Blood Cell Ratios as Predictors of Response to Platelet-Rich Plasma in Knee Osteoarthritis (PRP-NLR)

Baseline Neutrophil-to-Lymphocyte Ratio and Related Complete Blood Count-Derived Inflammatory Indices as Predictors of Clinical Response to Intra-Articular Platelet-Rich Plasma in Knee Osteoarthritis: A Prospective Single-Arm Cohort Study

Intra-articular platelet-rich plasma (PRP) injection is a widely used treatment for knee osteoarthritis, but patients respond to it very differently and there is currently no simple, inexpensive way to predict who will benefit. The neutrophil-to-lymphocyte ratio (NLR) and related indices derived from a routine complete blood count reflect a person's baseline inflammatory state. This prospective single-arm observational cohort study investigates whether the baseline NLR, together with the platelet-to-lymphocyte ratio (PLR), the systemic immune-inflammation index (SII), and the monocyte-to-lymphocyte ratio (MLR), predicts the clinical response to intra-articular PRP in patients with Kellgren-Lawrence grade 2 to 3 knee osteoarthritis. The investigators will enroll 120 patients aged 40 to 60 years, each of whom receives a standardized course of three leukocyte-poor PRP injections one week apart. Patients are followed for 6 months, and the primary clinical outcome is the change in the WOMAC osteoarthritis index at 6 months. Outcome assessors are blinded to patients' blood-count values. If a baseline blood ratio predicts response, it could become a low-cost tool to guide patient selection for PRP.

Study Overview

• Status: Not yet recruiting
• Conditions: Osteoarthritis; Knee Osteoarthritis

Detailed Description

Background and Rationale: Intra-articular platelet-rich plasma (PRP) is increasingly used for symptomatic knee osteoarthritis, but the clinical response is highly variable and no inexpensive, routinely available biomarker currently guides patient selection. Recent work indicates that the peripheral-blood inflammatory phenotype is associated with PRP response (Tonutti et al., 2025) and that the absolute neutrophil count is an independent early-response predictor (De Luca et al., 2025). However, simple complete-blood-count-derived ratios such as the neutrophil-to-lymphocyte ratio (NLR) have not been tested prospectively for this purpose. This study addresses that gap with a pragmatic, low-cost translational biomarker design.

Design: Prospective, single-arm, observational cohort study. Outcome assessors are blinded to patients' blood-count values; patients are not informed of their NLR; statistical analysis is conducted blinded.

Population and Setting: 120 patients aged 40 to 60 years with symptomatic Kellgren-Lawrence grade 2 to 3 knee osteoarthritis and a body mass index below 40, recruited over a 4-month window (target 30 enrollments per month) from the Department of Orthopaedics and Traumatology, University of Kyrenia, Dr. Suat Gunsel Hospital. Approximately 180 patients are anticipated to be screened, with a target of 102 completed, analyzable participants after an estimated 15 percent attrition.

Intervention (uniform, per protocol): Each participant receives three leukocyte-poor PRP injections at one-week intervals. PRP is prepared by manual double-spin centrifugation (soft spin 1500 rpm for 5 minutes, then hard spin 3300 rpm for 10 minutes) from 20 mL of whole blood per session (total 60 mL per patient across the three sessions), anticoagulated with 8.5 percent ACD-A, without exogenous activation, targeting a 4 to 6 fold platelet concentration. Injections are delivered under ultrasound guidance via a superolateral approach with skin infiltration of 1 percent lidocaine. A 48-hour restriction on non-steroidal anti-inflammatory drugs is applied after each injection.

Biomarkers: The primary predictor is the baseline NLR. Secondary predictors are PLR, SII, and MLR; tertiary predictors are C-reactive protein and erythrocyte sedimentation rate. All are derived from a routine baseline complete blood count.

Outcomes: The primary clinical outcome is the change in WOMAC total score at 6 months. Treatment response is defined a priori as at least 30 percent improvement in WOMAC together with fulfilment of the OMERACT-OARSI responder criteria. Clinical assessments occur at baseline and at 1, 3, and 6 months.

PRP Product Characterization: Quality control is performed in two tiers. Tier 1 (all 120 patients, all 360 batches) records the final platelet concentration, the total leukocyte count, and the final volume. Tier 2, a pre-specified validation subset of approximately 40 patients (the first 20 consecutive patients plus every fifth subsequent patient, approximately 120 batches), additionally records the leukocyte differential and erythrocyte contamination.

Statistical Analysis and Sample Size: The primary analysis is a multivariable linear regression of 6-month WOMAC change on baseline NLR, adjusted for age, body mass index, Kellgren-Lawrence grade, and baseline WOMAC. A secondary analysis evaluates the discriminative performance of baseline NLR for responder status by receiver operating characteristic analysis. For the primary regression (alpha 0.05, power 0.80, one numerator degree of freedom, five predictors, effect size f-squared 0.10), 82 participants are required; the secondary analysis requires 95. To satisfy both, the enrollment target is 120, anticipating 102 completers.

Ethics and Reporting: Ethics approval is sought from the Girne University Clinical Research Ethics Committee. Reporting follows the STROBE and REMARK recommendations, and the protocol follows SPIRIT guidance.

• Study Type: Observational
• Enrollment (Estimated): 120

Contacts and Locations

• Study Contact: Name: Utku Gurhan, MD; Phone Number: +90 539 112 6898; Email: utkugrhn@gmail.com

Study Locations

• Cyprus
  • Kyrenia, Cyprus
    • University of Kyrenia, Dr. Suat Gunsel Hospital - Department of Orthopaedics and Traumatology
    • Contact: Utku Gurhan, MD; Email: utkugrhn@gmail.com
    • Principal Investigator: Utku Gurhan, MD
    • Sub-Investigator: Fazli Levent Umur, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Adult patients aged 40 to 60 years presenting to the orthopedic clinic of the University of Kyrenia, Dr. Suat Gunsel Hospital, with symptomatic primary knee osteoarthritis of Kellgren-Lawrence grade 2 or 3, who are candidates for and scheduled to receive a course of intra-articular platelet-rich plasma for the index knee.

Description

Inclusion Criteria:

• Age 40 to 60 years
• Symptomatic primary knee osteoarthritis, Kellgren-Lawrence grade 2 or 3 on weight-bearing radiographs
• Body mass index below 40
• Candidate for and scheduled to receive a course of intra-articular platelet-rich plasma for the index knee
• Able and willing to provide written informed consent and to attend the 6-month follow-up schedule

Exclusion Criteria:

• Systemic inflammatory or autoimmune disease
• Active acute infection at the time of enrollment
• Current anticoagulant or antiplatelet therapy, or current or recent chemotherapy
• Any contraindication to platelet-rich plasma per the 2025 GRIIP recommendations
• Intra-articular injection of the index knee within the previous 6 months
• Inability to comply with the planned follow-up schedule

Study Plan

How is the study designed?

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in WOMAC total score at 6 months	Change from baseline in the total score of the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) at 6 months after the first injection. The primary analysis is a multivariable linear regression testing the baseline neutrophil-to-lymphocyte ratio (NLR) as the predictor of interest, adjusted for age, body mass index, Kellgren-Lawrence grade, and baseline WOMAC score.	Baseline to 6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Treatment response at 6 months (responder versus non-responder)	Treatment response is defined a priori as at least 30 percent improvement in WOMAC total score together with fulfilment of the OMERACT-OARSI responder criteria. The discriminative performance of the baseline NLR for responder status is assessed by receiver operating characteristic analysis with the optimal threshold identified by the Youden index.	Baseline to 6 months
Predictive value of PLR, SII, and MLR for 6-month WOMAC change	Association of the baseline platelet-to-lymphocyte ratio (PLR), systemic immune-inflammation index (SII), and monocyte-to-lymphocyte ratio (MLR) with the change in WOMAC total score at 6 months, evaluated by multivariable regression.	Baseline to 6 months
Change in WOMAC total score at 1 and 3 months	Change from baseline in WOMAC total score at the 1-month and 3-month assessments, describing the trajectory of clinical response.	Baseline to 1 month and to 3 months
Change in knee pain on a Visual Analogue Scale	Change from baseline in knee pain on a Visual Analogue Scale at the 1-month, 3-month, and 6-month assessments.	Baseline to 1, 3, and 6 months
Change in the Knee injury and Osteoarthritis Outcome Score (KOOS)	Change from baseline in the Knee injury and Osteoarthritis Outcome Score (KOOS) subscale scores at 6 months.	Baseline to 6 months
Association of baseline CRP and ESR with treatment response	Exploratory association of the baseline C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) with 6-month treatment response.	Baseline to 6 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Platelet-rich plasma product characterization	Two-tier quality control of the PRP product. Tier 1 (all 120 patients, all 360 batches): final platelet concentration, total leukocyte count, and final volume. Tier 2 (a pre-specified validation subset of approximately 40 patients, approximately 120 batches): leukocyte differential and erythrocyte contamination.	At the three injection sessions (study weeks 1, 2, and 3)

Collaborators and Investigators

• Sponsor: Utku Gürhan
• Investigators: Principal Investigator: Utku Gurhan, MD, University of Kyrenia; Sub-Investigator: Fazli Levent Umur, MD, University of Kyrenia; Sub-Investigator: Enes Sari, MD, Near East University; Sub-Investigator: Yakup Kahve, MD, Ankara City Hospital Bilkent

Publications and helpful links

General Publications

• Tonutti et al. Biomed Pharmacother. 2025. doi:10.1016/j.biopha.2025.118674
• De Luca et al. Nutrients. 2025. doi:10.3390/nu17193134
• Lee et al. BMC Musculoskelet Disord. 2024. doi:10.1186/s12891-024-07475-1
• Zhang et al. Front Med (Lausanne). 2026. doi:10.3389/fmed.2026.1787872
• Louis et al. Arthroscopy. 2021. doi:10.1016/j.arthro.2021.03.074
• GRIIP recommendations on intra-articular orthobiologics. Knee Surg Sports Traumatol Arthrosc. 2025. doi:10.1002/ksa.12682

Study record dates

Study Major Dates

• Study Start (Estimated): September 1, 2026
• Primary Completion (Estimated): July 1, 2027
• Study Completion (Estimated): July 1, 2027

Study Registration Dates

• First Submitted: May 20, 2026
• First Submitted That Met QC Criteria: May 20, 2026
• First Posted (Actual): June 1, 2026

Study Record Updates

• Last Update Posted (Actual): June 1, 2026
• Last Update Submitted That Met QC Criteria: May 20, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: knee osteoarthritis; biomarker; WOMAC; PRP; platelet-rich plasma; predictor; intra-articular injection; NLR; neutrophil-to-lymphocyte ratio; systemic immune-inflammation index; inflammatory index
• Additional Relevant MeSH Terms: Musculoskeletal Diseases; Arthritis; Joint Diseases; Rheumatic Diseases; Osteoarthritis; Osteoarthritis, Knee
• Other Study ID Numbers: PRP-NLR-2026

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: De-identified participant-level data will be made available upon reasonable request to the corresponding author after publication, subject to institutional and ethics-committee approval. Aggregated summary tables will accompany the published manuscript as supplementary material.
• IPD Sharing Time Frame: Beginning 6 months after manuscript publication, with no specified end date.
• IPD Sharing Access Criteria: Reasonable request for academic research purposes; a data use agreement to be signed.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; ANALYTIC_CODE

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No