Autologous platelet‐rich plasma injection enhances healing of chronic venous leg ulcer: A prospective randomised study

Abstract

Our aim was to compare the efficacy and safety of platelet‐rich plasma (PRP) application versus PRP injection for chronic venous leg ulcer (VLU) healing compared with compression therapy as a control. From July 2018 to December 2019, 90 chronic VLU patients were randomly assigned to PRP dressings (n = 30), local PRP injections (n = 30), and compression therapy alone (n = 30). Standard compression accompanied both PRP groups. The main endpoints were ulcer healing and area reduction within 3, 6, and 12 months. Complications and ulcer recurrence were also recorded. The study included 72 (80.0%) males and 18 (20.0%) females aged 22 to 66 years, having VLUs for 1 to 11 years. PRP injection promoted healing (24/30, 80%) more than PRP application (20/30, 66.7%) and compression (14/30, 46.7%), P = .007. Healing time was significantly shorter after PRP injection compared with the other two groups. A greater area reduction was observed after PRP injection compared with compression at all follow‐up visits, P = .013, .002, and < .001, and compared with PRP application only at 3 months post‐treatment, P = .016. Recurrence and complications were comparable among the groups. PRP injection enhances the healing of chronic venous ulcers more than each of PRP application and compression therapy. All had comparable recurrence and safety.

Key Message.

• venous leg ulcers (VLUs) resist healing in 30% and recur in 70% within 5 years of compression therapy alone

• platelet‐rich plasma (PRP) application versus injection for treatment of chronic VLU were evaluated regarding the healing and recurrence

• PRP injection supplies the wound with concentrated platelets and growth factors for longer times

• PRP injection had higher ulcer healing than PRP dressing and compression therapy alone, but no benefit in recurrence; it is a useful adjunctive not a curative therapy

1. INTRODUCTION

The most common form of chronic leg ulcers is the venous leg ulcer (VLU), which results from a prolonged state of venous hypertension. ¹ The standard treatment for VLU is the compression therapy plus local debridement, which can result in healing of 50% of VLUs within 4 months and approximately 60% to 80% within 6 months. However, the healing resistance and recurrence are as high as 30% and 70%, respectively, after 5 years of compression therapy alone. ²

The ideal treatment should, thus, provide effective and rapid ulcer healing with low recurrence rate. Recent guidelines recommend that optimisation of the resistant wound environment should proceed hand in hand with cutaneous venous hypertension eradication ³ through axial saphenous vein ablation ⁴ and/or reticular or perforator veins foam sclerotherapy ⁵ or thermal ablation, together with continuous standard compression.

Various modalities of local wound care have been advocated to enhance VLU healing, but none of them is considered satisfactory. These include different dressing materials, antimicrobials, hyperbaric oxygen therapy, negative pressure wound therapy, intermittent pneumatic compression, lasers, and infrared light in addition to platelet‐rich plasma (PRP).6, 7

It is believed that the resistance to healing, in this kind of wounds, is related to an imbalance of some factors that lead to excessive prolongation of the second phase of normal wound healing “inflammatory phase.” This entails an increase in cytokines, proteolytic activity, and metalloprotease activity together with reduced fibrin and growth factors content and activity. It is crucial to shut down the prolonged phase and to switch on further phases of wound healing; proliferation, and regeneration. ⁸

Autologous PRP contains concentrated platelets, fibrin, and growth factors (GFs), ⁹ such as platelet‐derived GF, vascular endothelial GF, epidermal GF, insulin‐like GF, and transforming GF. Therefore, it augments cellular migration, angiogenesis, proliferation, and differentiation and boosts epithelialisation, granulation tissue, and collagen formation. All of them are parts of the proliferative and regenerative phases. Hence, PRP has been advocated to enhance the healing of chronic VLU. ¹⁰

Several studies evaluating topical PRP use in chronic leg ulcers have demonstrated a reduction in healing time compared with conventional treatments particularly in diabetic foot ulcers, whereas the studies performed for evaluation of PRP effect on VLU healing produced conflicting results.10, 11 Moreover, most studies included wounds of different aetiologies, making the conclusion for the treatment effect on a single entity difficult. Additionally, the net number of VLUs included was relatively small to draw significant results, and the follow up periods were mostly short leaving no chance to detect any possible mid‐ or long‐term effect of this method to reduce recurrence.12, 13

The PRP may be applied locally, as a dressing, or injected intralesionally into the edges and centre of the VLU. Most authors described the local application while sparse studies implemented PRP injection, ¹⁴ whereas no studies compared both techniques for treatment of VLU.

The aim of the study was to evaluate the clinical efficacy of PRP application versus PRP injection for treatment of chronic VLU with regard to the rate of complete healing, size reduction, ulcer recurrence within 1 year, and the safety of PRP use.

2. PATIENTS AND METHODS

Between July 2018 and December 2019, a prospective randomised clinical study was conducted. It included 90 patients with chronic VLUs who met the inclusion requirements and presented to Tanta University Hospitals outpatient clinic, and to Vascular and Endovascular Surgery Department, (the study flow chart in Figure 1). The patients were randomised to treatment with PRP dressing application (group A); n = 30, local PRP injection inside the ulcer (group B); n = 30, or compression therapy alone (group C); n = 30, as a control group. Standard compression and treatment of the underlying venous pathology accompanied all forms of treatment included.

FIGURE 1.

The study CONSORT flow chart

2.1. Study design

2.1.1. Inclusion criteria

Adult patients having chronic VLUs (clinical, aetiological, anatomical, and pathological classification, CEAP, C6) without adequate healing tendency (less than 50% healing) for at least the last 6 weeks were enrolled in the study. The included patients had an Ankle/Brachial Pressure Index (ABPI) of not less than 0.9 and a platelet count of at 150 000 to 450 000/mm³.

2.1.2. Exclusion criteria

Patients were excluded from the study if they have any of the following: renal, hepatic or cardiac failure, uncontrolled diabetes mellitus, malignancy, connective tissue disorder, pregnancy, lactation, local active infection, ulcers with bone or tendon exposure, or antiplatelets, steroids, or immunosuppressive drug administration. Patients unwilling to sign the informed consent or providing a history of poor compliance to compression therapy were also excluded.

Informed consent was taken from all patients after detailed description of the procedure before entry to the study. The study was approved and registered by the Faculty Ethical Committee (registration number: 32481/07/18).

2.1.3. The study endpoints

The primary endpoints were the rate of ulcer complete healing and the percentage of ulcer area reduction after 3 and 6 months and 1 year, while the secondary endpoints were the treatment‐related early complications, and the rate of ulcer recurrence after complete healing within 1 year of follow up.

If the target ulcers showed no response or a much increase in its size from the initial size after 1 month; the treatment was discontinued.

2.1.4. Randomisation, sample size, and blinding

The eligible patients were randomly assigned to one of the treatment groups through closed, opaque random envelopes in a ratio of 1:1:1. The sample size was calculated using an online software: (https://www.masc.org.au/stats/PowerCalculator/PowerANOVA). It was assumed that the difference in the percentages of healed ulcers (primary endpoint) between the study and the control groups would be 40% as indicated in a previous study ¹¹ with a significance level of 0.05 and a power of 90%. This resulted in the inclusion of 27 ulcers in each group. To compensate for any withdrawals, the sample was increased to 30 ulcers.

The measurements and confirmation of wound healing/recurrence were performed by a physician who was blinded for the treatment method used. It was not possible to blind the patients for the used technique as a blood withdrawal was required only in PRP groups with either dressing or injection.

2.2. Preprocedural workup

2.2.1. Patients assessment

The history was taken and each patient was examined both generally and locally to confirm the diagnosis of a pure VLU and to fulfil the inclusion and rule out the exclusion criteria. For each patient, the followings were performed: assessment of demographic data including the age, sex, smoking, diabetes mellitus (DM), and body mass index (BMI). Local examination included lower extremity peripheral pulse palpation, ABPI measurement, and a series of blood tests including: complete blood count, glycosylated haemoglobin concentration, renal and liver function tests, erythrocyte sedimentation rate, and rheumatoid factor assay. Also, venous duplex was performed for identification and thus management of the reflux/obstruction source of venous hypertension.

2.2.2. Ulcers assessment

The ulcer assessment was centred upon the current ulcer's duration, laterality, edge, margin, floor, and the need for debridement or antibiotics plus history of any previous complete healing and the duration of the ulcer before this previous healing. A culture sensitivity and a 4‐quadrant biopsy were obtained to plan the associated antibiotic coverage and to exclude malignancy or a specific pathology.

The ulcer surface area was measured using “ulcer tracing technique” by applying a sterile transparent cellophane paper on the ulcer and delineating the edge by an indelible pen, a graph paper divided into 1 cm² squares was used to count the delineated area. In cases presented with multiple ulcers, we chose chronic (more than 6 weeks), large enough (to draw significant results) ulcer to be our target one.

2.3. Autologous PRP preparation and use

Autologous venous blood (20‐45 mL according to wound size) was withdrawn from the patient mixed with an anticoagulant (5 mL of 3.8% sodium citrate) using complete aseptic technique. Each 30 cc of blood gave 3 to 5 cc of PRP after centrifugation. A desktop centrifugation system (80‐2 Electronic Laboratory Medical Centrifuge, Shanghai, China) was used for centrifugation. The first cycle entailed 10 minutes of 2500 rpm to separate the blood into three levels; the upper two compartments were transferred into other disposable sterile tubes for another centrifugation at 3500 rpm for 5 minutes. The PRP, situated in the bottom, was aspirated and activated by adding calcium chloride 10% in a 1:4 ratio.

Ulcer debridement and systemic antibiotics were offered in case of gross infection, necrotic tissue, or positive cultures before starting treatment. In PRP groups, the activated PRP was applied onto the ulcers as a dressing application (group A) or injected into the ulcer edges and depth in equal volumes (group B). A local anaesthetic was applied over the ulcer and periulcer area, 5 minutes before PRP injection; Emla cream 5% (lidocaine 2.5% and prilocaine 2.5%, AstraZeneca). The ulcer was then dressed with a non‐absorbent dressing (Vaseline gauze), followed by a single layer of elastic bandage from the toes to just below the knee. Further PRP application or injection, in the PRP groups only, was performed every 2 weeks up to 8 weeks. Elastic bandages were reapplied till complete ulcer healing occurred, after which the compression was maintained by class II elastic stockings.

The patients were followed up monthly after the last treatment session till complete ulcer healing, then the follow up was continued through either patients' visits to the hospital clinic or by telephone calls for those unable to attend.

2.4. Statistical analysis

The treatment efficacy was analysed on an intention‐to‐treat (ITT) basis through comparing the baseline ulcer area with the ulcer area measured at 3, 6, and 12 months of treatment in each group, and also estimating the frequency of ulcer complete closure among the three groups at the same intervals. Data were analysed using version 26 of IBM SPSS (IBM). Qualitative data were represented by number and percentage, while quantitative parametric data were described using the mean and SD, and nonparametric data were described using the median and range. The Shapiro‐Wilks test was used to verify distribution normality. The analysis of variance (ANOVA) test was used for measuring the difference among the groups. A P value of <.05 was considered significant.

3. RESULTS

3.1. Baseline patients criteria

The study included 72 (80.0%) males and 18 (20.0%) females aging from 22 to 66 years with a body mass index (BMI) ranging from 17 to 37 kg/m². The randomisation method resulted in inclusion of comparable patients in the three groups with no significant differences with regard to patients' or ulcers' baseline criteria (Table 1). More than one third of the study patients gave a history of previous deep venous thrombosis (DVT) (37/90, 41%), and (20/90, 22.2%) patients had pervious great saphenous vein (GSV) stripping surgically (n = 19) or using radiofrequency ablation (n = 1).

TABLE 1.

Baseline ulcers and patients characteristics

Variable	PRP application n = 30	PRP injection n = 30	Compression n = 30	P value
Patients' characteristics
Age (years) mean ± SD	45.4 ± 9.35	43.4 ± 13	41.80 ± 13.3	.48
Range	22‐60	25‐61	23‐66
Males	26 (86.7%)	22 (73.3%)	24 (80.0%)	.65
BMI (kg/m2) mean ± SD	25.3 ± 7.3	26.8 ± 4.1	27.8 ± 5.6	.50
Range	17‐35	20‐34	18‐37
Smoking	14 (46.7%)	10 (33.3%)	12 (40.0%)	.879
DM	2 (6.7%)	1 (3.3%)	1 (3.3%)	.791
Previous DVT	12 (40%)	14 (46.7%)	11 (36.7%)	.908
Previous GSV stripping	8 (26.7%)	6 (20%)	6 (20%)	.732
Ulcers' characteristics
Medial ulcers	22 (73.3%)	24 (80.0%)	22 (73.3%)	.88
Single ulcer	24 (80.0%)	26 (86.7%)	28 (93.3%)	.56
Mean current ulcer duration (years)	6.2 ± 3.1	5.4 ± 2.6	6.4 ± 2.8	.45
Range	2‐10	1‐10	2‐11
Mean previous ulcer duration (years)	11.2 ± 3.5	9.7 ± 4.6	10.5 ± 4.8	.64
Range	2‐19	1‐18	2‐20
Recurrent ulcers	12 (40%)	14 (46.7%)	10 (33.3%)	.86

Note: P value is significant if P < .05, calculated by using the ANOVA test.

Abbreviations: BMI, body mass index; DM, diabetes mellitus; DVT, deep venous thrombosis; GSV, great saphenous vein; and PRP, platelet‐rich plasma.

3.2. Baseline ulcer criteria

In the whole study cohort, the duration of ulcers ranged from 1 to 11 years, the ulcers were medial in 68 (75.5%), single in 78 (86.7%), and recurrent in 36 (40%) of cases (Table 1).

3.3. Associated procedures

Debridement was needed for 36/90 (40%) of all study cases with no statistically significant differences among the groups. GSV stripping and phlebectomies for superficial varicosities were performed for some cases having GSV reflux with patent deep veins (24/90, 26.6%), and the refluxing periulcer perforators and reticular veins were ablated by ultrasound guided foam sclerotherapy (UGFS) in (8/90, 8.9%) using aethoxysklerol 1% (Kreussler Pharma, Wiesbaden, Germany) (Table 2).

TABLE 2.

Ulcer healing and associated procedures

Variable		PRP application (n = 30)	PRP injection (n = 30)	Compression therapy (n = 30)	P value
Associated procedures	GSV stripping	8 (26.7%)	10 (33.3%)	6 (20%)	.864
	Sclerotherapy	2 (6.7%)	4 (13.3%)	2 (6.7%)	.542
Ulcer healing at 3 months	Healed	10 (33.3%)	14 (46.7%)	4 (13.3%)	.003*
	Incomplete	20 (66.7%)	16 (53.3%)	26 (86.7%)	.003*
Ulcer healing at 1 year	Healed	20 (66.7%)	24 (80%)	14 (46.7%)	.007*
	Incomplete	8 (26.7%)	5 (16.7%)	12 (40%)	.04*
	Recurrent	2 (6.7%)	1 (3.3%)	4 (13.3%)	.326
Healing time (months)	Median (range)	5 (3–9)	3 (3‐6)	7 (4‐12)	P = .18*
					P1 = .009*
					P2 = .395
					P3 = .026*

Note: * indicates statistical significance. Data are presented as number and percentage or median and range; P1, comparing groups A and B; P2, comparing groups A and C; P3, comparing groups B and C, calculated by using the Kruskal‐Wallis test.

Abbreviations: GSV, great saphenous vein.

3.4. Efficacy endpoints “ulcer healing”

3.4.1. Ulcer area reduction

The included patients had a comparable initial ulcer surface area, P = .948; however, the reductions in ulcer area, after treatment, were significantly different among the groups at the three follow‐up visits, P = .015, .001, and <.001, respectively (Figure 2; Table 3).

FIGURE 2.

The mean ulcer area reduction in each follow‐up visit in different groups. Group A (PRP application), group B (PRP injection), and group C (compression)

TABLE 3.

Ulcer area reduction along the study period

Variable		Baseline	3 months	6 months	12 months
(A) PRP application	Mean ± SD	16.5 ± 8.2	5.8 ± 2.1	1.3 ± 0.6	1.2 ± 0.5
	Mean reduction %		65%	92%	92.7%
(B) PRP injection	Mean ± SD	15.7 ± 7.4	2.5 ± 1.3	1.6 ± 0.5	1.1 ± 0.4
	Mean reduction %		84%	90%	93%
(C) Compression	Mean ± SD	17.8 ± 5.4	8.5 ± 3.3	5.5 ± 2.7	3.8 ± 1.5
	Mean reduction %		52%	69%	78.6%
P value		.948	.015*	.001*	<.001*
P1 (A vs B)		.852	.016*	.079	.351
P2 (A vs C)		.868	.361	.003*	<.001*
P3 (B vs C)		.756	.013*	.002*	<.001*

Note: * Significant as P value <.05, P1, comparing groups A and B; P2, comparing groups A and C; P3, comparing groups B and C. Ulcer area was measured by cm².

To detect the impact of each treatment on this significant reduction of ulcer area, every two groups were compared separately. PRP injection achieved a significantly higher reduction in ulcer area than compression therapy during all follow‐up visits, P = .013, .002, and <.001, respectively. Similarly, a significantly higher ulcer area reduction was observed after PRP injection than PRP application at 3 months but not at 6 or 12 months of follow up, P = .016, .079, and .351, respectively. Finally, PRP application achieved a significantly higher ulcer area reduction than compression therapy only at 6 and 12 months of follow up, P = .003 and <.001, respectively (Table 3).

3.4.2. Ulcer complete healing rate

A superior ulcer healing was observed after PRP injection followed by application, then compression therapy along the whole follow‐up period (Table 2). At the final follow up, a significantly higher proportion of ulcers healed completely after PRP injection (24/30, 80%) than PRP application (20/30, 66.7%) and compression therapy (14/30, 46.7%), P = .007. The healing time, in the subgroup of healed ulcers, was significantly shorter after PRP injection (Figure 3A,B) compared with PRP application (Figure 3C,D) and compression, P = .009 and .026, respectively. However, PRP application was associated with a shorter but non‐significant healing time than compression therapy (Figure 3E,F), P = .395.

FIGURE 3.

A, Male patient 52 years with right chronic VLU since 2 years, on admission ulcer area 15 cm², treated by PRP application; B, complete healing after 3 months; C, Male patient 41 years old with chronic VLU since 7 years, on admission ulcer area 30 cm², treated by PRP injection; D, complete healing after 3.5 months; E, Male patient 28 years old with chronic VLU since 1 year, on admission ulcer area 18 cm², treated by compression therapy alone; F, complete healing after 4 months

3.4.3. Ulcer recurrence

Recurrence after complete closure was observed in 7/90 (7.8%) cases of the whole study population (Table 2; Figure 4). There was no significant difference among the groups with regard to the recurrence rate, P = .326. The commonest cause of recurrence was non‐compliance to compression therapy, which lead to five recurrences: two in PRP application group after 4 and 6 months of healing, and 3 in the compression group after 3, 4, and 6 months of healing. A recurrence in PRP injection group was met 4 months after healing caused by development of new perforators reflux in the perimeter of the healed ulcer. This patient was treated by UGFS injection for the perforators leading to 80% reduction of the ulcer area until the final follow up.

FIGURE 4.

Life table graph for ulcer recurrence after complete healing (Kaplan‐Meier method)

3.5. Safety endpoint

There was no major or systemic complications related to the treatment. Two patients (7.6%) in the compression group and another two patients (7.6%) in the PRP injection group developed cellulitis, which was treated by broad‐spectrum antibiotics. Superficial minute ulceration occurred due to tight compression in 2 (7.6%) patients: one in each of PRP application and injection groups. These were healed completely in 2 weeks.

4. DISCUSSION

Evidence to support the use of PRP to enhance the chronic VLUs healing is deficient. Recent systematic reviews and meta‐analyses and a Cochrane review made a recommendation supporting its use only in diabetic foot wounds but in other wounds, including the VLU, the conclusions were conflicting.8, 12, 13 The included studies, in these reviews, enrolled different types of ulcers, with only five studies investigating the use of PRP in a pure sample of venous ulcers.10, 11, 15, 16, 17 These studies had a small sample size (median of 20 patients), short follow‐up period (a range of 4‐36 weeks), and some were industrially funded. Additionally, the comparison between PRP application and PRP injection, in this disease entity, was not previously addressed. All these reasons indicate the need for further studies avoiding all or most of these limitations.

Therefore, we conducted this prospective randomised study enrolling 90 chronic VLUs to evaluate the relative efficacy of PRP injection versus PRP application with regard to the ulcer healing rate, percentage reduction of ulcer size, ulcer recurrence within 1 year, as well as the safety of the procedure.

The results of this study showed that PRP injection achieved significantly higher ulcer healing rate and faster area reduction than both PRP application and compression therapy, with superiority of PRP application over compression therapy except for an equivalent healing time. However, the three groups were comparable concerning the recurrence and complication rates.

Since PRP preparation was made using a simple bed‐side procedure, Anitua (1999) ¹⁸ advocated a weekly application, however, the method of preparation, frequency, and a minimum or a maximum number of PRP sessions were not standardised throughout the literature. In the present work, we adopted the use of PRP every other week till 8 weeks from the start of treatment. The theoretical basis of choosing PRP injection rather than local application resides in trying to supply the wound edges and depth with adequate concentrations of platelets and to maintain their release of growth factors for longer times than that provided by PRP applied as a local dressing. The local PRP application might be less effective as the fluid PRP usually spills over the wound edges or gets stuck to the secondary dressing.

Previous studies addressed the comparison between PRP application and compression therapy for VLU treatment, but no study previously compared between PRP injection and application. Two studies employed simultaneous perilesional ulcer injection together with local application of PRP in chronic leg ulcers of various aetiologies.14, 19

We opted to treat the pathological source of venous hypertension along with studying the PRP effect on wound healing. Although these procedures were not uniform for all cases, but fortunately they were distributed with no higher statistical benefit for one or another group. We think that sticking to the venous ulcers treatment guidelines is as important as adhering to the methodological design of a randomised trial. It is not ethical to neglect or defer the treatment of a known source of the studied disease for the sake of matching the study parameters even with the patient consented on that.

Due to much conflict in the literature concerning the effect of PRP on VLU healing; some studies agree with our findings, while others do not. Aguirre et al ¹¹ randomised 23 patients to either PRP application (n = 12) or silicone dressing (n = 11), 5 of the PRP‐treated ulcers healed in 8 weeks versus none in the control group, with an area reduction of approximately 82% versus 24%, respectively, P < .001. Ulcer healing time was 9.6 versus 23.7 weeks in the PRP versus the control groups, respectively, P < .001. Similarly, Somani and Rai, ¹⁷ randomised 15 patients to either PR fibrin application (n = 9) or saline dressing (n = 6), after 4 weeks of treatment, healing was observed in 55% versus 0% of the ulcers, respectively. Ulcer area reduction was 85.5% versus 42.7%, P < .001, respectively. Likewise, Cardenosa et al ¹⁶ in their randomised trial of PRP application (n = 55 ulcers) versus saline dressing (n = 47 ulcers) for VLUs observed an area reduction of 67.7% versus 11.1%, respectively, P = .001. Also, Anitua et al ²⁰ reported 73% versus 21%, P < .05, in the PRP versus the standard treatment groups, respectively.

In contrast, other clinical trials stated that PRP does not have any favourable impact on the healing of venous ulcers.10, 15 Stacey et al ¹⁰ randomised 86 patients to either platelet lysate application (n = 42) or placebo (n = 44). Complete healing was obtained in 75% of ulcers in each group within 3 months. They concluded that the treatment effect may be more obvious if their study included ulcers with a more protracted course. Similarly, Senet et al ¹⁵ randomised 15 patients into either frozen autologous platelets application after dilution with normal saline (n = 8) or saline application (n = 7). After 12 weeks, ulcer area reduction was 26.2% versus 15.2%, respectively, P = .94. Only one ulcer healed in each group.

The initial size and duration of a chronic VLU are two important predictors of its healing course: a less favourable and protracted course is associated with the larger and more chronic one.16, 21, 22, 23, 24 Robson et al ²⁴ determined that the cut‐off values for better prognosis, in VLUs, are an area of less than 15 cm² and a duration of less than 18 months. Our study included larger and much more chronic ulcers than these proposed values; that is why our ulcer healing time was longer than that reported in some previous studies. Table 4 The mean healing times in these studies ranged from 1 to 4.5 months. The nearest initial ulcer size and duration to ours was found in the study of Senet et al, ¹⁵ however, we had a higher percentage of complete ulcer healing at 3 months in both the PRP groups, 33.3%, 46.7% versus 12.5% in their PRP group; this may be attributed to the use of fresh rather than frozen PRP. The latter possesses lower immediate and 7‐day growth factors release than fresh PRP in spite of having similar or even higher platelet concentration. ²⁵

TABLE 4.

Initial ulcer area, duration, and ulcer complete healing in previous studies

Study	Intervention	Control	Ulcer area	Ulcer duration	Follow up
The present study	PRP injection 24/30(80%)	PRP application 20/30(66.7%)	16.5	72 months	1 year
Stacey et al 10	Frozen PRP 33/42 (78.6%)	Placebo 34/44 (77.3%)	2	3 months	36 weeks
Aguirre et al 11	PRP 5/12 (41.7%)	Silicone dressing 0/11 (0%)	9.6	4.5 months	8 weeks
Senet et al 15	Frozen PRP 1/8 (12.5%)	Saline 1/7 (14.3%)	12.5	60 months	12 weeks
Somani et al 17	PRP 5/9(55.5%)	Saline 0/6(0%)	8.14	≥ 6 months	4 weeks
Anuita et al 20	PRP 1/7(14.3%)	Saline 0/7(0%)	5.5	17 months	8 weeks

Coinciding with previous studies that considered PRP treatment as a safe systemic and local option,8, 10, 16, 26, 27 the complications, in our study, were limited to four occasions of periulcer mild cellulitis and two superficial ulcerations related to faulty application of the bandages.

Resistant venous ulcers are usually more prone to recurrence after healing as they possess local inherent wound and underlying pathological high risk factors for ulceration. Non‐compliance to compression therapy was accused for most recurrences, in our study, even after attacking of the underlying pathology. Studies evaluating PRP effect on VLU healing,10, 11, 15, 16, 17 had a shorter follow‐up period (4‐36 weeks only), accordingly, the recurrence rate was not set as an endpoint in any of them. Nevertheless, the efficacy of any treatment method for VLUs should evaluate ulcer recurrence rates as well as wound healing parameters. That is why we extended the follow‐up period to 1 year. Our study confirmed that PRP compares conventional therapy in this respect with no added benefit protecting from recurrence; thus it is considered a useful adjunctive therapy to enhance wound healing, together with compression and venous hypertension treatment, but not a curative therapy.

The inclusion of only venous ulcers together with evaluation of a separate group of isolated PRP injection in a randomised study and the setting of recurrence as an endpoint of the study are all unique features of the current study.

5. CONCLUSIONS

PRP injection enhances the healing of chronic venous ulcers more than each of PRP application and compression therapy. All had comparable recurrence and safety.

CONFLICT OF INTEREST

The authors declare no conflict of interest.

Elbarbary AH, Hassan HA, Elbendak EA. Autologous platelet‐rich plasma injection enhances healing of chronic venous leg ulcer: A prospective randomised study. Int Wound J. 2020;17:992–1001. 10.1111/iwj.13361