A case series of autologous platelet-rich plasma injection in treating chronic ulcers conducted in Saudi Arabia

Introduction

Diabetes mellitus (DM) is a major public health outcry, as it is increasing at rapid pace.[1] Its global prevalence grew from 108 million in 1980–422 million in 2014,[2,3] and according to global surveys on diabetes, the global diabetes prevalence in 2019 was estimated to be 463 million people, rising to 578 million by 2030 and 700 million by 2045.[4,5] In Saudi Arabia, one out of every four Saudi adults suffer from DM.[6] More than 44% of patients with 55 years old and older in Saudi Arabia had long-term complication related to severe or uncontrolled DM.[7] A gathering body of evidences indicate that nearly 25% of patients suffering from diabetes develop diabetic foot complications during their lifetime,[8,9] and the lifetime risk of foot ulcers has been found between 15% and 25% which may go up to 34%.[10]

The annual risk of diabetic foot ulcer (DFU) in diabetes patients has been reported to be around 2–2.8%, which may go up to 17–60% in the next 3 years, in patients with past medical history of foot ulcer.[11,12] In Saudi Arabia, the majority of lower limb amputations is attributed to DFU and it was reported to be the cause of amputation in 49.6% of cases during the past two decades[13] which is expected to increase further in the years to come.[14,15] A study from Saudi Arabia showed that diabetic foot was prevalent in 3.3% of 62,681 diabetic patients; with 2.05% suffered foot ulcer and 1.06% had amputation.[16] Age, diabetic duration, smoking, obesity, hypertension (HTN), osteomyelitis, poor ankle-brachial index, and high neutrophil/lymphocyte ratio were strongly linked to the development of DFU.[17,18] Moreover, according to a study, patients’ age and duration of diabetes increase the risk of diabetic foot complications by as high as 50%.[19] The previous history of DFU or amputation, insulin intake, gender, neuropathy, and foot deformity has been reported as independent risk factors of DFU indicating a multifactorial etiopathogenesis.[12] In the developed, DFUs accrue over 12–15% of total estimated cost of diabetes which increases up to 40% in the developing countries.[20] It is a common and major complication of both the type1 and type 2 DM, representing a major healthcare burden with significant morbidity.[21,22] Around half of the patients of DM would eventually develop DFU and it is also the cause of non-traumatic lower limb amputation in a majority of patients who have developed DFU.[23,24] DFU involves different degrees of neuropathy and angiopathy that affect the foot causing the destruction of tissues, infection, and ulceration.[17,25,26] There are several risk factors which are tied to diabetic foot occurrences including poor metabolic control, duration of diabetes, foot deformities, peripheral vasculopathy, older age, and poor knowledge of diabetics.[17] Among diabetics, years of poorly controlled hyperglycemia lead to multiple, primarily vascular, complications that affect small vessels (microvascular), large vessels (macrovascular), or both which only causes DFU but also nephropathy, retinopathy, and neuropathy including atherosclerotic disorders affecting cardiovascular system.[27]

There are several ulcer classification systems which have been adopted and were designed based on parameters such as extent of infection, neuropathy, ischemia, depth of penetration or extent of tissue loss, the presence of osteomyelitis or gangrene, and location.[28,29] Wagner classification is one of the most widely accepted and simple wound classification system designed so far for assessing DFUs and lesions.[28,30-32] Wagner classification ranges from grade “0” to “5.” According to the Wagner classification, Grade “0”: skin intact but bony deformities lead to “foot at risk;” Grade “1:” Superficial ulcer; Grade “2:” Deeper, full thickness extension; Grade “3”: Deep abscess formation or osteomyelitis; Grade “4:” Partial Gangrene of forefoot; and Grade “5:” Extensive Gangrene. A recent study reported that classification of diabetic foot patients and initiation of treatment plans based on their Wagner’s grade have helped lower rate of amputation and deaths. In addition, it lays emphasis on a multichannel management and exceptional attention to diabetes and lifestyle control which would significantly improve long-term outcomes.[31] However, this classification system, also, has some down sides which are its limitation to address two key parameters: Ischemia and infection.[30,33]

Alvarsson et al.[34] reported that up to 88% of all lower leg amputation is related to diabetic foot ulcer. The goal of the DFU treatment is to obtain ulcer closure as expeditiously as possible.[9,33] According to a study, in Saudi Arabia, mean prevalence of DFU has been reported to be 11.85% (4.7–19%), while another study reported it to be 1.8% between 2009 and 2010.[35] According to another study from Saudi Arabia, overall health-care expenditure in treating DFU was very high, with hospital admissions and surgical procedures added greatly to the total cost of treating DFU.[36] Accepted therapeutic objectives and standards of care for DFU include ulcer debridement, pressure relief at the area ulcerated, appropriate wound management (e.g., moist wound healing), infection management, ischemia management, medical management of comorbidities, and surgical management as needed,[37] However, in recent years, great progress has been made in the techniques of wound healing, of which autologous platelet-rich gel therapy has attracted the most attention.[38]

Platelet-rich plasma (PRP) is referred to as a portion of the plasma fraction of autologous blood having a platelet concentration above baseline. It is basically a platelet-enriched plasma, platelet-rich concentrate, autologous platelet gel, and platelet release.[39-41] PRP serves as a tissue sealant which initiates wound healing by releasing growth factors which may also reduce inflammation by suppressing cytokine release.[42,43] PRP has also been demonstrated to have some antimicrobial properties against microorganisms, such as Escherichia coli, MRSA, Candida albicans, and Cryptococcus neoformans.[44] PRP has been reported as an attractive choice in management of chronic non-healing diabetic ulcers if adequate blood supply and proper offloading has been provided.[45-48] PRP administration has been reported to have several benefits which include economical advantage, ease of administration as it does not require complex equipment or training. Moreover, it is primary of autologous origin, concerns of disease transmission or immunogenic reactions substantially less or nil. Thus, of late, platelet-enriched materials have become highly prescribed in the last decade and constitute a growing focus of experimental and clinical study in the context of wound healing and tissue regeneration.[49] The topical application of PRP for DFUs has resulted in superior healing rates and lower complication rates compared to controls.[50] In a randomized controlled trial, autologous PRP improved ulcer healing rate, shortened healing time, without an increase in the incidence of adverse events.[51]

Hence, this clinical case series of 14 cases of patients with unhealded chronic ulcers was aimed to investigate the positive therapeutic outcomes of using PRP in hastening the healing of chronic ulcers and also to highlight PRP as an adjunct therapy to standard of care in the treatment of diabetic wound and other chronic ulcers.

Methods

This is a formal, consecutive clinical case series of 14 cases of patients suffering from diabetic and other chronic unhealed wounds.

Patients with chronic unhealed ulcers were enrolled from the amputation prevention clinic by an interdisciplinary team includes podiatrist, general surgeon, orthopedic, vascular surgeon, and wound care nurses at Kahel Specialized Centre, a specialized center for managing foot and ankle diseases, located in Riyadh, Saudi Arabia [Table 1]. Those patients who presented with chronic wounds and showed no significant wound reduction despite following the standard wound care protocol for a minimum of 6 weeks were included in the study. There were no specific predetermined exclusion criteria when considering patients for treatment with this modality. Written informed consent was obtained from all patients for anonymized patient information to be published in this article. A general consent form to publish patient information was obtained from all the patients before the study. At the time of informed consent being obtained from each participant, digital photographs were taken of the reference wound. The CARE guidelines, a checklist to standardize reporting of case reports was followed and the study conducted in accordance with the ethical standards of the committee responsible for human experimentation (institutional and national), and with the Helsinki Declaration of 1975, as revised in 2013.

Table 1 Patients details

In this treatment plan of chronic ulcers, standard of care treatment was continued in addition to injection of PRP therapy. We followed the standards of obtaining PRP by Extracting 10 cc of blood, and filled it in a vacuum tube of sodium citrate and gel which manufactured by REGEN LAB. Then the tube was centrifuged in a centrifusion machine at 4000 rpm for 5 min, subsequently about 4–6 mL of plasma was separated. Plasma was extracted in a syringe and injected subcutaneous at the edges and directly to the granulating tissue, starting from the edges to the center to cover all area injured with a distance between each injection 3–5 mm. The injection procedure was repeated if needed every at least 7–10 days depending on size of ulcer, absence of infection signs, presence and amount of healthy tissue, and vascularity status.

Cases

Results and Discussion

This is a case series of chronic unhealed ulcers involving 14 cases belonging to age groups ranging from 19 to 85 years. The details about the type of patients have been presented in Table 1 and Figure 1. In this case series, majority (80%) of the patients were above 50 years of age, and 10 (66.7%) patients were male and 5 (33.3%) were female. Of all the cases presented to the amputation prevention clinic, majority (73.3%) reported suffering from T2DM and also, one reported T2DM (6.7%), one (6.7%) case involved patient who was healthy and one (6.7%) patient was nondiabetic but reported thyroidectomy and spina bifida with Varus hind foot deformity. Furthermore, majority of the cases showed secondary diabetes complications such as retinopathy, PNP, HTN, PVD, and dyslipidemia. Furthermore, many of them were smokers or ex-smokers. The etiology of the foot ulcer must be determined before starting the treatment plans. Furthermore, it has been reported that ulcer classification before the initiation of ulcer therapy aid in the approach to treatment and help predict the outcome of the therapy.[28,29] The ulcer should be assessed with regard to severity, location, presence of infection, stage of healing, temperature, and odor. In line with this approach, we have also recorded these parameters before starting the therapy. Neuropathic foot ulcer types present less challenges compared to neuro-ischemic or ischemic ulcers which pose a higher risk of adverse outcomes, including non-healing, infection, amputation, and death.[52] In this case series, we observed that 9 (60%) of the cases were on Wagner grade 3, 3 (20%) on Grade 4, 1(6.7%) on Grade 2 and 2 (13.3%) were not applicable to the grading system. Furthermore, all the cases of DFU received a combination of hydrogel and autologous PRP treatment and were put of suitable offloading devices, except one case which received Flaminal and PRP combination and also one case received a combination of Cadexomer iodine, hydrogel, and PRP treatment. The standard management practices in DFU include surgical debridement, topical wound dressings to provide a moist environment, proper off-loading way, vascular assessment, presence of infection, and glycemic control.[53,54] Furthermore, aiding the pressure relief by the use of suitable off-loading device such as total contact cast, removable cast walkers, or “half shoes” have been used as the mainstay of the initial management plan.[30] There are several adjuvant therapies which have been added to lower ulcer healing times and amputation rates. The add-on include the following categories: nonsurgical debridement agents, dressings and topical agents, oxygen therapies, negative pressure wound therapy, acellular bio products, human growth factors, energy-based therapies, and systemic therapies.[53,54] Non-surgical debridement includes hydrogel, clostridial collagenase ointment, maggot/larval therapy, and hydro surgery.[55] Dressings and topical agents include various dressing types, honey, topical antimicrobials,[56] silver dressings, and polyhedral preparations have been efficacious in healing diabetic foot ulcers.[57] Oxygen therapies include topical oxygen therapy, and hyperbaric oxygen therapy.[58] According to a recent case series, NATROX topical oxygen therapy was found to an advanced topical oxygen delivery system compared to other conventional oxygen delivery systems.[58] Furthermore, human growth factors have been used to facilitate ulcer healing and include fibroblast growth factor, epidermal growth factor, vascular endothelial growth factor, and platelet-derived growth factors.[59-63] In addition, there are energy based therapies which include treatment with electrical stimulation therapy, shock wave therapy, electromagnetic therapy, laser therapy, and phototherapy. Treatment with systemic therapy includes the use of insulin. The majority of treatment plans for DFUs address the altered biochemical composition of the diabetic ulcer while no single treatment have proven to be definitive for recommendation for the treatment of DFUs. Platelets are known to start the wound healing process through the release of locally active growth factors. PRP has been found to reduce inflammation and infection by the suppression of cytokine release and antimicrobial properties against several microorganisms. PRP has also been demonstrated to be of some antimicrobial properties against microorganisms, such as E. coli, MRSA, C. albicans, and C. neoformans. Although evidence supporting use of autologous PRP in wound healing is comparatively few, studies supporting its use in wound healing have increased during recent years. According to a study, treatment with PRP significantly increased the healing rate and over 86% of the patients who received PRP achieved complete healing in comparison to 68% who did not receive PRP treatment.[64] Another study reported that there was an increase in the likelihood of chronic wound healing, reduction in ulcer volume and time to complete healing, supporting the use of PRP for non-healing DFUs.[46,65] Some studies have reported the safety and efficacy of autologous PRP in DFU treatment.[66] A systematic review reported that PRP application, topically, for DFUs had resulted in higher healing rates and reduced the occurrence of complications in comparison to controls.[50]

Close

Figure 1

(a-c) The following are some of the representative pictures of patients with chronic unhealed ulcers taken at the time of treatment initiation until ulcer closure

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In the present case series, the treatment duration, from admission (to the amputation prevention clinic) to discharge (free of ulcer) varied from 3 to 14 weeks, and only 2–3 doses of autologous PRP were required for obtaining complete healing or maximum wound closure, supporting the previous studies showing efficacy of PRP in DFU treatment. The details about the treatments and duration of treatment of each case are presented in Table 2. This case series support other studies showing that PRP is an attractive and viable alternative treatment for managing chronic DFUs if adequate blood supply is maintained along with the use of suitable off loaders.[41,45,47] The strength of this study is that it is the first of its kind of study in Saudi Arabia, which has reported the benefits of PRP in chronic unhealed ulcers including diabetic ulcers. However, this case series was limited in term of sample size which is the number patients enrolled for the study. The sample size was very low to conclusively proclaim the benefits of PRP in speeding up the healing chronic ulcers, particularly of diabetic ulcers. Hence, this study warrants further study on a large number of sample to conclusively proclaim benefit of adding PRP to standard of care therapy for chronic ulcer healing particular of diabetic ulcers.

Table 2 Duration of treatments and ulcer healing

Conclusion

The present case series involving 14 cases of chronic unhealed ulcers, revealed that autologous PRP is efficacious in facilitating healing of ulcers supporting the findings of previous studies advocating the use of PRP as an attractive adjuvant therapy for the treatment of DFU’s and other types of chronic unhealed ulcers.

Consent to Participate

Written informed consent was obtained from all patients for anonymized patient information to be published in this article. A general consent form to publish patient information was obtained from all the patients before the study. At the time of informed consent being obtained from each participant, digital photographs were taken of the reference wound.

Conflict of Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Declaration

No data have been shared from this manuscript and no data were published in part or full elsewhere. The author(s) received no financial support for the research, authorship, and/or publication of this article.