Platelet-rich plasma is an autologous, unlicensed component that is widely used in diverse clinical settings. Platelets contain growth factor and cytokines, which are thought to play a role in reducing inflammation and also aid the healing process. Autologous platelet-rich plasma (aPRP) is easy to isolate and apply, and has an excellent safety profile. These factors contribute to its popularity in fields ranging from rheumatology to orthopedic surgery. The evidence, however, does not clearly demonstrate aPRP's efficacy in many clinical applications.
TEXT OF REVIEW
How it works: platelet physiology and wound healing
Platelets are small (2–3 μm diameter), anucleate megakaryocyte cell fragments containing secretory granules and a glycoprotein-rich membrane with multiple adhesion receptors. Platelet adhesion to vascular injury triggers release of clotting factors from platelets, including fibrinogen, von Willebrand factor, and factor V. These hemostatically active proteins are stored in alpha granules, an abundant platelet organelle (averaging 40–80 per platelet) . In addition, alpha granules contain chemokines (i.e., interleukin-8, β-thromboglobulin, neutrophil activating protein, platelet factor 4, RANTES), adhesion molecules (P-selectin), and growth factors [i.e., platelet-derived growth factor (PDGF), transforming growth factor β, vascular endothelial growth factor (VEGF), stromal-derived growth factor 1 (CXCL12), epidermal growth factor] . The chemokine and growth factor-rich alpha granule content is believed to impact wound healing, as evidenced by a mouse knockout model of Gray platelet syndrome. These mice, with their near absence of alpha granules, showed impaired dermal repair, reduced granulation tissue, and myofibroblast activity after wound formation .
Platelet-derived biologic mediators have two primary effects on wound healing: recruiting and activating cells that effect wound healing, and regulation of angiogenesis. Mesenchymal stromal cells display chemotaxis and proliferation in response to platelet-derived basic fibroblastic growth factor, and platelets promote adhesion of mesenchymal stromal cells to sites of injury [4,5][4,5]. Notably, alpha granules contain angiogenesis regulators such as VEGF, PDGF, endostatin, and angiostatin. A thrombocytopenic murine model demonstrated impaired blood flow recovery after ischemic injury, with their wild-type counterparts showing improved angiogenic response after platelet infusion . Phospholipids derived from platelet membranes may also contribute to angiogenesis . Sphingosine 1-phosphate, a lysophospholipid released from activated platelet membranes, stimulates DNA synthesis and chemotactic motility in human endothelial cells in vitro and neovessel formation in mice . The sum total of all these platelet-derived elements on wound healing appears greater than each individual component's effect, as studies of single growth factor agents have yielded inconsistent results on wound healing .
Autologous platelet-rich plasma composition
There is no consensus on the definition and composition of aPRP. Different preparations contain a wide range of platelet and WBC concentrations, largely because of the various separation methods used to isolate aPRP . As platelets are key to aPRP's effect, it follows that platelet number and concentration is important, but the appropriate dosage is uncertain. Some studies suggest that high platelet numbers work and lower doses, or may actually have negative effects . Whether WBCs should be present, and at what concentration, also remain open questions. The WBCs in standard blood components have been implicated in transfusion reactions such as febrile nonhemolytic reactions; however, it is not known whether some of aPRP's clinical effects may be due, in part, to leukocytes in the mix. As the actual mechanism for aPRP action is unknown, it may be that WBCs are an important factor in aPRP's action.
Autologous platelet-rich plasma manufacture and administration
aPRP is prepared from autologous anticoagulated whole blood. Different technologies are available for aPRP isolation, including small volume tube centrifugation methods and larger apheresis machines. The different systems concentrate the platelet fraction by two-fold to five-fold , although claims of seven-fold to ten-fold are sometimes advertised.
Smaller systems utilize 10–70 ml of whole blood injected into a filter cartridge, which may be directly loaded into small desktop centrifuges for fractionation. These devices vary by the methodology used. Specifically, there are one-step and two-step centrifugation methods, different centrifugation speeds, and variation in the type of collecting tube used. These set-ups are generally inexpensive and require minimal training and time to produce aPRP. The drawbacks include multiple manual steps that introduce potential sources of error and possible bacterial contamination. Unintended platelet activation also seems likely, because of the handling, injection step(s), and g-forces from the centrifugation. The composition of the aPRP produced with these smaller, highly popular systems is variable, with differences seen in plasma volume, growth factor concentration, and the amount of residual erythrocytes . More importantly, there is wide variation in leukocyte concentrations. A comparison of three small volume devices found a range of 0.06–8.71 neutrophils (103 μl−1), and a similar wide range in lymphocyte number [9,12][9,12].
Larger scale cell separators require access to an apheresis machine and a highly trained operator. This method involves expensive specialized equipment and disposables, and a greater time commitment from the patient; however, hundreds of milliliters of blood may be processed to isolate a relatively pure, highly concentrated preparation of aPRP. Comparisons of these methods have been performed in laboratory settings, and have shown that smaller systems yield lower platelet concentration and higher WBC counts. The clinical ramifications of these differences are unknown, as the authors found no studies that directly compared the clinical efficacy of different preparations of aPRP.
The delivery method for aPRP is largely dependent upon the type of product being used, and the area of injury. Some aPRP is harvested and directly injected into the area of injury, but other formulations add a platelet-activating agent, allow a gel to form, then apply the gel to the interface between healing tissues (aPRP gel). It has been theorized that this matrix may help to localize the growth factors released and so concentrate the effect on wound healing . In general, surgical procedures favor using a fibrin matrix laid along the suture line, whereas aPRP used to relieve chronic inflammation or ‘wear and tear’ injuries is usually injected without an activating agent.
Clinical applications and evidence for efficacy
As aPRP is purported to act as an agent to aid healing and reduce inflammation, it follows that it would have wide applications in medicine. Better wound healing is desired when treating diabetic skin ulcers or for faster resolution of a surgically repaired tear. Dampening inflammation and reducing its negative effects is the goal of multiple drugs, therefore having an anti-inflammatory autologous therapy with no serious side effects would be highly advantageous. Studies and clinical trials have been performed with aPRP applied to ulcers, acutely injured and chronically worn tendons, muscles and joints with osteoarthritis or cartilage defects.
aPRP gel has been used extensively to treat acute and chronic wounds, and is considered to be advanced therapy for healing. Studies have found decreased levels of growth factors in chronic wounds when compared to acute injuries . It is thought that the application of aPRP gel directly to the wound site would increase the level of key growth factors, and thus speed the healing process. Studies and trials have compared aPRP gel to standard of care treatments, including debridement, topical antibiotic gel, and daily dressing changes [15–17][15–17][15–17]. A systematic review that included seven trials found inconclusive results for the role of aPRP in the complete healing of chronic skin ulcers (see Table 1) . Of the seven trials assessed, three were considered to present high-quality evidence, three moderate-quality, and one was of low-quality. A second systematic review and meta-analysis included 21 studies for qualitative analysis and nine studies for a quantitative meta-analysis . This analysis found that cutaneous wounds treated with aPRP gel showed improved complete and partial wound healing when compared to controls; however, the quality of evidence was found to be very low to moderate in all but one of the papers cited. The single paper reported with a high quality rating found no difference in the rate of surgical site infection when aPRP was compared to standard incision care . A Cochrane review of aPRP in wound healing found that ‘there were no differences between the autologous aPRP and the control groups in terms of healing. However, these results require confirmation in adequately powered, well conducted RCTs’ .
Platelet-rich plasma is widely used with orthopedic patients to help treat injuries to tendons, ligaments and muscle. The theoretical basis for aPRP's use in orthopedic injuries is similar to that seen with wound healing: aPRP is a rich source of growth factors and cytokines, which should aid the healing process and reduce inflammation.
Randomized controlled trials (RCTs) have been conducted with chronic Achilles tendinopathy, comparing injections of aPRP versus saline control, and looking at pain and activity level as the final outcomes [22,23][22,23]. These trials found no significant difference between treatments with aPRP versus placebo after a 1-year follow up period.
Studies and trials have investigated aPRP in the setting of lateral epicondylitis, also known as ‘tennis elbow’. One of the first studies in this field looked at pain reduction after an injection of either aPRP or bupivacaine/epinephrine in 15 patients with five controls . At 4 and 8 weeks, the authors found a significant reduction in pain in the aPRP arm compared to control; however, three of the five control patients withdrew from the study after 8 weeks, rendering subsequent findings impossible to interpret. Larger and better controlled trials of aPRP treatment for lateral epicondylitis followed [25–28][25–28][25–28][25–28]. These trials compared: aPRP and corticosteroid injections at 1-year  and 2-year follow up ; aPRP versus saline versus glucocorticoid injections ; and aPRP versus autologous whole blood injections . When aPRP versus corticosteroid injections were compared at 1-year and 2-year time points [25,27][25,27], aPRP was associated with decreased pain in significantly more patients than the corticosteroid arm. The remaining two trials, however, found no difference between aPRP and control treatments [26,28][26,28]. A meta-analysis combined the results of the four trials cited above, and three additional trials of aPRP used in the setting of lateral epicondylitis [29▪]. This analysis found no support for the use of aPRP, and concluded that: ‘there is strong evidence that PRP injections are not efficacious in the management of chronic lateral elbow tendinopathy’ [29▪].
Two groups studied the use of aPRP in anterior cruciate ligament (ACL) healing. One trial compared standard surgery for ACL tears with surgery that applied either a bone plug, aPRP gel, or both, to the area of the repaired tear . MRI was used at 3 and 6 months after surgery to evaluate graft maturation. After 6 months, the trial found some differences in MRI signal intensity when comparing the treatment groups, but no statistically significant difference associated with aPRP. The second trial looked at ACL tears repaired by surgery alone, or surgery plus an application of aPRP gel . This prospective trial randomized 100 patients, and graded clinical improvement using the International Knee Documentation Committee score, radiographs and MRI findings. After a 2-year follow-up, no noticeable clinical or biomechanical effect of aPRP was identified.
Muscle tears and strains have been treated with aPRP, but no clear evidence has emerged to back its use. Hamstring injuries were assessed in a multicenter, double-blind RCT, which compared aPRP treatment to a saline control [32▪]. The primary outcome measure was ‘return-to-play’ duration, and the secondary outcome was re-injury rate. No statistical or clinically significant difference was found for either outcome measure.
The use of aPRP gel in rotator cuff tears has shown mixed results, but the majority of larger studies and RCTs found that aPRP gel does not improve the management of rotator cuff tears. One study compared surgical repair plus or minus the insertion of aPRP-gel along the muscle repair suture line. Although a close analysis of the data suggested that milder tears might benefit from aPRP treatment, MRI studies showed no significant difference in the healing rate of the rotator cuff tear between the two groups . Several other trials also found no significant differences in perioperative morbidity, clinical outcomes, or structural integrity when aPRP gel application was compared to a no-intervention cohort [34–36][34–36][34–36]. One group published two randomized trials comparing medium and large rotator cuff tears repaired with or without the addition of aPRP [37,38][37,38]. The trials included 48 and 74 patients, and shared similar trial designs, but differed slightly in their outcome measures. Both studies found a decreased re-tear rate and increased cross-sectional area of the supraspinatus muscle; however, all other measures including range of motion, muscle strength, and overall satisfaction were the same in both cohorts.
Although studies may be found in the orthopedic literature that showed some benefit from aPRP treatment, the heterogeneity of the patient populations, aPRP preparations, and applications in these studies and trials make interpretation of aPRP efficacy in orthopedic surgeries difficult. The few well-controlled trials judged to contain high-quality evidence with low risk of bias nearly all show a lack of efficacy of aPRP when compared to controls (Table 1).
Laboratory studies have shown that aPRP acts to stimulate hyaluronic acid production and decrease the levels of markers associated with cartilage catabolism . However, some of the growth factors in aPRP are thought to have negative effects on an osteoarthritic joint, calling into question the theoretical basis for aPRP use in osteoarthritis . In fact, studies of the pathophysiology of arthropathies have found that platelet-derived growth factors, such as VEGF and PDGF, may promote joint injuries in some settings . Clinical studies compared intra-articular injections of aPRP versus hyaluronic acid in 150 patients with cartilage degenerative lesions and early and severe osteoarthritis . Early follow-up showed similar improvements between groups; however, at 6 months follow-up, better improvements were observed in the aPRP group. A subgroup analysis found no differences between treatment groups in patients over 50 or with advanced osteoarthritis. A systematic review  and a separate meta-analysis [44▪] of the RCTs and studies of aPRP for osteoarthritis both found that intra-articular injections of aPRP may have beneficial effects in adult patients with mild to moderate osteoarthritis when compared to hyaluronic acid or controls. There was a general agreement that aPRP does not show any advantage in the treatment of severe osteoarthritis when compared to controls.
The lure of using an autologous product with a good safety profile has led many clinicians to use aPRP to treat injuries, skin ulcers, cartilage defects, and other orthopedic applications. Despite a large body of literature demonstrating weak support for its therapeutic value, enthusiasm for aPRP has not dimmed. Introducing aPRP into wounds, joints or tendons can create an imbalance in growth factors and cytokines, which may tilt the body toward healing, or toward chronic injury. Basic science explorations may help us understand how the mix of factors found in aPRP can be harnessed to help rather than harm the patient. These studies should be followed by well-designed clinical trials, which use highly standardized preparations of aPRP. In addition, the clinical laboratory needs to develop protocols and quality control tests to standardize aPRP applications. Using standardized preparations will facilitate clinical trials to produce better evidence for or against the use of aPRP.
Financial support and sponsorship
C.S.C. has received research funding and honoraria from Fenwal Inc., a Fresenius-Kabi company, and research funding from Octapharma Inc. E.L. is a consultant for CSL Behring, Octapharma, and Bayer and has received honoraria from CSL Behring, and Octapharma and received honoraria and research funding from TEM Systems Inc.
Conflicts of interest
There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
- ▪ of special interest
- ▪▪ of outstanding interest
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