Human Platelets Express Functional Pannexin-1

Abstract Abstract 1132 The protein family of pannexins (Panx) contains three members (Panx1, Panx2 and Panx3) that are highly evolutionarily conserved from worms to mammals, and that form hemichannels involved in the transport of ions like Ca2+ and small molecules such as ATP into and out of cells. Panx1 is ubiquitously expressed in human tissues, and has been shown to mediate ATP release in erythrocytes, taste buds, airway epithelia and astrocytes. In platelets, ATP serves as an important paracrine and autocrine signaling molecule, binding to P2X1 purinergic receptors on the platelet surface, regulating shape change, and amplifying platelet responses to agonists such as collagen. Based on the role of Panx and the significance of ATP release in platelets function, we investigate the expression and function of Panx1 in human platelets. Because the role of Panx1 in platelet function has not been studied previously, we sought to investigate the expression and function of Panx1 in human platelets. Materials and methods. Washed human platelets, isolated from ACD anticoagulated whole blood, were resuspended in Tyrode's saline solution-HEPES to a final concentration of 2.5 × 108/mL, stimulated with collagen and collagen related peptide (CRP), and their activation and secretion measured by whole-blood lumi-aggregometry in the presence or absence of Panx1-specific channel blockers: carbenoxolone (Cbnx) 100 μM; probenecid (Pbn) 100 μM and mefloquine (Mfq) 10 μM. Expression of Panx1 was determined by western blot, flow cytometry and fluorescence microscopy using a specific rabbit polyclonal anti-Panx 1 antibody. Panx hemichannel function was assessed by sulforhodamine B dye uptake taken up by ADP or collagen-stimulated platelet in the presence or absence of known Panx1 channel blockers. Results. Western blots of platelet lysates with rabbit anti-Panx1 antibody revealed a 47 kDa band corresponding to the known molecular weight of the Panx1 monomer. Flow cytometry performed on permeabilized platelets showed a significant shift in fluorescence intensity in platelets incubated with the anti-Panx1 antibody. Strong, specific staining was also observed by fluorescent microscopy of permeabilized platelets incubated with the anti-Panx1 antibody. Both platelet shape change and ATP release induced by CRP (0.5μg/ml) or collagen (1.0 μg/ml) were inhibited more than 50 % by Cbnx and Pbn; however, the most significant effect was obtained with platelets exposed to mefloquine 10 μM (see table): Platelet stimulation with Collagen or ADP induced an increase in sulforhodamine B uptake which could be significantly inhibited by preincubation with the Panx1 channel blocker probenecid. Conclusions. Our results demonstrated that human platelets express Panx1 Taken together, these data demonstrate that Panx1 is expressed by human platelets, evidenced by the presence of the protein by western blot, flow cytometry and immunofluorescence microscopy. From a functional standpoint, the significant effect of carbenoxolone, probenecid and especially mefloquine on collagen and CRP-induced shape change and ATP release, suggest that in human platelets Panx1 is involved in ATP release. In other cell types Panx1 channels can be opened by activation of P2 receptors; however, further studies are required to elucidate a possible association and functional interaction of Panx1 with P2X1 in platelets. Since purinergic signaling is a fundamental mechanism in platelet activation, inhibition of Panx1 hemichannels could have therapeutic potential when dampening platelet activation is desired. Disclosures: No relevant conflicts of interest to declare.

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Integrin-αIIbβ3-mediated outside-in signalling activates a negative feedback pathway to suppress platelet activation

Thrombosis and Haemostasis ◽

10.1160/th16-02-0096 ◽

2016 ◽

Vol 116 (11) ◽

pp. 918-930 ◽

Cited By ~ 8

Author(s):

Baiyun Dai ◽

Peng Wu ◽

Feng Xue ◽

Renchi Yang ◽

Ziqiang Yu ◽

...

Keyword(s):

Flow Cytometry ◽

Platelet Activation ◽

Negative Feedback ◽

Human Platelets ◽

Wild Type ◽

Integrin Αiibβ3 ◽

Atp Secretion ◽

Platelet Disaggregation ◽

Feedback Pathway

SummaryIntegrin-αIIbβ3-mediated outside-in signalling is widely accepted as an amplifier of platelet activation; accumulating evidence suggests that outside-in signalling can, under certain conditions, also function as an inhibitor of platelet activation. The role of integrin-αIIbβ3-mediated outside-in signalling in platelet activation is disputable. We employed flow cytometry, aggregometry, immunoprecipitation, and immunoblotting to investigate the role of integrin-αIIbβ3-mediated outside-in signalling in platelet activation. Integrin αIIbβ3 inhibition enhances agonist-induced platelet ATP secretion. Human platelets lacking expression of αIIbβ3 exhibited more platelet ATP secretion than their wild-type counterparts. Moreover, integrin-αIIbβ3-mediated outside-in signals activate SHIP-1, which in turn mediates p-Akt dep-hosphorylation, leading to inactivation of PI3K/Akt signalling. Furthermore, 3AC (SHIP-1 inhibitor) inhibits platelet disaggregation, and promotes platelet ATP secretion. Upon ADP stimulation, Talin is recruited to αIIbβ3, and it is dissociated from αIIbβ3 when platelets disaggregate. In addition, treatment with RUC2, an inhibitor of αIIbβ3, which blocks αIIbβ3-mediated outside-in signalling, can markedly prevent the dissociation of talin from integrin. SHIP1 Inhibitor 3AC inhibits the dissociation of talin from integrin-β3. These results suggest that integrin-αIIbβ3-mediated outside-in signalling can serve as a brake to restrict unnecessary platelet activation by activated SHIP-1, which mediated the disassociation of talin from β3, leading to integrin inactivation and blocking of PI3K/Akt signalling to restrict platelet ATP secretion.

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Role of Caspase in a Subset of Human Platelet Activation Responses

Blood ◽

10.1182/blood.v93.12.4222 ◽

1999 ◽

Vol 93 (12) ◽

pp. 4222-4231 ◽

Cited By ~ 119

Author(s):

Anna Shcherbina ◽

Eileen Remold-O’Donnell

Keyword(s):

Platelet Activation ◽

Caspase 3 ◽

Human Platelet ◽

Thrombus Formation ◽

Shape Change ◽

Vascular Wall ◽

Human Platelets ◽

Granule Secretion ◽

Platelets Function

Abstract Platelets function to protect the integrity of the vascular wall. A subset of platelet activation responses that are especially important for thrombus formation include exposure of phosphatidylserine and release of microparticles, which generate procoagulant surfaces. The resemblance of these platelet activation processes to events occurring in nucleated cells undergoing apoptosis suggests a possible role for caspases, which are major effector enzymes of nucleated cell apoptosis. We demonstrate here the presence of caspase-3 in human platelets and its activation by physiological platelet agonists. Using cell-permeable specific inhibitors, we demonstrate a role for a caspase-3–like protease in the agonist-induced (collagen plus thrombin or Ca2+ ionophore) platelet activation events of phosphatidylserine exposure, microparticle release, and cleavage of moesin, a cytoskeletal-membrane linker protein. The role of caspase-3 in platelet activation is restricted rather than global, because other activation responses,  granule secretion, shape change, and aggregation were unaffected by caspase-3 inhibitors. Experiments with two classes of protease inhibitors show that caspase-3 function is distinct from that of calpain, which is also involved in late platelet activation events. These findings show novel functions of caspase and provide new insights for understanding of platelet activation.

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Cyclin-dependent kinase 2 (Cdk2) controls phosphatase-regulated signaling and function in platelets

10.1101/2020.05.31.126953 ◽

2020 ◽

Author(s):

Paul R. Woods ◽

Brian L. Hood ◽

Sruti Shiva ◽

Thomas P. Conrads ◽

Sarah Suchko ◽

...

Keyword(s):

Cell Cycle ◽

Platelet Activation ◽

Human Platelets ◽

Cell Cycle Regulators ◽

Cyclin Dependent Kinase ◽

Erk Activation ◽

Src Signaling ◽

Energetic State ◽

And Function

AbstractCell cycle regulatory molecules including cyclin-dependent kinases can be recruited into non-nuclear pathways to coordinate cell cycling with the energetic state of the cell or with functions such as motility. Little is known about the role of cell cycle regulators in anucleate cells such as platelets. We report that cyclin-dependent kinase (cdk2) is robustly expressed in human platelets, is activated by thrombin and is required for platelet activation. Cdk2 activation required Src signaling downstream of the platelet thrombin receptor PAR1. Kinase-active cdk2 promoted the activation of downstream platelet kinases by phosphorylating and inactivating the catalytic subunit of protein phosphatase 1 (PP1). Erk was bound to PP1 in a complex with the PP1 regulator PPP1R12a (MYPT1) in platelets, and cdk2 inhibited the phosphatase activity of PP1 and PPP1R12a bound complexes. The requirement for cdk2 in Erk activation could be replaced by the phosphatase inhibitor calyculin if cdk2 was inhibited. Blockade of cdk2 kinase with chemical and peptide cdk2 inhibitors resulted in suppression of thrombin-induced platelet aggregation, and partially inhibited GPIIb/IIIa integrin activation as well as platelet secretion of P-Selectin and ATP. Together, these data indicate a requirement for cdk2 in platelet activation.

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Platelet Tissue Factor: Fast and Specific Clotting Activation Pathway Mediated by VWF-GPIba Interaction and Platelet Membrane FVII. Human Platelets Contain All the Components for Assembling the Prothrombinase Complex and Their Procoagulant Function Is Independent of Aggregation/Secretion and GPVI Function.

Blood ◽

10.1182/blood.v114.22.3000.3000 ◽

2009 ◽

Vol 114 (22) ◽

pp. 3000-3000

Author(s):

Olga Panes ◽

Valeria Matus ◽

Claudia G. Sáaez ◽

Jaime Pereira ◽

Diego Mezzano

Keyword(s):

Flow Cytometry ◽

Tissue Factor ◽

Platelet Activation ◽

Conflicts Of Interest ◽

Human Platelets ◽

Platelet Membrane ◽

Prothrombinase Complex ◽

Serotonin Secretion ◽

Trap Activation

Abstract Abstract 3000 Poster Board II-977 Human platelets synthesize and store functionally silent tissue factor (TF) which expresses procoagulant activity (PCA) after platelet activation. Fast activation of TF was elicited by VWF-Ristocetin (VWF-R) through GPIbαa activation and Src-Lyn transduction pathway (Blood, Nov 2008; 112:113). Given that GPVI, along with GPIb and TF have been found in “lipid rafts”, and the activated form of GPVI signals through Fyn, another member of the Src family, we tested if GPVI was involved in TF-initiated PCA. We also studied the time-course and pathway specificity of TF activation and the role of platelet FVII in PCA. Weak TF immunofluorescence and co-localization with GPIba were observed in non stimulated washed platelets. A mild increase of TF fluorescence was detected 2 min after TRAP activation, which augmented when the stimulus was VWF-R. Furthermore, striking enhancement of TF fluorescence occurred 2 min after depositing platelets over a VWF-coated surface, but not over fibrinogen or albumin. Platelets adherent to VWF matrix showed GPIb clustering and loss of co-localization with TF. Externalization of TF was confirmed by immunoprecipitation (Ip) of biotinylated membranes before and after platelet activation. Concomitantly, TF-dependent FXa generation increased 5-10-fold shortly after VWF stimulus. Washed platelets stimulated with VWF-R agglutinated normally when stirred in an aggregometer, and the fraction of platelets exposing anionic phospholipids (annexin V binding) was similar to parallel samples stimulated with TRAP. However, VWF-R induced null 14C-serotonin secretion and P-selectin exposure (flow cytometry) in washed platelets. In contrast, TRAP, collagen, ADP and convulxin induced full platelet aggregation, 14C-serotonin and P-selectin secretion at 2-5 min, but with no increase in FXa generation. Platelet PCA was inhibited by antibodies against TF, GPIba, FVIIa, as well as by SU6656 and PP2 (Src pathway inhibitors), but not by Gö6850 (a PKC inhibitor) or exogenous TFPI. p85, a subunit of PI-3K constitutively associated with GPIb complex, becomes strongly associated with TF after stimulation with VWF-R, though only weakly after TRAP activation, confirming the coordinate activation of GPIb and TF. FVII and FX were revealed in platelet membrane fractions by immunoblotting and both co-precipitate with TF in non-stimulated platelets. Two min after activation with VWF-R striking co-precipitations of TF with FVII and FX light chains were evidenced, denoting activation of platelet FVII and FX. When exogenous FX was added to the assay, the amount of FXa generated after 1 and 2 min stimulation was similar whether or not exogenous FVIIa was added. Platelets from four non-related patients with bleeding related to hereditary defect of GPVI had null aggregation and secretion with convulxin and collagen, less than 7% labeling of GPVI by flow cytometry and an immunoreactive membrane GPVI of Mr≈40kDa (native GPVI Mr=62kDa). All of them had normal agglutination with VWF-R and normal FXa generation. In summary, GPIb activation by VWF constitutes a unique and fast inducer of platelet TF-dependent PCA. This process requires anionic phospholipid exposure, but is independent of platelet GPIIb/IIIa and GPVI function. Platelet FVII can initiate FXa generation without need of plasma FVII. The associations of platelet FVII and FX with TF on membrane fractions, together with the large amount of FV in platelets, indicate that human platelets provide not just TF and a PCA phospholipid platform, but also all the components of the prothrombinase complex to trigger the clotting process. Taken together, our results underline the central role of platelets in the whole hemostatic process, unifying primary and secondary hemostasis and circumscribing thrombin generation and fibrin deposition where platelet plug is being formed. Platelet PCA should become a pharmacological target for preventing or managing bleeding and thrombotic disorders. Disclosures: No relevant conflicts of interest to declare.

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Role of Caspase in a Subset of Human Platelet Activation Responses

Blood ◽

10.1182/blood.v93.12.4222.412k34_4222_4231 ◽

1999 ◽

Vol 93 (12) ◽

pp. 4222-4231 ◽

Cited By ~ 2

Author(s):

Anna Shcherbina ◽

Eileen Remold-O’Donnell

Keyword(s):

Platelet Activation ◽

Caspase 3 ◽

Human Platelet ◽

Thrombus Formation ◽

Shape Change ◽

Vascular Wall ◽

Human Platelets ◽

Granule Secretion ◽

Platelets Function

Platelets function to protect the integrity of the vascular wall. A subset of platelet activation responses that are especially important for thrombus formation include exposure of phosphatidylserine and release of microparticles, which generate procoagulant surfaces. The resemblance of these platelet activation processes to events occurring in nucleated cells undergoing apoptosis suggests a possible role for caspases, which are major effector enzymes of nucleated cell apoptosis. We demonstrate here the presence of caspase-3 in human platelets and its activation by physiological platelet agonists. Using cell-permeable specific inhibitors, we demonstrate a role for a caspase-3–like protease in the agonist-induced (collagen plus thrombin or Ca2+ ionophore) platelet activation events of phosphatidylserine exposure, microparticle release, and cleavage of moesin, a cytoskeletal-membrane linker protein. The role of caspase-3 in platelet activation is restricted rather than global, because other activation responses,  granule secretion, shape change, and aggregation were unaffected by caspase-3 inhibitors. Experiments with two classes of protease inhibitors show that caspase-3 function is distinct from that of calpain, which is also involved in late platelet activation events. These findings show novel functions of caspase and provide new insights for understanding of platelet activation.

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Collagen-Induced Platelet Aggregation: -Evidence Against the Essential Role of Platelet Adenosine Diphosphate

Thrombosis and Haemostasis ◽

10.1055/s-0038-1657015 ◽

1979 ◽

Vol 42 (04) ◽

pp. 1193-1206 ◽

Cited By ~ 9

Author(s):

Barbara Nunn

Keyword(s):

Platelet Aggregation ◽

Time Course ◽

Essential Role ◽

Atp Release ◽

Adenosine Diphosphate ◽

Human Platelets ◽

High Doses ◽

Induced Aggregation

SummaryThe hypothesis that platelet ADP is responsible for collagen-induced aggregation has been re-examined. It was found that the concentration of ADP obtaining in human PRP at the onset of aggregation was not sufficient to account for that aggregation. Furthermore, the time-course of collagen-induced release in human PRP was the same as that in sheep PRP where ADP does not cause release. These findings are not consistent with claims that ADP alone perpetuates a collagen-initiated release-aggregation-release sequence. The effects of high doses of collagen, which released 4-5 μM ADP, were not inhibited by 500 pM adenosine, a concentration that greatly reduced the effect of 300 μM ADP. Collagen caused aggregation in ADP-refractory PRP and in platelet suspensions unresponsive to 1 mM ADP. Thus human platelets can aggregate in response to collagen under circumstances in which they cannot respond to ADP. Apyrase inhibited aggregation and ATP release in platelet suspensions but not in human PRP. Evidence is presented that the means currently used to examine the role of ADP in aggregation require investigation.

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Abstract 11947: Unraveling the Mechanism for the Stimulatory Role of Platelet GPIb-IX-V in Thrombin-Induced Platelet Activation

Circulation ◽

10.1161/circ.130.suppl_2.11947 ◽

2014 ◽

Vol 130 (suppl_2) ◽

Author(s):

Brian Estevez ◽

Michael K Delaney ◽

Aleksandra Stojanovic-Terpo ◽

Xiaoping Du

Keyword(s):

Platelet Activation ◽

Chinese Hamster Ovary Cells ◽

Chinese Hamster ◽

Human Platelets ◽

Platelet Glycoprotein ◽

Inhibitory Peptide ◽

Protease Activated Receptors ◽

Signaling Mechanism ◽

Ovary Cells

Numerous reports indicate that the platelet glycoprotein (GP) Ib-IX complex (GPIb-IX) binds directly to the potent platelet agonist thrombin and is important for promoting thrombin-induced platelet activation. However, how GPIb-IX contributes to thrombin-induced platelet activation is unclear. It has been suggested that thrombin binding to GPIb facilitates the cleavage, and thus activation, of the protease-activated receptors (PAR). Our data indicate that GPIb-IX promotes thrombin signaling through a GPIb-IX signaling mechanism. Pretreatment of human platelets with MPalphaC, an inhibitory peptide based on a critical 14-3-3 signaling protein binding site on the cytoplasmic domain of the GPIb alpha chain, inhibited thrombin-induced platelet activation. MPalphaC-treatment inhibited thrombin-induced activation of Rac1 and LIMK1, both of which are known to play essential roles in GPIb signaling. To more specifically determine the role of GPIb-IX, we reconstituted GPIb-IX-facilitated thrombin signaling in Chinese Hamster Ovary cells expressing PAR1. Thrombin induced signaling was significantly enhanced by GPIb-expression, and deletion of the cytoplasmic 14-3-3-binding domain of GPIb alpha abolished the stimulatory effect of GPIb on thrombin signaling. Furthermore, the role of GPIb-IX in promoting thrombin signaling requires Rac1, and GPIb-IX-dependent Rac1 activation and LIMK phosphorylation are abolished in delta 605 cells expressing a 14-3-3-binding defective mutant GPIb alpha. Taken together, these data suggest that the stimulatory role of GPIb in thrombin signaling requires a C-terminal 14-3-3-binding region which mediates activation of a Rac1/LIMK1 pathway that promotes thrombin signaling leading to platelet activation.

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Short fungal fractions of β-1,3 glucans affect platelet activation

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00907.2015 ◽

2016 ◽

Vol 311 (3) ◽

pp. H725-H734 ◽

Cited By ~ 8

Author(s):

Hélène Vancraeyneste ◽

Rogatien Charlet ◽

Yann Guerardel ◽

Laura Choteau ◽

Anne Bauters ◽

...

Keyword(s):

Platelet Activation ◽

Atp Release ◽

Human Platelets ◽

Receptor Expression ◽

Dependent Manner ◽

Platelet Activity ◽

Concentration Dependent Manner ◽

Wide Range ◽

Invasive Infections ◽

Life Threatening

Platelets are capable of binding, aggregating, and internalizing microorganisms, which enhances the elimination of pathogens from the blood. The yeast Candida albicans is a pathobiont causing life-threatening invasive infections. Its cell wall contains β-1,3 glucans that are known to trigger a wide range of host cell activities and to circulate during infection. We studied the effect of β-1,3 glucan fractions (BGFs) consisting of diglucosides (Glc2), tetraglucosides (Glc4), and pentaglucosides (Glc5) on human platelets, their mechanisms of action, and their possible impact on host defenses. The effect of BGFs on the coagulation process was determined by measuring thrombin generation. Platelets pretreated with BGFs were analyzed in terms of activation, receptor expression, aggregation, and adhesion to neutrophils and to C. albicans. The results show that BGFs affected the endogenous thrombin potential in a concentration-dependent manner. For platelet activation, BGFs at a low concentration (2 μmol/l) reduced ATP release and prevented the phosphorylation of protein kinase C. BGFs diminished the expression of P-selectin and the activation of αIIbβ3. BGFs decreased platelet aggregation and the interaction between thrombin-stimulated platelets and neutrophils, fibrinogen, and C. albicans. GLc5 decreased ATP release and TGF-β1 production in response to TLR4 upregulation in thrombin-stimulated platelets, but TLR4 blockage abolished the effect of BGFs on platelets. This study provides evidence that fungal pentaglucosides modulate platelet activity mediated via TLR4 stimulation and reduce platelet-neutrophil interaction.

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IκB kinase 2 is not essential for platelet activation

Blood Advances ◽

10.1182/bloodadvances.2019001044 ◽

2020 ◽

Vol 4 (4) ◽

pp. 638-643

Author(s):

Manuel Salzmann ◽

Sonja Bleichert ◽

Bernhard Moser ◽

Marion Mussbacher ◽

Mildred Haase ◽

...

Keyword(s):

Platelet Activation ◽

Active Site ◽

Bleeding Time ◽

Thrombus Formation ◽

Human Platelets ◽

Iκb Kinase ◽

Specific Deletion

Abstract Platelets are small anucleate cells that release a plethora of molecules to ensure functional hemostasis. It has been reported that IκB kinase 2 (IKK2), the central enzyme of the inflammatory NF-κB pathway, is involved in platelet activation, because megakaryocyte/platelet-specific deletion of exons 6 and 7 of IKK2 resulted in platelet degranulation defects and prolonged bleeding. We aimed to investigate the role of IKK2 in platelet physiology in more detail, using a platelet-specific IKK2 knockout via excision of exon 3, which makes up the active site of the enzyme. We verified the deletion on genomic and transcriptional levels in megakaryocytes and were not able to detect any residual IKK2 protein; however, platelets from these mice did not show any functional impairment in vivo or in vitro. Bleeding time and thrombus formation were not affected in platelet-specific IKK2-knockout mice. Moreover, platelet aggregation, glycoprotein GPIIb/IIIa activation, and degranulation were unaltered. These observations were confirmed by pharmacological inhibition of IKK2 with TPCA-1 and BMS-345541, which did not affect activation of murine or human platelets over a wide concentration range. Altogether, our results imply that IKK2 is not essential for platelet function.

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Neutrophil P-selectin-glycoprotein-ligand-1 binding to platelet P-selectin enhances metalloproteinase 2 secretion and platelet-neutrophil aggregation

Thrombosis and Haemostasis ◽

10.1160/th05-05-0344 ◽

2005 ◽

Vol 94 (12) ◽

pp. 1230-1235 ◽

Cited By ~ 21

Author(s):

Haissam Abou-Saleh ◽

Jean-François Théorêt ◽

Daniel Yacoub ◽

Yahye Merhi

Keyword(s):

Platelet Activation ◽

Human Platelets ◽

Vascular Remodelling ◽

Adhesive Interaction ◽

Platelet Binding ◽

Enhanced Secretion ◽

Thrombin Activation ◽

Neutrophil Aggregation ◽

And Function ◽

The Impact

SummaryPlatelets and neutrophils constitute a high source of metalloproteinases (MMPs), and their interactions via P-selectin and Pselectin- glycoprotein-ligand-1 (PSGL-1) are involved in thrombosis, vascular remodelling, and restenosis. We investigated the impact of these interactions on platelet MMP-2 secretion and function in platelet and neutrophil aggregation. The secretion of MMP-2 from human platelets was significantly increased threefold after thrombin activation, and enhanced two-fold in the presence of neutrophils. Neutrophil supernatant had no effect on platelet MMP-2 secretion. While no MMP-2 was detected in the supernatant of neutrophils, a high amount of MMP-9 was released by neutrophils, and remained unchanged upon thrombin activation or in the presence of platelets. Platelet P-selectin, which increased significantly after activation, triggered platelet binding to neutrophils that was completely inhibited by P-selectin or PSGL-1 antagonists, and was reduced by 50% with a GPIIb/ IIIa antagonist. P-selectin or PSGL-1 antagonism abolished the enhanced secretion of platelet MMP-2 in the presence of neutrophils and reduced platelet-neutrophil aggregation. Platelet activation and binding to neutrophils enhance the secretion of platelet MMP-2 via an adhesive interaction between P-selectin and PSGL-1, which contribute to increase platelet-neutrophil aggregation.

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