What is Alpha-2-Macroglobulin (A2M)?

There is a growing body of evidence to suggest that orthobiologics, in particular platelet rich plasma (PRP) injections, can help to reduce pain/swelling and improve function to a greater degree than “standard” injections such as corticosteroid or viscosupplements.   PRP is a concentrated volume of platelets extracted from the patient’s own venous blood.  Along with the cellular components there are acellular molecules/proteins that may have anti-inflammatory properties, one of which is Alpha-2 Macroglobulin (A2M). 
Alpha 2 macroglobulin (A2M) is a naturally occurring autologous protein found in the platelet-poor-plasma (PPP) at relatively high levels (2-4 mg/ml), as well in the joint fluid at lower concentrations.58 A2M is known as a ubiquitous proteinase inhibitor, which contains a ‘bait region’, resulting in a cleavage site for proteinases and is identified as one of the active substances in PRP.1  

Among the mechanisms responsible for cartilage degradation in the setting of OA, disintegrin-metalloproteinases with thrombospondin motifs (ADAMTSs) and the matrix metalloproteinases (MMPs) have been identified as key players.2-7  It has been established that in early OA,  ADAMTSs are the main proteinases responsible for the breakdown of aggrecan and cartilage oligomeric matrix protein (COMP), a prominent non-collagenous component of cartilage leading to progression of further cartilage loss. 2-5 Later in the OA process, MMPs are more prominent in the continued degradation of collagen.6 Of the collagenases, MMP‑13 cleaves primarily type II collagen while MMP-1 and MMP-8 cleaves types III and I.2 In addition to collagen, MMP-13 also degrades the proteoglycan molecule, aggrecan, resulting in a dual role in matrix destruction.9-10 Thus, strategies at blocking the biological activities of ADAMTSs and MMPs could theoretically slow the progression of early to late osteoarthritis with potential improvement in pain and function and stave off more invasive procedures such as total joint replacement.  

 

In animal models, concentrated supplemental intra-articular A2M has demonstrated chondral protection in post-traumatic knee OA (PTOA) decreasing both MMP and IL-1, indicating a potential disease modulating effect.8,11 It has furthermore been demonstrated that lower intrinsic levels and inhibition of A2M result in increased progression of osteoarthritis.12  A2M however, has been shown to be too big of a protein to get into the synovial fluid, which may account for its higher serum levels in platelet-poor-plasma (PPP) than synovial fluid.13,14 

 

Concentrated injections of  intra-articular A2M  has demonstrated chondral protection in post-traumatic knee OA decreasing both matrix metalloproteinase (MMP) and IL-1, indicating a potential disease modulating effect (slowing effect) in osteoathritis.6,15 It has furthermore been demonstrated that lower intrinsic levels and inhibition of A2M result in increased progression of osteoarthritis.16  Therefore, intra-articular autologous concentrated A2M with its ability to bind pro-inflammatory molecules such as tumor necrosis factor-α (TNF- α), tumor necrosis factor- β (TNF-β), matrix metalloproteinase (MMP), interleukin-1β (IL-1β), and ADAMTS may be of benefit in treating and slowing progression of OA.17-20, 21-23 

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How is it harvested?

It is harvested by taking 60-180cc (depending on treatment area) of blood from the patient and spinning it in a centrifuge separate the platelet-rich-plasma (PRP), from the platelet poor plasma (PPP). The PPP is then cycled through a proprietary filter system, which has a high molecular weight cutoff designed to trap larger molecules including A2M (720 kDa). This results in a concentrated amount of A2M proteins. 

Is it safe?

A2M is naturally found in the serum (Blood) and synovial fluid, and in PRP preparations in concentrated amounts. Montesano P. Et al. published their case series in 2017 on 40 patients who received intradiscal injection of autologous concentrated A2M.24  The concentration of A2M was not reported. They showed statistically significant improvement in patients that were Fibronectin-Aggrecan complex (FAC) positive, at 6-month follow-up in both pain and Oswestry disability index (ODI). There were no reported adverse events.24 Klein D, et al reported their results at American Orthopedic Society for Sports Medicine (AOSSM) annual convention in 2020 on their blinded randomized controlled trial comparing A2M, LP-PRP (Arthrex ACP system), and corticosteroids (CCS).  In this study 75 patients with symptomatic knee osteoarthritis with Kellgren-Lawrence grade 2 or 3 were randomized into one of three cohorts receiving intra-articular injection. One group was given LP- PRP (N=23), one group was given A2M (N=23), and one group was given Depo Medrol (N=24). They also reported no adverse outcomes. 

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What is the recovery like?

When tendons, ligaments, and meniscus are treated, patients are sorer with increased pain for about 2 weeks. Then the pain waxes and wanes for about 2-6 weeks, with some decreased pain days intermixed with days where it is very painful. It takes about 6 weeks for tendons to heal and remodel on repeat imaging. Anecdotally, most patients are not pain free until 6-12 weeks after treatment, but this can vary from patient to patient. The recovery is different for different tendons and ligaments and can vary from patient to patient. This will be reviewed at the time of consultation.

When joints are treated, initially it is sorer for the first 2-3 days, then the pain subsides, and some patients already start feeling improvement. It takes about 4-6 weeks on average for patients to see the full effects of the treatment.

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What to consider when choosing A2M

The risks of any procedure involving a break in the skin include, infection, neurovascular or tendinous soft tissue injury and failure to provide relief. Ultrasound makes risk of iatrogenic injury to neurovascular structures and anatomic variants lower as the anatomic is viewed throughout the procedure. Transiently increased pain at the site of the procedure (varies based on site and tissue treated) and pain at venipuncture site are the most common complaints.

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Is it FDA approved?

It is not FDA approved but FDA compliant if “minimally manipulated”. This means that it must be harvested and immediately reinjected. We do not store it or modify the product collected in anyway.

As with all procedures, patients are encouraged to gather information on the treatment option before pursuing it.

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Reference Publications

See the full list of Dr. Pourcho's reference publications on this topic

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