Archived Policies - Prescription Drugs

Recombinant and Autologous Platelet-Derived Growth Factors as a Primary Treatment of Wound Healing and Other Miscellaneous Conditions


Effective Date:07-15-2017

End Date:10-31-2018


Medical policies are a set of written guidelines that support current standards of practice. They are based on current peer-reviewed scientific literature. A requested therapy must be proven effective for the relevant diagnosis or procedure. For drug therapy, the proposed dose, frequency and duration of therapy must be consistent with recommendations in at least one authoritative source. This medical policy is supported by FDA-approved labeling and nationally recognized authoritative references. These references include, but are not limited to: MCG care guidelines, Hayes, DrugDex (IIb level of evidence or higher), NCCN Guidelines (IIb level of evidence or higher), NCCN Compendia (IIb level of evidence or higher), professional society guidelines, and CMS coverage policy.

Recombinant platelet-derived growth factor (i.e., becaplermin) may be considered medically necessary when used as an adjunct to standard wound management for the following indications:

Neuropathic diabetic ulcers extending into the subcutaneous tissue (when used according to the U.S. Food and Drug Administration [FDA] labeled indication), AND when meeting ALL of the following criteria:

o Adequate tissue oxygenation, as measured by a transcutaneous partial pressure of oxygen of 30 mm Hg or greater on the foot dorsum or at the margin of the ulcer, and

o Full-thickness ulcer (i.e., Stage III or IV), extending through dermis into subcutaneous tissues, and

o Participation in a wound management program, which includes sharp debridement, pressure relief (i.e., non-weight bearing), and infection control.

Pressure ulcers extending into the subcutaneous tissue when meeting ALL the following criteria:

o Full-thickness ulcer (i.e., Stage III or IV), extending through dermis into subcutaneous tissues, and

o Ulcer in an anatomic location that can be offloaded for the duration of treatment, and

o Albumin concentration >2.5dL, and

o Total lymphocyte count >1,000, and

o Normal values of vitamins A and C.

Other applications of becaplermin are considered experimental, investigational and/or unproven including, but not limited to, ischemic ulcers, ulcers related to venous stasis and ulcers not extending through the dermis into the subcutaneous tissue.

Use of autologous blood-derived preparations (i.e., platelet-rich plasma) is considered experimental, investigational and/or unproven for all indications including but not limited to the following:

Treatment of acute or chronic wounds, including surgical wounds and nonhealing ulcers.

For all orthopedic indications including but not limited to:

o Primary use (injection) for the following conditions:

1. Achilles tendinopathy

2. Lateral epicondylitis

3. Osteochondral lesions

4. Osteoarthritis

5. Plantar fasciitis

o Adjunctive use in the following surgical procedures:

1. ACL reconstruction

2. Hip fracture

3. Long-bone nonunion

4. Patellar tendon repair

5. Rotator cuff repair

6. Spinal fusion

7. Subacromial decompression surgery


This policy addresses the use of blood-derived growth factors, including recombinant platelet-derived growth factors (PDGF) and platelet-rich plasma (PRP), as a treatment of wounds or other miscellaneous conditions.


A variety of growth factors have been found to play a role in wound healing, including platelet-derived growth factors (PDGF), epidermal growth factor, fibroblast growth factors, transforming growth factors, and insulin-like growth factors. Autologous platelets are a rich source of PDGF, transforming growth factors (that function as a mitogen for fibroblasts, smooth muscle cells, and osteoblasts), and vascular endothelial growth factors. Recombinant PDGF has also been extensively investigated for clinical use in wound healing.

Autologous platelet concentrate suspended in plasma, also known as PRP, can be prepared from samples of centrifuged autologous blood. Exposure to a solution of thrombin and calcium chloride degranulates platelets, releasing the various growth factors and results in the polymerization of fibrin from fibrinogen, creating a platelet gel. The platelet gel can then be applied to wounds or may be used as an adjunct to surgery to promote hemostasis and accelerate healing. In the operating room setting, PRP has been investigated as an adjunct to a variety of periodontal, reconstructive, and orthopedic procedures. For example, bone morphogenetic proteins are a type of transforming growth factors, and thus PRP has been used in conjunction with bone-replacement grafting (using either autologous grafts or bovine-derived xenograft) in periodontal and maxillofacial surgeries. Alternatively, PRP may be injected directly into the tissue. PRP has also been proposed as a primary treatment of miscellaneous conditions, such as epicondylitis, plantar fasciitis, and Dupuytren’s contracture. Injection of PRP for tendon and ligament pain is theoretically related to prolotherapy. However, prolotherapy involves injection of chemical irritants that are intended to stimulate inflammatory responses and induce release of endogenous growth factors.

PRP is distinguished from fibrin glues or sealants, which have been used for many years as a surgical adjunct to promote local hemostasis at incision sites. Fibrin glue is created from platelet-poor plasma and consists primarily of fibrinogen. Commercial fibrin glues are created from pooled homologous human donors; Tisseel® (Baxter) and Hemaseel® are examples of commercially available fibrin sealants. Autologous fibrin sealants can be created from platelet-poor plasma. This policy does not address the use of fibrin sealants.

Regulatory Status

Becaplermin gel (Regranex)

A recombinant PDGF product, becaplermin gel (Regranex®, McNeil Pharmaceutical) has been approved by the U.S. Food and Drug Administration (FDA). The labeled indication is as follows: "Regranex Gel is indicated for the treatment of lower extremity diabetic neuropathic ulcers that extend into the subcutaneous tissue or beyond and have an adequate blood supply. When used as an adjunct to, and not a substitute for, good ulcer care practices including initial sharp debridement, pressure relief and infection control, Regranex Gel increases the complete healing of diabetic ulcers. The efficacy of Regranex Gel for the treatment of diabetic neuropathic ulcers that do not extend through the dermis into subcutaneous tissue or ischemic diabetic ulcers has not been evaluated." In 2008, the manufacturer added this black box warning to the labeling for Regranex, “An increased rate of mortality secondary to malignancy was observed in patients treated with 3 or more tubes of Regranex Gel in a post-marketing retrospective cohort study. Regranex Gel should only be used when the benefits can be expected to outweigh the risks. Regranex Gel should be used with caution in patients with known malignancy.”

Patients are typically treated once daily for up to 20 weeks or until complete healing. Application of the gel may be performed by the patient in the home.

Becaplermin gel (Regranex) is available in 2-, 7.5-, and 15-g tubes and is applied in a thin continuous layer, about 1/16 of an inch thick, i.e., the thickness of a dime. The amount of the gel used will depend on the size of the ulcer, measured in square centimeters. However, an average-sized ulcer, measuring 3 cm2, treated for an average length of time of 85 days, will require a little more than one 15-g tube. If the ulcer is treated for the maximum length of time of 140 days, 1.75 of the 15-g tubes would be required.

Platelet-rich plasma (PRP)

Blood products such as PRP are regulated by the Center for Biologics Evaluation and Research (CBER). (28) CBER is responsible for regulating human cells, tissues, and cellular and tissue-based products. The regulation process for these products is described in the U.S. Food and Drug Administration’s (FDA) 21 CFR 1271 of the Code of Federal Regulations. Under these regulations, certain products including blood products such as PRP are exempt and therefore do not follow the traditional FDA regulatory pathway. To date, the FDA has not attempted to regulate activated PRP.

There are numerous PRP preparation systems on the market today with FDA clearance. Many of these systems have 510(k) clearance for producing platelet-rich preparations intended to be used to mix with bone graft materials to enhance bone grafting properties in orthopedic practices. The Aurix System™ (previously called AutoloGel™ from Cytomedix) and SafeBlood® (SafeBlood Technologies) are two related but distinct autologous blood-derived preparations that can be prepared at the bedside for immediate application. Both AutoloGel and SafeBlood have been specifically marketed for wound healing. Other devices may be used in the operating room setting, such as Medtronic Electromedics, Elmd-500 Autotransfusion system, the Plasma Saver device, or the Smart PreP device. The Magellan Autologous Platelet Separator System (Medtronic) includes a disposables kit designed for use with the Magellan Autologous Platelet Separator portable tabletop centrifuge. BioMet Biologics received marketing clearance through FDA’s 510(k) process for a gravitational platelet separation system (GPS®II), which uses a disposable separation tube for centrifugation and a dual cannula tip to mix the platelets and thrombin at the surgical site. Filtration or plasmapheresis may also be used to produce platelet-rich concentrates. The use of different devices and procedures can lead to variable concentrations of active platelets and associated proteins, increasing variability between studies of clinical efficacy.


This policy was originally developed in 1993 and has been updated with searches of scientific literature through April 17, 2016. This section of the current policy has been substantially revised. The following is a summary of the key literature to date.

Recombinant Platelet-Derived Growth Factor (Becaplermin Gel)

Diabetic Neuropathic Ulcers:

This policy regarding the use of becaplermin gel was originally based on a 1999 TEC Assessment, (1) which concluded that the evidence supports the conclusion that becaplermin treatment, in conjunction with good wound care, improves the health outcomes of patients with chronic neuropathic diabetic ulcers that meet the patient selection criteria defined here. Becaplermin gel plus good wound care resulted in a 43% complete wound-closure rate, compared to 28% for patients treated with good wound care alone. Becaplermin gel also appeared to reduce the average time to complete wound closure. A systematic review from 2014 identified 6 RCTs with a total of 992 patients that compared recombinant platelet derived growth factors (PDGFs) with placebo or standard care. (2) There was a combined odds ratio of 1.53 (95% confidence interval [CI], 1.14 to 2.04; p=0.004) favoring recombinant PDGF for complete healing rate.

An industry-sponsored study assessed the effectiveness of recombinant platelet-derived growth factors (PDGF) on diabetic neuropathic foot ulcers in actual clinical practice. (3) Subjects (from a cohort of 24,898 patients in wound-care centers) whose wounds did not heal over an 8-week observation period were eligible for the study and were assessed over a period of 20 weeks or until they healed. Any individual with an open wound who was lost to follow-up was considered unhealed. Of the nearly 25,000 patients treated for foot ulcers, 2,394 (9.6%) received recombinant PDGF. A propensity score method with covariates to statistically model treatment selection was used to adjust for selection bias; results were stratified by 5 propensity score groups. Overall, the rate of healing was 26.5% in the control group and 33.5% in the patients treated with recombinant PDGF. The relative risk, controlling for the propensity to receive PDGF, was 1.32 for healing and 0.65 for amputation (6.4% vs. 4.9%, respectively). Analysis also indicated that those who received PDGF were more likely to be younger, male, and have older wounds, factors not known to affect wound healing. These results support clinical effectiveness of recombinant PDGF for treatment of diabetic neuropathic foot ulcers in actual clinical practice.

Pressure Ulcers:

Results of a randomized study focusing on the use of becaplermin gel as a treatment of pressure ulcers was published in 1999. (4) The patient selection criteria for this study are but most importantly included full-thickness ulcers and an anatomic location where pressure could be off-loaded during treatment. This latter patient selection criterion may limit the number of patients with pressure ulcers who would be considered candidates for becaplermin therapy. Patients were randomized to 1 of 4 parallel treatment groups and received either a placebo or 1 of 3 doses of becaplermin. All patients received a standardized program of good wound care. In the 2 groups of patients treated with once daily doses of becaplermin (either 100 or 300 µg/g), the incidence of complete healing was significantly improved compared to the placebo group. There was no difference in outcome between the 100 and 300 µg/g group, suggesting that there is no clinical benefit in increasing the dose above100 µg/g. A third group of patients received becaplermin 100 µg/g twice a day. This group did not report an improved outcome compared to placebo, a finding that is unexplained.

Venus Leg Ulcers:

In 2011, Senet et al. published results of a multicenter randomized double-blind controlled trial of becaplermin gel as a treatment of hypertensive ulcers. (5) There was no significant difference between the becaplermin (n=28) and control hydrogel (n=31) groups for any of the outcome measures, which included complete closure rates after 8 and 12 weeks, changed ulcer area, and changed ulcer-related pain and quality of life.

Traumatic Wounds:

Topical recombinant PDGF has also been investigated for repair of work-related fingertip injuries. A 2005 prospective controlled trial in the United States alternately assigned 50 patients (fingertip wound area of 1.5 cm or more, with or without phalangeal exposure) to daily treatment with PDGF (n=25) or surgical reconstruction (n=25). (6) Statistical analysis showed that the baseline characteristics of the two groups were similar for patient age, wound area (2.2–2.4 cm), and distribution of fingertip injuries across the digits. Assessment by an independent physician showed that in comparison with the surgical intervention, treatment with recombinant PDGF resulted in faster return to work (10 vs. 38 days, respectively) and wound healing (25 vs. 35 days, respectively) and a reduction in functional impairment (10% vs. 22%, respectively) and need for physiotherapy (20% vs. 56%, respectively). Fingertips treated with PDGF were also reported to have satisfactory esthetic results, while surgically treated fingertips were shorter and often unsightly. These results, if confirmed, could lead to improvement in health outcomes for patients with fingertip injury. However, the present study is limited by the small sample size, the method of randomization, and the potential for investigator bias (although the investigators did blind the examining physician from treatment allocation, the actual treatment may have been obvious). Additional RCTs are needed.

Adverse Effects:

Growth factors cause cells to divide more rapidly. It is for this reason that the manufacturer continued to monitor studies begun before Regranex was approved in December 1997 for any evidence of adverse effects, such as increased numbers of cancers. In a long-term safety study completed in 2001, more deaths from cancer occurred in people who used Regranex than in those who did not use it. Following the report of the study completed in 2001, an additional study was performed using a health insurance database that covered the period from January 1998 through June 2003. This study used the database to identify two groups of patients with similar diagnoses, drug use, and use of health services, one of which used Regranex and one group that did not. The results of this study showed that deaths from cancer were higher for patients who were given 3 or more prescriptions for treatment with Regranex than those who were not treated with Regranex. No single type of cancer was identified, but deaths from all types of cancer combined were observed. In 2008, the U.S. Food and Drug Administration (FDA) concluded that the increase in the risk of death from cancer in patients who used 3 or more tubes of Regranex was 5 times higher than in those patients who did not use Regranex. The risk of getting new cancers among Regranex users was not increased compared to non-users, although the duration of follow-up of patients in this study was not long enough to detect new cancers.

Summary of Evidence for Recombinant Platelet-Derived Growth Factor (Becaplermin Gel)

Results from randomized controlled trials show improved rates of healing with use of recombinant platelet-derived growth factor for diabetic lower extremity ulcers and pressure ulcers. The increase in rate of healing must be balanced with the potential for increased risk from cancer. Evidence is insufficient to determine whether becaplermin gel improves health outcomes when used to treat other types of wounds, including venous ulcers or acute traumatic wounds.

Platelet-rich plasma (PRP) or PRP gel

The evidence review on platelet-derived wound-healing formulae was originally derived from a 1992 TEC Assessment, (7) which primarily focused on the Procuren process. This preparation method is no longer commercially available. A number of systematic reviews of the evidence on PRP have been published; these will be the focus of the evidence review. At the present time, there are a large number of techniques available for the preparation of platelet-rich plasma (PRP) or PRP gel. The amount and mixture of growth factors produced by different cell separating systems are variable, and it is also uncertain whether platelet activation before injection is necessary. (29-34)

A number of systematic reviews of the evidence on PRP have been published. A 2012 Cochrane review included 9 RCTs (325 participants) of PRP for treating chronic wounds. (8) This review was restricted to trials where PRP was compared with no additional treatment or placebo. Four RCTs included patients with mixed chronic wounds, 3 included patients with venous leg ulcers, and 2 included patients with diabetic foot ulcers. Only 1 trial was considered to be at low risk of bias. After a median treatment duration of 12 weeks, there was no significant difference between the PRP and control groups in complete healing of diabetic foot ulcers, venous leg ulcers, or mixed chronic wounds. There was no significant difference in the area epithelialized in 3 RCTs of mixed chronic wounds. In 2 RCTs of mixed chronic wounds, there was a significant difference favoring PRP in the wound area that was healed. However, the review concluded that there was no current evidence to suggest that autologous PRP is of value for treating chronic wounds, given the small number of RCTs included, most of which are either at high or unclear risk of bias.

Other systematic reviews reached similar conclusions. For example, one from 2009 identified 42 controlled trials on PRP; of these, 20 were RCTs and were included in the systematic review, which found results to be inconclusive. (9) The 20 RCTs comprised 11 trials on oral and maxillofacial surgery, 7 on chronic skin ulcers, and 2 on surgery wounds. An industry-funded systematic review from 2011 included 21 studies of PRP gel for cutaneous wound healing, 12 of which were RCTs. (10) There were 3 main types of wounds, including open chronic wounds, acute surgical wounds with primary closure, and acute surgical wound with secondary closure. Study quality varied considerably, with 3 studies rated as high quality and 6 rated as poor quality. Two additional studies could not be rated because they were published only as an abstract and letter. Meta-analysis of the effect of PRP on complete wound healing of chronic wounds was limited by the inclusion of poor-quality studies. No high-quality RCTs showed improvement in complete healing with PRP.

A 2015 systematic review of PRP for diabetic foot ulcers identified 6 small RCTs published between 1992 and 2011. (11) Although 5 of the studies reported positive results with PRP, the studies were small and the possibility of selective publication bias was not assessed.

Acute Traumatic Wounds

Kazakos et al (2009) reported a prospective RCT that evaluated treatment of acute traumatic wounds (open fractures, closed fractures with skin necrosis, and friction burns) with platelet gel in 59 consecutive patients (27 PRP, 32 controls). (12) Conventional treatment consisted of topical washing and cleaning of the wounds, removal of the necrotic tissue, and dressing with Vaseline gauze every 2 days. In all patients with open tibial fractures, an external fixation system was applied. PRP gel, prepared with specialized tubes and a bench-top centrifuge, was applied to the wounds after surgical débridement and placement of the external fixation system. The time needed for preparation and application of the PRP gel was 52 minutes. Thereafter, PRP gel was applied to the wounds once weekly in the outpatient clinic until there was adequate tissue regeneration (mean, 21 days) sufficient to undergo reconstructive plastic surgery. Control patients receiving conventional treatment required a mean of 41 days for adequate tissue regeneration. Pain scores were significantly lower in PRP-treated patients at 2 and 3 weeks (visual analog scale score, 58 PRP vs 80 controls). Although these results are encouraging, additional study with a larger number of patients is needed.

Acute Surgical Wounds

Aortic Arch Repair

In 2015, Zhou et al. reported a double-blind RCT with 80 patients that assessed the effect of PRP on the amount of blood transfused in the perioperative period for elective ascending and transverse aortic arch repair. (35) The anesthesiologist prepared the PRP behind the surgical curtain and the surgeon was unaware of the treatment group. The volume of PRP transfused was 726 mL, and led to a reduction in transfusion rates for red blood cells, frozen plasma, cryoprecipitate, and platelets by 34% to 70% (p<0.02). Hospital length of stay was also reduced (9.4 days vs 12.7 days). There was no difference in mortality between the 2 groups (1 patient in each group) and no significant difference in postoperative complications or other outcome measures. Corroboration of the effect of PRP on perioperative blood transfusion is needed.

Sternotomy Wounds

In 2015, Serraino et al. reported a large series with historical controls that assessed the occurrence of deep sternal wound infections in patients who underwent cardiac surgery either with (2010-2012, 422 consecutive patients) or without (2007-2009, 671 consecutive patients) application of PRP. (36) The 2 groups were comparable at baseline. At the end of cardiac surgery, PRP gel was applied on the sternum before the closure of subcutaneous tissue. The occurrence of both deep and superficial wound infection were reduced in the patients treated with PRP (deep: 0.2% vs 1.5%, superficial: 0.5% vs 2.8%). Interpretation of these results is limited by likely differences in treatments over time. RCTs are needed to evaluate this potential use of PRP.

PRP for Mixed Indications

A 2012 systematic review addressed a wide variety of orthopedic indications. This publication included 23 randomized trials and 10 prospective cohort studies that compared PRP with placebo, corticosteroids, or a standard procedure. (37) For most of the studies, the outcome measures differed, but 6 RCTs (n=358) and 3 prospective cohort studies (n=88) reported results of PRP using a visual analog score (VAS) and were combined for analysis. These studies assessed injuries to the acromion, rotator cuff, lateral humeral epicondyle, anterior cruciate ligament (ACL), patella, tibia, and spine. Follow-up ranged from 6 weeks to 24 months. Of 22 RCTs that evaluated functional outcomes, 6 showed a functional benefit of PRP, 15 showed no difference between PRP and the control, and 1 showed a significant functional advantage for the control group. Interpretation of this systematic review is limited by the combination of a wide variety of conditions, as well as the lack of standardization of platelet-separation techniques and outcome measures in the primary literature.

PRP as a Primary Treatment of Tendinopathies

There are a large number of small RCTs that evaluate treatment of tendinopathies at various locations. In 2014, Andia et al. published a systematic review of PRP in the treatment of painful tendinopathies. (38) They included 13 prospective controlled trials (12 RCTs, 1 controlled study that was not randomized) with data from 636 patients included in the meta-analysis. The number of studies on various tendinopathies included 7 studies on chronic elbow tendinopathy, 2 on supraspinatus, 3 on patellar, and 1 study on Achilles tendinopathy. Nearly all studies used leukocyte-rich PRP, and the PRP preparation protocol was the same in about half of the studies. The number of injections ranged from 1 (9 studies) to 3 (1 study). Control interventions included physical therapy (1 study), extracorporeal shock wave therapy (1 study), corticosteroid (3 studies), autologous blood (3 studies), saline (3 studies), and dry needling (2 studies).

Risk of bias was considered to be low in 4 studies, unclear in 3, and high in 6. Meta-analysis found that PRP was not better than control interventions in reducing pain at 1 or 2 month follow-up. A small significant effect in pain reduction was found at 3 months (weighted mean difference [WMD], -0.61). At 1 year, the WMD between PRP and control interventions was significant at -1.56. Due to heterogeneity between studies, these findings had low power and precision.

The evidence on specific tendinopathies is reviewed next.

Achilles Tendinopathy

A single center, randomized, double-blind, placebo-controlled trial of PRP injection in patients with chronic midportion Achilles tendinopathy was reported by de Vos et al. in 2010. (39) Fifty-four patients were randomized to receive PRP or saline injection, and all patients performed eccentric exercises. The Victorian Institute of Sports Assessment-Achilles (VISA-A) questionnaire evaluating pain score and activity level was completed at baseline and at 6, 12, and 24 weeks. The mean VISA-A score improved significantly after 24 weeks in both groups, and the between-group difference was not statistically significant. There were no significant differences on secondary measures of patient satisfaction and number of patients returning to their desired sport. The authors conclude that “in patients treated with an eccentric exercise program, a PRP injection compared with saline injection did not result in greater improvement in pain and activity.”

No additional trials of PRP for chronic Achilles tendinopathy were identified in a 2013 Cochrane review. (40)

Lateral Epicondylitis (Tennis Elbow)

A double-blind randomized trial of PRP for lateral epicondylitis was reported by Peerbooms and colleagues in 2010 (13), with 2-year follow-up reported by Gosens et al. in 2011. (14) One hundred patients with chronic (longer than 6 months) epicondylitis were randomized, 49 to receive corticosteroid injection and 51 to receive PRP injection. Success was defined as 25% reduction in pain on VAS or Disabilities of the Arm, Shoulder, and Hand (DASH) outcomes measure score after 1 year without a re-intervention. Initially, mean VAS was 70.1 in the PRP-treated patients and 65.8 in the corticosteroid group. DASH scores were 161.3 and 131.2, respectively (p<0.001). At 4 and 8 weeks after injection, outcomes on VAS and DASH scores were significantly better in the corticosteroid group. At 12 weeks, between-group differences were not significant. After 1 year, 73% of PRP and 49% of corticosteroid-treated patients met criteria for success on pain VAS; 73% of the PRP group and 51% the steroid group were successful using DASH outcome measures (p=0.005). At 2 years, both VAS and DASH scores were significantly better in the PRP group (21.3 and 17.6, respectively) compared to the corticosteroid group (42.4 and 36.5). Success on the DASH was achieved by 73% of the PRP group and 39% of the corticosteroid group, while more patients in the corticosteroid group (47% vs. 14%) had deteriorated at 2 years.

In 2013, Krogh et al. reported a double-blind placebo-controlled RCT in 60 patients with chronic lateral epicondylitis. (15) Patients were randomized to receive either a blinded injection of PRP, saline, or corticosteroid injection. In order to maintain blinding, a blood sample was taken from all patients, and patients were blindfolded during the blood sampling and injections. At 1 month, corticosteroid injections reduced pain to a greater extent than either PRP or saline. At 3-month follow-up, there was no significant difference between the groups in the primary endpoint of pain reduction. Corticosteroid injection was more effective than saline or PRP in reducing color Doppler activity and tendon thickness.

Numerous RCTs have been published for treatment of lateral epicondylitis with PRP. A 2014 systematic review concluded that there is strong evidence that PRP is not effective for lateral epicondylar tendinopathy. (41) Six studies were included in the review, 4 of which were considered to be of high quality based on the PEDro score. The authors reported that 3 of 4 high-quality studies and 2 low-quality studies showed no significant benefit when compared with a control group (corticosteroids, autologous whole blood, saline, needling), while 1 high-quality study showed a beneficial effect of a PRP injection when compared with a corticosteroid injection.

PRP as a Primary Treatment of Nontendon Soft Tissue Injury or Inflammation

Plantar Fasciitis

There are at least 3 small RCTs on the treatment of plantar fasciitis. In 2014, Franceschi et al. published a qualitative systematic review of the literature on PRP for chronic plantar fasciitis. (42) Eight prospective studies were identified, 3 of which were randomized. The 3 single-blinded RCTs had a total of 90 patients and compared treatment with PRP with corticosteroids (n=60) or prolotherapy (n=30). The largest RCT (N=40) by Monto et al. in 2014 compared PRP with corticosteroid injection and had follow-up to 24 months. (43) There was an apparent difference in the age and baseline score of the two groups. Blinded assessment with American Orthopaedic Foot and Ankle Society (AOFAS) hindfoot score at 3, 6, 12, and 24 months showed a temporary improvement in the corticosteroid group with a return to near baseline levels (score, 58) by 12 months. In the PRP group the AOFAS score increased from 37 at baseline to 95 at 3 months and remained elevated through 24 months with a final score of 92 (difference of 46 from controls, p=0.001). Confirmation of these results in a larger double-blind RCT with other concentration systems would allow greater certainty regarding the efficacy of PRP in plantar fasciitis.

PRP as a Primary Treatment of Focal Cartilage Lesions and Osteoarthritis

Osteochondral Lesions

No RCTs on treatment of osteochondral lesions were identified. In 2012, Mei-Dan et al. reported a quasi-randomized trial of 29 patients with 30 osteochondral lesions of the talus assigned to 3 intra-articular injections of hyaluronate or PRP. (44) At 28-week follow-up, scores on the AOFAS Ankle-Hindfoot Scale improved to a greater extent in the PRP group (from 68 to 92) than the hyaluronate group (from 66 to 78). Subjective global function also improved to a greater extent in the PRP group (from 58 to 91) than the hyaluronate group (from 56 to 73). Interpretation of the composite measures of VAS pain and VAS function is limited by differences in the groups at baseline. Neither the patients nor the evaluators were blinded to treatment in this small study.


There are at least 5 RCTs and several quasi-randomized trials published on treatment of osteoarthritis. A 2014 systematic review of PRP for degenerative cartilage pathology included 5 RCTs, 3 quasi-randomized controlled trials, and 8 single-arm prospective series (total N=1543 patients) comparing PRP with hyaluronic acid (HA; 4 RCTs, 2 quasi-randomized) or saline (1 RCT). (45) Meta-analysis of functional outcomes found that the effectiveness of PRP was greater than that of HA and improved over 12 months. Fewer than 3 injections, single spinning, and lack of additional activators led to greater uncertainty in the treatment effects. PRP also had lower efficacy in patients with higher degrees of cartilage degeneration. Results were consistent when analyzing only RCTs, but asymmetry in funnel plots suggested significant publication bias. Additional study in high-quality RCTs with a larger number of patients, and with comparisons to alternatives other than HA, is needed to determine the efficacy of PRP for this common condition.

PRP as an Adjunct to Surgery


A 2008 double-blind RCT assessed the efficacy of PRP following tonsillectomy in 70 children, aged 4 to 15 years. (23) PRP was prepared during the surgery and placed into the tonsil beds of half of the children, where it was directly visible. To compare pain symptoms and recovery, a daily diary was completed by either the patient or family member for 10 days after surgery. A FACES Pain Scale was used for children aged 4 to 7 years, while a numbered pain scale was used for children older than 7 years. Diaries from 83% of patients showed no differences in pain, medication doses, activity, and days eating solid foods between the 2 conditions.

Wound Closure

A 2011 Norwegian trial of PRP applied to saphenous vein harvest sites after wound closure found no difference in the incidence of wound infection or cosmetic result. (24)

ACL Reconstruction

A large number of controlled trials have been published on PRP as an adjunct to anterior cruciate ligament (ACL) reconstruction. A 2013 Cochrane review of platelet-rich therapies for musculoskeletal soft tissue injuries identified 4 trials (203 patients) on PRP used in conjunction with ACL reconstruction. (40) Pooled data found no significant difference in International Knee Documentation Committee (IKDC) scores between the PRP and control groups. A 2015 qualitative systematic review by Figuera et al. included 11 RCTs or prospective cohort studies with a combined total of 516 patients. (46) Four studies found significantly faster graft maturation while 3 found no significant difference. One study showed faster tunnel healing while 5 showed no benefit. One study showed better clinical outcomes and 5 showed no improvement in clinical outcomes when using PRP. The largest trial is by Nin et al. who randomized 100 patients to undergo arthroscopic ACL reconstruction with or without PRP. (47) The use of PRP on the graft and inside the tibial tunnel in patients treated with bone-patellar tendon-bone allografts had no discernable clinical or biomechanical effect at 2-year follow-up.

Hip Fracture

One RCT was identified for treatment of hip fracture. In 2013, Griffin et al. reported a single-blind randomized trial of PRP for the treatment of hip fractures in patients aged 65 years and older. (48) Two hundred patients underwent internal fixation of a hip fracture with cannulated screws and were randomly assigned to receive standard-of-care fixation or standard-of-care fixation with injection of PRP into the fracture site. The primary outcome measure was the failure of fixation within 12 months, defined as any revision surgery. The overall risk of revision by 12 months was 36.88% and the risk of death was 21.5%. There was no significant risk reduction (39.74% control, 34.15% PRP) or significant difference between groups in most of the secondary outcome measures. For example, mortality was 23% in the control group and 20% in the PRP group. The length of stay was significantly reduced in the PRP-treated group (median difference, 8 days). There is a potential for bias from the nonblinded treating physician in this measure.

Long-Bone Nonunion

A 2012 Cochrane review found only 1 small (N=21) RCT of PRP for long-bone healing. (49) However, only studies where PRP was compared with no additional treatment or a placebo were included in the review; therefore, the authors did not include the larger RCT by Calori et al. described next.

Calori et al. compared application of PRP or recombinant human bone morphogenetic protein-7 (rhBMP-7) for the treatment of long-bone nonunions in an RCT with 120 patients and 10 surgeons. (50) Inclusion criteria were posttraumatic atrophic nonunion for at least 9 months, with no signs of healing over the last 3 months, and considered as treatable only by means of fixation revision. Autologous bone graft had been used in a prior surgery in 23 cases in the rhBMP-7 group and in 21 cases in the PRP group. Computer-generated randomization was developed to create 2 homogeneous groups; there were generally similar numbers of tibial, femoral, humeral, ulnar, and radial nonunions in the 2 groups. Following randomization, patients underwent surgery for nonunion, including bone grafts according to the surgeon’s choice (66.6% of rhBMP-7 patients, 80% of PRP patients). Clinical and radiologic evaluations by 1 radiologist and 2 surgeons trained in the study protocol revealed fewer unions in the PRP group (68%) compared with the rhBMP-7 group (87%). Clinical and radiographic healing times were also found to be slower by 13% to 14% with PRP.

Patellar Tendon Harvest

One small RCT evaluated PRP as an adjunct to patellar tendon repair. In 2012, de Almeida et al. reported a small (N=27) randomized trial of the effect of PRP gel on the harvest site of the patellar tendon during ACL reconstruction. (51) VAS for pain in the postoperative period was significantly lower in the PRP group compared with the control group (3.8 vs 5.1). At 6 months, assessment by magnetic resonance imaging showed a smaller gap in the patellar tendon in the PRP group (4.9 mm vs 9.4 mm), but there was no significant difference between groups for the Tegner questionnaire or isokinetic testing.

Rotator Cuff Repair

The literature on PRP for rotator cuff repair consists of a number of small double-blind RCTs that have evaluated the efficacy of PRP membrane or matrix combined with surgical repair of the rotator cuff. Most of these studies show no significant benefit of PRP. Pooling of data from these trials shows no statistically or clinically significant benefit of PRP. (16-21)

A 2013 Cochrane review that pooled data for long-term function from 6 trials of PRP applied with rotator cuff repair showed no statistically or clinically significant differences between the PRP and control groups. (40) A 2015 systematic review included 8 RCTs with sample sizes ranging from 28 to 88 and a combined total of 464 patients. (52) Meta-analysis showed no significant differences between the PRP and control groups in retear rate (relative risk=0.94; p=0.66), Constant score (mean difference, 1.12; p=0.38), or University of California at Los Angeles (UCLA) score (mean difference, -0.68; p=0.32). The strength of the evidence based on GRADE was considered to be low for retear, moderate for Constant score, and low for UCLA shoulder score.

Spinal Fusion

No randomized trials on PRP in spinal fusion were identified; however, 2 controlled but not randomized studies found no difference in fusion rates with use of platelet gel or platelet glue. (53, 54)

Subacromial Decompression Surgery

One small RCT used PRP as an adjunct to subacromial decompression surgery. Everts et al reported a rigorously conducted, small (N=40) double-blinded RCT of platelet and leukocyte-rich plasma (PLRP) gel following open subacromial decompression surgery in a carefully selected patient population. (22) Blood was drawn from all patients after induction of anesthesia to maintain blinding. PLRP with autologous thrombin was injected into both the subacromial intracapsular space and the subcutaneous layer covering the incision during wound closure. Postoperative examinations at 1, 2, 4, and 6 weeks were performed by independent evaluators; unique patient identifier codes were used to maintain patient and investigator blinding. Neither self-assessed nor physician-assessed instability were improved. Both subjective pain and use of pain medication were lower in the PLRP group across the 6 weeks of measurements. For example, at 2 weeks after surgery, VAS scores for pain were lower by about 50% in the PLRP group (close to 4 in the control group, close to 2 in the PLRP group), and only 1 patient (5%) was taking pain medication compared with 10 (50%) control patients. Objective measures of range of motion showed clinically significant improvement in the PLRP group across the 6-week assessment period, while patients reported improvements in activities of daily living such as ability to sleep on the operated shoulder at 4 weeks after surgery and earlier return to work.

Total Knee Arthroplasty

One small RCT with 40 patients found no significant differences between the PRP and untreated control groups in bleeding, range of motion, swelling around the knee joint, muscle power recovery, pain, Knee Society Scores or Knee Injury and Osteoarthritis Outcome Score. (55)

Summary of Evidence of PRP

The evidence base on the efficacy of platelet-rich plasma (PRP) treatment consists of numerous small controlled trials for a wide variety of orthopedic conditions. Recent literature indicates an increasing number of randomized controlled trials (RCTs), and a search of the clinical trials database (available at reveals that many more RCTS are in progress. Current results of PRP trials are mixed, with some trials reporting improvement with PRP and other trials reporting no improvement. It is uncertain whether the mixed results are due to variability in the conditions studied and outcomes measured; to differences in platelet separation technique, concentration or activation; or to differences in the timing and frequency of administration. Additional studies are needed to resolve these issues.

The evidence for PRP in individuals who have nonhealing wounds or acute surgical or traumatic wounds includes a number of small controlled trials. Relevant outcomes are symptoms, change in disease status, morbid events, quality of life, and treatment-related morbidity. The potential benefit of PRP has received considerable interest due to its appeal as a simple, safe, low-cost, and minimally invasive method of applying growth factors. Current results of trials using PRP are mixed and the studies are limited in both size and quality. The evidence is insufficient to determine the effects of the technology on health outcomes.

Ongoing and Unpublished Clinical Trials

A search of identified a large number of ongoing and unpublished trials with PRP.

Table 1. Summary of Key Trials


Trial Name

Planned Enrollment

Completion Date



Impact of Platelet Rich Plasma Over Alternative Therapies in Patients With Lateral Epicondylitis (IMPROVE)


January 2017


Effectiveness of Autologous Platelet Rich Plasma in the Treatment of Chronic Non-Healing Wounds


March 2016


Randomized, Placebo-controlled, Blind-assessor Study to Evaluate the Safety and Efficacy of Autologous Platelet Rich Plasma Gel Prepared With the RegenKit-BCT Plus Family of Kits for the Treatment of Diabetic Foot Ulcer


August 2016


A Prospective, Randomized Clinical Trial of ECLIPSE PRP™ Wound Biomatrix in Non-Healing Diabetic Foot Ulcers


January 2017


Efficacy of Autologous Platelet-Rich Plasma in the Treatment of Vascular Ulcers in Primary Care: Clinical Trial Phase III


December 2017



A Multi-Center, Randomized Trial Comparing the Effectiveness of APIC-PRP to Control, When Added to Standard of Care in the Treatment of Non-healing Diabetic Foot Ulcers


December 2015

NCT: national clinical trial.

Practice Guidelines and Position Statements

American Academy of Orthopaedic Surgeons

The American Academy of Orthopaedic Surgeons (AAOS) 2013 guidelines were unable to recommend for or against growth factor injections and/or PRP for patients with symptomatic osteoarthritis of the knee. (56) A recommendation of inconclusive is based on a single low-quality study and conflicting findings that do not allow a recommendation for or against the intervention. The AAOS recommendation is based on 3 studies that were published before May 2012.

National Institute for Health and Clinical Excellence

In 2009, the United Kingdoms’ National Institute for Health and Clinical Excellence (NICE) issued guidance on use of autologous blood injection for tendinopathy. (25) NICE concluded that the current evidence on the safety and efficacy of autologous blood injection for tendinopathy is inadequate in quantity and quality. NICE recommends this procedure should only be used with special arrangements for clinical governance, consent, and audit or research.

In 2013, NICE issued guidance on use of autologous blood injection (with or without techniques for producing PRP) for plantar fasciitis. (26) NICE concluded that the evidence on autologous blood injection for plantar fasciitis raises no major safety concerns but that the evidence on efficacy is inadequate in quantity and quality. Therefore, this procedure should only be used with special arrangements for clinical governance, consent and audit or research. In addition, physicians should ensure that patients understand the uncertainty about the procedure's efficacy, be aware of alternative treatments, and be provided with clear written information.


Each benefit plan, summary plan description or contract defines which services are covered, which services are excluded, and which services are subject to dollar caps or other limitations, conditions or exclusions. Members and their providers have the responsibility for consulting the member's benefit plan, summary plan description or contract to determine if there are any exclusions or other benefit limitations applicable to this service or supply. If there is a discrepancy between a Medical Policy and a member's benefit plan, summary plan description or contract, the benefit plan, summary plan description or contract will govern.


For situations other than injection (when 0232T would be reported), no specific CPT codes describe the preparation of autologous blood-derived products but CPT code 86999 can be used. It has been reported that providers have used CPT code 20926 to describe the overall procedure. It is questionable whether platelet-rich plasma is appropriately considered a tissue graft.

The American Medical Association’s Department of Coding instructs that placement of platelet-rich plasma into an operative site is an inclusive component of the operative procedure performed and not separately reported.


Disclaimer for coding information on Medical Policies

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.

The presence or absence of procedure, service, supply, device or diagnosis codes in a Medical Policy document has no relevance for determination of benefit coverage for members or reimbursement for providers. Only the written coverage position in a medical policy should be used for such determinations.

Benefit coverage determinations based on written Medical Policy coverage positions must include review of the member’s benefit contract or Summary Plan Description (SPD) for defined coverage vs. non-coverage, benefit exclusions, and benefit limitations such as dollar or duration caps.


The following codes may be applicable to this Medical policy and may not be all inclusive.

CPT Codes

0232T, 0481T


G0460, P9020, S0157, S9055

ICD-9 Diagnosis Codes

Refer to the ICD-9-CM manual

ICD-9 Procedure Codes

Refer to the ICD-9-CM manual

ICD-10 Diagnosis Codes

Refer to the ICD-10-CM manual

ICD-10 Procedure Codes

Refer to the ICD-10-CM manual

Medicare Coverage:

The information contained in this section is for informational purposes only. HCSC makes no representation as to the accuracy of this information. It is not to be used for claims adjudication for HCSC Plans.

The Centers for Medicare and Medicaid Services (CMS) does have a national Medicare coverage position.

A national coverage position for Medicare may have been changed since this medical policy document was written. See Medicare's National Coverage at <


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Policy History:

Date Reason
7/15/2017 Reviewed. No changes.
6/1/2016 Document updated with literature review. 1) The following was added the experimental, investigational and/or unproven listing of indications for becaplermin: “ulcers not extending through the dermis into the subcutaneous tissue”. 2) The following was added to the experimental, investigational and/or unproven listing of autologous blood-derived preparations (i.e., platelet-rich plasma): surgical wounds. 3) The following orthopedic indications for primary use were added to the experimental, investigational and/or unproven listing: achilles tendinopathy, lateral epicondylitis, osteochondral lesions and osteoarthritis. 3) The following orthopedic indications for adjunctive use in the following surgical procedures were added to the experimental, investigational and/or unproven listing: ACL reconstruction, hip fracture, long-bone nonunion, patellar tendon repair, rotator cuff repair, spinal fusion and subacromial decompression surgery.
8/1/2015 Reviewed. No changes.
2/15/2014 Document updated with literature review. The following was added to the experimental, investigational and unproven coverage statement for autologous blood-derived preparations (i.e., platelet-rich plasma): “Experimental, investigational and unproven for all indications including but not limited to”. In addition, the following was also added to the listing of examples of experimental investigational and unproven indications for autologous blood-derived preparations (i.e., platelet-rich plasma): “adjunctive use in surgical procedures (e.g. orthopedic, reconstructive)”.
7/15/2008 Revised/updated entire document; this policy is no longer scheduled for routine literature review and update.
11/15/2006 Revised/updated entire document
6/1/2001 Revised/updated entire document
11/1/2000 Revised/updated entire document
4/1/1999 Revised/updated entire document
6/1/1998 Revised/updated entire document
7/1/1995 Revised/updated entire document
4/1/1993 Revised/updated entire document
1/1/1993 New medical document

Archived Document(s):

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