is
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associated with pain and loss of mobility and can significantly impair quality of life. It is
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one of the top causes of disability in the United States5.
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The goals for the treatment of knee OA are relieving pain, improving function and quality of life and reducing disability. A variety of modalities have been used in the
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treatment of knee OA, including both conservative methods and surgical methods.
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Surgical options include arthroscopy, osteotomy, and arthroplasty. Although surgical
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treatments can be effective, they are associated with some serious complications such as
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infection, deep vein thrombosis, prosthesis loosening and are thus often reserved after
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failure of non-surgical or minimally invasive methods. Conservative methods include
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oral medications (such as anti-inflammatory agents), topical agents, therapeutic exercise ,
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braces, in-shoe orthotics, acupuncture, and injections including intra-articular
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corticosteroid and hyaluronic acid (HA) viscosupplementation injections. However,
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concerns. Their benefits are often limited to short term without impact on the natural
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history of the disease, and some may even have negative impact on knee structures6.
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Therefore, innovative methods are needed to more effectively treat knee OA, especially if
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the disease process itself can be altered.
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Recent development in biologic research has highlighted the importance of
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growth factors in maintenance of normal tissue structure and tissue lesion repair6,7.
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Platelet-rich plasma (PRP) is the concentrated platelets from centrifuged- spun whole
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blood8. This product contains a concentration of multiple growth factors that can be
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utilized for tissue regeneration. PRP was first used in the dental field in the healing
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process of implants and jaw reconstruction. It has now been widely explored in numerous
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medical specialties, including neurosurgery, ophthalmology, dermatology,
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otolaryngology, orthopedic surgery and sports medicine. Because PRP is relatively
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simple, potentially low-cost and minimally invasive, it has generated substantial interest
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in the treatment of knee OA in recent years. However, its clinical efficacy remains
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unclear.
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The aim of this study was to systematically synthesize the literature on the utilization of PRP for intra-articular injections of the knee and its efficacy in the
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treatment of knee OA.
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METHODS
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Systematic literature review Systematic literature reviews were conducted in PubMed, EMBASE and CINAHL on October, 30 2013, using the keywords “platelet-rich plasma” and “knee” and
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“osteoarthritis”. Two levels of screening were applied. At level 1, titles and abstracts
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were reviewed to exclude irrelevant studies; at level 2, full-text articles were reviewed to
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determine the relevance of the studies. In addition, the bibliographies of the articles were
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reviewed to identify additional relevant studies that had not been included in the level 1
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and 2 searches.
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Inclusion criteria included 1) studies with human subjects, 2) prospective clinical
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studies (including either clinical trials or observational studies), and 3) full-text articles
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published in English. Exclusion criteria were: 1) animal studies, 2) retrospective studies;
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3) patients with prior surgical intervention with total knee arthroplasty or reconstruction
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of the anterior cruciate ligaments, and 4) non-English articles.
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Literature synthesis
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Identified studies were reviewed systematically. The following information was
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extracted from each study: year and geographic locations, study design, treatment arms,
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major inclusion/exclusion criteria, PRP treatment, patient baseline characteristics, study
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duration, outcomes measures (function, pain, quality of life and others), and key findings.
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RESULTS
Description of included studies
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A total of 319 abstracts and titles were reviewed (60 from PubMed, 250 from EMBASE and 9 from CINAHL). A total of 8 relevant journal articles were identified,
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all of which were published between 2010 and 2013 (Table 1). Two studies (Kon et al.,
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2010 and Filardo et al., 2011) were kin studies presenting results at different follow-up
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times9,10. Half of the studies were prospective observational studies including only PRP
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treatment; the rest were prospective comparative studies including both PRP and controls
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– two of them were randomized controlled trials. Of the 4 comparative studies, three
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compared PRP with HA, which was considered as a commonly used effective treatment
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for knee OA; the other one used saline injection (i.e., placebo) as the control. Sample
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size for the PRP arm varied substantially, ranging from 14 knees to 115 knees; however,
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the majority (5 studies) had a sample size of 50 to 60 in the PRP groups. Three studies
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had 6 months follow up; 4 had 12 months; and 1 study had a 2-year follow up. Of the 8
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studies, 5 were conducted in Europe (4 in Italy and 1 in Slovakia), 1 in the US, 1 in India
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and 1 conducted jointly in the US and Italy.
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All studies included only adults and required patients to have symptomatic knee
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degeneration (Table 2). The mean/median age of the studies was relatively comparable
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(between 47 and 58 years) though the age range varied across studies. Mean body mass
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index (BMI) was also comparable across studies, ranging from 25 to 27. However,
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substantial differences were observed across these studies. Particularly, the degree of
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degeneration (mostly measured as Kellgren-Lawrence grade) and proportion of patients
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receiving prior surgical treatment varied considerably in the study populations.
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The administration of PRP also varied in terms of frequency and treatment
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intervals. The intervention ranged from single administration to three times in the
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treatment course. If multiple administrations were implemented, the interval ranged from
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one week to one month.
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With respect to outcomes assessed in these studies, all studies included function and pain measures (Table 3). Six studies also included quality of life outcomes. The
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most commonly used measurements included IKDC subjective scale, WOMAC, KOOS,
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pain VAS and EQ VAS. In addition, some studies also included IKDC objective
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assessment and ultrasound assessments.
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Outcomes associated with PRP
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Regardless of the outcome measures, all studies have consistently demonstrated the efficacy of PRP in improving function and quality of life and reducing pain among
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patients with knee OA (Table 3). The onset of treatment effects appeared fairly early in
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the treatment (within 2 months of treatment initiation)6,9,11,12,13. However, it seemed that
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the effects were only stable in the short term. In multiple studies, numerically worse
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outcomes were observed with longer follow up period. For example, some studies
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showed that WOMAC, pain VAS and EQ VAS were slightly worse at 6 months
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compared to the outcomes measured at 2 and 3 months6,7,9,11. Only two studies
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demonstrated that improved outcomes were maintained up to 12 months13,14. The only
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study with a follow up time beyond one year10 showed clearly worse outcomes at 2 years
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compared to those at 1 year, although the outcomes were still better compared at baseline.
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The median duration of clinical improvement was only 9 months10.
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The findings from the only placebo-controlled RCT demonstrated that PRP has superior efficacy in improving pain, stiffness and physical function compared to placebo
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impact the treatment outcomes11. The studies comparing PRP vs. HA revealed mixed
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findings. While the two prospective observational studies6,7 showed that PRP was
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generally associated with better function and reduced pain compared to HA, the RCT12
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suggested no differences in outcomes between the two groups in the overall trial
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population.
Several studies also assessed the outcomes of PRP in patient subgroups. Although
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most of the analyses suffered small sample size and was thus inconclusive, the findings
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consistently indicated that PRP might have better outcomes in patients with lower degree
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of degeneration and younger patients 6,10,11,12.
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PRP formulations and WBCs
The authors of this review acknowledged the concentrations of PRP utilized in the
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studies. One study derived 200% concentration of whole blood values 14. Another study
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provided 6 billion platelets per injection 10. This variation can be attributed to a few
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factors- the first being the quantity of venipuncture sample. Kon et al in 2010 collected
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150 mL of whole blood where as Sampson et al collected 54 mL. The addition and type
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of anticoagulant also varied in each study. One study utilized 1ml of CPDA for each ml
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of whole blood collected where as another used 1mL if 0.106 M Sodium Citrate 7,11. The
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amount of centrifugations, the rpms, and the duration of each cycle differed within each
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study (Table 1). One studied centrifuged the whole blood thrice where as another study
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utilized just one cycle at 1500 rpm 9,11. Even more, certain studies chose to include white
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blood cells into the PRP at different concentrations where as one study elected to exclude
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them using leukocyte filters 7,11,12. Two studies failed to mention a concentration of
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WBCs utilized in their respective methods 6,10.
DISCUSSION
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PRP has been gaining popularity in the treatment of knee OA due to its simplicity, low cost and minimally invasive nature. While this innovative approach showed
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promising results in some preliminary clinical studies, no confirmative findings have
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been demonstrated in its efficacy. The current review systematically synthesized the
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clinical evidence on the impact of PRP on function, pain and quality of life among
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patients with knee OA. Overall, the clinical research with this regard is very limited.
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The existing studies suggest that PRP could be an effective treatment in the short term to
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improve patients’ function and quality of life and reduce pain. However, its long-term
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efficacy remains unclear. The only long-term study (2 years) suggests that the benefits of
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PRP are not sustainable10, which may limit the utility of this new treatment in the clinical
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use. In addition, the incremental value of PRP compared to the existing treatments,
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particularly HA, remains a question, as the only RCT12 did not reveal superiority of PRP.
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More evidence is indicated before PRP is widely adopted in the treatment of knee OA.
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Also, it’s important to acknowledge the variation in both platelet and leukocyte
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concentrations since they are the major forces behind the inflammatory responses after
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PRP administration. A systematic review of PRP literature revealed that only 1 of its 21
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reports included an analysis of WBCs, platelet, and RBC contents of their PRP
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formulations 15. Dragoo et al revealed that the synthetic capacities of chondrocytes were
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increased by 71% upon PRP administration but no prior study has been conducted on the
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varying concentrations of white blood cells were administered to patients. Some
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formulations in the study were leukocyte rich where as others were not. Some
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formulations also contained RBCs where as others did not. Ultimately, the study
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concluded that leukocyte rich PRP and PRP with RBCs were cytotoxic to synioviocytes
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but it failed to find a discernable pattern between WBC and RBC inclusion in different
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concentrations, PRP formulations and the overall efficacy.
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Similarly, the authors of this review found that only a few studies included
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information on WBC concentrations, whereas others did not (Table 1). This confounding
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variable, along with the variations in venipuncture sample, centrifuge cycles and
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duration, and the amount and type of anticoagulant, all play a role in obscuring a clear
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connection between PRP and its benefits. Therefore, future research must focus on
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reducing these variations in order to establish a direct and clear correlation between PRP
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and its benefits.
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The current review also sheds light on future research directions. First, the
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existing studies are limited by small sample size and their observational nature. In order
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to demonstrate the efficacy of PRP in knee OA, larger-scale multi-center RCTs are
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needed. Second, knee OA is a chronic disease and long-term outcomes should be an
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important consideration in evaluating new treatments. Hence, clinical trials with longer
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follow up are indicated. Third, the current findings suggest that PRP may have
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differential impacts across patient subgroups. In order to further assess the value of PRP,
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it is desirable to identify patients who can benefit most from this innovative treatment,
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particularly compared to the existing conservative treatments with proved efficacy.
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CONCLUSIONS
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OA for patients who do not adequately symptomatically respond to more traditional
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treatments. However, current studies are, at best, inconclusive regarding the efficacy of
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PRP treatment. Significant variations in administration schedule, platelet concentration,
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and inclusion or exclusion of WBCs and RBCs, make it difficult to draw definitive
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conclusions about PRP in general. A large multicenter randomized clinical trial
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employing a uniform method of administration schedule that stratifies subgroups with
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long-term follow up is needed to further assess the efficacy of PRP treatment for patients
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with knee osteoarthritis.
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ACKNOWLEDGEMENTS: The authors would like to thank Dr. Gautam
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Malhotra for reviewing the manuscript.
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1. R.C. Lawrence, D.T. Felson, C.G. Helmick, L.M. Arnold, H. Choi, R.A. Deyo et al. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part II. Arthritis Rheum, 58 (2008), pp. 26–35. 2. Centers for Disease Control and Prevention. Osteoarthritis. Accessed November 17, 2013, at:http://www.cdc.gov/arthritis/basics/osteoarthritis.htm. 3. Cushnaghan J, Dieppe P. Study of 500 patients with limb joint osteoarthritis. I. Analysis by age, sex, and distribution of symptomatic joint sites. Ann Rheum Dis. 1991 Jan;50(1):8-13. 4. U.S. Nguyen, Y. Zhang, Y. Zhu, J. Niu, B. Zhang, D.T. Felson. Increasing prevalence of knee pain and symptomatic knee osteoarthritis: survey and cohort data. Ann Intern Med, 155 (2011), pp. 725–732. 5. Centers for Disease Control and Prevention. Accessed November 29, 2013, at: http://www.cdc.gov/Features/dsAdultDisabilityCauses/. 6. Kon E, Mandelbaum B, Buda R, Filardo G, Delcogliano M, Timoncini A, Fornasari PM, Giannini S, Marcacci M. Platelet-rich plasma intra-articular injection versus hyaluronic acid viscosupplementation as treatments for cartilage pathology: from early degeneration to osteoarthritis. Arthroscopy. 2011 Nov;27(11):1490-501. 7. Spaková T, Rosocha J, Lacko M, Harvanová D, Gharaibeh A. Treatment of knee joint osteoarthritis with autologous platelet-rich plasma in comparison with hyaluronic acid. Am J Phys Med Rehabil. 2012 May;91(5):411-7. 8. Paoloni J, De Vos RJ, Hamilton B, Murrell GA, Orchard J. Platelet-rich plasma treatment for ligament and tendon injuries. Clin J Sport Med. 2011;21:37-45. 9. Kon E, Buda R, Filardo G, Di Martino A, Timoncini A, Cenacchi A, Fornasari PM, Giannini S, Marcacci M. Platelet-rich plasma: intra-articular knee injections produced favorable results on degenerative cartilage lesions. Knee Surg Sports Traumatol Arthrosc. 2010 Apr;18(4):472-9. 10. Filardo G, Kon E, Buda R, Timoncini A, Di Martino A, Cenacchi A, Fornasari PM, Giannini S, Marcacci M. Platelet-rich plasma intra-articular knee injections for the treatment of degenerative cartilage lesions and osteoarthritis. Knee Surg Sports Traumatol Arthrosc. 2011 Apr;19(4):528-35. 11. Patel S, Dhillon MS, Aggarwal S, Marwaha N, Jain A. Treatment with plateletrich plasma is more effective than placebo for knee osteoarthritis: a prospective, double-blind, randomized trial. Am J Sports Med. 2013 Feb;41(2):356-64. 12. Filardo G, Kon E, Di Martino A, Di Matteo B, Merli ML, Cenacchi A, Fornasari PM, Marcacci M. Platelet-rich plasma vs hyaluronic acid to treat knee degenerative pathology: study design and preliminary results of a randomized controlled trial. BMC Musculoskelet Disord. 2012 Nov 23;13:229. 13. Sampson S, Reed M, Silvers H, Meng M, Mandelbaum B. Injection of plateletrich plasma in patients with primary and secondary knee osteoarthritis: a pilot study. Am J Phys Med Rehabil. 2010 Dec;89(12):961-9.
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14. Gobbi A, Karnatzikos G, Mahajan V, Malchira S. Platelet-rich plasma treatment in symptomatic patients with knee osteoarthritis: preliminary results in a group of active patients. Sports Health. 2012 Mar;4(2):162-72. 15. Van buul GM, Koevoet WL, Kops N, et al. Platelet-rich plasma releasate inhibits inflammatory processes in osteoarthritic chondrocytes. Am J Sports Med. 2011;39(11):2362-70. 16. Braun HJ, Kim HJ, Chu CR, Dragoo JL. The effect of platelet-rich plasma formulations and blood products on human synoviocytes: implications for intraarticular injury and therapy. Am J Sports Med. 2014;42(5):1204-10.
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Kon et al 2011
Three treatment centers in Bologna, Italy and Santa Monica, CA, USA
Single arm prospective observational study
12 months Measurements were conducted at 2, 6, and 12 months
PRP (n=91 patients and 115 knees)
Three injections were administered 3 weeks apart; 1st unit: lab analysis 2nd unit: injected within 2 hours of initial draw 3rd-4th unit stored at (-30° C) – were thawed in dry thermostat at (37° C) for 30 minutes before application
Single arm prospective observational study
52 weeks Measurements were conducted at 2, 5, 11, 18 and 52 weeks
PRP (n=14)
Three injections were performed 4 weeks apart
Prospective comparative observational study
6 months Measurements were conducted at 2 and 6 months
PRP Formulations
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PRP treatment and image guidance
Initial venipuncture sample: 150 mL collected in 21 ml of sodium citrate Centrifugations: 2. (1st- 1,800 rpm for 15 minutes to separate erythrocytes, 2nd- 3,500 rpm for 10 minutes to concentrate platelets) Quantity of PRP used: 20mL total, 5ml units Concentration: total number of platelets per ml in PRP mean more than 6 million platelets given in every injection Other: CaCl2 was added before the injection No data on WBCs were recorded Initial venipuncture sample: 54 mL mixed with 6ml of anticoagulant citrate
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Santa Monica, CA, USA
Duration of study
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Sampson et al 2010
Bologna, Italy
Study Design
PRP n=50; hyaluronic acid high molecular weight (HW HA) n=50; hyaluronic acid low molecular weight (LW HA) n=50
Three injections were administered 2 weeks apart 1st unit: lab analysis 2nd unit: injected within 2 hours of initial draw 3rd-4th unit stored at (-30° C) – were thawed in dry thermostat at (37° C) for 30 minutes before application
EP
Kon et al 2010
Geographic location
AC C
Table 1. Study
dextrose formula A.
Centrifugations: 1. (15 minutes at 1700g) Quantity of PRP used: 6 mL Concentration: Not specified Other: 0.6 mL of a 1000U/mL bovine thrombin suspension in 10% CaCl2 was added to PRP prior to injection No data on WBCs were recorded Initial venipuncture sample: 150 mL Centrifugations: 2. (1st- 1,480 rpm for 6 minutes to separate erythrocytes, 2nd- 3,400 rpm for 15 minutes to concentrate platelets) Quantity of PRP used: 20mL total, 5mL units Concentration: total number of platelets per ml in PRP mean more than 6 billion platelets given in every injection Other: CaCl2(Ca+2 = 0.22 mEq X dose) was added before the injection No data on WBCs were recorded
ACCEPTED MANUSCRIPT
Spakova et al 2012
Kosice, Slovakia
Single arm prospective observational study
Prospective comparative observational study
SC
RI PT
Initial venipuncture sample: 150 mL Centrifugations: 2(1st- 1,800 rpm for 15 minutes to separate erythrocytes, 2nd- 3,500 rpm for 10 minutes to concentrate platelets) Quantity of PRP used: 20mL total, 5mL units Concentration: total number of platelets per ml in PRP mean more than 6 billion platelets given in every injection Other: CaCl2 was added before the injection No data on WBCs were recorded
Initial venipuncture sample: 8 mL Centrifugations: 1. (3,500 rpm for 9 minutes) Quantity of PRP used: 4 mL Concentration: 200% of whole blood values Other: Pretreatment blood analysis of patients showed an average platelet count of 261,000 platelets. After centrifugation of 8mlm platelet recovery of >95% and leukocyte recovery of 58% (mononuclear cell recovery, 93%) in 4 ml of PRP. 2-fold increase of platelets. No solution was added to activate PRP before injections. Initial venipuncture sample: 27 mL collected in 3 10-mL containers of 1mL if 0.106 M Sodium Citrate. Centrifugations: 3 (1st- 3,200 rpm for 15 minutes to separate erythrocytes/leukocytes/plasma, 2nd- 1,500 rpm for 10 minutes to separate leukocytes, 3rd- 3,200 rpm for 10 minutes was performed to obtain a two-part plasma: upper part consisting of platelet-poor plasma and the lower part consisting of PRP. The platelet-poor plasma was first discarded to avoid its mixing up with PRP. The tubes were shaken vigorously for 30 secs to suspend platelets. The buffy coat layer, consisting of platelets, was then gently aspirated into a syringe in a volume of 3mL of plasma and used for intraarticular injection within 30 minutes.
M AN U
Milan, Italy
PRP (n=90 patients, 114 knees)
2 years
Two injections with 1month intervals in between
12 months Measurements were conducted at 6 and 12 months
PRP (n=50)
6 months Measurements were conducted at 3 and 6 months
PRP n=60; HA n=60
TE D
Gobbi et al 2012
Single arm prospective observational study
Three injections were administered with weekly intervals.
EP
Bologna, Italy
AC C
Filardo et al 2011
Three injections were administered 3 weeks apart; 1st unit: lab analysis 2nd unit: injected within 2 hours of initial draw 3rd-4th unit stored at (-30° C) – were thawed in dry thermostat at (37° C) for 30 minutes before application
ACCEPTED MANUSCRIPT
RI PT
Quantity of PRP used: 3mL Concentration: 450% of whole blood values Other: Aliquot was removed to determine the intial platelet count. WBCs were incorporated in the PRP.
Bologna, Italy
Patel et al 2013
Chandigarh, India
Randomized active-controlled trial
12 months Measurements were conducted at 2, 6, and 12 months
PRP n=54 HA n=55
Three injections were administered with weekly intervals. 1st unit: lab analysis 2nd--4th unit: stored at (30° C) No data shows thawing temperature or duration before application
Double-blinded randomized controlled placebocontrolled trial
AC C
EP
Filardo et al 2012
TE D
M AN U
SC
Platelet count in the whole blood had a mean value of 150 ± 30 x 106 platelets/ml, and platelet count in PRP had a mean value of 680 ± 132 x 106 platelets/ml. The mean platelet density increased by 450% (4.5fold) in average when compared with the whole blood. Complete blood count after centrifugation increased white blood cell count concentration 3.6-fold. (6.4± 2.3 x 103/µl to 23.2± 7.6 x 103/ µl) and decreased the red blood cell concentration by 40% (3.8± 0.6 x 106/µl to 1.4± 0.9 x 106/ µl)
6 months Measurements were conducted at 6 weeks, 3 months and 6 months
PRP single injection n=52 knees; PRP 2 injections n=50 knees; saline n=46 knees
One group: single injection
Second group: two injections with 3 weeks apart
The centrifuge increased the concentration 3.6 fold Initial venipuncture sample: 150 mL Centrifugations: 2 (1st- 1,480 rpm for 6 minutes to separate erythrocytes, 2nd- 3,400 rpm for 15 minutes to concentrate platelets) Quantity of PRP used: 20 mL total, 5 mL units Concentration: Total number of platelets per mL in PRP represented a mean increase of 5 times compared with whole blood values. Platelet concentration the prescence of leukocytes was 1.2 times with respect to normal blood values. Other: WBCs were incorporated in the PRP. The centrifuge increased the WBC concentration 1.2 fold Initial venipuncture sample: 100 mL collected in a 100-mL bag with CPA-A1 (citrate phosphate dextrose and adenine) Centrifugations: 1 (1st- 1,500 rpm for 15 minutes to separate PRP and residual red blood cells with the buffy coat)
ACCEPTED MANUSCRIPT
Kon et al 2010
Major inclusion/exclusion criteria
1. History of chronic (>=4 months) pain or swelling of the knee and imaging findings of degenerative changes in the joint. 2. Exclusion criteria were systemic disorders, such as diabetes, rheumatoid arthritis, major axial deviation (varus[5 , valgus[5 ), hematological diseases (coagulopathies), severe cardiovascular diseases, infections, immunodepression, patients in therapy with anticoagulants–antiaggregants, use of NSAIDs in the 5 days before blood donation, patients with Hb values of 3 months; d)Patients with stable knees, normal tibiofemoral alignment, or patellofemoral tracking. 2. Exclusion criteria include: a) Patients with blood diseases, systemic metabolic, immunodeficiency, hepatitis B or C, HIV-positive status, infection and septicemia, local infection; b) Patients with advanced and tricompartmental osteoarthritis, rheumatoid or polyarticular arthritis, symptomatic hip osteoarthritis, or symptomatic contralateral knee osteoarthritis; c) Significant joint swelling or clinical signs of acute inflammation (possible inflammation or infection); d) Varus-valgus malalignment above 5°, patellofemoral maltracking or untreated instability, and total or subtotal meniscectomy (> 2/3 excised); e) Pretreatment blood platelets value 25% below the reference value or alcoholism, smoking, drugs; f) Treatment with corticosteroids < 3 months or medication < 7 days that could interfere with platelet aggregation
AC C
Gobbi et al 2012
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
Age: 47.7 years 62% men Kellgren: 22% in 1, 38% in 2 and 40% in 3 Prior surgery: 50%
SC M AN U
TE D
EP AC C
Spakova et al 2012
1. History of chronic pain of the knee lasting at least 12 months and the radiologic signs of knee OA Grade 1, 2, and 3 according to Kellgren and Lawrence classification. All patients had previously been treated conservatively using analgesics and nonsteroidal anti-inflammatory drugs without success for at least 6 mos. 2. The exclusion criteria were thrombocytopenia (platelet count, G100 109/liter), anemia (hemoglobin, G10 g/dl), systemic disease, hematologic disease, history of tumor or active tumor or hematologic malignant disease, severe cardiovascular disease, infection, immunosuppressive status, active anticoagulant therapy, and application of intra-articular depot glucocorticoid injection or HA within 3 months before application of tested substance. Using anti-inflammatory drugs was not permitted from 5 days before the beginning of treatment to 7 days after the last treatment dose of
RI PT
ACCEPTED MANUSCRIPT
52.5% men Age: mean 53 years BMI: mean 27.9 Kellgren: 3.3% in 1; 63.3% in 2; 33.3% in 3.
1. History of chronic (at least 4 months) pain or swelling of the knee and imaging findings (X-ray or MRI) of degenerative changes of the joint. 2. Exclusion criteria were systemic disorders such as diabetes, rheumatoid arthritis, major axial deviation (varus >5 degree , valgus >5 degree), hematological diseases (coagulopathy), severe cardiovascular diseases, infections, immunodepression, patients in therapy with anticoagulants or antiaggregants, the use of NSAIDs in the 5 days before blood donation and patients with Hb values of
