The activation and osteoinduction effects of thrombin in the maxillary sinus augmentation process: does thrombin only display activation effects on platelet-rich plasma?

We write in reference to an article about the effect of platelet-rich plasma (PRP) on bone regeneration in maxillary sinus augmentation by Khairy et al. In this study, the authors investigated the effects of growth factor release from PRP on bone regeneration in sinus augmentation. They combined PRP with thrombin/calcium chloride to form a gel to activate the PRP. However, the authors ignored the influence of thrombin itself on bone regeneration. PRP usually needs to be activated by thrombin or/and calcium ionophores to release growth factors; however the thrombin displays bone regeneration effects during implantation. Therefore, their methods and the related results are debatable. Indeed, the authors did not consider the cytotoxicity of thrombin. In a study performed by our group, we distinguished between ‘PRP alone’ and PRP in combination with thrombin and calcium chloride, which we named ‘activated PRP’.

Khairy et al. are incorrect in their assertion that the effects were the result of the PRP, because the PRP contained thrombin, and thus the effects of this ‘activated PRP’ included the effects of thrombin itself. Therefore, the effects are not attributable to simple PRP. ‘Activated PRP’ leads to the release of growth factors, which facilitate angiogenesis, haemostasis, and osteogenesis. Therefore, the results of Khairy et al. are worth considering.

Thrombin is a multifunctional serine protease that is expressed ubiquitously at sites of vascular injury. It efficiently triggers platelet secretion of all types of granules. Thrombin stimulates both proliferation and migration of primary bone marrow stromal cells, osteoprogenitor cells, and irritated proliferation of differentiated osteogenic cells, which play a role in stimulating the recruitment of osteoprogenitors. The effects are dependent on the interaction between the thrombin catalytic sites and protease-activated receptor 1 (PAR-1). Activation relies on the cleavage of thrombin receptors PAR-1 and PAR-4. PAR cleavage produces a new amino terminus initiated by thrombin receptor-activating peptide. Thrombin has been showed to be a specific agonist for a variety of functional responses of cells, including osteoblasts. Thrombin can also inhibit apoptosis induced by serum deprivation or dexamethasone in osteoblasts and osteoblast-like cells. Furthermore, osteoblasts express two of the three known thrombin receptors. The mechanism by which thrombin inhibits osteoblast apoptosis would seem to result from the synthesis and secretion of a survival factor by the osteoblasts, which then acts in an autocrine fashion to restrain apoptosis.

Platelet activation would result in apoptosis to some degree when PRP is activated by thrombin/calcium chloride. Cell migration may be stimulated by thrombin during wound healing, which is generated from prothrombin during the blood coagulation cascade. Thrombin cleaves fibrinogen to polymerize fibrin and activates clotting co-factors such as factors V and VIII, which accelerate the coagulation process and stabilize the blood clot. In addition to serving an essential role in forming the fibrin matrix, thrombin has been shown to interact with specific cell surface receptors and stimulate a variety of events including platelet activation. Thrombin activates intracellular signalling pathways by interacting with transmembrane domain G protein-coupled receptors. The receptors are activated by proteolytic cleavage of an extracellular domain, therefore exposing a new amino terminus that acts as a tethered ligand. Thrombin, through interaction with PAR, stimulates proliferation and migration of a variety of cell types. The inhibition of thrombin generation or PAR-1 signalling on cells expressing α-smooth muscle actin and CD34 inhibits intimal hyperplasia and promotes tissue regenerative repair.

Platelet-rich fibrin (PRF) has a natural fibrin network and does not require additives such as thrombin for activation to improve bone regeneration. Therefore, PRF has potential value for use in bone defect repair in the future.

Funding

None.

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Jan 17, 2018 | Posted by in Oral and Maxillofacial Surgery | Comments Off on The activation and osteoinduction effects of thrombin in the maxillary sinus augmentation process: does thrombin only display activation effects on platelet-rich plasma?
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