Does Double Centrifugation Lead to Premature Platelet Aggregation and Decreased TGF-β1 Concentrations in Equine Platelet-Rich Plasma?

Blood-derived autologous products are frequently used in both human and equine medicine to treat musculoskeletal disorders. These products, especially the platelet-rich plasma (PRP), may contain high concentrations of growth factors (GFs), and thus improve healing in several tissues. Nevertheless, the procedures for preparation of PRP are currently non-standardized. Several protocols, which are based on distinct centrifugation patterns (rotation speed and time), result in PRPs with different characteristics, concerning platelet and GFs concentrations, as well as platelet activation. The aim of the present study was to compare two different protocols for PRP preparation: protocol (A) that is based on a single-centrifugation step; protocol (B), which included two sequential centrifugation steps (double-centrifugation). The results here reported show that the double-centrifugation protocol resulted in higher platelet concentration, while leukocytes were not concentrated by this procedure. Although platelet activation and aggregation were increased in this protocol in comparison to the single-centrifugation one, the TGF-β1 concentration was also higher. Pearson’s correlation coefficients gave a significant, positive correlation between the platelet counts and TGF-β1 concentration. In conclusion, although the double-centrifugation protocol caused premature platelet aggregation, it seems to be an effective method for preparation of PRP with high platelet and TGF-β1 concentrations.

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Activation of human platelets by immune complexes prepared with cationized human IgG

Blood ◽

10.1182/blood.v82.10.3045.bloodjournal82103045 ◽

1993 ◽

Vol 82 (10) ◽

pp. 3045-3051

Author(s):

M Schattner ◽

M Lazzari ◽

AS Trevani ◽

E Malchiodi ◽

AC Kempfer ◽

...

Keyword(s):

Platelet Aggregation ◽

Platelet Activation ◽

Immune Complexes ◽

Platelet Rich Plasma ◽

Human Platelets ◽

Human Igg ◽

Experimental Conditions ◽

Induce Platelet Aggregation ◽

Soluble Immune Complexes ◽

High Concentrations

The present study shows that the ability of soluble immune complexes (IC), prepared with human IgG and rabbit IgG antibodies against human IgG, to trigger platelet activation was markedly higher for IC prepared with cationized human IgG (catIC) compared with those prepared with untreated human IgG (cIC). CatIC induced platelet aggregation and adenosine triphosphate release in washed platelets (WP), gel-filtered platelets (GFP), or platelet-rich plasma (PRP) at physiologic concentrations of platelets (3 x 10(8)/mL) and at low concentrations of catIC (1 to 30 micrograms/mL). On the contrary, under similar experimental conditions, cIC did not induce aggregation in PRP, WP, or GFP. Low aggregation responses were only observed using high concentrations of both WP (9 x 10(8)/mL) and cIC (500 micrograms/mL). Interestingly, catIC were also able to induce platelet activation under nonaggregating conditions, as evidenced by P-selectin expression. Cationized human IgG alone did not induce platelet aggregation in PRP but triggered either WP or GFP aggregation. However, the concentration needed to induce these responses, was about eightfold higher than those required for catIC. The responses induced either by catIC or cationized human IgG were completely inhibited by treatment with heparin, dextran sulphate, EDTA, prostaglandin E1, or IV3, a monoclonal antibody against the receptor II for the Fc portion of IgG (Fc gamma RII). The data presented in this study suggest that IgG charge constitutes a critical property that conditions the ability of IC to trigger platelet activation.

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Activation of human platelets by immune complexes prepared with cationized human IgG

Blood ◽

10.1182/blood.v82.10.3045.3045 ◽

1993 ◽

Vol 82 (10) ◽

pp. 3045-3051 ◽

Cited By ~ 12

Author(s):

M Schattner ◽

M Lazzari ◽

AS Trevani ◽

E Malchiodi ◽

AC Kempfer ◽

...

Keyword(s):

Platelet Aggregation ◽

Platelet Activation ◽

Immune Complexes ◽

Platelet Rich Plasma ◽

Human Platelets ◽

Human Igg ◽

Experimental Conditions ◽

Induce Platelet Aggregation ◽

Soluble Immune Complexes ◽

High Concentrations

Abstract The present study shows that the ability of soluble immune complexes (IC), prepared with human IgG and rabbit IgG antibodies against human IgG, to trigger platelet activation was markedly higher for IC prepared with cationized human IgG (catIC) compared with those prepared with untreated human IgG (cIC). CatIC induced platelet aggregation and adenosine triphosphate release in washed platelets (WP), gel-filtered platelets (GFP), or platelet-rich plasma (PRP) at physiologic concentrations of platelets (3 x 10(8)/mL) and at low concentrations of catIC (1 to 30 micrograms/mL). On the contrary, under similar experimental conditions, cIC did not induce aggregation in PRP, WP, or GFP. Low aggregation responses were only observed using high concentrations of both WP (9 x 10(8)/mL) and cIC (500 micrograms/mL). Interestingly, catIC were also able to induce platelet activation under nonaggregating conditions, as evidenced by P-selectin expression. Cationized human IgG alone did not induce platelet aggregation in PRP but triggered either WP or GFP aggregation. However, the concentration needed to induce these responses, was about eightfold higher than those required for catIC. The responses induced either by catIC or cationized human IgG were completely inhibited by treatment with heparin, dextran sulphate, EDTA, prostaglandin E1, or IV3, a monoclonal antibody against the receptor II for the Fc portion of IgG (Fc gamma RII). The data presented in this study suggest that IgG charge constitutes a critical property that conditions the ability of IC to trigger platelet activation.

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Platelet Activation Is Not Crucial for Platelet-Rich Plasma (PRP), When Used As Autologous Therapeutic Product, and Could be Lyophilized without Any Growth Factor Loss

Blood ◽

10.1182/blood.v128.22.2639.2639 ◽

2016 ◽

Vol 128 (22) ◽

pp. 2639-2639

Author(s):

Letícia Queiroz da Silva ◽

Stephany Cares Huber ◽

Silmara Aparecida De Lima Montalvão ◽

Fernanda Dutra Santiago Bassora ◽

Erich Vinicius De Paula ◽

...

Keyword(s):

Platelet Aggregation ◽

Growth Factor ◽

Therapeutic Effect ◽

Platelet Activation ◽

Freeze Drying ◽

Platelet Rich Plasma ◽

Therapeutic Product ◽

Platelet Concentration ◽

Factor Measurement ◽

The Mean

Abstract Platelet-rich Plasma (PRP) has been widely used in different fields of medicine as autologous therapeutic product. The main component that appears to be associated with the therapeutic effect is the presence of growth factors (GF). However, many protocols available induce high methodology variability. In addition, is still unclear what is the best platelet activator and the necessity for the clinical practice. The traditional PRP used (Fresh PRP) can vary to each preparation and it has also been difficult to use in a time manager, especially for emergency care. Freeze-drying processes come out as a PRP standardization possibility, offering a low-risk proliferative microorganisms. This study aims to compare in vitrothe fresh PRP with the lyophilized PRP, in terms of platelet concentration capacity, and the GF potential release. For fresh and lyophilized PRP production, plasma from twenty-two male healthy individuals were obtained, with mean age of 28.6 ± 5.6 years. The blood was collected with ACD tubes (BD Vacutainer), than centrifuged twice: first with a spin at 300 g for 5 minutes and second with 700 g for 17 minutes. At the end of the double spin, the top layer plasma was characterized as platelet poor plasma and the lower layer was considered the PRP. The pellet were homogenized slowly, and adjusted to 1,2x106 platelets/µL before being frozen at -80ºC. For lyophilized PRP a stabilizing buffer were add and samples were frozen for 1 hour at -80ºC. After that, the PRP was lyophilized by Christ Alpha Plus for 20 hours. To compare fresh and lyophilized PRP, the platelets were evaluated for number of concentration, functionality, and the capacity of GF release, such as VEGF, PDGF, EGF and TGFβ. Non-parametric statistics were used in all analysis (Graph Pad 5.0). The PRP was able to recover high concentrations of platelets. The mean of platelet concentration was 1622 x 103 cells/µl, which represents 5.3 folds higher from the basal number (303 x 103 cells/µl). The recovery of platelets after freeze-drying was 54% compared to the initial concentration (1200 x 103 cells/µl). Platelet function was evaluated pre and post fresh PRP preparation and after freeze-drying, with two agonists ADP and epinephrine, to check the capacity of then to induce platelet aggregation. Results were evaluated trough amplitude of aggregation curve. Interestingly, high amplitude was observed only for samples from pre fresh PRP preparation (ADP median 86% from 71% to 100 % and epinephrine median 86 % from 74% to 103%). Despite the high concentration obtained from PRP (5 folds higher the basal number), no amplitude curve for platelet aggregation was observed for samples post fresh PRP preparation (ADP median 19% from 0% to 85% and epinephrine median 2% from 1% to 37%), even for lyophilized PRP (ADP median 1% from 0% to 2% and epinephrine median 1.5 % from 0 % to 3%), figure 1. The GF levels were similar for both products, with any grow factor loss after freeze-drying. The mean and standard deviation for level of GF were: PDGF 49365 pg/ml ± 17410 for fresh PRP and 60207 pg/ml ± 18472 for lyophilized PRP; VEGF 1250 pg/ml ±1171 for fresh PRP and 954,3 pg/ml ± 644,6 for lyophilized PRP; TGFβ 140373 pg/ml ± 91454 for fresh PRP and 111991 pg/ml ± 19827for lyophilized PRP; EGF 771,6 pg/ml ± 320,4 for fresh PRP and 739,1 pg/ml ± 324,1 for lyophilized PRP, figure 2. The results showed that fresh or lyophilized PRP were unable to show normal aggregation function, suggesting that these samples had been already activated by several conditions of preparation, such as the manual manipulation, temperature, pressure that the platelet is subjected inside the needle, among others. This result confirms that platelet activation with thrombin, or calcium chloride before PRP application is not crucial. Anyhow, the GF that is considered an important component for PRP regarding the therapeutic effect, were preserved. In addition, the lyophilized PRP appears as a possible replacement of fresh PRP, adding minor technical variability with a single process production, enabling a large-scale, with shelf life increased. Figure 1 Represents aggregation percentage generated after two antagonists addition. The results demonstrate that post-PRP has no platelet activation. Figure 2. Represents growth factor measurement in Fresh PRP and lyophilized PRP. The only difference between both preparations was PDGF (p=0, 0464). Figure 1. Represents aggregation percentage generated after two antagonists addition. The results demonstrate that post-PRP has no platelet activation. Figure 2. Represents growth factor measurement in Fresh PRP and lyophilized PRP. The only difference between both preparations was PDGF (p=0, 0464). Disclosures No relevant conflicts of interest to declare.

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Effects of Halothane on Platelet Function

Thrombosis and Haemostasis ◽

10.1055/s-0038-1650105 ◽

1980 ◽

Vol 44 (03) ◽

pp. 143-145 ◽

Cited By ~ 19

Author(s):

J Dalsgaard-Nielsen ◽

J Gormsen

Keyword(s):

Platelet Aggregation ◽

Platelet Function ◽

Platelet Rich Plasma ◽

Human Platelets ◽

Halothane Anaesthesia ◽

Inhibition Of Platelet Aggregation ◽

Transient Impairment ◽

High Concentrations ◽

Uptake And Release ◽

Platelet Functions

SummaryHuman platelets in platelet rich plasma (PRP) incubated at 37° C with 0.3–2% halothane for 5–10 min lost the ability to aggregate with ADP, epinephrine and collagen.At the same time uptake and release of 14C-serotonin was inhibited. When halothane supply was removed, platelet functions rapidly returned to normal. However, after high concentrations of halothane, the inhibition of platelet aggregation was irreversible or only partially reversible.The results suggest that halothane anaesthesia produces a transient impairment of platelet function.

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FUNDC2 regulates platelet activation through AKT/GSK-3β/cGMP axis

Cardiovascular Research ◽

10.1093/cvr/cvy311 ◽

2018 ◽

Vol 115 (11) ◽

pp. 1672-1679 ◽

Cited By ~ 1

Author(s):

Qi Ma ◽

Weilin Zhang ◽

Chongzhuo Zhu ◽

Junling Liu ◽

Quan Chen

Keyword(s):

Platelet Aggregation ◽

Platelet Activation ◽

Platelet Rich Plasma ◽

Thrombus Formation ◽

Mitochondrial Protein ◽

Dependent Manner ◽

Clot Retraction ◽

Akt Phosphorylation ◽

Gsk 3Β

Abstract Aims AKT kinase is vital for regulating signal transduction in platelet aggregation. We previously found that mitochondrial protein FUNDC2 mediates phosphoinositide 3-kinase (PI3K)/phosphatidylinositol-3,4,5-trisphosphate (PIP3)-dependent AKT phosphorylation and regulates platelet apoptosis. The aim of this study was to evaluate the role of FUNDC2 in platelet activation and aggregation. Methods and results We demonstrated that FUNDC2 deficiency diminished platelet aggregation in response to a variety of agonists, including adenosine 5′-diphosphate (ADP), collagen, ristocetin/VWF, and thrombin. Consistently, in vivo assays of tail bleeding and thrombus formation showed that FUNDC2-knockout mice displayed deficiency in haemostasis and thrombosis. Mechanistically, FUNDC2 deficiency impairs the phosphorylation of AKT and downstream GSK-3β in a PI3K-dependent manner. Moreover, cGMP also plays an important role in FUNDC2/AKT-mediated platelet activation. This FUNDC2/AKT/GSK-3β/cGMP axis also regulates clot retraction of platelet-rich plasma. Conclusion FUNDC2 positively regulates platelet functions via AKT/GSK-3β/cGMP signalling pathways, which provides new insight for platelet-related diseases.

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Enhanced platelet aggregation and activation under conditions of hypothermia

Thrombosis and Haemostasis ◽

10.1160/th07-03-0189 ◽

2007 ◽

Vol 98 (12) ◽

pp. 1266-1275 ◽

Cited By ~ 41

Author(s):

Ruben Xavier ◽

Ann White ◽

Susan Fox ◽

Robert Wilcox ◽

Stan Heptinstall

Keyword(s):

Cardiac Surgery ◽

Platelet Aggregation ◽

Platelet Function ◽

Whole Blood ◽

Platelet Rich Plasma ◽

Baseline Levels ◽

Spontaneous Aggregation ◽

High Concentrations ◽

Induced Aggregation ◽

P2y12 Antagonist

SummaryThe effects on platelet function of temperatures attained during hypothermia used in cardiac surgery are controversial. Here we have performed studies on platelet aggregation in whole blood and platelet-rich plasma after stimulation with a range of concentrations of ADP, TRAP, U46619 and PAF at both 28°C and 37°C. Spontaneous aggregation was also measured after addition of saline alone. In citrated blood, spontaneous aggregation was markedly enhanced at 28°C compared with 37°C. Aggregation induced by ADP was also enhanced. Similar results were obtained in hirudinised blood. There was no spontaneous aggregation in PRP but ADP-induced aggregation was enhanced at 28°C. The P2Y12 antagonist AR-C69931 inhibited all spontaneous aggregation at 28°C and reduced all ADP-induced aggregation responses to small, reversible responses. Aspirin had no effect. Aggregation was also enhanced at 28°C compared with 37°C with low but not high concentrations of TRAP and U46619. PAF-induced aggregation was maximal at all concentrations when measured at 28°C, but reversal of aggregation was seen at 37°C. Baseline levels of platelet CD62P and CD63 were significantly enhanced at 28°C compared with 37°C. Expression was significantly increased at 28°C after stimulation with ADP, PAF and TRAP but not after stimulation with U46619. Overall, our results demonstrate an enhancement of platelet function at 28°C compared with 37°C, particularly in the presence of ADP.

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Centrifugation Conditions in the L-PRP Preparation Affect Soluble Factors Release and Mesenchymal Stem Cell Proliferation in Fibrin Nanofibers

Molecules ◽

10.3390/molecules24152729 ◽

2019 ◽

Vol 24 (15) ◽

pp. 2729 ◽

Cited By ~ 4

Author(s):

Melo ◽

Luzo ◽

Lana ◽

Santana

Keyword(s):

Growth Factor ◽

Transforming Growth Factor ◽

Platelet Rich Plasma ◽

Clinical Practices ◽

Soluble Factors ◽

Tnf Α ◽

Platelet Concentration ◽

Tgf Β1

Leukocyte and platelet-rich plasma (L-PRP) is an autologous product that when activated forms fibrin nanofibers, which are useful in regenerative medicine. As an important part of the preparation of L-PRP, the centrifugation parameters may affect the release of soluble factors that modulate the behavior of the cells in the nanofibers. In this study, we evaluated the influences of four different centrifugation conditions on the concentration of platelets and leukocytes in L-PRP and on the anabolic/catabolic balance of the nanofiber microenvironment. Human adipose-derived mesenchymal stem cells (h-AdMSCs) were seeded in the nanofibers, and their viability and growth were evaluated. L-PRPs prepared at 100× g and 100 + 400× g released higher levels of transforming growth factor (TGF)-β1 and platelet-derived growth factor (PDGF)-BB due to the increased platelet concentration, while inflammatory cytokines interleukin (IL)-8 and tumor necrosis factor (TNF)-α were more significantly released from L-PRPs prepared via two centrifugation steps (100 + 400× g and 800 + 400× g) due to the increased concentration of leukocytes. Our results showed that with the exception of nanofibers formed from L-PRP prepared at 800 + 400× g, all other microenvironments were favorable for h-AdMSC proliferation. Here, we present a reproducible protocol for the standardization of L-PRP and fibrin nanofibers useful in clinical practices with known platelet/leukocyte ratios and in vitro evaluations that may predict in vivo results.

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Evaluation of allogeneic freeze-dried platelet lysate in cartilage exposed to interleukin 1-β in vitro

BMC Veterinary Research ◽

10.1186/s12917-019-2118-z ◽

2019 ◽

Vol 15 (1) ◽

Cited By ~ 3

Author(s):

Livia Camargo Garbin ◽

C. Wayne McIlwraith ◽

David D. Frisbie

Keyword(s):

Musculoskeletal Diseases ◽

Platelet Rich Plasma ◽

Autologous Blood ◽

Interleukin 1 ◽

Platelet Lysate ◽

Freeze Dried ◽

Platelet Concentration ◽

High Concentrations ◽

Disease Modifying Treatment

Abstract Background Platelet-rich plasma (PRP) as well as other platelet-derived products have been used as a potential disease-modifying treatment for musculoskeletal diseases, such as osteoarthritis (OA). The restorative properties of such products rely mainly on the high concentrations of growth factors, demonstrating encouraging results experimentally and clinically. Yet, the autologous blood-derived nature of the PRP product lead to limitations that precludes it’s widespread use. The main limitations for PRP use are; product variability, the need for minimum laboratory settings in most cases, and the need for storage at low temperatures to preserve its properties. Based on these limitations, the objective of this study was to investigate an allogeneic off-the-shelf platelet lysate (PL) in cartilage exposed to interleukin 1β (IL-1β). For this purpose, blood and cartilage were harvested from eight skeletally mature and healthy horses. Blood was processed into PL aliquots and divided into three groups (Frozen, Freeze-dried and Filtered freeze-dried), used in autologous and allogeneic conditions and in three different concentrations (1.5, 3 and 6-fold). Different PL preparations were then applied in cartilage culture with interleukin-1 beta and cultured for 10 days. Cartilage and media samples were collected and analyzed for total GAG and 35SO4-labeled GAG content. Results No significant differences between the controls and PL groups in cartilage and media were demonstrated. The effects of PL on cartilage matrix were concentration dependent and intermediate concentrations (3-fold) in PL showed increased 35SO4-labelled GAG in cartilage. Conclusion In conclusion, the allogeneic freeze-dried PL presented equivalent effects compared to frozen autologous PL. Intermediate platelet concentration on average demonstrated improved results, demonstrating less GAG loss compared to other concentrations.

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Platelet Activation and Biofilm Formation by Aerococcus urinae, an Endocarditis-Causing Pathogen

Infection and Immunity ◽

10.1128/iai.00469-10 ◽

2010 ◽

Vol 78 (10) ◽

pp. 4268-4275 ◽

Cited By ~ 29

Author(s):

Oonagh Shannon ◽

Matthias Mörgelin ◽

Magnus Rasmussen

Keyword(s):

Platelet Aggregation ◽

Platelet Activation ◽

Biofilm Formation ◽

Platelet Rich Plasma ◽

Protein Structures ◽

Prostaglandin E ◽

Bacterial Surface ◽

Fibrinogen Receptor ◽

Aerococcus Urinae

ABSTRACT The Gram-positive bacterium Aerococcus urinae can cause infectious endocarditis (IE) in older persons. Biofilm formation and platelet aggregation are believed to contribute to bacterial virulence in IE. Five A. urinae isolates from human blood were shown to form biofilms in vitro, and biofilm formation was enhanced by the presence of human plasma. Four of the A. urinae isolates caused platelet aggregation in platelet-rich plasma from healthy donors. The Au3 isolate, which induced platelet aggregation in all donors, also activated platelets, as determined by flow cytometry. Platelet aggregation was dependent on bacterial protein structures and on platelet activation since it was sensitive to both trypsin and prostaglandin E1. Plasma proteins at the bacterial surface were needed for platelet aggregation; and roles of the complement system, fibrinogen, and immunoglobulin G were demonstrated. Complement-depleted serum was unable to support platelet aggregation by Au3 and complement blockade using compstatin-inhibited platelet activation. Platelet activation by Au3 was inhibited by blocking of the platelet fibrinogen receptor, and this isolate was also shown to bind to radiolabeled fibrinogen. Removal of IgG from platelet-rich plasma by a specific protease inhibited the platelet aggregation induced by A. urinae, and blockade of the platelet FcRγIIa hindered platelet activation induced by Au3. Convalescent-phase serum from a patient with A. urinae IE transferred the ability of the bacterium to aggregate platelets in an otherwise nonresponsive donor. Our results show that A. urinae exhibits virulence strategies of importance for IE.

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A New Role for FcγRIIA in the Potentiation of Human Platelet Activation Induced by Weak Stimulation.

Blood ◽

10.1182/blood.v106.11.1648.1648 ◽

2005 ◽

Vol 106 (11) ◽

pp. 1648-1648

Author(s):

Ilaria Canobbio ◽

Lucia Stefanini ◽

Gianni F. Guidetti ◽

Cesare Balduini ◽

Mauro Torti

Keyword(s):

Platelet Aggregation ◽

Tyrosine Kinase ◽

Tyrosine Phosphorylation ◽

Lipid Rafts ◽

Platelet Activation ◽

Human Platelets ◽

G Protein Coupled Receptors ◽

Weak Stimulation ◽

High Concentrations ◽

G Protein Coupled

Abstract The low affinity receptor for immunoglobulin G, FcγRIIA, is expressed in human platelets, mediates heparin-associated thrombocytopenia, and participates in platelet activation induced by von Willebrand factor. Activation of FcγRIIA occurs upon clustering of the receptor induced by immunocomplexes, and consists in the phosphorylation of two tyrosine residues within the ITAM, typically promoted by an associated Src kinase. The phosphorylated receptor acts as a docking site for SH2 domain-containing signaling proteins, including the tyrosine kinase Syk. This event initiates an intracellular tyrosine kinase-based signaling cascade that eventually leads to phosphorylation and activation of phospholipase C (PLC) γ2, and elicits cellular responses. To date, very little is known on the possible involvement of FcγRIIA in platelet activation induced by soluble agonists. We have found that stimulation of platelets with agonists acting on G-protein-coupled receptors resulted in Src-kinase-mediated tyrosine phosphorylation of FcγRIIA. Treatment of platelets with the blocking monoclonal antibody IV.3 against FcγRIIA, but not with control IgG, inhibited platelet aggregation induced by TRAP1, TRAP4, the thromboxane A2 analogue U46619, and low concentrations of thrombin. By contrast, platelet aggregation induced by high doses of thrombin was unaffected by blockade of FcγRIIA. We also found that the anti-FcγRIIA monoclonal antibody IV.3 inhibited pleckstrin phosphorylation and calcium mobilization induced by low, but not high, concentrations of thrombin. Thrombin- and U46619-induced tyrosine phosphorylation of Syk and PLCγ2, which represent substrates typically involved in FcγRIIA-mediated signaling, was clearly reduced by incubation with anti-FcγRIIA antibody IV.3. Morever, we were able to demonstrated that platelet stimulation by thrombin induced the association of FcγRIIA with Syk. Signaling through immunoreceptor typically takes places in characteristic membrane microdomains called lipid rafts. Upon stimulation with thrombin, FcγRIIA relocated in lipid rafts, and thrombin-induced tyrosine phosphorylation of FcγRIIA occurred within these membrane domains. Controlled disruption of lipid rafts by depleting membrane cholesterol prevented tyrosine phosphorylation of FcγRIIA, and impaired platelet aggregation induced by U46619 or by low, but not high, concentrations of thrombin. These results indicate that FcγRIIA can be activated in human platelets downstream G-protein-coupled receptors, and initiates a tyrosine kinase-based signaling pathway that significantly contributes to platelet activation and aggregation in response to weak stimulation.

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