Angiopoietin2 is associated with coagulation activation and tissue factor expression in extracellular vesicles in COVID-19.

Coagulation activation in immunothrombosis involves various pathways distinct from classical hemostasis, offering potential therapeutic targets to control inflammation-induced hypercoagulability while potentially sparing hemostasis. The Angiopoietin/Tie2 pathway, previously linked to embryonic angiogenesis and sepsis-related endothelial barrier regulation, was recently associated with coagulation activation in sepsis and COVID-19. This study explores the connection between key mediators of the Angiopoietin/Tie2 pathway and coagulation activation. The study included COVID-19 patients with hypoxia and healthy controls. Blood samples were processed to obtain platelet-free plasma, and frozen until analysis. Extracellular vesicles (EVs) in plasma were characterized and quantified using flow cytometry, and their tissue factor (TF) procoagulant activity was measured using a kinetic chromogenic method. Several markers of hemostasis were assessed. Levels of ANGPT1, ANGPT2, and soluble Tie2 correlated with markers of coagulation and platelet activation. EVs from platelets and endothelial cells were increased in COVID-19 patients, and a significant increase in TF+ EVs derived from endothelial cells was observed. In addition, ANGPT2 levels were associated with TF expression and activity in EVs. In conclusion, we provide further evidence for the involvement of the Angiopoietin/Tie2 pathway in the coagulopathy of COVID-19 mediated in part by release of EVs as a potential source of TF activity.

Sacral Bioneuromodulation: The Role of Bone Marrow Aspirate in Spinal Cord Injuries.

Spinal cord injury (SCI) represents a severe trauma to the nervous system, leading to significant neurological damage, chronic inflammation, and persistent neuropathic pain. Current treatments, including pharmacotherapy, immobilization, physical therapy, and surgical interventions, often fall short in fully addressing the underlying pathophysiology and resultant disabilities. Emerging research in the field of regenerative medicine has introduced innovative approaches such as autologous orthobiologic therapies, with bone marrow aspirate (BMA) being particularly notable for its regenerative and anti-inflammatory properties. This review focuses on the potential of BMA to modulate inflammatory pathways, enhance tissue regeneration, and restore neurological function disrupted by SCI. We hypothesize that BMA's bioactive components may stimulate reparative processes at the cellular level, particularly when applied at strategic sites like the sacral hiatus to influence lumbar centers and higher neurological structures. By exploring the mechanisms through which BMA influences spinal repair, this review aims to establish a foundation for its application in clinical settings, potentially offering a transformative approach to SCI management that extends beyond symptomatic relief to promoting functional recovery.

The role of orthobiologics in chronic wound healing.

Chronic wounds, characterized by prolonged healing processes, pose a significant medical challenge with multifaceted aetiologies, including local and systemic factors. Here, it explores the complex pathogenesis of chronic wounds, emphasizing the disruption in the normal phases of wound healing, particularly the inflammatory phase, leading to an imbalance in extracellular matrix (ECM) dynamics and persistent inflammation. Senescent cell populations further contribute to impaired wound healing in chronic lesions. Traditional medical management focuses on addressing underlying causes, but many chronic wounds resist to conventional treatments, necessitating innovative approaches. Recent attention has turned to autologous orthobiologics, such as platelet-rich plasma (PRP), platelet-rich fibrin (PRF) and mesenchymal stem cells (MSCs), as potential regenerative interventions. These biologically derived materials, including bone marrow aspirate/concentrate (BMA/BMAC) and adipose tissue-derived stem cells (ADSCs), exhibit promising cytokine content and regenerative potential. MSCs, in particular, have emerged as key players in wound healing, influencing inflammation and promoting tissue regeneration. This paper reviews relevant scientific literature regarding basic science and brings real-world evidence regarding the use of orthobiologics in the treatment of chronic wounds, irrespective of aetiology. The discussion highlights the regenerative properties of PRP, PRF, BMA, BMAC and SVF, showcasing their potential to enhance wound healing. Despite advancements, further research is essential to elucidate the specific roles of each orthobiologic and determine optimal applications for different wound types. The conclusion underscores the evolving landscape in chronic wound management, with a call for more comprehensive studies to refine treatment strategies and maximize the benefits of regenerative medicine.

Platelet-Rich Plasma Power-Mix Gel (ppm)-An Orthobiologic Optimization Protocol Rich in Growth Factors and Fibrin.

Platelet- and fibrin-rich orthobiologic products, such as autologous platelet concentrates, have been extensively studied and appreciated for their beneficial effects on multiple conditions. Platelet-rich plasma (PRP) and its derivatives, including platelet-rich fibrin (PRF), have demonstrated encouraging outcomes in clinical and laboratory settings, particularly in the treatment of musculoskeletal disorders such as osteoarthritis (OA). Although PRP and PRF have distinct characteristics, they share similar properties. The relative abundance of platelets, peripheral blood cells, and molecular components in these orthobiologic products stimulates numerous biological pathways. These include inflammatory modulation, augmented neovascularization, and the delivery of pro-anabolic stimuli that regulate cell recruitment, proliferation, and differentiation. Furthermore, the fibrinolytic system, which is sometimes overlooked, plays a crucial role in musculoskeletal regenerative medicine by regulating proteolytic activity and promoting the recruitment of inflammatory cells and mesenchymal stem cells (MSCs) in areas of tissue regeneration, such as bone, cartilage, and muscle. PRP acts as a potent signaling agent; however, it diffuses easily, while the fibrin from PRF offers a durable scaffolding effect that promotes cell activity. The combination of fibrin with hyaluronic acid (HA), another well-studied orthobiologic product, has been shown to improve its scaffolding properties, leading to more robust fibrin polymerization. This supports cell survival, attachment, migration, and proliferation. Therefore, the administration of the "power mix" containing HA and autologous PRP + PRF may prove to be a safe and cost-effective approach in regenerative medicine.

Platelet-Rich Plasma Gel Matrix (PRP-GM): Description of a New Technique.

Several musculoskeletal conditions are triggered by inflammatory processes that occur along with imbalances between anabolic and catabolic events. Platelet-rich plasma (PRP) is an autologous product derived from peripheral blood with inherent immunomodulatory and anabolic properties. The clinical efficacy of PRP has been evaluated in several musculoskeletal conditions, including osteoarthritis, tendinopathy, and osteonecrosis. When used in combination with hyaluronic acid (HA), a common treatment alternative, the regenerative properties of PRP are significantly enhanced and may provide additional benefits in terms of clinical outcomes. Recently, a new PRP-derived product has been reported in the literature and is being referred to as "plasma gel". Plasma gels are obtained by polymerizing plasmatic proteins, which form solid thermal aggregates cross-linked with fibrin networks. Plasma gels are considered to be a rich source of growth factors and provide chemotactic, migratory, and proliferative properties. Additionally, clot formation and the associated fibrinolytic reactions play an additional role in tissue repair. There are only a few scientific articles focusing on plasma gels. Historically, they have been utilized in the fields of aesthetics and dentistry. Given that the combination of three products (PRP, HA, and plasma gel) could enhance tissue repair and wound healing, in this technical note, we propose a novel regenerative approach, named "PRP-HA cellular gel matrix" (PRP-GM), in which leukocyte-rich PRP (LR-PRP) is mixed with a plasma gel (obtained by heating the plasma up) and HA in one syringe using a three-way stopcock. The final product contains a fibrin-albumin network entangled with HA's polymers, in which the cells and biomolecules derived from PRP are attached and released gradually as fibrinolytic reactions and hyaluronic acid degradation occur. The presence of leukocytes, especially monocytes and macrophages, promotes tissue regeneration, as type 2 macrophages (M2) possess an anti-inflammatory feature. In addition, HA promotes the viscosuplementation of the joint and induces an anti-inflammatory response, resulting in pain relief. This unique combination of biological molecules may contribute to the optimization of regenerative protocols suitable for the treatment of degenerative musculoskeletal diseases.

The Mechanism of Action between Pulsed Radiofrequency and Orthobiologics: Is There a Synergistic Effect?

Radiofrequency energy is a common treatment modality for chronic pain. While there are different forms of radiofrequency-based therapeutics, the common concept is the generation of an electromagnetic field in the applied area, that can result in neuromodulation (pulsed radiofrequency-PRF) or ablation. Our specific focus relates to PRF due to the possibility of modulation that is in accordance with the mechanisms of action of orthobiologics. The proposed mechanism of action of PRF pertaining to pain relief relies on a decrease in pro-inflammatory cytokines, an increase in cytosolic calcium concentration, a general effect on the immune system, and a reduction in the formation of free radical molecules. The primary known properties of orthobiologics constitute the release of growth factors, a stimulus for endogenous repair, analgesia, and improvement of the function of the injured area. In this review, we described the mechanism of action of both treatments and pertinent scientific references to the use of the combination of PRF and orthobiologics. Our hypothesis is a synergic effect with the combination of both techniques which could benefit patients and improve the life quality.

Contact and intrinsic coagulation pathways are activated and associated with adverse clinical outcomes in COVID-19.

Coagulation activation is a prominent feature of severe acute respiratory syndrome coronavirus 2 (COVID-19) infection. Activation of the contact system and intrinsic pathway has increasingly been implicated in the prothrombotic state observed in both sterile and infectious inflammatory conditions. We therefore sought to assess activation of the contact system and intrinsic pathway in individuals with COVID-19 infection. Baseline plasma levels of protease:serpin complexes indicative of activation of the contact and intrinsic pathways were measured in samples from inpatients with COVID-19 and healthy individuals. Cleaved kininogen, a surrogate for bradykinin release, was measured by enzyme-linked immunosorbent assay, and extrinsic pathway activation was assessed by microvesicle tissue factor-mediated factor Xa (FXa; MVTF) generation. Samples were collected within 24 hours of COVID-19 diagnosis. Thirty patients with COVID-19 and 30 age- and sex-matched controls were enrolled. Contact system and intrinsic pathway activation in COVID-19 was demonstrated by increased plasma levels of FXIIa:C1 esterase inhibitor (C1), kallikrein:C1, FXIa:C1, FXIa:α1-antitrypsin, and FIXa:antithrombin (AT). MVTF levels were also increased in patients with COVID-19. Because FIXa:AT levels were associated with both contact/intrinsic pathway complexes and MVTF, activation of FIX likely occurs through both contact/intrinsic and extrinsic pathways. Among the protease:serpin complexes measured, FIXa:AT complexes were uniquely associated with clinical indices of disease severity, specifically total length of hospitalization, length of intensive care unit stay, and extent of lung computed tomography changes. We conclude that the contact/intrinsic pathway may contribute to the pathogenesis of the prothrombotic state in COVID-19. Larger prospective studies are required to confirm whether FIXa:AT complexes are a clinically useful biomarker of adverse clinical outcomes.

The role of platelet-rich plasma in the mild and severe stages of atherosclerotic disease in mice.

Background: Platelet-rich plasma (PRP) has a high concentration of growth factors (GFs), which present a therapeutic wound healing effect. Despite having been correlated with an immunomodulatory function, the administration of PRP has not yet been investigated in atherosclerosis models. Aim: Evaluate the effect of lyophilized PRP on atherosclerosis in mice models through serum analysis. Methods: Animals received a high-fat diet for disease induction and a weekly PRP retro-orbital application. Effectiveness was evaluated by measuring inflammatory markers in plasma following the treatment of mice with either PRP or saline solution. Results: PRP was well characterized for platelet and GF concentrations; the atherosclerotic profile was established. Cytokine concentrations were altered after PRP applications. Conclusion: PRP could modulate the inflammatory pattern in the early stages of atherosclerosis.

Platelet-rich plasma (PRP) contains growth factors, which stimulate normal wound healing. This product seems to be a good modulator of white blood cells and has not been investigated in atherosclerosis. This study aimed to evaluate PRP in atherosclerosis using mice models. The PRP was produced from animals and preserved using the lyophilization technique; the product was then applied weekly in the vein. For atherosclerosis induction, genetically modified animals were fed a high-fat diet. The effectiveness was evaluated by measuring plasma inflammatory markers after treatment, and PRP seemed to alter cell-signaling molecules (cytokines). This study concluded that PRP was capable of modulating the inflammatory pattern during the early stages of atherosclerosis.

Characterization of autologous platelet rich plasma (PRP) and its biological effects in patients with Behçet's Disease.

INTRODUCTION: Behçet's disease (BD) is an immune-mediated chronic systemic vasculitis, characterized by clinical manifestations that include: mucocutaneous ulcers, ocular involvement, immunological alterations, vascular and neurological implications. The available treatments present limitations such as high cost and side effects, and the search for a low-cost biological treatment with immunomodulatory potential becomes of great value. Platelet rich plasma (PRP) has some characteristics that indicate a possible use as an immunomodulator due to the wide range of secreted cytokines, especially through the participation of TGF-ß1 in the differentiation of T regulatory cells (Treg). This study aimed to characterize the PRP poor in leukocytes (P-PRP) of patients with BD and active ulcers and to evaluate its effects as an immunomodulator through a subcutaneous application. METHODS: We selected patients with a diagnosis of BD, with a low dose of prednisone and with no central nervous system or ocular involvement. Platelet and leukocyte count and quantification of 17 cytokines were evaluated in P-PRP. The effects of P-PRP were evaluated by cell frequency of TCD4 +, TCD8 +, Treg, natural killer (NK), and activated NK, as well as by the cytokine profile in patient's plasma, and the clinical manifestations through score and questionnaire. Also, it was evaluated the number and timing of oral ulcer closure. PRP was used as an adjuvant, with 9 applications of 3 mL, over 6 months, with a follow-up of one year. RESULTS: The results using PRP showed adequate values and no significant inter-and intra-individual variations. The systemic evaluations during the use of PRP showed significant alterations, characterized by the increase in Treg cell frequency (p = 0.0416) and a decrease in activated NK cells (p = 0.0010). However, no clinical correlation was observed through score analysis. The most relevant clinical data was the decrease in the closing time of ulcers throughout the application period. CONCLUSION: In a pilot study with BD patients, P-PRP promoted an anti-inflammatory profile characterized by increased Treg cells and decreased activated NK cells and alterations in cytokines. A clinical improvement was observed with a decrease in the number and time of closure of oral ulcers.

Human platelet lysate - A potent (and overlooked) orthobiologic.

The knowledge of the essential role of platelets in tissue healing is gradually increasing and as regenerative medicine prompts new solutions, platelet-derived bioproducts have been proposed as a potential tool in this field. In orthopaedics and sports medicine, the use of PRP has been rapidly increasing in popularity as patients seek novel non-surgical approaches to acute and chronic musculoskeletal conditions. The concept of having platelets as a secretory organ other than a mere sponge-like coagulation component opens up new frontiers for the use of the platelet secretome. Platelet lysate is a solution saturated by growth factors, proteins, cytokines, and chemokines involved in crucial healing processes and is administered to treat different diseases such as alopecia, oral mucositis, radicular pain, osteoarthritis, and cartilage and tendon disorders. For this purpose, the abundant presence of growth factors and chemokines stored in platelet granules can be naturally released by different strategies, mostly through lyophilization, thrombin activation or ultrasound baths (ultrasonication). As a result, human platelet lysate can be produced and applied as a pure orthobiologic. This review outlines the current knowledge about human platelet lysate as a powerful adjuvant in the orthobiological use for the treatment of musculoskeletal injuries, without however failing to raise some of its most applicable basic science.

Orthobiologics in the treatment of hip disorders.

Orthobiologics are biological materials that are intended for the regeneration or healing of bone, cartilage and soft tissues. In this review we discuss the use of orthobiologics for hip disorders providing an update. The orthobiologics included in this article are hyaluronic acid, platelet rich plasma, bone marrow, adipose tissue and expanded mesenchymal stem cells. We explain the concepts and definitions of each orthobiological product, and the literature regarding its use in the hip joint. The paucity of guidelines for the production and characterization of the biological products leads to uneven results across the literature. Each biologic therapy has indications and benefits; however, noteworthy are the characterization of the orthobiologics, the application method and outcome analysis for further improvement of each technique.

A case series of platelet rich plasma in chronic venous ulcers.

INTRODUCTION: Venous ulcers are the most common type of leg wounds (80%) and the main cause is chronic venous insufficiency. Autologous platelet-rich plasma (PRP) is a potential wound healing treatment due to its great variety of growth factors. The aim of this study was to describe in a case series the results of poor-leukocyte PRP (P-PRP) or saline for the treatment of chronic non-healing ulcers of the lower extremity. METHODS: Eight patients were treated according to the topical therapy: saline solution or P-PRP gel. All patients used double compression stocks and were assisted by a vascular practitioner for up to 12 months or until wound healing. The treatment was performed weekly with cleaning of the affected area, macroscopic evaluation (area measurement and photos) and P-PRP or saline application, and closure with Tegaderm®. Trial Registration: Retrospectively approved by Brazilian Clinical Trials, register number RBR-7zhgb3 (http://www.ensaiosclinicos.gov.br/rg/RBR-7zhgb3/). RESULTS: All patients showed signs of wound healing with a reduction in wound size and ulcer numbers, but more evident with P-PRP application. CONCLUSIONS: The results suggested that P-PRP presented a better result when compared to saline solution in the healing process of long clinical course chronic venous ulcers, when associated to compressive stocks and topical care.

The effect of lyophilized platelet rich-plasma on skin aging: a non-randomized, controlled, pilot trial.

Platelet-rich plasma (PRP) showed positive results in the improvement of skin aging. Lyophilized PRP can be interesting in clinical practice due to the facility to obtain many samples in a single blood collection and can be used in multiple injections. To evaluate the effect of lyophilized PRP in the treatment of skin aging, through a Phase II pilot study. Nineteen women (54 years ± 7 years) with Glogau photoaging II and III types were select for this non-randomized, split-face controlled study. They received monthly intradermal injections of lyophilized PRP and saline solution (as control) into the facial skin, during a period of 2 months. The evaluation was performed by imaging method, histological techniques, and multiphoton microscopy. Although lyophilized PRP presented 10 times the platelet baseline value (P < .0001) and growth factors in adequate levels, only saline solution showed an increase of dermis thickness (p = .0009). Collagen pre and post-application remained the same for both types of treatments. The use of lyophilized PRP by mesotherapy showed no improvement on skin aging. TRIAL REGISTRATION APPROVAL: RBR-3n9wxw, UTN U1111-1226-6093-retrospectively registered.

Metabolic syndrome and subchondral bone alterations: The rise of osteoarthritis - A review.

Metabolic syndrome (MS) has become one of the top major health burdens for over three decades not only due to its effects on cardiovascular health but also its implications in orthopedics. Extensive research has shown that MS is tightly linked to osteoarthritis and inflammation, a process which appears to primarily occur in the subchondral bone via the incidence of bone-marrow lesions (BMLs). Numerous studies identify obesity, dyslipidemia, insulin resistance and hypertension as the top metabolic risk factors, the so-called "deadly quartet". These factors are responsible for the disruptive physiological processes that culminate in detrimental alterations within the subchondral bone, cartilage damage and, overall, the predominant pro-inflammatory joint microenvironment. Although it has long been thought that osteoarthritis was limited to the cartilage component of the joint, other studies indicate that the disease may originate from the harmful alterations that occur primarily in the subchondral bone, especially via means of vascular pathology. Since metabolic risk factors are manageable to a certain extent, it is therefore possible to decelerate the progression of OA and mitigate its devastating effects on the subchondral bone and subsequent articular cartilage damage. METHODS: Literature was reviewed using PubMed and Google Scholar in order to find a correlation between metabolic syndrome and osteoarthritic progression. The investigation included a combination of nomenclature such as: "metabolic syndrome", "obesity", "insulin resistance", "hypertension", "dyslipidemia", "low-grade systemic inflammation", "osteoarthritis", "subchondral bone", "cartilage" and "inflammatory biomarkers". CONCLUSION: Based on several studies, there seems to be a significant association between The Deadly Quartet (metabolic syndrome), dysregulation of both pro- and anti-inflammatory biomarkers, and osteoarthritic progression arising from unbridled systemic inflammation.

From Hemophilia to Deep Venous Thrombosis Patient Samples: How to Perform an Easy Coagulometer Validation Process According to Available Guidelines.

Validation protocols for the evaluation of coagulometers are needed to help professionals select the most suitable system for their regular laboratory routines. The objective of this study was to show how high standard protocols for the coagulometer validation process can fit into the daily laboratory routine. For this study, 45 healthy individuals and 112 patient samples were analyzed. From the patient samples, 51 were investigated for deep venous thrombosis, 27 for coagulopathy, 19 for antivitamin K therapy, and 15 for hemophilia. For the assessment, the performance of the 3 coagulometers and 1 point-of-care device was considered. One of the coagulometers was a new acquisition evaluated for precision, linearity, throughput, and carryover in the first moment, and the new coagulometer was then compared with the other well-established equipment in the laboratory. In normal plasma, coefficient of variation was ≤1.8% for total precision in screening tests and ≤3.5% for within-run precision in specific assays. For prothrombin time/international normalized ratio, no significant difference was found when comparing methods. Our study showed how to compare the capacity of a reagent in order to discriminate patients with severe hemophilia from patients with moderated hemophilia, and the κ coefficient agreement was 0.669 (95% confidence interval: 0.3-1.0; P < .001). d-dimer evaluated in patients with deep venous thrombosis and controls showed a 20% discrepancy between the methods. In our experience across Latin America, the number of laboratories that has performed this process is limited. In this study, we demonstrated how to adapt the validation process for the hemostasis laboratory routine to help the professional chose the best and more suitable option.

Bone marrow-derived products: A classification proposal - bone marrow aspirate, bone marrow aspirate concentrate or hybrid?

Degenerative musculoskeletal disorders are one of the top causes of pain and disability in the adult population. Current available alternatives to mitigate symptoms include conservative treatments such as the administration of pharmacological agents and an educative approach towards lifestyle modification. The use of certain analgesics, such as opiates and corticosteroids, delivers short term results but do not address the etiological source of pain and disability. Also, prolonged use of such medications may cause additional complications. Therefore, the demand for musculoskeletal tissue regeneration has led to an alternative approach referred to as "orthobiologics". This alternative is based on cellular and molecular components capable of inducing and promoting tissue repair. Bone marrow (BM) aspirate (BMA) and concentrate are well-known orthobiologics used to treat musculoskeletal conditions. Orthobiologics derived from the BM have been discussed in the literature; however, the lack of standardization regarding collection and processing protocols presents a challenge for generalization of study outcomes and determination of efficacy. Since BM-derived orthobiologics have not yet been classified, to our knowledge, this manuscript proposes the ACH classification system, which speaks to BMA (A), BMA and concentrate (C) and hybrid (H), which combines A and C. This classification proposes and describes 8 parameters that are relevant for the quality of biological products. The more parameters used would imply greater characterization and complexity of the evaluation of the biological product used. The ACH classification envisages a necessary contribution to the comprehension of both clinical procedures and research outcomes, ultimately ushering in a standardization of best practice.

Low prevalence of Post-thrombotic syndrome in patients treated with rivaroxaban.

Post-thrombotic syndrome (PTS) is a complication of deep vein thrombosis (DVT). Residual vein thrombus (RVT) on Doppler Ultrasound can be associated with PTS. Limited data are available on the effect of direct oral anticoagulants (DOACs) on the long-term outcome of PTS. This study aimed to compare the prevalence of PTS and RVT, in patients with previous DVT treated with rivaroxaban or enoxaparin/warfarin. A total of 129 patients with previous proximal lower limb DVT and treated with rivaroxaban (n = 71) or enoxaparin/warfarin (n = 58) for at least 3 months were included. The Villalta scale for PTS was performed after treatment. The median duration of the DVT symptoms before anticoagulation was 7 days for both groups. The rate of PTS was 50.7% in the patients treated with rivaroxaban and 69% in the enoxaparin/warfarin group. Enoxaparin/warfarin showed an increased prevalence of PTS (P = .018). An analysis in 3 different models showed that the relative risk of PTS decreased by 76% with rivaroxaban use when compared with enoxaparin/warfarin treatment. In addition, 93 of the 129 patients were evaluated regarding the presence of RVT, of which, 11 (24.4%) and 31 (64.6%) presented with RVT for rivaroxaban and enoxaparin/warfarin, respectively (P < .0001). The RVT analysis excluded the possibility of RVT as a mediator of the association between type of treatment and PTS when comparing rivaroxaban with enoxaparin/warfarin (odds ratio (OR) = 0.14; 95% confidence interval (CI): 0.1-1.0, P = .051) with rivaroxaban compared with enoxaparin/warfarin. Rivaroxaban treatment was associated with a lower risk of PTS when compared to enoxaparin/warfarin; RVT however, was not a mediator in the association between PTS and type of treatment.

Leukocyte-rich PRP versus leukocyte-poor PRP - The role of monocyte/macrophage function in the healing cascade.

The mechanism of action of Platelet Rich Plasma (PRP) is thought to be related to the biomolecules present in α-granules. However, for the healing process to occur, an inflammatory phase is also deemed necessary. Leukocytes present in the inflammatory phase release both pro- and anti-inflammatory molecules. The latter may play an important role in the process of "inflammatory regeneration". Thus, we propose that in the context of healing, both platelets and leukocytes play an important role, specifically due to the macrophage's plasticity to switch from the M1 to M2 fraction. Therefore, we propose that PRP products derived from the buffy coat may be more beneficial than detrimental from a standpoint of the regenerative potential of PRP.