Platelet Rich Plasma use in Musculoskeletal Injury · progenitor cells: • Mesenchymal Stem Cells...

Atul Gupta, MD

Department of Physical Medicine and Rehabilitation

May 5th, 2019

Platelet Rich Plasma use in Musculoskeletal Injury

© 2018 Virginia Mason Medical Center

Disclosures

• None


Does treatment success in the professional athlete imply potential success for my every day patient?

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Agenda

• Understand What Platelet Rich Plasma is

• Mechanism of Action

• Technical Considerations

• Efficacy in Osteoarthritis

• Efficacy in Tendinopathy


Epidemiology

• Osteoarthritis (OA) is a leading cause of disability worldwide

• Knee and hip OA reduce life expectancy 1

• More dependency and assistance required with knee OA than with heart disease2

• Tendon injuries represent 50% of all sports injuries 3

1 Hawker GA, Croxford R, Bierman AS, et al: All-cause mortality and serious cardiovascular events in people

with hip and knee osteoarthritis: A population based cohort study. PLoS One 2014;9: e91286.2 Guccione AA, Felson DT, Anderson JJ, et al: The effects of specific medical conditions on the functional

limitations of elders in the Framingham Study. Am J Public Health 1994;84:351-3583 Maffulli et al. 2003; Andarawis et al. 2015

The economic burden of musculoskeletal diseases

approaches $1 trillion annually in the United States, comprising approximately 7.4% of the GDP


The 21st Century Cures Act

• Enacted December 2016

• Increased funding for medical research, for combating the opioid epidemic

• New measures to streamline approval of new therapies for clinical trials

• Accelerated FDA approval for a regenerative medicine therapy that is intended to treat a serious or life-threatening disease or condition


Tendinopathy

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• Longer tendons are more

likely to degenerate

• Microdisruption of tendon

fibers

• Neovascularization

• Neural ingrowth is thought to

be responsible for the

clinical symptoms of

tendinopathy


Healing Phases

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Osteoarthritis

• Breakdown of “joint organ” –hyaline cartilage, synovium, subchondral bone, capsule

• Pathologic OA seen on imaging and cadaveric studies is a process of aging

• Symptomatic OA is what we are trying to prevent and treat in medicine

• Symptoms linked to the intra-articular milieu rather than gross anatomic findings

• Intra-articular milieu is modifiable

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Treatment Options

Conservative Treatments:

Physical Therapy

Pain Medications

Corticosteroid Injections

Viscosupplementation

Shock Wave Therapy

Dry Needling

Prolotherapy

Invasive Treatments:

Joint Replacement

Open Surgical Tenotomy

Orthobiologics:

Platelet Rich Plasma

Mesenchymal Stem Cells

Lipoaspirate concentrate

Bone Marrow Aspirate Concentrate

Amniotic Products

Orthokine/Regenokine

Alpha 2 Macroglobulin

Exosomes


Increased Chondrocyte Death after Steroid and Local Anesthetic Combination Farkas et al 2009

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Betamethasone Prednisolone

Betamethasone +

Lidocaine

Prednisolone +

Lidocaine


Platelet Review

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• Non-nucleate

• 7-10 days of life

• First responders to

inflammation or injury

• Alpha and Dense granules

secrete growth factors,

cytokines and chemokines



• Supraphysiologic concentration of platelets

• The number above baseline is debated

• PRP Lysate

• Platelet rich fibrin matrix (PRFM)


PRP Historical Perspective 1909 Autologous fibrin

glue in clinical use (Bergel)

1980s –

Early 1

990s First used

clinically in the United States (‘87) to facilitate wound healing after cardiac surgery

Platelet concentrates replace fibrin glue

1990s Use in

maxillofacial surgery & periodontics to improve healing

2006 Mishra & Pavelko

publish 1st use in musculoskeletal medicine

2006-P

resent Expansion into

non-operative and operative orthopedics

The global PRP market was valued at approximately $185M

in 2017 and is expected to generate revenue of around $438M by the end of 2024,

growing at a CAGR of around 12.90% between 2018 and 2024

– Zion Market Research


Technical Aspects


• Mitogenic (growth) factors – i.e. PDGF, FGF, HGF, IGF, etc.

• Recruit and multiply cells

• Roughly 80% stored in platelets, 20% soluble in plasma

• Angiogenic factors – i.e. VEGF• Roughly 80% stored in platelets,

20% soluble in plasma

• Matrix-building proteins• Fibrinogen, fibronectin, vitronectin

• Available in the plasma, not the platelets

• Anti-inflammatory proteins

• Alpha-2-Macroglobulin (A2M) –Enzyme-inhibition

• IL-1RAP (aka IRAP, Orthokine) –Blocks IL-1 receptor, masks inflammation

• Higher concentrations in BM plasma than blood plasma

What is in PRP?


PRP Variable Factors

- Activation: Endogenous or exogenous. Calcium, thrombin, collagen are main activators

- The anticoagulant used during blood extraction

- Landmark or ultrasound guided injections

- The use of local anesthetic

- The rehabilitation program after PRP treatment

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PRP intrinsic Variability

• Lack of standardization of PRP preparation for clinical use has contributed at least in part to the varying clinical efficacy in PRP use

• Variation exists in the concentration of blood components, including platelets, red blood cells, leukocytes, pH, and glucose


AAOS recommendations for ALL autologous conditioned plasma

• Registry and Biorepository for PRP

• Understand the influence of variable PRP composition on clinical outcomes

• Assist in stratifying patient disease state, as well as for performing biomarker, molecular, and genomic analyses

• Pilot PRP Registry at the Veterans Hospital in Palo Alto, California


PRP’s Effects

• PRP’s effects depends on presence of progenitor cells:

• Mesenchymal Stem Cells

• Osteoblasts

• Chondrocytes

• The cytokines in PRP orchestrate the proliferation and remodeling process

Indirect Therapy

One time dose of growth factors

Growth factors only affect cells

If there are no cells, then PRP has no

effect

If there are cells present,

PRP can have effect


Contraindications

• Antiplatelet agents

• Poglitazone

• Thrombocytopenia

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Commercially Available Kits

40 + Kits available on the market at this time


____________________________1 If WBC are present (+) the % of neutrophils should also be reported.2 The method of exogenous activation should be reported.

A Call for Standard Classification System for Future Biologic Research: The Rationale for New PRP Nomenclature

Kenneth Mautner, MD, Gerard A. Malanga, MD, Jay Smith, MD, Brian Shiple, DO, Victor Ibrahim, MD, Steven Sampson, DO, Jay E. Bowen, DO. April 2015


PRP in Knee OA Studies

Currently the most Level 1 data available of any nonoperative

treatment for knee OA


PRP versus Placebo

1 injection 2 injections

Treatment with Platelet-Rich Plasma is More Effective Than Placebo for Knee Osteoarthritis: A Prospective, Double-Blind, Randomized Trial

Sandeep Patel, et al. AM J Sports Med 2013 41:356 originally published online Jan 8, 2013


PRP versus Placebo


PRP versus Hyaluronic Acid for Knee OsteoarthritisIntra-Articular Injections of Platelet-Rich Plasma versus Hyaluronic Acid in the Treatment of Osteoarthritic Knee Pain: A Randomized Clinical Trial in the Context of the Spanish National Health Care System

Elvria Montanez-Heredia et al. International Journal of Molecular Sciences, 2016

• 58 patients (28 PRP, 27 HA); 30 controls with no injection; Knee OA 1,2,3 (4 excluded)

• WOMAC, KOOS, EUROQL, VAS

• HU group after 6 months 56% to 66% had worsened and 43% to 33% had no improvement

• PRP had greater reduction in pain at 3 & 6 months; was more effective with lower OA scores


PRP Versus Hyaluronic Acid for Hip Osteoarthritis

Results indicated that intra-articular PRP injections offer a significant clinical improvements compared with the other tested treatments in patients with hip OA without relevant side effects. The benefit was significantly more stable up to 12 months

Ultrasound-Guided Injection of Platelet-Rich Plasma and Hyaluronic Acid, Separately and in Combination, for Hip Osteoarthritis: A Randomized Controlled Study

Dante Dallari et al. AJSM, 2016


Leukocyte Rich versus Leukocyte Poor PRP

Conclusion Drawn: Evidence that LP-

PRP may have a greater effect on

functional outcome scores than LR-

PRP. Adverse reactions are equivocal

between the groups.

Effect of Leukocyte Concentration on the Efficacy of Platelet-Rich Plasma in the

Treatment of Knee Osteoarthiritis

Jonathan C. Riboh et al. AJSM, 2014


PRP in Knee OA: Systematic Review

Efficacy of Intra-articular Platelet-Rich Plasma Injections in Knee Osteoarthritis: A Systematic Review

Carlos J. Meheux et al. Arthroscopy, 2016

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Conclusion: In patients with symptomatic

knee OA, PRP injection results in

significant clinical improvements up to 12

months post-injection.


PRP for Patellar Tendinopathy

Platelet-Rich Plasma as a Treatment for Patellar Tendinopathy

A Double-Blind, Randomized Controlled Trial

Jason L. Dragoo et al. Am J Sports Med, 2014


PRP for Lateral Epicondylitis

Positive Effect of an Autologous Platelet Concentrate in Lateral Epicondylitis in a Double-Blind Randomized Controlled Trial: Platelet-Rich Plasma Versus Corticosteroid Injection With a 1-Year Follow-up

Joost C. Peerbooms et al. Am J Sports Med, 2010

Conclusion: PRP better than steroid .


PRP versus Corticosteroid Injection for Gluteal TendinopathyThe Effectiveness of Platelet-Rich Plasma Injections in Gluteal Tendinopathy. A Randomized, Double-Blind Controlled Trial Comparing a Single Platelet-Rich Plasma Injection With a Single Corticosteroid Injection

Jane Fitzpatrick et al. AJSM, 2018

Leukocyte Rich PRP improved patient related outcomes at 12 weeks

while corticosteroid did not


PRP for Rotator Cuff Tendinopathy

Comparative Effectiveness of Injection Therapies in Rotator Cuff Tendinopathy: A Systematic Review, Pairwise and Network Meta-Analysis of Randomized Controlled Trials

Meng-Ting Lin et al. Archives of Physical Medicine and Rehabilitation, 2018

2 arms of injection therapies (including

corticosteroid, NSAIDs, HA, BTX, PRP,

prolotherapy, placebo) were eligible for

inclusion. The number or guidance

method of injection had no restriction


PRP for Achilles Tendinopathy

Effect of platelet-rich plasma on healing tissues in acute ruptured Achilles tendon: a human immunohistochemistry study.

Alsousou J et al. Lancet, 2015

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METHODS:

Tendon tissue biopsy samples were obtained from 20 patients with ruptured Achilles tendon by means of ultrasound-guided needle biopsies from the healing area of the Achilles tendon 6 weeks after treatment with PRP or placebo controls (10 patients each). All samples were embedded in paraffin wax, sectioned, and stained with haematoxylin and eosin and alcianblue. Immunohistochemistry markers were used to identify collagen I and III, lymphocytes (CD45), proliferation (KI67), and blood vessels (CD34). All images were masked and analysed with Image J software.

FINDINGS:

Cellularity and glycosaminoglycans content were significantly higher in PRP-treated tendons than in controls (p=0·01 and p<0·001, respectively). Fibre structure of the tissue was

significantly better in the PRP group than in the control tissue (p<0·001). Although both groups showed high collagen I staining, content of collagen I was significantly higher in PRP-treated tendons than in control tendons (p=0·0079), whereas collagen III content was not different (p=1·0). The ratio of collagen III to collagen I was significantly lower in PRP samples (p=0·007). There was no significant difference in CD45 expression (p=0·33). However, PRP samples had fewer blood vessels

than did control samples (p=0·023). The overall modified Bonar score was significantly lower in PRP samples, which indicates improved early tendon healing.

INTERPRETATION:

This is the first study, to our knowledge, to report the immunohistochemical response of ruptured human Achilles tendonto

PRP. The findings reveal that locally applied PRP enhanced the maturity of the healing tendon tissues by promoting better collagen I deposition, decreased cellularity, less vascularity, and higher glycosaminoglycan content when compared with control samples. Further work is required to determine the longer term effects of the use of

PRP in musculoskeletal diseases.


PRP for Tendinopathy Meta-Analysis The Effectiveness of Platelet-Rich Plasma in the Treatment of Tendinopathy. A Meta-analysis of Randomized Controlled Clinical Trials

Jane Fitzpatrick et al. Am J Sports Medicine, 2017

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Exercise-Mobilized Platelet-Rich Plasma: Short-Term Exercise Increases Stem Cell and Platelet Concentrations in Platelet-Rich Plasma Anz et al Arthroscopy 2019

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Plasma Based System Buffy Coat Based System

Platelet and other cellular components of PRP can be

consistently manipulated with exercise before blood

harvest


PRP Conclusions

• Need to standardize what we are injecting

• Platelet counts

• Leukocyte +/-

• Differential between neutrophils, lymphocyptes, monocytes

• RBC +/RBC –

• Need to standardize the procedure

• Ultrasound guidance

• Activation

• Rehabilitation methods

• Immobilization

• Rehabilitation

• The “one size fit all” approach is not sustainable due to the complexity of joint and tendon pathology


PRP Summary

• Clinical evidence supports the use of PRP for the treatment of pain and disability from knee OA

• Studies show that PRP’s outcomes are more effective than Hyaluronic Acid

• PRP has more of an effect on milder OA (grades 1-2)• PRP does NOT reverse the effects of OA or “regrow

cartilage”.• Can help to stimulate remodeling of a tendon and

reduce the pain associated with tendinopathy• PRP’s safety profile and ease of use is appealing• Standardization of PRP concentrations and the ideal

milieu of leukocytes & cytokines remains a goal of future research

• Insurances currently provide minimal to no coverage for PRP

• The field of orthobiologics continues to evolve and grow at a quick pace

Individual Clinical

Experience

Patient Values &

Expectations

Best External Evidence

Thank You!

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Department of Physical Medicine and Rehabilitation

1100 Ninth Ave , G2-PMRSeattle, WA 98101

(206)223-6746

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Platelet Rich Plasma use in Musculoskeletal Injury · progenitor cells: • Mesenchymal Stem Cells...

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