The Effectiveness of Autologous Whole Blood Injection in the Treatment of Tendinopathy

A comprehensive search to identify randomized controlled trials and case control
studies on the subject of autologous whole blood injections (ABI) for tendinopathy.
For example subacromial impingement, rotator cuff tendinopathy, tennis elbow,
golfers elbow, patella tendonitis, Achilles tendonitis and plantar fasciitis.

sulting in recurrent microtrauma leading to tendon degeneration, micro tears and eventual failure of healing processes" [4]. These changes common to tendinopathies in general have been identified histologically with evidence of "fibroblast proliferation, vascular hyperplasia and angio fibroblastic hyperplasia" [4] without the presence of a chronic inflammatory component. The molecular pathology of tendinopathy is also characteristic with much work having been conducted over the last fifteen years on the role of matrix metalloproteinases [MMP] and their effect on proteoglycans [2].
That there is in vitro evidence that fluoroquinolone antibiotics are thought to be able to induce tendinopathies via their effect on MMP expression by tenocytes highlights the importance of biologically active mediators in tendinopathy [2].
Common sites for tendinopathy include the "rotator cuff, biceps tendon, the lateral and medial distal humeral epicondyle, patella tendon, Achilles tendon and the plantar fascia" [4]. The above clinical and histological findings are common to these conditions, indicating a possible common aetiology which goes someway to validate the similar forms of treatment that are commonly applied to these various conditions. Current treatments include "rest, anti-inflammatory medication, analgesia, orthotics, physiotherapy, local corticosteroid injection, extra-corporeal shockwave therapy and surgical debridement" [4]. There is no clear consensus on the optimal management of these tendinopathies. More recent treatments have focused upon the delivery of local growth factors to the site of tendinopathy [3]. "The basic science behind tendon healing following injury and the role of growth factors in modulating and initiating this process is well established" [4]. There are "three stages to tendon repair and regeneration" and all of these stages are influenced by local growth factors [2]. After an initial acute inflammatory response following tendon injury, migration of blood cells occurs and release of pro-inflammatory cytokines and angiogenic factors [2,4]. The proliferative stage continues with recruitment and proliferation of fibroblasts [2,4]. Fibroblasts are responsible for synthesis of collagen and proteoglycans essential for tendon repair. In the final remodeling stage the ratio of type one to type three collagen increases along with reorganization of collagen fibers into longitudinal bundles [2,4]. This final stage is usually complete at ap- and Bone morphogenic proteins 12, 13 and 14 (BMP-12, BMP-13, BMP-14) [2,4] . These growth factors are found throughout the body but appear to be found in high concentrations within blood [4]. Much recent research has focussed on platelets in particular which are a rich and readily available source of PDGF, VEGF, EGF and BMP 12-14 [2,4]. It must be noted that other factors not partic-ularly concentrated in platelets like TGF-B1, b-FGF and IGF-1 are also found within other components of blood [4]. There are a wide variety of methods via which these growth factors can be harvested and delivered to the zone of healing. Techniques that have received the most attention include leucocyte depleted low yield PRP, leucocyte rich high yield "buffy coat" PRP and ABI [5]. Every preparation is subtly different, and it must be appreciated that each of these preparations "contain many thousands of biologically active substances which have received very little attention in the literature concerning growth factor augmented soft tissue healing" [5].
Platelet rich plasma preparations are created following centrifugation of anti-coagulated autologous blood. The supernatant is discarded, and the platelet rich plasma is often activated for example with calcium chloride prior to its injection into the site of tendinopathy [5]. There are a number of features that have driven the use of platelet rich plasma. The cost of the treatment is low compared to the cost of recombinant growth factors [e.g. OP1 etc.].
Also, there are few barriers to its implementation in the form of governmental regulation as the injected product is autologous. In contrast to PRP, ABI involves the direct injection of whole blood with no preparation into the site of tendinopathy [5]. Though some of the previously mentioned growth factors are present in higher quantities in PRP than in ABI there is growing evidence that "less maybe more" [5], inferring that the optimal concentration of growth factors may in fact be present in whole blood as compared to PRP.
The aim of this work is to systematically review the literature concerning ABI in the treatment of tendinopathy and if possible, to determine if the results of the trials identified can be synthesised into a more generalisable argument.

Inclusion Criteria
Randomized controlled trials and prospective studies with a comparator arm in English will be found that investigate.

Population
Human, Adults with tendinopathy affecting the rotator cuff, The Consort statement will be used to critically appraise the selected papers and to help guide the process of synthesising this data into a more generalisable format.

Critical Appraisal
The two studies investigating plantar fasciitis were chosen for review [6,7]. By focusing the critical appraisal on plantar fasciitis this assignment can comprehensively review the subject of autologous blood injections to treat plantar fasciitis. Lee et al "Intralesional autologous blood injection compared to corticosteroid injection for treatment of chronic plantar fasciitis. A prospective, randomized, controlled trial" [7]. This prospective randomised controlled study from Kuala Lumpur compared the efficacy of autologous  it was recognized that fat pad atrophy can be a complication of steroid treatment though this complication was not observed in the trial population. The trial was not registered with a trial registry, no funding sources were declared, and the full trial protocol does not appear to be available to the public.
The overall generalizability of this study is low primarily due to the poor choice of outcome measures. There are a variety of specific outcome measures available that should have been used to provide greater external validity. The study does provide some weight to the argument that steroid is more effective in the short term, however the similar outcomes at six months and the absence of longer term outcomes are consistent with research in other areas which demonstrates that steroid is not more effective in the medium term. Clearly there were insufficient processes in place to assure patient safety during the course of this trial. This prospective randomized controlled trial was not randomized and given the 100% follow up and issues with patient safety in terms of spotting untoward complications it appears likely that the trial was not prospective either.
The lack of power calculation, small numbers in each group, complete absence of explanation of which statistical tests were used when mean that this trial has little to no internal validity let alone external validity.

Search Summary
Twenty-six publications were identified with the above search

Studies Identified
a) 10 review articles excluded b) One article on injection of cultured tenocytes excluded [9] c) 6 studies investigating platelet rich plasma excluded d) One study on cerebral palsy patients excluded [10] e) Four studies were not randomized and had no control group i.e. they were case series [11][12][13][14]

Summary of Evidence
With regard to lateral epicondylitis there are three randomized controlled trials. In 2011 Creaney [5] published a trial comparing the patient derived tennis elbow evaluation score in patients who received autologous blood injections or platelet rich plasma injections to treat chronic lateral epicondylitis that had failed conservative management. This study showed that both treatments provid- In 2010 Kazemi [15] published results of a randomized controlled trial from a teaching hospital in Tehran. This study compared autologous blood injection to steroid injection in new patient referrals with tennis elbow. The outcome measures involved were VAS scores, the quick DASH score, the Nirschl score and muscle strength testing. The results of this trial show that both treatments work very well to relieve pain but also surprisingly show that autologous blood injections were in this patient group overwhelmingly superior to steroid injection for all outcome measures. All P values when comparing the two groups were < 0.001. Given the small sample sizes involved finding such overwhelmingly positive results in favour of autologous blood injections, which are at odds with other studies on similar patients, appear to be perhaps slightly unbelievable! Ozturan [16] reported findings of a study comparing ABI to steroid injection to extracorporeal shock wave therapy in the treatment of tennis elbow. Sixty patients were randomized (with no description of randomization and no power calculation) to the three treatments. The steroid injection technique involved perforating the area of tendinopathy at least five times. Dry needling in itself is a treatment for tendinopathy [6] and this is a significant confounder. The trial showed that all three studies showed an improvement in visual analogue scores post provocative Thompson testing-a non-validated measure of elbow function. Steroid injection was superior to the other two treatments at 4 weeks [p < 0.01] these differences disappeared at 12 weeks and by 26 weeks the ABI group and shockwave group showed reduced pain compared to steroid injection [p < 0.01] -this difference was maintained until 52 weeks the end point of the study. The study recommends the use of autologous blood injections on the grounds that it is superior to steroid injection and equivalent in efficacy to shockwave therapy with the benefit of being cheaper than shockwave therapy.

Implications for Clinical Practise
To date there are five randomized studies comparing autologous blood injection with existing treatments for tendinopathy.
None of these studies have shown adequate demonstration of power calculation, randomization or blinding. Most of these studies fail to account for obvious confounding variables such as the effect of dry needling in the process of injection. The evidence base seems to suggest that most of the current treatments available are effective in the treatment of tendinopathy. Four out of five studies suggest that ABI is superior or equivalent to control groups. Given the small sample sizes and large number of confounders there is significant scope for both type 1 and type 2 error in conclusions drawn from the current evidence base. Compared to other treatments ABI is remarkable in its low price and ease of application -a point which is raised repeatedly [4,6,16]. From this small and fairly weak evidence base one can conclude that ABI is likely to be similar in its acceptability to patients compared to controls [15] an assertion which also passes the test of face validity. A significant problem is the use of the steroid comparator as high-quality research has shown that although steroid is superior to placebo in the short term, it is harmful in the medium and longer term [Coombes JAMA].

Implications for Future Research
A key failing in all of these studies is the lack of a power calculation and poor descriptions of randomization. Unfortunately, we would not recommend using any of the currently described datasets as the base for a power calculation for further studies due to the paucity of validated outcome measures used in the studies described above. A pilot study is required assessing a type of tendinopathy which has a well validated outcome measure associated with it. Given its high incidence within the population [1] and the development of very well validated outcome measures such as the Oxford shoulder score [17] and the Constant score [17] rotator cuff tendinopathy would be the best starting point for this investigation into tendinopathy. This pilot study should compare ABI with an adequate comparator. A significant failure of the summarized studies is the adequacy of the comparator arms; ultimately a placebo comparator would be optimal in order to assess the effectiveness of ABI and this could be done alongside a steroid injection arm, as this is the most widely used in current clinical practice. [1]. The results of this pilot study should guide the power calculation in the design of a randomized controlled trial to compare the effect of ABI vs. placebo vs steroid injection in the treatment of rotator cuff tendinopathy.
This study would definitively show if ABI is effective in the treatment of tendinopathy and if it is superior to existing treatment.

Competing Interests
The authors declare that they have no competing interests.