Application of platelet concentrates in periodontal regeneration

Introduction:

With our improved understanding regarding cellular and molecular mechanisms involved in periodontal wound healing, various regenerative techniques including “Root surface biomodification”, “Guided tissue regeneration”, “guided bone regeneration”, “Application of growth factors”, and “Application of platelet concentrates” have been introduced to achieve maximum periodontal regeneration. Application of platelet concentrates has been our focus of research for quite some time now. We have strong evidence derived from medical and dental literature supporting the use of autogenous PRP in clinical practice 1, 2. PRP was approved for clinical use in 1998 3. Since then there have been numerous uses of platelet concentrates including: dental implant procedures, bone grafting, periodontal surgeries and its application directly into extraction sockets to facilitate healing.

In the present discussion we shall study in detail various forms of platelet concentrates and their application in periodontal regeneration.

Importance of platelets during wound healing:

Wound healing is a complex process which involves many cell types and growth factors 4-6. Platelets contain high quantities of key growth factors, which are involved in cell proliferation, matrix remodelling and angiogenesis. These include PDGF-AB (platelet-derived growth factor AB), IGF (insulin like growth factors), TGF β-1 (transforming growth factor β-1) and VEGF (vascular endothelial growth factor), which have a well established role during wound healing 7-9. The rationale behind use of platelet concentrates is to provide these growth factors in high concentration in the healing area promoting the healing and hence the regenerative process. These growth factors have been shown to improve cell migration and proliferation, as well as extra-cellular matrix formation.

Growth factors in platelet concentrates and their role in periodontal regeneration 10:

Studies on platelet concentrates have identified following important growth factors in the alpha granules of the sequestered platelets:

  1. Platelet-derived growth factor (PDGF)
  2. Transforming growth factor-β
  3. Platelet-derived Epidermal Growth Factor (PDEGF)
  4. Platelet-derived Angiogenesis Factor  (PDAF) or Vascular Endothelial Growth Factor (VEGF)
  5. Insulin-like growth factor-1 (IGF–1)
  6. Platelet Factor 4 (PF – 4)

Also, Fibrin, fibronectin, and vitronectin are present in PRP, which of course are not growth factors, but they are cell-adhesion molecules.

Growth factors secreted by platelets and their target cells and functions 10 

Growth factors
Target cell
Action
PDGFFibroblasts
Glial cells
Smooth muscle cells
Macrophages
Neutrophils
Stimulates chemotaxis/mitogenesis of fibroblasts/glial cells/smooth muscle cells.
Regulates collagen synthesis.
Stimulates macrophage/neutrophil chemotaxis.
TGF-βFibroblasts
Marrow stem cells
Endothelial cells
Epithelial cells
Pre-osteoblasts
Stimulates/inhibits endothelial, fibroblastic, osteoblastic mitogenesis.
Regulates collagen synthesis/secretion.
Regulates mitogenic effect of other growth factors.
Stimulates endothelial chemotaxis and angeogenesis.
PDEGFEndothelial cells
Epithelial cells
Fibroblasts
Stimulates endothelial chemotaxis/angiogenesis.
Regulates collagen secretion.
Stimulates epithelial/mesenchymal mitogenesis.
PDAFEndothelial cellsIncreases angiogenesis and vessel permeability.
Stimulates mtogenesis of endothelial cells by direct or indirect actions.
Several cytokines and growth factors up-regulate PDAF including IGF-I, TGF-α and β, PDGF, FGF, PDEGF and IL-I β.
IGF-IOsteoblasts
Macrophages
Monocytes
Chondrocytes
Stimulate cartilage growth, bone matrix formation and replication of pre-osteoblasts and osteoblasts.
Acts as autocrine and paracrine factor.
In combination with PDGF can enhance rate and quality of wound healing.
PF-4Fibroblasts
Neutrophils
Chemoattractant for fibroblasts and neutrophils.
Potent anti-heparin agent.
PDGF: Platelet derived growth factor.
TGF-β: Tissue growth factor beta.
PDEGF: Platelet derived epidermal growth factor.
PDAF: Platelet derived angiogenesis factor.
IGF-I: Insulin like growth factor I
PF-4: Platelet factor 4.
bFGF: Basic fibroblast growth factor.

After injury clot is formed which is made up of a fibrin network in which various cells like RBCs, platelets and PMNs are embedded. Platelets contain three types of secretory granules viz………………………..

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Process of regeneration starts with the growth factors released from the platelets including PDGF, TGF-β and IGF. PDGF specifically acts as a mitogen for osteoblast, endothelial cell, and mesenchymal stem cell proliferation. TGF-β is also a potent mitogen for undifferentiated mesenchymal cells, but also promotes angiogenesis and osteoblastic differentiation. The IGF acts on the endosteal osteoblasts that line the trabeculae of grafted cancellous bone and promote their proliferation. The fibrin mesh also has cell adhesion molecules such as fibrin, fibronectin, and vitronectin. These cell-adhesion molecules act as a surface matrix for the vascular ingrowth, cell proliferation, and cell migration occurring during this phase.

By third day postoperatively, capillaries can be seen to penetrate the graft and by 17 to 21 days, the capillary penetration of the graft is complete and the osteoprogenitor cells have vastly increased in number. As the wound matures, the expression of PDGF is downregulated and macrophage-derived growth and angiogenic factors take over (days 5 to 7). Most of the actions of macrophage-derived growth and angiogenic factors are similar to PDGF and IGF. By 4th week most of the re-vascularization of the healing area is over and oxygen gradient fades away and immature bone stats forming. During next phases of healing, the maturation of the immature bone takes place. A continuous remodelling of the newly formed bone goes on for many years. 

Thus, from the above discussion it is clear that platelets play a vital role during initial wound healing. The platelet concentrates provide a high concentration of growth factors in the healing area, thus promoting the wound healing and regeneration.

Clinical applications:

Bone regeneration:

  1. Sinus lift grafting
  2. Ridge augmentation
  3. Repair of bone defects created by removal of teeth or small cyst
  4. Ridge preservation techniques
  5. Periodontal defects
  6. Closure of cleft lip and palate defects
  7. Repair of oro-antral fistulas
  8. Craniofacial reconstruction

Soft tissue regeneration:

  1. Periosteal and connective tissue flaps
  2. Free connective tissue and gingival grafts
  3. Root coverage procedures
  4. Controlling soft tissue healing and tissue maturity

Contraindications:

  1. Unexplained anaemia where Hb is <12.5 g%
  2. Thrombocytopenia < 100,000 / cu. mm
  3. Diagnosed and treated anaemia Hg < 10.0 g%
  4. Patients who have metastatic disease
  5. Presence of tumour in the wound bed
  6. History of platelet dysfunction
  7. Active wound infection and sepsis requiring systemic antibiotics
  8. Patients with poor prognosis associated with other disease process
  9. Patient with bovine sensitivity
  10. Patients with religious beliefs that prevent the use of blood.

How it started?

Initially, platelet concentrates were used for the treatment of……………………

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Knighton et al. 12 in 1986, developed an efficient clinical application for the treatment of chronic non-healing cutaneous ulcers, using a preparation using a 2-step centrifugation procedure and named “platelet-derived wound healing factors” (PDWHF). In other articles published during the same time, the same technique was named “platelet-derived wound healing formula (PDWHF)”. Whitman et al. 13 in 1997 showed that platelet concentrates improved healing can be used in place of fibrin glues. Since then there has been a lot of research on platelet concentrates. Marx et al. 14 in 1998 used the term “Platelet-Rich Plasma” (PRP) in a study about the effect of a platelet-rich preparation during maxillofacial bone reconstruction.

Dohan et al. 15 in 2006, developed technique to obtain a  second  family of materials initially called platelet rich fibrin (PRF). In this technique, no anticoagulant is added to blood. The blood is immediately centrifuged with moderate forces during 12 minutes. Three layers appear then in the tubes: the red blood cells are gathered at the bottom, acellular plasma is at the top of the tube and a strongly polymerized fibrin clot called PRF is formed between 16.

To understand the types of platelet concentrates, we must know how these are obtained and processed.

Basic clinical procedure to obtain platelet concentrates:

Platelet concentrates are obtained from autologous blood, subjecting it to gradient density centrifugation. The processing of PRP involves the sequestration and concentration of platelets, and, therefore the many growth factors they contain. The strategy is to amplify and accelerate the effect of growth factors contained in platelets, which are the universal initiators of almost all wound healing 17. In all available PRP techniques, the blood is collected with or without anticoagulant just before or during surgery and is immediately processed by centrifugation. The time for platelet concentrate preparation is variable but is always completed within an hour. The collected blood is centrifuged at varying speeds until it separates into 3 layers: platelet poor plasma (PPP), platelet rich plasma (PRP), and……………………

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In the recent past, many companies have come up with automated kits to obtain different type of plasma concentrates, exploiting their widespread popularity. The basic procedure of collection of blood and centrifugation remain the same in all the techniques, but method of isolation of platelet rich plasma varies.

Platelet concentrates, their derivatives and biological actions

Platelet concentrates their derivatives and biological actions

Advantages of platelet concentrates:

  • It is a safe procedure. It is an autologous blood product, with no risk of infectious disease transmission or clerical errors, thus making it a safe product
  • It is non-invasive (other than phlebotomy) and…………………………..

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Classification of platelet concentrates 18:

Dohan et al. 19 have described the classification of platelet concentrates according to POSEIDO recommendations. According to the recommendations, irrespective of whatever their form or cell content, all  the  products  of  this  category  are  regrouped  under  the  general  term  of “platelet concentrates”. Secondly, it is important to highlight the key influence of the leukocyte content 20-22. and  fibrin  architecture 23, 24 in  the  potential  clinical  or  experimental  effects  of  these  products, and that each product refers to a specific biological imprint 25, 26. So, according to the recommendations, the platelet concentrates can be classified as,

  1. Pure platelet rich plasma (P-PRP)
  2. Leukocyte and platelet rich plasma (L-PRP)
  3. Pure platelet rich fibrin (P-PRF)
  4. Leukocyte and platelet rich fibrin (L-PRF)

Pure PRP (P-PRP):

To obtain pure PRP (P-PRP), PPP and superficial BC are transferred to another tube. After hard spin centrifugation, most of the PPP layer is discarded. The final P-PRP concentrate consists of an undetermined fraction of BC (containing a large number of platelets) suspended in some fibrin-rich plasma. Most leucocytes are not collected.

The method of collection of pure platelet rich plasma was initially referred to as……………………..

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PRGF/Endoret (Plasma Rich in growth factors, BTI BioTechnology Institute, Vitoria, Spain):

The scientific basis for the development of this system is that, upon activation with calcium chloride or autologous thrombin, platelets pour out their growth factor content to the local milieu. In addition, the fibrinogen present in plasma is cleaved to form fibrin and then cross-linked with factor XIIIa, creating a three dimensional fibrin scaffold that retains part of the released protein content, maintains the regenerative space and serves as matrix for endogenous cells 27.

In this system, blood is collected into 9 mL tubes containing sodium citrate as anticoagulant. Blood is then subjected to centrifugation at 580 g for 8 minutes. The platelet poor plasma (PPP) is drawn off avoiding the buffy coat. The remaining plasma is then activated with calcium chloride. This high platelet concentrate is then applied to the surgical area. According to the manufacturers, the supernatant after coagulation is rich in growth factors involved in healing process, thus facilitating healing.

Leukocyte and platelet rich plasma (L-PRP):

Leukocyte- and platelet-rich plasma (L-PRP) contains high concentrations of platelet, leukocytes and other bio-active molecules, which play a prominent role in both bone and soft tissue healing processes. To obtain leukocyte rich PRP (L-PRP), the PPP, the entire BC layer and some residual RBCs are……………………

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SmartPReP PRP (Harvest Corp, Plymouth, MA, USA):

It is a multifunction system with a specific collection and separation kit requiring little manipulation when used. This two-chamber device is designed to transfer automatically the upper layers (PPP and buffy coat) into the second chamber based on variations in weight and centrifugation speed. The centrifuge can also be used to concentrate stem cells from bone marrow aspirates 19. The final platelet concentrate has a viable platelet levels four-fold or more over baseline which can be can be used to accelerate wound healing, enhance management of graft material, improve graft fixation on surgical areas and optimize healing of bone and soft tissue 14.

Curasan PRP kit (Curasan, Pharma Gmbh AG, Lindigstrab, Germany):

In this system, 8 ml autologous whole blood is collected in the sample tube which is spun in a standard centrifuge for 10 minutes at 2400 r.p.m. This first spin separates the red blood cell from plasma. The platelet poor plasma and the buffy coat of platelet rich plasma is then transferred to separate tube which is then centrifugated for 15 minutes at 3600 rpm. 0.6–0.7 mL of pure PRP can be obtained from 8 ml of blood.

Friadent PRP (Friadent-Schütze, Vienna, Austria):

8.5 ml of blood is taken from the antecubital vein and is citrated to stop coagulation. The tube is then centrifugated for 10 min at 2400 r.p.m. Subsequently, the yellow plasma (containing the platelets) is taken up into a monovette with a long cannula using an additional air-intake cannula. It is then centrifugated for 15 min at 3600 r.p.m. According to the manufacturer, a high platelet concentrate with leucocytes can be obtained with this system.

Platelet rich fibrin (PRF):

The platelet rich fibrin was first developed in France by Choukroun et al. 28 for use in the field of oral and maxillofacial surgery. It is a second-generation platelet concentrate which contains platelets and growth factors in the form of fibrin membranes prepared from the patient’s own blood free of any anticoagulant or other artificial biochemical modifications. It is one of the simplest and inexpensive methods of obtaining autologous platelet concentrate. PRF has a dense fibrin network containing leukocytes, cytokines, structural glycoproteins and growth factors. Because natural clotting process is undisturbed in obtaining PRF, the coagulated plasma can be compressed to make PRF fibrin membrane. When placed over healing area it becomes a good source of growth factors during healing. These growth factors are released during ≥ 7 days 29.

Figure 68.2 Platelet-rich fibrin

PRP preparation Blood after centrifugation

(a)

PRP preparation collected PRF

(b)

collected PRF

(c)

Advantages of PRF over PRP 30:

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There are various commercially available systems to obtain PRF including,

  • Vivostat PRF (pure platelet-rich plasma)
  • Fibrinet PRF (without leukocytes)

Vivostat PRF (Vivolution, Alleroed, Denmark):

This is a fully automated system designed to obtain platelet rich fibrin from autologous blood perioperatively. This system comprises of following components:

  • PRF preparation unit: The PRF preparation unit is a device that extracts platelets and fibrin from the blood into platelet rich fibrin. A tubing assembly is attached to the PRF preparation unit.
  • Citrate/TA (PRF):   A vial containing a sterile solution of citrate (anticoagulant) and 100 mg tranexamic acid (antifibrinolytic).
  • Codan Spike:  The dispensing spike is used to access the Citrate Vial and connect to the PRF preparation Unit.
  • Sugi swap: The two non sterile Sugi swaps are used to clean the valve after the tubing assembly has been removed from the PRF preparation unit.
  • pH4: The pH4 syringe is loaded into the PRF preparation unit prior to processing. After processing, this syringe contains the platelet rich fibrin solution and is referred to as the fibrin syringe.
  • Replacement Cap: The Replacement Cap is used to protect the luer tip of the fibrin syringe.
  • Disinfection swab: Used for disinfection of the rubber membrane on the Citrate/TA (PRF).

Fibrinet PRFM kit by Cascade Medical (New Jersey, USA):

The kit contains two tubes, one for blood collection and another for PRFM clotting, together with a transfer device. The procedure involves collection of 9 ml of venous blood form antecubital vein in collection tube which already contains tri-sodium citrate as anti-coagulant and a proprietary separator gel. The tube is then centrifugated for 6 minutes at high speed. It results in formation of three distinct layers of of RBCs, buffy coat and PPP. The buffy coat and PPP are transferred to another tube containing CaCl2 and immediately centrifugated for 15 minutes. At the end of the procedure a stable clot of PRFM can be collected. As there is no added bovine thrombin in the procedure, the manufacturers of the kit claim formation of a ‘natural’ platelet concentrate. But, it may not be correct because the procedure involves addition of anticoagulant and separation gel which may create un-natural conditions during formation of fibrin rich platelet concentrate.

Leukocyte and platelet rich fibrin (L-PRF):

The easiest and most inexpensive method to obtain leukocyte and platelet rich fibrin (L-PRF) is Choukroun’s method. The Choukroun’s PRF is prepared by collecting 9 ml of blood from patient immediately prior to the surgery. It is poured in a 10 ml tube and put in the centrifugation device, immediately centrifugating it at a rate of…………………………..

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Various commercially available kits for platelet concentrate preparation 

Platelet concentrate
Preparation procedure
Commercially name and manufacturer
Pure platelet rich plasmaFully automatedCell separator PRP (experimental).
Partially automatedPRGF/Endoret (Plasma Rich in growth factors, BTI BioTechnology Institute, Vitoria, Spain).
E-PRP (Eye Platelet-rich Plasma, experimental).
Nahita PRP (Nahita, Navarra, Spain).
Leukocyte and platelet rich plasmaFully automatedSmartPReP PRP (Harvest Corp, Plymouth, MA, USA).
PCCS PRP (Platelet Concentrate Collection System, Palm Beach Gardens, FL, USA).
Magellan PRP (Magellan APS (Autologous platelet separator), Medtronic, Minneapolis, MN, USA).
GPS PRP (Gravitational Platelet Separation system, Biomet Biologic, Warsaw, IN, USA).
Angel PRP (Angel Whole Blood Processing System (AWBPS), Sorin Group, Mirandola, Italy).
Partially automatedCurasan PRP (Curasan, Kleinostheim, Germany).
Regen PRP (Regen Laboratory, Mollens, Switzerland).
Friadent PRP (Friadent-Schütze, Vienna, Austria).
Plateltex PRP (Plateltex, Prague, Czech Republic).
Ace PRP (Surgical Supply and Surgical Science Systems, Brockton, MA, USA).
Pure platelet rich fibrinFully automatedVivostat PRF (Vivolution, Alleroed, Denmark).
Partially automatedFibrinet PRFM (Cascade Medical, Wayne, NJ, USA).
Leukocyte and platelet rich fibrinPartially automatedIntra-Spin L-PRF (Intra-Lock, Boca Raton, FL, USA).
Titanium-prepared PRF (experimental).

Literature review:

Effect of platelet concentrates in on wound healing:

It has been also proposed that PRP accelerates wound maturity and epithelialization, hence decreased scar formation. PDGF and epidermal growth factor (EGF) are the main growth factors involved in fibroblast migration, proliferation, and collagen synthesis. Increased concentrations of these growth factors are likely the reason for the accelerated soft tissue wound healing, which is suggested to be at least 2–3 times faster than that of normal 31.

Platelets in PRP also play a role in host defense mechanism at the wound site by producing signaling proteins that attract macrophages 32. It has also been demonstrated that PRP may suppress cytokine release and limit inflammation, interacting with macrophages to improve tissue healing and regeneration 33 and promote new capillary growth 34.

On role of platelet concentrates in periodontal regeneration:

Initially it was demonstrated by Choukron et al. that PRF used in implant surgery was able to enhance the healing properties of the bone 28. Chang et al. 35 elaborated the mechanism by which PRF enhance the healing properties of the bone. They hypothesised that PRF promotes the expression of phosphorylated extracellular signal-regulated protein kinase (p-ERK) and stimulates the production of osteoprotegerin (OPG) which in turn causes proliferation of osteoblasts.

A study done on human dental pulp cells demonstrated that PRF stimulated the osteogenic differentiation of these cells by upregulating osteoprotegerin and alkaline phosphatase expression 36.  The PRF membrane has been used as a barrier membrane for guided tissue regeneration as a grafting material. It has been shown to have good spacemaking effect which facilitates cell events that are favorable for periodontal regeneration leading to mineralized tissue formation. A randomized controlled trial done on 3-wall intrabony defects showed a statistically significant improvement in pocket depth reduction and bone fill in test group (PRF) than in controls 37.

In a split-mouth study, 25 patients with intrabony periodontal defects were treated randomly using surgical procedure with and without application of autologous platelet concentrate (APC). Radiological evaluation at 3 and 6 months postoperatively suggested a better bone density gain in the sites treated with the platelet concentrate. However at 12 month post-surgery bone density gain in the control sites appeared to be greater. Authors concluded that the improved periodontal regeneration in test group as compared to controls was questionable 38.

Regenerative potential of platelet concentrates used with autogenous bone grafts:

Marx et al 14 reported the first clinical dental results of PRP in 1998. In this study, they placed……………………………..

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Anitua 39 demonstrated that extraction sites treated with a combination of autogenous bone and PRP demonstrated better epithelialization and more compact mature bone with well-organized trabeculae than did the group receiving autogenous bone alone.

In a randomized, blinded, prospective pilot study, four equal 8 mm diameter cranial bone defects were created and immediately grafted with autogenous bone, PRP alone, autogenous bone and PRP, and no treatment as a control. The defects were evaluated by digital subtraction radiography with step-wedge calibration, histology, and histomorphometric analysis performed at 1, 2, and 4 months. The results of the study demonstrated a significant increase in histomorphometric bone area and radiographic bone density in both bone and bone and PRP samples as compared with the control and PRP alone 40.

Also, many studies have reported contradictory findings questioning the effectiveness of PRP 41-43.  Differences in the technique of platelet concentrate preparation is one of the reasons which can alter their regenerative potential.

Regenerative potential of platelet concentrates used with allografts/xenografts/alloplasts:

Researchers have suggested that addition of PRP to osteoconductive grafting materials can potentiate osteoinduction 44, 45. In one study, Aghaloo et al. 46 created 4 rabbit cranial defects in each of 15 rabbits. They were grafted with either Bio-Oss, Bio-Oss with PRP, or autogenous bone or were left empty as a control. Histomorphometric evaluation showed that the addition of PRP significantly increased the % of bone formation over that of Bio-Oss alone at all three time periods (1, 2 and 4 months). However, in this study, the autogenous bone was still significantly better than either Bio-Oss or Bio-Oss with PRP.

In a controlled clinical trial Jaske et al. 47, compared the combination of the xenograft bovine porous bone mineral (BPBM) and PRP versus BPBM alone and PRP alone. Six-month postoperative evaluations revealed superior regenerative effects in the PRP-treated groups.

Choukroun et al. 48 evaluated the potential of PRF in combination with freeze-dried bone allograft (FDBA) (Phoenix; TBF, France) to enhance bone regeneration in sinus floor elevation procedure. In this study, nine sinus floor augmentations were performed where in 6 sites, PRF was added to FDBA particles (test group), and in 3 sites FDBA without PRF was used (control group). Four months later for the test group and 8 months later for the control group, bone specimens were harvested from the augmented region during the implant insertion procedure. After 4 months of healing time, histologic maturation of the test group appears to be identical to that of the control group which was for a period of 8 months. Also, it was seen that the quantities of newly formed bone in both controls and cases was almost equivalent.

In a sinus floor augmentation study, where FDBA was used with PRP, results showed the application of PRP will only result in accelerated new bone formation if target cells such as osteoblasts and osteocytes are present 41.

On the contrary, some studies have doubted the effectiveness of platelet concentrated used with bone grafts in regeneration. Aghaloo et al. 49 in one study compares bone healing in four cranial defects in the rabbit grafted with freeze-dried mineralized bone (FMB) alone, FMB+PRP, freeze-dried demineralized bone (FDDB) alone, and FDDB+PRP. In this randomized, blind, prospective pilot study, fifteen New Zealand white rabbits were utilized. Radiographic and histomorphometric analysis were done at 1, 2, and 4 months. This study failed to show a radiographic or histomorphometric increase in bone formation with the addition of PRP to either FMB or FDDB in non-critical-sized defects in the rabbit cranium.

Conclusion:

The application of platelet concentrates in periodontal regeneration has been extensively studied. As discussed above, many studies show significant improvement in periodontal regeneration after platelet concentrate application whereas many others show no significant improvement. Since, platelets play an important role during wound healing, platelet concentrates can be used to improve healing. Presently, dozens of kits are available commercially exploiting the widespread popularity of platelet concentrates. Irrespective of what the manufacturers claim, one need to go through the literature to judicially apply these concentrates for better clinical results.

Know more………….

Controversy regarding classifying various commercially available platelet concentrate systems:

It must be noted that according to the cellular composition of the platelet concentrate derived from various commercially systems discussed above, their category may be changed or new sub-categories can be defined. On the basis of platelet content, number of leucocytes present, and quality of fibrin network, the classification may be redefined.

Prime requirement of a system used to obtain platelet concentrate is the consistency and uniformity of that system during multiple readings. There have been multiple studied done comparing various commercially available platelet concentrate systems.

 

 

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