Autologous platelets as a source of proteins for healing and tissue regeneration

Platelets are known for their role in haemostasis where they help prevent blood loss at sites of vascular injury. To do this, they adhere, aggregate and form a procoagulant surface leading to thrombin generation and fibrin formation. Platelets also release substances that promote tissue repair and influence the reactivity of vascular and other blood cells in angiogenesis and inflammation. They contain storage pools of growth factors including PDGF, TGF-beta?and VEGF as well as cytokines including proteins such as PF4 and CD40L. Chemokines and newly synthesised active metabolites are also released. The fact that platelets secrete growth factors and active metabolites means that their applied use can have a positive influence in clinical situations requiring rapid healing and tissue regeneration. Their administration in fibrin clot or fibrin glue provides an adhesive support that can confine secretion to a chosen site. Additionally,the presentation of growth factors attached to platelets and/or fibrin may result in enhanced activity over recombinant proteins. Dental implant surgery with guided bone regeneration is one situation where an autologous platelet-rich clot clearly accelerates ossification after tooth extraction and/or around titanium implants. The end result is both marked reductions in the time required for implant stabilisation and an improved success rate. Orthopaedic surgery, muscle and/or tendon repair, reversal of skin ulcers, hole repair in eye surgery and cosmetic surgery are other situations where autologous plate-lets accelerate healing. Our aim is to review these advances and discuss the ways in which platelets may provide such unexpected beneficial therapeutic effects.

[1]  Reinhold Förster,et al.  CD40 ligand on activated platelets triggers an inflammatory reaction of endothelial cells , 1998, Nature.

[2]  C. Peterson,et al.  Plasminogen Activator Inhibitor Type 1 Promotes the Self-association of Vitronectin into Complexes Exhibiting Altered Incorporation into the Extracellular Matrix* , 2002, The Journal of Biological Chemistry.

[3]  K. Preissner,et al.  RANK ligand and osteoprotegerin: paracrine regulators of bone metabolism and vascular function. , 2002, Arteriosclerosis, thrombosis, and vascular biology.

[4]  K. Schrör,et al.  Platelet surface membranes are highly mitogenic for coronary artery smooth muscle cells--A novel mechanism for sustained proliferation after vessel injury? , 1999, Biochemical and biophysical research communications.

[5]  M. Nasu,et al.  Bioactivity of the Vascular Endothelial Growth Factor Trapped in Fibrin Clots: Production of IL-6 and IL-8 in Monocytes by Fibrin Clots , 2001, Pathophysiology of Haemostasis and Thrombosis.

[6]  M. Karpatkin,et al.  Risks of using platelet rich plasma gel. , 1998, Journal of oral and maxillofacial surgery : official journal of the American Association of Oral and Maxillofacial Surgeons.

[7]  Brian Savage,et al.  Specific Synergy of Multiple Substrate–Receptor Interactions in Platelet Thrombus Formation under Flow , 1998, Cell.

[8]  S. Bhanot,et al.  Current Applications of Platelet Gels in Facial Plastic Surgery , 2002, Facial plastic surgery : FPS.

[9]  A. Weyrich,et al.  Platelets, endothelial cells, inflammatory chemokines, and restenosis: complex signaling in the vascular play book. , 2002, Circulation.

[10]  P. Branemark,et al.  Response of bone marrow to titanium implants: osseointegration and the establishment of a bone marrow-titanium interface in mice. , 1993, The International journal of oral & maxillofacial implants.

[11]  D. Margolis,et al.  Effectiveness of platelet releasate for the treatment of diabetic neuropathic foot ulcers. , 2001, Diabetes care.

[12]  Ying Yu,et al.  PDGF stimulates pulmonary vascular smooth muscle cell proliferation by upregulating TRPC6 expression. , 2003, American journal of physiology. Cell physiology.

[13]  Hiroshi Tanaka,et al.  Effect of platelet‐derived growth factor on DNA synthesis and gene expression in bone marrow stromal cells derived from adult and old rats , 1995, Journal of cellular physiology.

[14]  Gideon A. Rodan,et al.  Control of osteoblast function and regulation of bone mass , 2003, Nature.

[15]  D. Dixon,et al.  Activated platelets mediate inflammatory signaling by regulated interleukin 1β synthesis , 2001, The Journal of cell biology.

[16]  J. Karp,et al.  Effect of Platelet Releasate on Bone Cell Migration and Recruitment In Vitro , 2003, The Journal of craniofacial surgery.

[17]  F. Rendu,et al.  The platelet release reaction: granules' constituents, secretion and functions , 2001, Platelets.

[18]  W. Siess,et al.  Platelet signal transduction mechanisms induced by eicosanoids. , 1992, Eicosanoids.

[19]  I. Chaiken,et al.  Tissue factor regulates plasminogen binding and activation. , 1998, Blood.

[20]  K. Wakabayashi,et al.  Platelet‐Derived Growth Factor BB Secreted From Osteoclasts Acts as an Osteoblastogenesis Inhibitory Factor , 2002, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[21]  R. McEver P-selectin and PSGL-1: Exploiting Connections Between Inflammation and Venous Thrombosis , 2002, Thrombosis and Haemostasis.

[22]  E. Ruoslahti,et al.  Platelet-derived Growth Factor Receptor β and Vascular Endothelial Growth Factor Receptor 2 Bind to the β3Integrin through Its Extracellular Domain* , 2000, The Journal of Biological Chemistry.

[23]  J. J. de Obarrio,et al.  The use of autologous growth factors in periodontal surgical therapy: platelet gel biotechnology--case reports. , 2000, The International journal of periodontics & restorative dentistry.

[24]  J. Krijgsveld,et al.  Thrombocidins, Microbicidal Proteins from Human Blood Platelets, Are C-terminal Deletion Products of CXC Chemokines* , 2000, The Journal of Biological Chemistry.

[25]  K. Hatakeyama,et al.  Tissue Factor Induces Migration of Cultured Aortic Smooth Muscle Cells , 1996, Thrombosis and Haemostasis.

[26]  J. Wiltfang,et al.  Different preparation methods to obtain platelet components as a source of growth factors for local application , 2001, Transfusion.

[27]  Y. Nemerson,et al.  Platelets, circulating tissue factor, and fibrin colocalize in ex vivo thrombi: real-time fluorescence images of thrombus formation and propagation under defined flow conditions. , 2002, Blood.

[28]  E. Allan,et al.  Plasminogen‐dependent activation of latent transforming growth factor beta (TGFβ) by growing cultures of osteoblast‐like cells , 1993, Journal of cellular physiology.

[29]  R. Hynes,et al.  Integrin receptors are required for cell survival and proliferation during development of the peripheral glial lineage. , 2001, Developmental biology.

[30]  R. Haas,et al.  Influence of platelet-rich plasma on osseous healing of dental implants: a histologic and histomorphometric study in minipigs. , 2003, The International journal of oral & maxillofacial implants.

[31]  H. Klüter,et al.  Preparation of autologous platelets for the ophthalmologic treatment of macular holes , 1999, Transfusion.

[32]  M. Lind,et al.  Growth factor stimulation of bone healing. Effects on osteoblasts, osteomies, and implants fixation. , 1998, Acta orthopaedica Scandinavica. Supplementum.

[33]  M. Tischler Platelet rich plasma. The use of autologous growth factors to enhance bone and soft tissue grafts. , 2002, The New York state dental journal.

[34]  J. Wozney,et al.  Transforming Growth Factor-β Gene Family Members and Bone* , 1994 .

[35]  J. Badimón,et al.  Membrane-associated CD40L and sCD40L in atherothrombotic disease , 2003, Thrombosis and Haemostasis.

[36]  S. Rafii,et al.  Trophic Effects of Platelets on Cultured Endothelial Cells are Mediated by Platelet-associated Fibroblast Growth Factor-2 (FGF-2) and Vascular Endothelial Growth Factor (VEGF) , 2002, Thrombosis and Haemostasis.

[37]  M. Wolzt,et al.  Large amounts of vascular endothelial growth factor at the site of hemostatic plug formation in vivo. , 1999, Arteriosclerosis, thrombosis, and vascular biology.

[38]  W. Giannobile,et al.  Gene Transfer and Expression of Platelet-derived Growth Factors Modulate Periodontal Cellular Activity , 2001, Journal of dental research.

[39]  C. Heldin,et al.  Involvement of platelet-derived growth factor in disease: development of specific antagonists. , 2001, Advances in cancer research.

[40]  E. Wagner,et al.  Fosl1 is a transcriptional target of c-Fos during osteoclast differentiation , 2000, Nature Genetics.

[41]  G. Burnstock Purinergic Signaling and Vascular Cell Proliferation and Death , 2002, Arteriosclerosis, thrombosis, and vascular biology.

[42]  G. Murrell,et al.  The Roles of Growth Factors in Tendon and Ligament Healing , 2003, Sports medicine.

[43]  T. Orfeo,et al.  Osteonectin in matrix remodeling. A plasminogen-osteonectin-collagen complex. , 1994, The Journal of biological chemistry.

[44]  J. Meijers,et al.  Identification of thrombin activatable fibrinolysis inhibitor (TAFI) in human platelets. , 2003, Blood.

[45]  J. Romashkova,et al.  NF-κB is a target of AKT in anti-apoptotic PDGF signalling , 1999, Nature.

[46]  Patrick André,et al.  Platelet-derived CD40L: the switch-hitting player of cardiovascular disease. , 2002, Circulation.

[47]  K. Preissner,et al.  Molecular Interactions and Functional Interference between Vitronectin and Transforming Growth Factor-β , 2002, Laboratory Investigation.

[48]  E. Anitua Plasma rich in growth factors: preliminary results of use in the preparation of future sites for implants. , 1999, The International journal of oral & maxillofacial implants.

[49]  M. Broberg,et al.  GpIIb/IIIa is the main receptor for initial platelet adhesion to glass and titanium surfaces in contact with whole blood. , 2002, Journal of Laboratory and Clinical Medicine.

[50]  P. Carmeliet,et al.  Role of tissue factor in embryonic blood vessel development , 1996, Nature.

[51]  G. FitzGerald,et al.  Arachidonic Acid in Platelet Microparticles Up-regulates Cyclooxygenase-2-dependent Prostaglandin Formation via a Protein Kinase C/Mitogen-activated Protein Kinase-dependent Pathway* , 1999, The Journal of Biological Chemistry.

[52]  H. Plosker,et al.  The use of autologous platelet-rich plasma (platelet gel) and autologous platelet-poor plasma (fibrin glue) in cosmetic surgery. , 2001, Plastic and reconstructive surgery.

[53]  Nathan E. Carlson,et al.  Platelet-rich plasma: clinical applications in dentistry. , 2002, Journal of the American Dental Association.

[54]  M. Cerletti,et al.  Growth Factor-Dependent Proliferation and Invasion of Muscle Satellite Cells Require the Cell-Associated Fibrinolytic System , 2002, Biological chemistry.

[55]  J. Vane Back to an Aspirin a Day? , 2002, Science.

[56]  P. Sheridan,et al.  Is platelet-rich plasma the perfect enhancement factor? A current review. , 2003, The International journal of oral & maxillofacial implants.

[57]  A. Verin,et al.  Sphingosine 1-phosphate promotes endothelial cell barrier integrity by Edg-dependent cytoskeletal rearrangement. , 2001, The Journal of clinical investigation.

[58]  D. M. Green,et al.  Platelet gel: an autologous alternative to fibrin glue with applications in oral and maxillofacial surgery. , 1997, Journal of oral and maxillofacial surgery : official journal of the American Association of Oral and Maxillofacial Surgeons.

[59]  M. Gimbrone,et al.  A role for Smad6 in development and homeostasis of the cardiovascular system , 2000, Nature Genetics.

[60]  Andreas Peschel,et al.  Chemokines Meet Defensins: the Merging Concepts of Chemoattractants and Antimicrobial Peptides in Host Defense , 2002, Infection and Immunity.

[61]  I. Mujika,et al.  Plasma rich in growth factors to treat an articular cartilage avulsion: a case report. , 2003, Medicine and science in sports and exercise.

[62]  D. Monroe,et al.  Platelets and thrombin generation. , 2002, Arteriosclerosis, thrombosis, and vascular biology.

[63]  K. Ikeda,et al.  Transforming Growth Factor-β Stimulates the Production of Osteoprotegerin/Osteoclastogenesis Inhibitory Factor by Bone Marrow Stromal Cells* , 1998, The Journal of Biological Chemistry.

[64]  T. Grosser,et al.  Role of Prostacyclin in the Cardiovascular Response to Thromboxane A2 , 2002, Science.

[65]  A. Sahni,et al.  FGF‐2 but not FGF‐1 binds fibrin and supports prolonged endothelial cell growth , 2003, Journal of thrombosis and haemostasis : JTH.

[66]  D. Buchbinder,et al.  Maxillary sinus augmentation with deproteinated bovine bone and platelet rich plasma with simultaneous insertion of endosseous implants. , 2003, Journal of oral and maxillofacial surgery : official journal of the American Association of Oral and Maxillofacial Surgeons.

[67]  G. Gronowicz,et al.  Integrin-mediated signaling in osteoblasts on titanium implant materials. , 2000, Journal of biomedical materials research.

[68]  M. Slater,et al.  Involvement of platelets in stimulating osteogenic activity , 1995, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[69]  M E Bolander,et al.  Transforming growth factor-beta and the initiation of chondrogenesis and osteogenesis in the rat femur , 1990, The Journal of cell biology.

[70]  P. Nurden,et al.  Immunolocalization of P2Y1 and TPα Receptors in Platelets Showed a Major Pool Associated with the Membranes of α-Granules and the Open Canalicular System , 2003 .

[71]  E. Canalis,et al.  Complex pattern of insulin‐like growth factor binding protein expression in primary rat osteoblast enriched cultures: Regulation by prostaglandin E2, growth hormone, and the insulin‐like growth factors , 1994, Journal of cellular physiology.

[72]  F. Karreth,et al.  Platelet-released supernatants stimulate formation of osteoclast-like cells through a prostaglandin/RANKL-dependent mechanism. , 2002, Bone.

[73]  D. Tziafas,et al.  Role of exogenous TGF-beta in induction of reparative dentinogenesis in vivo. , 1998, European journal of oral sciences.

[74]  A. Lansdown Calcium: a potential central regulator in wound healing in the skin , 2002, Wound repair and regeneration : official publication of the Wound Healing Society [and] the European Tissue Repair Society.

[75]  Z. Jing,et al.  Platelet-derived growth factor (PDGF)-AA: a self-imposed cytokine in the proliferation of human fetal osteoblasts. , 2000, Cytokine.

[76]  A. Cullinane,et al.  Effects of autologous platelet concentrate and serum on retinal wound healing in an animal model , 2001, Graefe's Archive for Clinical and Experimental Ophthalmology.

[77]  E. Spencer,et al.  Characterisation of insulin-like growth factor-binding protein-3 binding to a novel receptor on human platelet membranes. , 2001, The Journal of endocrinology.

[78]  K. Ley,et al.  Deposition of Platelet RANTES Triggering Monocyte Recruitment Requires P-Selectin and Is Involved in Neointima Formation After Arterial Injury , 2002, Circulation.

[79]  K. Yoshikawa,et al.  Cutaneous Wound Healing: An Update , 2001, The Journal of dermatology.

[80]  G. Hafner,et al.  Growth factor levels in platelet-rich plasma and correlations with donor age, sex, and platelet count. , 2002, Journal of cranio-maxillo-facial surgery : official publication of the European Association for Cranio-Maxillo-Facial Surgery.

[81]  F. Nociti,et al.  Platelet-derived growth factor/insulin-like growth factor-1 combination and bone regeneration around implants placed into extraction sockets: a histometric study in dogs. , 2000, Implant dentistry.

[82]  R. Marx,et al.  Platelet-rich plasma: Growth factor enhancement for bone grafts. , 1998, Oral surgery, oral medicine, oral pathology, oral radiology, and endodontics.

[83]  A. Beaulieu,et al.  Human plasma fibronectin potentiates the mitogenic activity of platelet‐derived growth factor and complements its wound healing effects , 2003, Wound repair and regeneration : official publication of the Wound Healing Society [and] the European Tissue Repair Society.

[84]  A. Bikfalvi,et al.  Domain swapping in a COOH-terminal fragment of platelet factor 4 generates potent angiogenesis inhibitors. , 2002, Cancer research.

[85]  R. Bareille,et al.  Effect of 1,25(OH)2D3 on bone morphogenetic protein‐3 mRNA expression , 1999, Journal of cellular biochemistry.

[86]  G. Giannini,et al.  The Role of Autologous Fibrin-Platelet Glue in Plastic Surgery: A Preliminary Report , 2002, The International journal of artificial organs.

[87]  C. Gemmell,et al.  Platelet interactions with titanium: modulation of platelet activity by surface topography. , 2001, Biomaterials.

[88]  D. Ory,et al.  A Glanzmann’s mutation in β3 integrin specifically impairs osteoclast function , 2001 .

[89]  J. Müller,et al.  Effects of fibrin glue and growth factors released from platelets on abdominal hernia repair with a resorbable PGA mesh: experimental study. , 1999, The Journal of surgical research.

[90]  P. Nurden,et al.  Labeling of the internal pool of GP IIb-IIIa in platelets by c7E3 Fab fragments (abciximab): flow and endocytic mechanisms contribute to the transport. , 1999, Blood.

[91]  G. Lowery,et al.  Use of autologous growth factors in lumbar spinal fusion. , 1999, Bone.

[92]  J. Wozney,et al.  Recombinant human bone morphogenetic protein-2 stimulation of bone formation around endosseous dental implants. , 1999, Journal of periodontology.

[93]  J. Sahel,et al.  Effect of autologous platelet concentrate in surgery for idiopathic macular hole: results of a multicenter, double-masked, randomized trial. Platelets in Macular Hole Surgery Group. , 1999, Ophthalmology.

[94]  M. Bryckaert,et al.  Platelet factor 4 inhibits FGF2-induced endothelial cell proliferation via the extracellular signal-regulated kinase pathway but not by the phosphatidylinositol 3-kinase pathway. , 2002, Blood.

[95]  E. Farrior,et al.  Recovery from deep-plane rhytidectomy following unilateral wound treatment with autologous platelet gel: a pilot study. , 2001, Archives of facial plastic surgery.

[96]  L. Ignarro,et al.  Platelets modulate gastric ulcer healing: Role of endostatin and vascular endothelial growth factor release , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[97]  B. Engelmann,et al.  Platelet ADP receptors contribute to the initiation of intravascular coagulation. , 2004, Blood.

[98]  G. Karsenty,et al.  The osteoblast: a sophisticated fibroblast under central surveillance. , 2000, Science.

[99]  M. Selsted,et al.  Antimicrobial Peptides from Human Platelets , 2002, Infection and Immunity.

[100]  J. Palmblad,et al.  Angiogenesis Research: Guidelines for Translation to Clinical Application , 2001, Thrombosis and Haemostasis.

[101]  E. Tuddenham,et al.  Factor Xa and thrombin, but not factor VIIa, elicit specific cellular responses in dermal fibroblasts , 2003, Journal of thrombosis and haemostasis : JTH.

[102]  H. Ueno,et al.  Synergistic effect of sphingosine 1-phosphate on thrombin-induced tissue factor expression in endothelial cells. , 2003, Blood.

[103]  S. Atri,et al.  Use of homologous platelet factors in achieving total healing of recalcitrant skin ulcers. , 1990, Surgery.

[104]  J. Hatzfeld,et al.  Fibrinogen potentiates the effect of interleukin-3 on early human hematopoietic progenitors. , 1993, Blood.

[105]  J. Jansen,et al.  Mandibular reconstruction: a clinical and radiographic animal study on the use of autogenous scaffolds and platelet-rich plasma. , 2002, International journal of oral and maxillofacial surgery.

[106]  D. Camerini,et al.  Platelet Chemokines and Chemokine Receptors: Linking Hemostasis, Inflammation, and Host Defense , 2003, Microcirculation.

[107]  R. Timpl,et al.  Structure and Function of Collagen‐Derived Endostatin Inhibitors of Angiogenesis , 2002, IUBMB life.

[108]  F. Gilsanz,et al.  Treatment of leg ulcers in β‐thalassaemia intermedia: use of platelet‐derived wound healing factors from the patient's own platelets , 2001, British Journal of Haematology.