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 Table of Contents  
ORIGINAL ARTICLE
Year : 2017  |  Volume : 30  |  Issue : 1  |  Page : 139-146

Application of platelet-rich plasma preparation rich in growth factors in knee osteoarthritis


1 Department of Clinical Pathology, Faculty of Medicine, Menoufia University, Shebeen El-Kom, Egypt
2 Department of Orthopaedic Surgery, Faculty of Medicine, Menoufia University, Shebeen El-Kom, Egypt
3 Shebeen El-Kom Teaching Hospital, Shebeen El-Kom, Egypt

Date of Submission13-Dec-2015
Date of Acceptance10-Jan-2016
Date of Web Publication25-Jul-2017

Correspondence Address:
Mohamed A Helwa
Clinical Pathology department, Faculty of Medicine, Menoufia University, Shebeen El-Kom, Menoufia, 32511
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/mmj.mmj_512_15

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  Abstract 


Objective
The aim of this study was to determine the regenerative properties of intra-articular injections of autologous platelet-rich plasma (PRP) in improving knee osteoarthritic patients and to determine the correlation of platelet count and transforming growth factor-β1 (TGF-β1) with clinical improvement.
Background
Platelets have an important role in primary as well as secondary hemostasis; however, its regenerative capability is not widely studied. Osteoarthritis (OA) is a cartilage degenerative process. No treatment is available to improve this process.
Patients and methods
The study was conducted on 28 patients suffering from primary knee OA grades II and III injected with PRP preparation after failure of conservative treatment. Patients received two injections 3 weeks apart, and then were followed up for 6 months using the Western Ontario and McMaster Universities Arthritis Index and radiography. Platelet count and TGF-β1 were measured in PRP to ensure platelet activation and release and to evaluate their role in improvement of the condition.
Results
At the end of follow-up period, there were no adverse events reported and all Western Ontario and McMaster Universities Arthritis Index parameters were significantly improved. Better results were recorded in patients with a low degree of cartilage degeneration (P = 0.004). Platelets and TGF-β1 showed a highly significant increase in PRP compared with their basal level (P < 0.001). Patients achieving an excellent response had statistically higher platelet counts and TGF-β1 in PRP. To predict excellent response to PRP, platelet count in PRP had a cutoff of 1001.25 × 109/l, whereas TGF-β1 had at a cutoff concentration of 128.25 ng/ml.
Conclusion
Intra-articular injection with autologous PRP is a safe, minimally invasive, low-cost procedure to deliver growth factors for cartilage healing and regeneration. Hence, it is useful for the treatment of OA of the knee, aiming to reduce pain and improve knee function and quality of life. Platelet count and TGF-β levels in PRP are important predictors of improvement.

Keywords: knee joint, osteoarthritis, platelet-rich plasma, transforming growth factor-β1


How to cite this article:
Montasera LM, Eid TA, Helwa MA, Mesregah MK. Application of platelet-rich plasma preparation rich in growth factors in knee osteoarthritis. Menoufia Med J 2017;30:139-46

How to cite this URL:
Montasera LM, Eid TA, Helwa MA, Mesregah MK. Application of platelet-rich plasma preparation rich in growth factors in knee osteoarthritis. Menoufia Med J [serial online] 2017 [cited 2019 Aug 19];30:139-46. Available from: http://www.mmj.eg.net/text.asp?2017/30/1/139/211512




  Introduction Top


Osteoarthritis (OA) is the most common form of arthritis, affecting millions of people around the world, occurring when the protective cartilage on the ends of bones wears down over time [1]. Knee OA is more important not only for its high prevalence rate compared with other types of OA but also for its presentation in earlier age groups, particularly in younger age groups of obese women [2]. Pain and other symptoms of OA may have a profound effect on the quality of life, affecting both physical function and psychological parameters [3]. The treatment of OA includes a wide spectrum of approaches, but at present, with the exception of surgery, these approaches are merely palliative [4]. Platelet-rich plasma (PRP) is blood plasma that has been enriched with platelets, as a concentrated source of autologous platelets [5]. PRP may affect soft tissue healing by growth factors that are released after platelet degranulation, such as transforming growth factor-β1 (TGF-β1), platelet-derived growth factor, and insulin-like growth factor. The potential of a characterized platelet-derivative, known as 'preparation rich in growth factors', to enhance the limited capacity of cartilage to repair itself encouraged the idea of treating degenerative joint conditions with this autologous preparation [6]. Because of this potential benefit, clinicians have begun to inject PRP for the treatment of tendon, ligament, muscle, and cartilage injuries and early OA [7]. PRP is a simple, efficient, and minimally invasive method of obtaining a natural concentration of autologous growth factors from the blood [8].

Aim

The aim of this study was to determine the nonhemostatic regenerative efficacy of intra-articular injections of autologous PRP in patients with knee OA and to determine the correlation of platelet count and TGF-β1 with clinical improvement.


  Patients and Methods Top


The study was conducted on 28 (seven male and 21 female) patients. Their ages ranged from 40 to 63 years with a mean ± SD of 53.1 ± 6.3 years and BMI ranged from 26.2 to 45 kg/m 2 with a mean ± SD of 33.9 ± 3.6 kg/m 2. They were suffering from primary knee OA grades II (19 patients) and III (nine patients). Patients were selected from outpatient orthopedic clinic at Menoufia University Hospital. An approval from the Ethics Committee of Faculty of Medicine, Menoufia University was taken.

Patients included in this study were chosen according to the following criteria:

Inclusion criteria

  • Primary knee OA with a history of chronic pain with or without swelling and imaging study of grades II and III with degenerative knee changes
  • No improvement with medical treatment and physiotherapy.


Exclusion criteria

  • Secondary OA
  • Presence of other diseases on the knee
  • First and fourth grade of knee OA
  • History of steroid injection since 3 months ago
  • Thrombocytopenic patients.


All patients were subjected to the following:

  • Patient consent for the procedure
  • Full history taking and thorough clinical examination
  • Imaging radiography of the knee in standing position anteroposterior and lateral
  • Complete blood count including platelet count, leukocyte count, red blood cell count, and hemoglobin Level
  • Platelet count determination in the PRP prepared
  • Quantification of TGF-β1 in the PRP prepared to ensure platelet activation. It was detected using enzyme-linked immunosorbent assay (ELISA) kit (Human TGF-β1 Platinum ELISA; Affymeteix eBioscience, San Diego, CA, USA) [9].


Injection treatment and follow-up

The injection treatment was used for 28 patients after failure of conservative treatment. After taking patient consent, patients received two injections 3 weeks apart with 6 months of follow-up with radiograph and the Western Ontario and McMaster Universities Arthritis Index (WOMAC), which is a standardized questionnaire used by health professionals to evaluate the condition of patients with OA of the knee and hip, including pain, stiffness, and physical function of the joint. It can be self-administered and was developed at Western Ontario and McMaster universities in 1982. The WOMAC measures five items for pain (score range: 0–20), two for stiffness (score range: 0–8), and 17 for functional limitation (score range: 0–68) [10].

PRP preparation and injection

After taking patient consent, we collected 50 ml of blood using vacutainer system in 10 sterile tubes each containing 750 μl acid citrate dextrose [11] (supplied from Spectra group company, 31 Off El Tayaran St., Rabaa Al Adaweyah, Nasr City, Cairo Governorate). Thereafter, the 10 tubes were first centrifuged at 200g for 15 min, and plasma was separated in five plain sterile tubes using sterile syringes with around 5 ml collected in each tube. After that, the five tubes containing the plasma underwent a second centrifugation at 1200g for 10 min. The supernatant containing platelet-poor plasma was discarded using sterile syringe, keeping only 1.0 ml plasma in the bottom of each tube, and platelet pellet was mixed with this 1.0 ml plasma left. Finally, 5.0 ml of PRP was collected using sterile syringe from the five tubes in one plain sterile tube. Just before injection, 250 μl of CaCl2 10% (sterilized by autoclaving and divided into sterile Eppendorfs) was added to the prepared 5 ml PRP sample (50 μl for each 1 ml PRP) [12] using sterile syringe. 0.5 ml was added into 2 ml plastic Eppendorf for platelet counting and estimation of TGF-β1, and the remaining 4.5 ml of activated PRP was rapidly injected into the patient knee under complete aseptic conditions using a classic lateral approach with a 22 G needle.

Measurement of transforming growth factor-β1

TGF-β1 was measured by using the commercially available ELISA Kit supplied by Affymeteix eBioscience [9]. The kit uses a double-antibody sandwich ELISA to measure the level of TGF-β1 in samples. The microtiter plate provided in this kit has been precoated with a monoclonal antibody specific to TGF-β1. Standards and samples were added to the appropriate microtiter plate wells with an assay buffer and incubated. Biotin-conjugated detection antibody was then added to each microplate well, incubated, and washed. Thereafter, a streptavidin conjugated to horseradish peroxidase was added to each well, incubated, and washed. Thereafter, TMB substrate solution was added to each microplate well and incubated. Wells exhibited a change in color. The enzyme-substrate reaction was terminated by the addition of stop solution and the color change was measured spectrophotometrically at a wavelength of 450 nm. The concentration of TGF-β1 in the samples was then determined by comparing the OD of the samples to the standard curve.

Statistical analysis

The data were collected and tabulated and analyzed using statistical package for the social science (SPSS) SPSS Inc., Chicago, Illinois, USA, version 22.0 on IBM compatible computer. Data were expressed as percentage, mean, and SD. The c2-test was used to study the association between two qualitative variables. The Wilcoxon signed-rank test (nonparametric test) is a test of significance used for comparison between two related groups not normally distributed having quantitative variables. The analysis of variance (f) test is a test of significance used for comparison between three or more groups having quantitative variables. Spearman's correlation coefficient (r) (nonparametric test) is a test used to measure the association between two quantitative variables. Level of significance was set as P value of less than 0.05. The receiver operating characteristic curve is a graphic representation of the relationship between sensitivity and specificity at different cutoff points for a diagnostic test [12]. They were used in this study to measure the diagnostic accuracy of platelet count and TGF-β1 concentration in the PRP prepared and injected in knee osteoarthritic patients.


  Results Top


The baseline count of platelets of cases ranged from 150 to 322 × 109/l with a mean ± SD of 235.9 ± 48.6 × 109/l. Platelet count in PRP of first injection ranged from 685 to 1920 × 109/l PRP with a mean ± SD of 1189.4 ± 373.2 × 109/l, and platelet count in PRP of second injection ranged from 723 to 1972 × 109/l PRP with a mean ± SD of 1062.3 ± 282.2 × 109/l PRP [Table 1].
Table 1 Platelet number in osteoarthritic patients

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TGF-β1 in PRP of first injection ranged from 105 to 180 ng/ml with a mean ± SD of 136.1 ± 18.8 ng/ml, whereas TGF-β1 of the second injection ranged from 112.5 to 183 ng/ml with a mean ± SD of 131.3 ± 15.3 ng/ml [Table 2].
Table 2 Transforming growth factor-β1 of osteoarthritic patients

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The clinical success of studied cases was excellent in 64.3% (18 cases), good in 28.6% (eight cases), and poor in 7.1% (two cases) [Table 3] and [Figure 1].
Table 3 Clinical success of osteoarthritic patients

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Figure 1: Clinical success percentage.

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Cases that had an excellent response had a statistically higher platelet count in PRP of first injection (P = 0.002) and second injection (P = 0.03) than those who had good and poor responses [Table 4]. Similarly, they had a statistically higher TGF-β1 in PRP of first injection (P = 0.002) and second injection (P = 0.04) than those who had good and poor responses [Table 5].
Table 4 Comparison between clinical success grades as regards platelet count in platelet-rich plasma of first and second injection of osteoarthritic patients

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Table 5 Comparison between clinical success grades as regards transforming growth factor-β1 in platelet-rich plasma of first and second injection of osteoarthritic patients

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There was a significant difference between excellent, good, and poor cases as regards grades of OA; grade II osteoarthritis had a better response (P = 0.004; [Table 6]).
Table 6 Comparison between clinical success grades as regards grades of osteoarthritic patients

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There was a positive correlation between platelet count and TGF-β1 in PRP of first and second injection [Figure 2] and [Figure 3].
Figure 2: Correlation between platelets in PRP and TGF-β1 in PRP of first injection. PRP, platelet-rich plasma; TGF-β1, transforming growth factor-β1.

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Figure 3: Correlation between platelets and TGF-β1 in PRP of second injection. PRP, platelet-rich plasma; TGF-β1, transforming growth factor-β1.

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The cutoff platelet count of 1001.25 × 109/l predicts an excellent success with a sensitivity of 88.9%, specificity of 90%, PPV of 94.1%, NPV of 81.1%, and accuracy of 89.3%, and the cutoff level of TGF-β1 of 128.25 ng/ml predicts an excellent success with a sensitivity of 88.9%, specificity of 80%, PPV of 88.9%, NPV of 80%, and accuracy of 85.7% [Table 7] and [Figure 4] and [Figure 5].
Table 7 Evaluation of platelets and transforming growth factor-β1 level for the prediction of excellent success

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Figure 4: ROC curve of evaluation of platelet level for the prediction of excellent success. ROC, receiver operating characteristic.

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Figure 5: ROC curve for evaluating TGF-β1 for the prediction of excellent cases. ROC, receiver operating characteristic; TGF-β1, transforming growth factor-β1.

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There were no changes in radiography findings before injection and after 6 months of follow-up period after injection [Figure 6] and [Figure 7].
Figure 6: Primary knee osteoarthritis before injection.

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Figure 7: Primary knee osteoarthritis at 6 months after injection.

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  Discussion Top


OA is one of the most debilitating joint diseases and has major influences on the lifestyle, and is characterized by cartilage deterioration, loss of joint space, osteophytes, and loss of joint function [12]. The targets of OA treatment are to decrease pain, increase function and mobility, prevent or correct the deformity, and slow the progression of the disease. There are numerous conservative treatments for knee OA that have short-term efficacy and have their own benefits and disadvantages – for example, NSAIDs and intra-articular corticosteroid are common treatments for arthritis [13]. Common treatments for cartilage tissue repair rarely achieve an ideal level of functional capacity for the patient [14]. Because of the high costs of knee OA management, therapeutic options that are effective on tissue healing have been taken into consideration in recent years to prevent the progression of OA [15]; among these are growth factors that are effective factors for the healing of cartilage in OA with promising results [16]. PRP contains various growth factors that play important roles in cell proliferation, chemotaxis, cell differentiation, and angiogenesis

[17]. TGF-β1 plays a major role in bone and cartilage development and is an important regulator of chondrocyte proliferation and differentiation [18]. PRP is derived from centrifuging the person's own whole blood, which has a platelet concentration higher than that of whole blood, and is the cellular component of plasma that settles after centrifugation. Its main advantages include its availability, affordability, and minimally invasive harvest, as it is produced from the patient's own blood after collection by means of simple venipuncture and safe with no serious complications [19].

This study tried to highlight on the application of PRP injection in primary knee OA showing its advantages and disadvantages and to correlate the clinical outcome with platelet count and TGF-β1. This study was conducted on 28 patients with primary OA grade II and grade III. They received two injections of PRP treatment and were followed up for 6 months. The follow-up was carried out with the WOMAC and radiologically using radiographs.

In the present study, platelet count increased 4–6-fold in PRP compared with their counts in peripheral blood. There was a highly significant difference between platelet number in PRP and their number in peripheral blood (P < 0.001), and there was a significant difference between platelet number in PRP and clinical improvement (P = 0.001). This proved that the platelets in PRP had an effective role in OA treatment; this platelet preparation had an increased platelet concentration, which was activated to release growth factors that had a role in reducing pain and clinical improvement. This is in agreement with the study by Marco et al. [17], who reported that PRP should have a platelet concentration at least 200% to eight times of the basal peripheral blood platelet count. This is also in agreement with the findings of Eduardo et al. [20], who reported that the clinical efficacy of PRP preparations is expected to show a 2–6-fold increase in platelet count from baseline value.

In the present study, TGF-β1 increased 6–8-fold in the PRP prepared than in its plasma basal level, and there was a direct correlation between TGF-β1 and platelet counts in PRP (P < 0.001). This is in agreement with the findings of Marco et al. [17], who reported that the number of platelets is a crucial point in determining the total amount of growth factor administered, and is in agreement with the study by Xuetao et al. [21], who reported that variations in the initial volume of whole blood used as well as the efficiency of platelet preparation varies markedly among PRP techniques and was associated with high variations in growth factor concentration and availability from 3 to 27-fold. This is due to the release of TGF-β1 in PRP from α-granules, and also these results are in agreement with the findings of Nuukhet et al. [22], who reported that the higher the concentration of platelets obtained from the centrifugation of autologous blood, the higher the concentration of growth factors in PRP. The present study proved a significant association between TGF-β1 level in PRP and clinical improvement (P = 0.002); this proves its effective role in improvement of OA. This is in agreement with the findings of Eduardo et al. [20], who reported that intra-articular infiltrations of preparation rich in growth factor in patients with knee OA reduce the pain and therefore are clinically efficacious in OA treatment, and Blaney et al. [23], who reported that TGF-β1 is essential for cartilage integrity and is a powerful tool to prevent or repair cartilage damage, and hence it is effective in OA improvement.

The present study showed a significant association between grade of osteoarthritis and clinical success (P = 0.004); the greater the increase in grade of OA, the less the improvement. This can be attributed to the fact that the older and more degenerative joints tend to have less viable cells and hence a smaller potential for growth factor response. This is in agreement with the findings of Chiang et al. [24], who reported better results achieved in patients with a low degree of cartilage degeneration. This is in agreement with João et al. [25] as well, who reported that more degeneration of knee joint resulted in a decreased potential for PRP injection therapy, and is in agreement with the findings of Paul et al. [26], who reported that the improvement was mainly achieved in patients not affected by advanced degeneration.

In the present study, the cutoff level of platelets needed to produce significant improvement was 1001.25 × 109 platelets/l in 5 ml. This can predict excellent success, with a sensitivity of 88.9% and a specificity of 90%, PPV of 94.1%, NPV of 81.1%, and accuracy of 89.3%. These results are nearly similar to the findings of Belén et al. [27], who reported that PRP containing 1 000 000 platelets/μl was needed and lower concentrations do not lead to the same healing effect.

In the present study, the level of TGF-β1 at a cutoff point of 128.25 ng/ml predicts an excellent success, with a sensitivity of 88.9%, specificity of 80%, PPV of 88.9%, NPV of 80%, and accuracy of 85.7%. This is attributed to the properties of TGF-β1 as an especially significant factor in chondrogenic differentiation of MSCs, and numerous research studies have been reported on correlation between TGF-β and chondrogenesis [28].

The present study showed an overall success rate of 92.8%; around 64.3% of cases had excellent results (18 cases), around 28.6% had good results (eight cases), and 7.1% had poor results (two cases). As a concentrated form of autologous platelets, PRP contains and releases through degranulation several growth factors that stimulate healing of cartilage, and hence improves pain, dysfunction, and the osteoarthritic condition. This is in agreement with the findings of Francesca et al. [29], who reported that the use of PRP leads to clinical improvements in the pain and dysfunction that result from knee OA. Xie and colleagues [21] also reported that a series of intra-articular injections of PRP provide some short-term clinical benefit in symptomatic arthritis of the knee as demonstrated by improved clinical scores and decreased pain at 6-month follow-up. Marco and colleagues [17] reported that patients were satisfied after PRP treatment and they maintained these positive results for at least 12 months without other medications or treatments. Hunziker and colleagues [19] reported that PRP injection for knee OA is efficacious up to 6 months. João and colleagues [25] also reported a statistically significant improvement in the scores in patients who received PRP injections after 3–6 months of follow-up.

In the present study, no obvious changes were found in radiographs performed 3 and 6 months after injection. This can be attributed to the fact that PRP cannot affect bone changes in such a short duration of follow-up. However, patient satisfaction and clinical improvement achieved may be attributed to the healing of ulcers and other soft tissue injuries.


  Conclusion Top


Intra-articular injection of autologous PRP is a safe, minimally invasive, low-cost procedure to deliver growth factors for cartilage healing and regeneration, and hence it is useful for the treatment of OA of the knee, aiming to reduce pain and improve knee function and the quality of life. Platelet count and TGF-β levels in PRP are important predictors of improvement.

This study recommends that the initial amount of blood drawn (according to patient blood platelet count) be changed to ensure an adequately high PRP platelet count (≥1001.25 × 109 platelets/l in 5 ml) and subsequent high dose of growth factors to achieve improvement of OA.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7]


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