Where Are We Now?
Hemophilic arthropathy is a particular type of secondary osteoarthritis (OA) that occurs because of recurrent hemarthrosis in patients with hemophilia Types A or B, which are rare X-linked inherited bleeding disorders caused by a complete or partial deficiency in or the absence of coagulation factors VIII and IX . Recent epidemiologic work suggested that hemophilia, although not common, is more prevalent than once believed, and it appears to infect more than 30,000 men in the United States alone .
Despite advances in the clinical treatment of hemophilia, hemophilic OA remains a major problem [10, 18]. Once hemophilic arthropathy is established, evidence supporting the use of intra-articular injections of various drugs (such as hyaluronic acid, corticosteroids, platelet-rich-plasma [PRP], and cell-based therapies) remains very low . Therefore, we need clinical studies to assess the efficacy of clinically available treatments to improve the pain and function of patients suffering from this condition.
In this issue of Clinical Orthopaedics and Related Research®, Duan al.  compared the effect of PRP with that of placebo in patients with hemophilic knee arthritis at 2 years of follow-up. This randomized controlled study did not find any evidence that PRP reduces pain or improves clinical function in patients with hemophilic arthritis; therefore, the authors recommended against using these injections. I agree.
Where Do We Need To Go?
Orthobiologic approaches (such as PRP or bone marrow aspirate concentrate) to treating various musculoskeletal conditions continue to attract interest [5, 13, 16]. Despite advances, further basic and translational research is required, as well as well-designed randomized controlled trials to better determine the best indications for and efficacy of orthobiologics.
Because there is a continued need for evidence-based orthopaedic practice to better inform patient care, studies with both positive and no-difference (or negative) findings are important . Overall, many studies have had conflicting clinical findings regarding the use of PRP for knee OA. Despite limitations and methodologic flaws in previous studies [6, 11, 15, 20], PRP to treat knee OA may be as or more effective than other available nonsurgical treatments in terms of pain, function, and adverse events. However, in primary OA, when considering direct and unpaid indirect costs, PRP injections have been deemed to be not cost-effective compared with TKA, mainly because there is little established evidence supporting its clinical efficacy in relieving pain, improving function, and delaying TKA . However, PRP may have value for higher-risk patients who have greater perioperative complication rates, TKA revision rates, or poorer postoperative outcomes . Identifying these potential indications remains of paramount importance.
Additionally, not all PRP preparations are the same . The reporting of PRP preparation protocols in clinical studies has been highly inconsistent , and most studies do not provide sufficient information to allow the protocol to be reproduced. This heterogeneity in the reporting of PRP preparation and composition also hinders comparison among PRP products and PRP studies . Future studies will need to expand on PRP formulations that appear to decrease pain or improve function more effectively than others.
Furthermore, there are still gaps regarding our understanding of disease pathogenesis for symptomatic primary OA and secondary arthritis, and the mechanism of disease needs to be better understood in order to allow a better understanding of treatment for these conditions.
Similar to primary OA, in hemophilic arthritis, there is a need for not only new treatments but also biomarkers that can help with early screening for joint disease for more rapid diagnosis and to help monitor progression so that timely interventions might be administered [10, 11, 14].
How Do We Get There?
The presence of different OA phenotypes and patient subgroups raises the opportunity for more-targeted, patient-specific approaches to prevention and treatment . For example, degradomics (genomic and proteomic approaches devoted to identifying protease and protease-substrate repertoires, or “degradomes”) of OA cartilage (such as HtrA1) may explain OA proteolytic pathways and provide new biomarkers . An enhanced understanding of disease mechanisms and pathogenesis will then shed light on new treatment targets.
A difference is only important if it makes a difference. Effect size should be the focus of our clinical research, and we should take care to report clinical thresholds such as the minimum clinically important difference, substantial clinical benefit, and the patient-acceptable symptom state to determine the clinical effect of new treatments . These thresholds relate to clinical significance to help determine whether the results or outcomes used to assess the effectiveness or efficacy of a treatment modality will have genuine and quantifiable clinical effects. When interpreting a clinical study, statistically significant results may not be of clinical importance; on the other hand, results that are of clinical importance may not be statistically significant.
As PRP research continues, further basic and translational research is still required to elucidate which factors in PRP affect patients who are responders. Different PRP formulations may be needed for different tissues and pathologies, and an improved understanding of the underlying structural and compositional deficiencies of the diseased tissue will help to identify the biologic needs that can be targeted with PRP. This will allow the field to progress to more sophisticated PRP preparations. Finally, well-design randomized control trials and prospective studies will be required to determine the efficacy of and best indications for orthobiologics. Overall, studies with negative findings such as the one by Duan et al.  may seem disappointing; however, they provide an essential step in our search to advance patient care.
1. Bhutada S, Li L, Willard B, Muschler G, Piuzzi N, Apte SS. Forward and reverse degradomics defines the proteolytic landscape of human knee osteoarthritic cartilage and the role of the serine protease HtrA1. Osteoarthritis Cartilage. Published online March 23, 2022. DOI: 10.1016/j.joca.2022.02.622
2. Buccheri E, Avola M, Vitale N, Pavone P, Vecchio M. Haemophilic arthropathy: a narrative review on the use of intra-articular drugs for arthritis. Haemophilia. 2019;25:919-927.
3. Centers for Disease Control. A new study of hemophilia occurrence finds many more cases in the United Sates. Available at: https://www.cdc.gov/ncbddd/hemophilia/features/keyfinding-hemophilia-occurrence-US.html
. Accessed June 7, 2022.
4. Chahla J, Cinque ME, Piuzzi NS, et al. A call for standardization in platelet-rich plasma preparation protocols and composition reporting: a systematic review of the clinical orthopaedic literature. J Bone Joint Surg Am.
5. Chu CR, Rodeo S, Bhutani N, et al. Optimizing clinical use of biologics in orthopaedic surgery: consensus recommendations from the 2018 AAOS/NIH U-13 conference. J Am Acad Orthop Surg.
6. Costa LAV, Lenza M, Irrgang JJ, Fu FH, Ferretti M. How does platelet-rich plasma compare clinically to other therapies in the treatment of knee osteoarthritis? A systematic review and meta-analysis. Am J Sports Med.
7. Duan W, Su X, Yu Z, et al. No benefit to platelet-rich plasma over placebo injections in terms of pain or function in patients with hemophilic knee arthritis: a randomized trial. Clin Orthop Relat Res.
8. Emara AK, Klika AK, Piuzzi NS. Evidence-based orthopedic surgery-from synthesis to practice. JAMA Surg.
9. Gooding R, Thachil J, Alamelu J, Motwani J, Chowdary P. Asymptomatic joint bleeding and joint health in hemophilia: a review of variables, methods, and biomarkers. J Blood Med.
10. Gualtierotti R, Solimeno LP, Peyvandi F. Hemophilic arthropathy: current knowledge and future perspectives. J Thromb Haemost.
11. Lewis E, Merghani K, Robertson I, et al. The effectiveness of leucocyte-poor platelet-rich plasma injections on symptomatic early osteoarthritis of the knee: the PEAK randomized controlled trial. Bone Joint J.
12. Mantripragada VP, Csorba A, Bova W, et al. Assessment of clinical, tissue, and cell-level metrics identify four biologically distinct knee osteoarthritis patient phenotypes. Cartilage. 2022;13:1947603522107400.
13. Murray IR, Chahla J, Frank RM, Piuzzi NS, Mandelbaum BR, Dragoo JL. Rogue stem cell clinics. Bone Joint J.
14. Orr MN, Klika AK, Gagnier JJ, Bhandari M, Piuzzi NS. A call for a standardized approach to reporting patient-reported outcome measures: clinical relevance ratio. J Bone Joint Surg Am.
15. Piuzzi NS, Chughtai M, Khlopas A, et al. Platelet-rich plasma for the treatment of knee osteoarthritis: a review. J Knee Surg.
16. Piuzzi NS, Dominici M, Long M, et al. Proceedings of the signature series symposium “cellular therapies for orthopaedics and musculoskeletal disease proven and unproven therapies-promise, facts and fantasy,” International Society for Cellular Therapies, Montreal, Canada, May 2, 2018. Cytotherapy. 2018;20:1381-1400.
17. Rajan PV, Ng MK, Klika A, et al. The cost-effectiveness of platelet-rich plasma injections for knee osteoarthritis: a Markov decision analysis. J Bone Joint Surg Am.
18. Rodriguez-Merchan EC. Management of musculoskeletal complications in patients with hemophilia: literature review and expert recommendations. Cardiovasc Hematol Disord Drug Targets. 2021;21:162-166.
19. Rossi LA, Murray IR, Chu CR, Muschler GF, Rodeo SA, Piuzzi NS. Classification systems for platelet-rich plasma. Bone Joint J.
20. Szwedowski D, Mobasheri A, Moniuszko A, Zabrzyński J, Jeka S. Intra-articular injection of platelet-rich plasma is more effective than hyaluronic acid or steroid injection in the treatment of mild to moderate knee osteoarthritis: a prospective, randomized, triple-parallel clinical trial. Biomedicines. 2022;10:991.