Inhibition of Fenton reaction is a novel mechanism to explain the therapeutic effect of intra‐articular injection of PRP in patients with chronic haemophilic synovitis

Abstract

Introduction and Aim: Haemarthroses cause major morbidity in haemophilia resulting in chronic haemophilic synovitis (CHS) and arthropathy. Oxidation of haemoglobin-coupled iron released in synovium after haemolysis induces chondrocytes death and cartilage damage, allowing postulate using iron-chelating drugs as potential therapeutic tool for haemophilic joint damage. Considering that albumin, the most abundant plasma protein, is a physiologic iron chelator, we aim to demonstrate that impediment of haemoglobin oxidation is exerted by plasma as a mechanism involved in the therapeutic effect of intra-articular injection of platelet-rich plasma in CHS. Methods: Oxidation of haemoglobin (Hb) to methaemoglobin (MeHb) through Fenton reaction was induced in vitro by addition of potassium ferricyanide in the presence or absence of peripheral blood-derived platelets-rich or platelets-poor plasma (PRP/ PPP) or albumin. The relevance of in vitro findings was analysed in synovial fluid (SF) samples from one patient with CHS obtained before and after 6 months of PRP intraarticular injection. Results: MeHb formation was completely impaired either by of PPP, PRP or albumin indicating that PRP exerts an anti-oxidative effect, probably due by plasma albumin. Analysis of SF samples revealed the presence of MeHb levels and haemosiderinladen macrophages in SF obtained before PRP treatment. Reduction of synovial MeHb, normalization of cellular composition and improvement of health joint haemophilic score, pain and bleeding episodes were registered after 6 months of PRP intra-articular injection. Conclusion: Inhibition of Fenton reaction and the consequent normalization of joint cellular composition is a noncanonical mechanism underlying the therapeutic effect of PRP intra-articular injection in CHS. K E Y W O R D S haemophilia, methaemoglobin, platelets-rich plasma, PRP intra-articular injection, synovitis e188 | CAVIGLIA et AL.

Platelet-rich plasma vs platelet-rich plasma plus hyaluronic acid for haemophilic knee arthropathy treatment

“…Our previous, in vitro, experimental study demonstrated that oxidation of Hb (hemoglobin) to MeHb was completely inhibited either by PRP, PPP or albumin as a physiologic iron chelator and ROS scavenger, it is possible that plasma albumin contributes to the anti-oxidative role of PRP. This could explain the therapeutic effect of intra-articular joint injection of PRP in patients with haemophilia (31). It is also feasible that the albumin applied with the PRP, reduces the amount of intra-articular ROS and prevents the degradation of hyaluronic acid.…”

“…Acta Orthopaedica Belgica, Vol. 87 -4 -2021 hypothesis that ROS are responsible for the accelerated degradation of HA in rheumatoid joints (29,31).…”

Moving toward targeting the right phenotype with the right platelet-rich plasma (PRP) formulation for knee osteoarthritis

“…PRP interfered with the conversion of haemoglobin to methaemoglobin and was effective in patients with chronic haemophilic synovitis pain and bleeding episodes. 56…”

DNA extracellular traps as potential biomarker of chronic haemophilic synovitis and therapeutic perspective in patients treated with PRP: A pilot study

“…5 In addition, and in the context of CHS, we have recently demonstrated that dampening haemoglobin oxidation (and the consequent tissue damage) by plasma is a possible new and non-canonical mechanism underlying the therapeutic effect of PRP in CHS. 6 In this sense, three different clinical groups including ours at the Hospital Fernández in Argentina, have reported that the intraarticular injection of PRP reduces the bleeding episodes in patients with CHS and improves clinical parameters of articular damage. [7][8][9] However, the therapeutic mechanisms underlying PRP in CHS remain to be elucidated, leading to questioning the use of PRP in this pathology.…”

“…On the other hand, plasma offers a fibrin scaffold for regeneration and controls the proliferative and oxidative homeostasis during wound healing 5 . In addition, and in the context of CHS, we have recently demonstrated that dampening haemoglobin oxidation (and the consequent tissue damage) by plasma is a possible new and non‐canonical mechanism underlying the therapeutic effect of PRP in CHS 6 . In this sense, three different clinical groups including ours at the Hospital Fernández in Argentina, have reported that the intraarticular injection of PRP reduces the bleeding episodes in patients with CHS and improves clinical parameters of articular damage 7–9 .…”