Platelet-rich Plasma Evidence

The role of platelets in hemostasis and triggering healing suggest that platelet-rich plasma (PRP) preparations may be likely to enhance healing. Some acute wound studies reported improved acute wound healing and reduc edwound-related pain of PRP-treated burns¹ and split-thickness skin graft (STSG) donor sites.² However, the observed effects may have resulted from procedural artifacts such as use of moisture-retentive dressings to seal the PRP in place or variables other than the PRP interventions.³ A recent review reported inconsistent PRP effects among wound outcomes of 5 randomized clinical trials on acute wound healing and called for more accurate, uniform reporting of platelet concentrations, harvesting, activation and preparation procedures, formulations, frequency and routes of administration, and more consistent outcomes reporting to allow stronger conclusions about PRP effects on acute wound healing and patient-centered outcomes.⁴ Effects of PRP on chronic wounds also remain controversial. Chronic diabetic foot ulcers (DFUs) were reported to heal faster when treated with autologous PRP,⁵ but issues of adherence to protocol prevented a full intent-to-treat analysis, opening these results to question. The 2 studies described here, 1 on STSG⁶ and 1 on DFUs,⁷ clarify some questions surrounding PRP effects on acute or chronic wounds while raising some interesting possibilities for the mechanism of action.

Laura Bolton, PhD
Adjunct Associate Professor
Department of Surgery
Rutgers Robert Wood Johnson Medical School
New Brunswick, NJ

Reference: Waiker V, Shivalingappa S. Comparison between conventional mechanical fixation and use of autologous platelet rich plasma (PRP) in wound beds prior to resurfacing with split-thickness skin graft. World J Plast Surg. 2015;4(1):50-59.

Rationale. Platelet-rich plasma (PRP) has recognized healing, adhesive, and hemostatic properties.

Objective. Explore the healing and take of skin grafts anchored to the graft site of patients with acute or chronic trauma or infected burn wounds using a layer of PRP as compared to those held in place with conventional closure techniques.

Methods. A single-center prospective randomized clinical trial (RCT) randomly assigned 100 subjects each to graft anchoring with PRP or conventional sutures, staples, or tissue glue (control). Patients with infected or noninfected burns or surgical scar-release or traumatic wounds were included regardless of diabetic or hypertensive status. Aspirin medication was withdrawn 72 hours before surgery and resumed 48 hours after surgery. Individuals positive for HIV, with active hepatitis B or hepatitis C infection, or those with a coagulation disorder or malignancy, were excluded. Autologous PRP samples were harvested from the anesthetized patient and prepared aseptically from two 10 ml anticoagulant-lined syringes of femoral vein blood. Six ml of this blood was gently poured into a vacutainer containing 1 ml citrate-phosphate-dextrose-adenine anticoagulant, minimizing cell damage, then centrifuged at 1000 rpm for 5 minutes to separate the contents into 3 layers: PRP supernatant, white blood cells, and red blood cells. After wound bed debridement, hemostasis, and lavage, about 5 ml of PRP supernatant (about 10 million platelets) was applied through the syringe canula to each 100 cm² of the graft recipient site area before the graft was applied. An assistant blinded to study conditions confirmed graft anchorage by moving the graft with a gloved finger. Grafts on subjects in the control group were sutured, stapled, or glued in place at the wound edges and covered with a nonadhesive mesh under a layer of povidone iodine-soaked cotton wool, then secured by a bolus dressing or tie-over compression wrap as indicated. Both groups’ dressings were changed when the outer layer became wet or odor or pain was noticeable. Outcomes analyzed using chi-square statistics were differences between PRP and control proportions revealing instant graft adhesion, graft edema, discharge, hematoma, or significant graft loss during the first 2 weeks after grafting dressing change frequency and scar hypertrophy 3 months after surgery.

Results. Subjects in both groups were comparable on all parameters at baseline. All PRP patients’ grafts adhered well within seconds of application compared to 0% of control subjects. Platelet-rich plasma subjects experienced earlier first graft inspection, less-frequent dressing changes, shorter hospital stays, less graft edema, discharge, or hematoma formation during 2 weeks after surgery, and less scar hypertrophy at 3 months compared to control subjects (P < 0.001).

Authors’ Conclusions. The adhesive nature of the PRP permitted more graft take with significant benefits for graft recipients with burn, trauma, infected, or scar revision wounds.

Reference: Li L, Chen D, Wang C, et al. Autologous platelet-rich gel for treatment of diabetic chronic refractory cutaneous ulcers: A prospective, randomized clinical trial[published online ahead of print April 7, 2015]. Wound Repair Regen. doi: 10.1111/wrr.12294.

Rationale. The costs and burden of chronic nonhealing diabetic foot ulcer (DFU) care could be reduced by use of safe, effective foot and ulcer care and education. Prior RCTs of autologous PRP gel had > 20% dropouts or subjects who did not follow the protocol.

Objective. Explore safety and efficacy of topical autologous platelet-rich gel (APG) in healing chronic refractory DFUs using procedures that optimize APG formulation, uniform APG dosage, and adherence to protocol.

Methods. A prospective RCT in the diabetic foot care center of a Chinese hospital from 2007-2011 enrolled 117 consenting subjects over 18 years of age. The patients had an ankle/brachial index > 0.6, platelet count > 100,000/mm³, chronic ulcers that did not improve during 2 weeks of standard treatments, and diabetes. They received either 12 weeks of topical therapy with APG (n = 59) with standard of care (SOC), or SOC alone (n = 58). Those unable to adhere to the protocol, with malignancy or radiation of target DFU within 3 weeks of enrollment, immunosuppressive or chemotherapy, with diabetic acidosis, or with uncontrolled infection were excluded. Baseline measures of capacity to heal were based on the validated⁸ S(AD)SAD system and included area based on image analysis, depth, sepsis, arteriopathy, and denervation. Standard of care included patient nutritional support and medications to manage diabetes, hypertension, dyslipidemia, or infection, as well as DFU cleansing, debridement of necrotic tissue, and topical ointment (ie, petrolatum 94.8%, bismuth subgallate 4.5%, borneol 0.7%), and covering with bandages that were changed every 3 days. Amputation or vascular reconstruction was performed as needed. Autologous platelet-rich gel treatments were repeated if the DFU area did not decrease by 80% or the wound area was more than 1 cm² two weeks after the first treatment. The primary outcome was percent area reduction at week 12, graded by a professional researcher blinded to group allocation where “1” indicated 100%, “2” indicated 80%-99%, “3” indicated 40%-79%, and “4” indicated < 40%. Secondary outcomes were safety and time to complete wound closure.

Results. Autologous platelet-rich gel and SOC groups were comparable at baseline on S(AD)SAD scores and other ulcer-related parameters, and in subjects lost to follow-up. Most ulcers were on the foot (ie, DFU): n = 48 in the APG group and n = 55 in the SOC group. Kaplan-Meier survival analysis revealed significantly shorter time to healing for the APG group (P = 0.02). At 12 weeks, the percent of DFU healed was 85.4% in the APG group and 67.3% in the SOC group. This difference was not tested for statistical significance, but there was an overall trend for a higher percentage of subjects in the APG group achieving higher “grades” or percents of healing at 12 weeks (P = 0.03) and closing at a higher velocity (P = 0.02) than control group wounds. Safety results were comparable for the 2 groups.

Authors’ Conclusions. The APG group of refractory DFUs experienced earlier complete healing at a faster rate than SOC alone with comparable safety results, supporting a conclusion that the APG is safe and effective in the treatment of these DFUs.

It would be interesting to explore whether effect on donor sites⁶ is due to PRP biochemical activity or the gel’s physical properties as an adhesive and/or humectant. Would a similarly viscous, sticky fluid such as 1% hyaluronic acid or honey confer similar benefits in sealing split-thickness skin grafts to the recipient sites? The effect of APG on DFUs⁷ seems clear and robust.

Is there a hidden pearl in this study, alerting us to the possibility that PRP should be applied in a viscous, sticky moisture-retentive vehicle? If so, what is more important: viscosity, adherence to the wound base, or capacity of the primary dressing to seal the rich broth of natural growth factors and enzymes we call exudate over the wound bed cells that have evolved for millions of years to flourish and function in this environment? Have we been mismanaging wound exudate by wicking it away from the wound surface?

What would happen if platelet-derived growth factor or other cytokines were delivered from such a viscous, sticky, moisture-retentive vehicle? Have these molecules been reported as only marginally effective because they were administered under saline gauze, long recognized as substandard practice,⁹ increasing healing time, infection rate, and wound pain?^10,11 These findings suggest that PRP may work in unexpected ways and that administering any active agent under a gauze-based secondary dressing may be obscuring its efficacy.

This article was not subject to the Wounds peer-review process.