2 Lacci: Platelet-rich plasma
thopedic and trauma surgery [12,15-17], THE PRODUCTION AND
ACTIVATION OF PLATELET-RICH
cosmetic and plastic surgery [17,18], spinal
surgery [8,9], heart bypass surgery , and
burns . PRP is easy to produce with minimal
effort [14,18] and can be prepared as
needed at the point of care . In a two-
MECHANISM OF ACTION OF
step process, whole blood from the patient
is first centrifuged to separate the plasma
PRP functions as a tissue sealant and from packed red blood cells and then fur-
drug delivery system , with the platelets ther centrifuged to separate PRP from
initiating wound repair by releasing locally platelet-poor plasma . This concentrate
acting growth factors [7,21,22] via α- is then activated with the addition of throm-
granules degranulation . The secretory bin or calcium [16,33], resulting in a gelat-
proteins contained in the α-granules of inous platelet gel . Clinically valuable
platelets include platelet-derived growth fac- PRP contains at least one million platelets
tor (PDGF-AA, BB, and AB isomers) per microliter [2,16]. Lesser concentrations
[6,13,19,22-27], transforming growth factor- cannot be relied on to enhance wound heal-
β (TGF-β) [6,13,18,19,22-27], platelet factor ing, and greater concentrations have not
4 (PF4) [13,19,22], interleukin-1 (IL-1), been shown to increase wound healing .
platelet-derived angiogenesis factor (PDAF) Predictable and efficient  compact
[6,13,19,22], vascular endothelial growth systems to develop PRP can be used in both
factor (VEGF) [12,23,24], epidermal growth office and hospital settings [18,23,29].
factor (EGF) [6,12,13,19,26,27], platelet-de- While medical practitioners are able to
rived endothelial growth factor (PDEGF) , apply blood products in the office, as is
epithelial cell growth factor (ECGF), insulin- done with PRP , they are not licensed to
like growth factor (IGF) , osteocalcin infuse or re-infuse blood or blood products
(Oc), osteonectin (On), fibrinogen (Ff), vit- in an office setting. Because PRP producing
ronectin (Vn), fibronectin (Fn), and throm- systems only require a small amount of
bospondin-1 (TSP-1) . These growth blood to produce, there is no need for rein-
factors aid healing by attracting un-differen- fusion , and studies have shown that
tiated cells in the newly formed matrix and these frequent but small blood draws do not
triggering cell division . PRP may sup- have an effect on hemoglobin, hematocrit,
press cytokine release and limit inflamma- or platelet count .
tion, interacting with macrophages to Not all currently marketed PRP devices
improve tissue healing and regeneration , are equivalent because not all concentrate
promote new capillary growth [5,29], and ac- viable platelets in sufficient numbers to en-
celerate epithelialization  in chronic hance healing, with these differences ac-
wounds. counting for many of the criticisms
Platelets in PRP also play a role in host regarding the efficacy of PRP . Although
defense mechanism at the wound site by pro- previous PRP studies have used a wide
ducing signaling proteins that attract range of devices for the preparation of PRP
macrophages ; PRP also may contain a , not all have been approved for use in
small number of leukocytes [15,18] that syn- humans. The only autologous PRP separa-
thesize interleukins as part of a non-specific tion system currently indicated for use in di-
immune response. Previous studies of PRP abetic ulcers is the AutoloGel™ System
have demonstrated antimicrobial activity (Cytomedix, Inc., Rockville, MD), which
against Escherichia coli, Staphylococcus au- contains all materials, including bovine
reus [30,31], including methicillin-resistant thrombin, necessary to activate the PRP gel
Staphylococcus aureus , Candida albi-  and can be used by health care
cans , and Cryptococcus neoformans providers without specialized technicians
Lacci: Platelet-rich plasma 3
ROLE OF PRP IN PATIENT CARE tects against contamination, does not cause
IN ADDITION TO STANDARD
trauma when removed, and leaves no debris
on wound bed . Dressings that retain
Topical growth factor products are typ- moisture are less likely to be associated with
ically used as adjuvant treatments along with infections than conventional dressings .
the standard of care for treatment of diabetic There is no evidence to support one type of
foot ulceration, including debridement, off- dressing over another [44,45], and no single
loading, frequent dressing changes, and dressing is appropriate for every type and lo-
compression for wounds with an origin of cation of ulcer . Moist saline or hydro-
vascular insufficiency. The efficacy of these colloid dressings create a moist wound bed
therapies has been shown in previous stud- that enhances the healing process and pre-
ies, and their importance cannot be stressed vents desiccation of the wound .
enough. Compression is considered first-line
Debridement is the most important step therapy for venous ulcers [38,46] and is
to promote healing in diabetic foot ulcera- more effective in healing these ulcers than
tion, with a goal of removing all devitalized no compression [45,46]. Methods of com-
tissue, including callus, necrotic, and in- pression vary and may include stockings,
fected tissue, and leaving only healthy tissue multilayer bandages, high-pressure com-
[5,36-38], effectively converting a chronic pression boots, intermittent pneumatic com-
wound into an acute wound [36,39]. De- pression, and Unna boots . Compression
bridement reduces the bacterial load of an relieves edema and stasis by reducing dis-
ulcer even in the absence of overt infection tention in superficial veins and assisting the
 and can be used on both neuropathic and calf muscle pump action .
venous ulcers . Previous studies have
suggested that foot ulcers that are debrided
are more likely to heal that those that are not, METHODS
independent of treatment group , sup- A thorough review of the literature was
porting frequent debridement as an impor- performed in multiple sessions between July
tant adjuvant treatment in these wounds. 2008 and March 2009. PubMed was
Pressure, sheer, and friction have been searched for literature on PRP and rhPDGF-
shown to impede wound healing [5,41], and BB using the keywords platelet-rich
the off-loading of high pressure areas is im- plasma/PRP/platelet releasate/platelet
portant in managing diabetic foot ulcers gel/platelet concentrate, Platelet-derived
[42,43]. Although the gold standard for off- growth factor/PDGF/rhPDGF-BB/becapler-
loading is plaster casting or total contact min, and diabetic foot ulcers/neuropathic
casts [4,5,36,37,41], they are indicated only foot ulcers/chronic diabetic foot ulcers. Only
if ulcers are clean and free from infection; sources available in English were used. The
therefore, the wounds must be inspected and reference lists of appropriate studies and re-
dressings must be changed daily, which is view articles were reviewed for additional
impossible with these devices , making sources regarding the use of PRP and rh-
them impractical for everyday use. Many PDGF-BB.
physicians advocate the use of a removable
contact walker with custom orthotic, which
has the same amount of pressure reduction STUDIES SUPPORTING THE USE
OF PLATELET-RICH PLASMA
as total contact casts and can be removed
daily for wound inspection and dressing Due to the novelty of PRP and its more
changes. Although compliance may be an recent discovery, few studies have been con-
issue with these easily removable devices ducted on its efficacy in human subjects.
, they are more practical for everyday use. PRP has been found to be effective in sev-
The ideal dressing removes excess exu- eral case control studies in addition to sev-
date, maintains a moist environment, pro- eral non-controlled clinical trials. Only one
4 Lacci: Platelet-rich plasma
prospective, randomized, controlled clinical fectiveness of platelet releasate (PR) in the
trial has been reported regarding the use of treatment of diabetic neuropathic foot ul-
autologous PRP for the treatment of diabetic cers. Of the 26,599 patients included in the
foot ulcers. study, 21 percent were treated with PR by
McAleer et al. (2006) found that the use the end of the 12-week run-in period before
of autologous PRP was successful in healing the 20-week study period began. The inves-
a chronic lower extremity wound in a case tigators used logistic regression-derived
study of a 57-year-old man with type 2 dia- propensity scores to account for selection
betes and a wound of six months duration. bias. The relative risk for a wound to heal
The treatment of this man’s wound with PRP after treatment with PR, when compared to
followed a failed attempt at a living skin the standard of care, was 1.14 (95 percent CI
graft application accompanied by off-load- 1.03-1.27) to 1.59 (1.49-1.70). Overall, 43.1
ing and daily wet-to-dry dressing changes. percent of patients healed within 32 weeks,
The autologous PRP was synthesized in the including 50 percent of patients treated with
treating clinician’s office, and wound in- PR and 41 percent of patients not treated
spection, debridement, and reapplication of with PR treatment. The investigators con-
platelet gel were performed weekly. Com- cluded that PR was more likely to be used
plete closure of the ulcer was achieved by in more severe wounds and was also more
the fourth week of treatment with PRP. Al- effective in treating these wounds than the
though this study is limited as a case study standard of care. One limitation of this study
involving a single patient, it suggested that was the varying timing of commencement
PRP can be successful in healing wounds of PRP treatment, such that patients did not
that have failed to heal by other treatment always receive 20 full weeks of PRP ther-
techniques . apy. However, this study was one of the first
Salemi et al. (2008) was a more recent to incorporate the most severe wounds,
case study evaluating the effectiveness of a which were excluded from the majority of
combination of autologous adipose tissue previous studies, and suggested that PR
and PRP in a lower extremity ulcer of three would be appropriate for use in these
years duration in a non-diabetic 65-year-old wounds . In addition, the authors of this
male patient. This study lasted for four study found that the percentage of healed di-
weeks with follow-up at one, three, six, and abetic foot ulcers leveled off after 20 weeks,
15 months. Although no statistical analysis indicating little incremental continued heal-
was done in this study, the researchers noted ing after this time  and setting a prece-
that the graft appeared to take well and the dent for the use of a 20-week study period
patient suffered no local infection or any in future growth factor studies.
other complications. At a 15-month follow- Crovetti et al. (2004) published a
up, the wound had healed completely with prospective non-blinded study regarding the
regained functioning of the limb and a efficacy of platelet gel (PG) in healing cuta-
greatly enhanced quality of life reported by neous chronic wounds. The wounds of the
the patient. This study, although also limited 24 patients enrolled in this study varied in
as a case study involving a single patient, origin, and etiologies included diabetes-re-
further supported previous findings suggest- lated, vascular insufficiency, infectious dis-
ing that PRP may be successful in the treat- ease, post-traumatic, neuropathic, and
ment of wounds that have failed to heal vasculitis-related. The protocol for this study
using other treatment modalities. This study consisted of once-weekly PG applications of
differed from previous studies due to the in- either autologous or homologous origin. At
vestigators’ use of autologous adipose tissue the time of the study publication, nine pa-
in addition to PRP for the treatment of a tients had healed completely, two went on to
chronic lower extremity ulcer . receive cutaneous grafts, four had stopped
Margolis et al. (2001) was a retrospec- treatment, and nine had responded partially
tive cohort study devised to estimate the ef- and were still receiving treatment. Although
Lacci: Platelet-rich plasma 5
pain was reported as reduced with the appli- this study was to evaluate the safety of PRP
cation of PG, neither patients nor clinicians and the incidence of complete wound clo-
were blinded to the treatment, possibly in- sure, defined as 100 percent re-epithelializa-
troducing bias to the self-report of pain. In tion, when compared to the control
addition to being a non-blinded study, it is treatment, and a secondary objective was
limited in that only three of the 24 subjects rate of wound closure. Patients were ran-
were able to perform autologous blood do- domized into two groups — standard of care
nations, meaning that the majority of pa- with PRP gel or control (saline gel) — and
tients received PG of homologous origin were evaluated biweekly for 12 weeks. After
. excluding 32 patients from the final per-pro-
O’Connell et al. (2008) presented prom- tocol analysis because of failure to complete
ising findings from a pilot study involving treatment and protocol violations, the au-
the treatment of chronic lower-extremity ul- thors found that 68.4 percent (13/19) of pa-
cers with autologous platelet-rich fibrin ma- tients in the PRP group and 42.9 percent
trix membrane (PRFM). This prospective (9/21) in the control group had wounds that
trial (n = 21) of eligible patients aged 18 to healed. Wounds in the PRP group healed
85 included 12 patients with 17 venous after a mean of 42.9 days (SD 18.3) vs. 47.4
lower-extremity ulcers and nine patients days (SD 22.0) in the control group. This
with 13 nonvenous lower-extremity ulcers, study was limited somewhat because it ex-
all who had failed to respond to at least four cluded ulcers with “challenging presenta-
weeks of conventional treatment. The pri- tions” such as mild to moderate vascular
mary endpoints were the incidence and time disease and exposed tendon or bone, in ad-
to complete closure, and the secondary end- dition to patients with hyperglycemia and/or
points were the incidence and time to 75 per- inadequate nutritional status; however, this
cent closure. The study duration was 12 study is the first published to use the Autolo-
weeks with follow-up at one month. Com- Gel™ System .
plete healing was achieved in 66.7 percent
of the patients with venous lower-extremity
ulcers in 7.1 weeks (median six weeks) fol- STUDIES NOT SUPPORTING THE
USE OF GROWTH FACTOR
lowing an average of two applications of
PRFM per patient. Of the nonvenous lower-
extremity ulcer group, 44 percent of patients Margolis et al. (2002) carried out a ret-
treated with PRFM healed completely dur- rospective cohort study of 31,106 individu-
ing the study period. Although this study is als in order to evaluate risk factors in
limited as a small-scale pilot, it suggests that patients with diabetic neuropathic foot ul-
platelet-rich substances such as PRFM have cers that may help predict who will and will
the potential to heal chronic lower-extremity not heal among patients receiving standard
ulcers that have failed to heal by conven- therapy for their wounds. The patients re-
tional methods . ceiving an adjuvant therapy such as PR,
Driver et al. (2006) carried out the first PDGF, or graft skins were found to have
reported prospective, randomized, con- wounds that were less likely to heal, al-
trolled multicenter trial in the United States though including these therapies in a multi-
regarding the use of autologous PRP for the variate model did not change the point
treatment of diabetic foot ulcers. Participants estimate of any risk factor by more than 10
included 72 patients with type 1 and type 2 percent, suggesting that these therapies had
diabetes between the ages of 18 and 95 from little effect on the study results. The authors
14 investigation sites suffering from an ulcer of this study attributed this effect to selection
of at least four weeks duration. In this study, bias, with physicians likely selecting those
investigators compared the effectiveness of patients doing poorly to receive adjuvant
autologous PRP gel to that of normal saline care. It also was noted that many patients did
gel for 12 weeks. The primary objective of not receive a full 20 weeks of any adjuvant
6 Lacci: Platelet-rich plasma
therapy. For further support of this attribu- 58,60], wound depth , wound duration
tion, the authors cited a previous study by [6,21,53,57,58,60], and wound location
Margolis et al. (2001), which showed that . Other possible confounding variables
PR was successful in treating even the most include variation in PRP characteristics be-
severe diabetic neuropathic foot ulcers. In tween studies, as growth factor content of
addition to selection bias, information bias autologous PRP can vary from patient to pa-
may have led to systematic differences in re- tient [2,17,20,61], even in patients with sim-
porting of presence or absence of certain risk ilar platelet counts . The extent of
factors or differences in the way risk factors platelet activation before application of gel
were measured . may vary as well [2,20]. It is unclear if these
One randomized prospective double- factors are relevant in studies regarding the
blind placebo-controlled study by Krupski use of PRP in diabetic foot ulceration.
et al. (1991) investigated the use of autolo-
gous platelet-derived wound healing for-
mula (PDWHF), a mixture of growth factors RATIONALE TO USE AUTOLOGOUS
PLATELET-RICH PLASMA RATHER
including PDGF, platelet factor 4 (PF-4),
THAN RECOMBINANT HUMAN
TGF-β, platelet-derived epidermal growth PLATELET-DERIVED GROWTH
factor (PDEGF), and platelet-derived angio- FACTOR-BB ISOMER
genesis factor (PDAF) . PDWHF was
investigated in 18 patients with 26 lower ex- The use of PRP represents a greater
tremity wounds of at least eight weeks dura- similarity to the natural healing process,
tion (mean of 5.5 ± 4.3 months duration). with the application of multiple growth fac-
Only 78 percent of the patients were diabetic tors in their biologically determined ratios,
and all were men ranging from 57 to 75 more closely than the addition of a single
years old. Over the 12-week study period, growth factor such as rhPDGF-BB . The
the investigators did not find any improve- autologous nature of PRP distinguishes it
ment in wound healing with the use of from recombinant human growth factors
PDWHF. Three (33 percent) wounds healed such as rhPDGF-BB, which are purely
in two patients in the control group, and four human but are foreign growth factors to that
(24 percent) wounds healed in three patients individual, synthesized by a culture of Chi-
in the PDWHF group (p > 0.05). The nese hamster ovarian cells with a human
wounds in the PDWHF group increased in gene inserted into the nucleus through a bac-
size during treatment, averaging -4.3 ± 12.2 terial plasmid vector . In addition, growth
cm2/week, while healing in the control group factors may be more effective when directly
was 1.9 ± 2.7 cm2/week. While this study delivered via a “depot” platelet plug, allow-
was limited by a small sample size, its re- ing a slow release of these factors than when
sults suggested that treatment of chronic administered in a bolus dose [24,63] such as
wounds with PDWHF is no better than tra- commonly performed with rhPDGF-BB
ditional therapy . treatment.
The short shelf life of recombinant
human growth factors such as rhPDGF-BB
is not a concern with the use of PRP, which
VARIABLES IN THESE STUDIES
can be made as needed from an autologous
Several possible confounding variables donation . More recent studies linked
exist in these studies, including the variation the expression of PDGF-BB to malignant
in patient characteristics between patients transformation in human cells , and a
with type 1 and type 2 diabetes mellitus black box warning was added to Regranex
[5,53,54], duration of diabetes diagnosis (becaplermin) in June 2008 following a
[5,55], patient age [21,27,47,53,56-59], pa- post-market epidemiologic study linking the
tient gender [27,47,53,56,58,60], patient use of more than three tubes of becaplermin
race , initial wound area [6,21,53,56- to a five times increased risk of mortality in
Lacci: Platelet-rich plasma 7
patients with a history of malignancy. Al- dition to a decreased rate of amputation,
though the risk of developing a new malig- thereby improving the quality of life for di-
nancy during treatment with becaplermin abetic patients suffering from diabetic foot
was not increased , these recent findings ulceration. If PRP proves to be a more effec-
remain cause for concern. tive treatment for diabetic foot ulceration
Finally, PRP may be a more cost-effec- than rhPDGF-BB, there is potential for its
tive and economical use of resources for the use in other chronic wounds of varying eti-
treatment of diabetic foot ulcers. Dougherty ology and of greater surface area.
(2008) carried out an evidence-based model Many unanswered questions remain re-
of 200,000 hypothetical patients comparing garding the use of topical growth factors in
the cost-effectiveness of PRP to a wide the treatment of chronic ulceration. Future
range of current therapies for diabetic foot studies should focus on the use of these
ulceration and found that the use of PRP re- growth factors in wounds of varying etiol-
sulted in an improved quality of life and was ogy and greater surface area. In addition,
less expensive over an estimated five-year prospective studies with greater follow-up
period when compared to other treatment periods are necessary to verify the long-term
modalities, including rhPDGF-BB. While safety of PRP, as the use of the growth factor
this economic model is hypothetical and preparation rhPDGF-BB has been associ-
used peer-reviewed data to simulate ex- ated with an increased risk of mortality in
pected costs and outcomes of treatment with patients with a history of malignancy and is
PRP, this study further suggests the promise not recommended for use in these patients.
of PRP in treatment of these ulcers in the fu- In spite of these remaining questions, PRP
ture. shows promise as an effective treatment
modality in the setting of diabetic foot ulcer-
RATIONALE TO USE AUTOLOGOUS
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