PRP With Protein-Rich Plasma for Knee Osteoarthritis

Overview

Boulder Biologics offers an orthopedic biologic approach that pairs platelet-rich plasma (PRP) with a protein-rich plasma fraction derived from platelet-poor plasma (PPP). This strategy is designed to emphasize key soluble plasma proteins, particularly alpha-2-macroglobulin (A2M) and fibrinogen, while limiting cellular and inflammatory components that may exacerbate symptoms in sensitive joints.

This approach differs from traditional high-density PRP by focusing less on platelet dose and more on modulating the joint microenvironment, particularly in patients with mild-to-moderate osteoarthritis (OA) seeking non-surgical symptom management.

Why a Protein-Rich Plasma Fraction?

PRP is not a single uniform product. Differences in platelet concentration, leukocyte content, and red blood cell contamination meaningfully alter the intra-articular inflammatory response. Established PRP classification frameworks (PAW, DEPA) emphasize that biologic injectates must be matched to tissue biology and clinical intent, not applied interchangeably. (1,2)

A protein-rich plasma fraction is intended to:

  • Increase concentrations of anti-catabolic plasma proteins (e.g., A2M)

  • Provide matrix-associated proteins (e.g., fibrinogen) in a controlled manner

  • Reduce reliance on high platelet density when inflammation tolerance is limited

Alpha-2-Macroglobulin (A2M): Rationale in Osteoarthritis

Mechanistic basis

A2M is a large circulating plasma protein that functions as a broad-spectrum protease inhibitor. In OA, cartilage degradation is driven in part by matrix metalloproteinases (MMPs) and aggrecanases (ADAMTS-4 and ADAMTS-5). A2M has been shown to bind and inhibit these enzymes, positioning it as an endogenous regulator of cartilage catabolism. (3,4)

Preclinical and translational evidence

  • A2M inhibits ADAMTS-4/5 activity in vitro and is degraded preferentially by these enzymes, supporting its role as a feedback inhibitor. (3)

  • Animal models of post-traumatic OA demonstrate that intra-articular supplementation of A2M attenuates cartilage degeneration and slows disease progression. (4,5)

Clinical Evidence

Clinical studies of A2M-rich orthobiologics report modest improvements in pain and function, generally comparable to other injection strategies over short-term follow-up. (6) These data support A2M-enriched approaches as reasonable to consider for symptom management, while reinforcing that outcomes vary and should not be overstated.

Fibrinogen: Potential Benefits and Required Caution

Why fibrinogen is of interest

Fibrinogen is a soluble plasma protein that can be converted to fibrin, forming a provisional matrix involved in tissue repair. In controlled contexts, fibrinogen-related matrices may:

  • Provide structural support within the joint

  • Bind and localize growth factors

  • Influence cell–matrix interactions relevant to joint homeostasis

Clinical interest in fibrinogen-based strategies is reflected in studies evaluating hyaluronic acid conjugated to plasma-derived fibrinogen, which reported favorable symptom trends and acceptable safety in knee OA. (7)

Important Considerations and Theorized Contraindications for Fibrinogen-Enriched Plasma

While fibrinogen may be beneficial in selected OA phenotypes, substantial immunology and arthritis literature demonstrate that fibrin and fibrinogen can be pathogenic in inflammatory joint disease. For this reason, fibrinogen-enriched strategies require careful patient selection.

Autoimmune and inflammatory arthritis (relative contraindication)

In rheumatoid arthritis and other immune-mediated arthropathies:

  • Fibrin deposition is prominent in synovium and cartilage surfaces (8)

  • Fibrinogen acts as a damage-associated molecular pattern (DAMP), activating innate immune pathways and amplifying inflammation (9,10)

  • Animal models show that disruption of fibrinogen signaling reduces arthritis severity (10)

Accordingly, fibrinogen-enriched joint injections are generally avoided in patients with known autoimmune or inflammatory arthritis.

High-inflammatory OA phenotypes

Some OA patients exhibit active synovitis and inflammatory effusions. In these settings:

  • Fibrin deposition is already increased (8)

  • Additional fibrinogen exposure could theoretically worsen synovial inflammation

For these patients, lower-inflammatory injectates (e.g., PRP alone or PPP without protein enrichment) may be more appropriate.

Coagulation considerations

Although systemic risk is low, patients with known hypercoagulable disorders or complex anticoagulation issues warrant careful evaluation before any fibrinogen-enriched intra-articular therapy.

Why Concentrate Proteins From PPP?

PPP retains valuable soluble proteins even after platelet reduction. Concentrating proteins from PPP may:

  • Increase levels of anti-catabolic mediators like A2M without increasing cellular inflammation

  • Support joint homeostasis rather than inflammatory stimulation

  • Provide an alternative strategy when high-density PRP is poorly tolerated

Related platforms, described as autologous protein solutions, demonstrate that point-of-care processing can enrich for anti-inflammatory mediators, though randomized trials show mixed results, underscoring the need for conservative counseling and individualized use. (11,12)

Clinical Application and Expectations

This approach is generally considered for:

  • Symptomatic mild-to-moderate knee OA

  • Patients seeking non-surgical symptom management

  • Patients without autoimmune arthritis or active synovitis

The goal is pain reduction and functional improvement, not cartilage regeneration or reversal of disease.

Regulatory Disclosure

PRP and plasma-derived protein concentrates are autologous blood products. These products are not approved by the U.S. Food and Drug Administration (FDA) as drugs or biologics for the treatment of osteoarthritis. Clinical use is based on physician judgment, current evidence, and individualized patient evaluation. No outcomes can be guaranteed.

 

References

1.     DeLong JM, Russell RP, Mazzocca AD. Platelet-rich plasma: the PAW classification system. Am J Sports Med. 2012;40(4):106–114.

2.     Magalon J, Chateau AL, Bertrand B, et al. DEPA classification: a proposal for standardising PRP use. BMJ Open Sport Exerc Med. 2016;2:e000060.

3.     Tortorella MD, Arner EC, Hills R, et al. α2-Macroglobulin is an endogenous inhibitor of ADAMTS-4 and ADAMTS-5. J Biol Chem. 2004;279:17554–17561.

4.     Wang S, Wei X, Zhou J, et al. Identification of α2-macroglobulin as a master inhibitor of cartilage-degrading factors. Arthritis Rheumatol. 2014;66:1843–1853.

5.     Li DRS, et al. Early supplemental α2-macroglobulin attenuates cartilage degeneration in a rat OA model. J Orthop Res. 2019.

6.     Klein D, et al. Comparison of A2M-rich plasma, PRP, and corticosteroid for knee OA. Orthop J Sports Med. 2020.

7.     Kandel L, Agar G, Elkayam O, et al. Hyaluronic acid conjugated to plasma fibrinogen for knee OA. Heliyon. 2020;6:e04475.

8.     Hügle T, Geurts J, Nüesch C, et al. Fibrin deposition in osteoarthritis and rheumatoid arthritis. Arthritis Res Ther. 2022;24:135.

9.     Flick MJ, Du X, Witte DP, et al. Fibrin(ogen) exacerbates inflammatory joint disease. J Clin Invest. 2007;117:3224–3235.

10.   Adams RA, Bauer J, Flick MJ, et al. Fibrin-derived peptides drive autoimmune inflammation. Nat Med. 2007;13:1467–1472.

11.   O’Shaughnessey K, Matuska A, Hoeppner J, et al. Autologous protein solution from OA patient blood. J Orthop Res. 2014.

12.   Ross M, Zhou Y, English M, et al. Intra-articular autologous protein solution for knee OA: randomized trial. Bone Joint J. 2024;106-B:907–915.