scholarly journals SARS-CoV-2 infection is associated with a pro-thrombotic platelet phenotype

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Dario Bongiovanni ◽  
Melissa Klug ◽  
Olga Lazareva ◽  
Simon Weidlich ◽  
Marina Biasi ◽  
...  
Keyword(s):  
Platelet Activation ◽  
Transmembrane Proteins ◽  
Surface Expression ◽  
Cardiovascular Complications ◽  
Healthy Controls ◽  
Mass Cytometry ◽  
Activation Markers ◽  
Median Signal Intensity ◽  
Novel Coronavirus

AbstractNovel coronavirus disease 2019 (COVID-19) is associated with a hypercoagulable state, characterized by abnormal coagulation parameters and by increased incidence of cardiovascular complications. With this study, we aimed to investigate the activation state and the expression of transmembrane proteins in platelets of hospitalized COVID-19 patients. We investigated transmembrane proteins expression with a customized mass cytometry panel of 21 antibodies. Platelets of 8 hospitalized COVID-19 patients not requiring intensive care support and without pre-existing conditions were compared to platelets of healthy controls (11 donors) with and without in vitro stimulation with thrombin receptor-activating peptide (TRAP). Mass cytometry of non-stimulated platelets detected an increased surface expression of activation markers P-Selectin (0.67 vs. 1.87 median signal intensity for controls vs. patients, p = 0.0015) and LAMP-3 (CD63, 0.37 vs. 0.81, p = 0.0004), the GPIIb/IIIa complex (4.58 vs. 5.03, p < 0.0001) and other adhesion molecules involved in platelet activation and platelet–leukocyte interactions. Upon TRAP stimulation, mass cytometry detected a higher expression of P-selectin in COVID-19 samples compared to controls (p < 0.0001). However, we observed a significantly reduced capacity of COVID-19 platelets to increase the expression of activation markers LAMP-3 and P-Selectin upon stimulation with TRAP. We detected a hyperactivated phenotype in platelets during SARS-CoV-2 infection, consisting of highly expressed platelet activation markers, which might contribute to the hypercoagulopathy observed in COVID-19. In addition, several transmembrane proteins were more highly expressed compared to healthy controls. These findings support research projects investigating antithrombotic and antiplatelet treatment regimes in COVID-19 patients, and provide new insights on the phenotypical platelet expression during SARS-CoV-2 infection.

scholarly journals Neutrophil more than platelet activation associates with thrombotic complications in COVID-19 patients

2020 ◽  
Author(s):  
E Petito ◽  
E Falcinelli ◽  
U Paliani ◽  
E Cesari ◽  
G Vaudo ◽  
...  
Keyword(s):  
Platelet Activation ◽  
Neutrophil Activation ◽  
Low Molecular Weight ◽  
Healthy Controls ◽  
Activation Markers ◽  
Extracellular Traps ◽  
Thrombotic Complications ◽  
Metalloproteinase 9 ◽  
Clinical Worsening

Abstract Background SARS-CoV-2 infection is associated with hypercoagulability which predisposes to venous thromboembolism (VTE). We analyzed platelet and neutrophil activation in COVID-19 patients and their association with VTE. Methods Hospitalized COVID-19 patients and age- and sex-matched healthy controls were studied. Platelet and leukocyte activation, neutrophil extracellular traps (NETs), and matrix metalloproteinase-9 (MMP-9), a neutrophil-released enzyme, were measured. Four patients were re-studied after recovery. The activating effect of COVID-19 plasma on control platelets and leukocytes and the inhibiting activity of common antithrombotic agents on it were studied. Results 36 COVID-19 patients and 31 healthy controls were studied; 8/36 COVID-19 patients (22.2%) developed VTE. Platelets and neutrophils were activated in COVID-19 patients. NET, but not platelet activation, biomarkers correlated with disease severity and were associated with thrombosis. Plasmatic MMP-9 was significantly increased in COVID-19 patients. Platelet and neutrophil activation markers, but less so NETs, normalized after recovery. In vitro, plasma from COVID-19 patients triggered platelet and neutrophil activation and NET formation, the latter blocked by therapeutic dose low-molecular weight heparin, but not by aspirin or dypiridamole. Conclusions Platelet and neutrophil activation are key features of COVID-19 patients. NET biomarkers may help to predict clinical worsening and VTE, and may guide LMWH-treatment intensity.

scholarly journals Reticulated platelet mass cytometry reveals unexplored therapeutic targets in patients with chronic coronary syndrome

2021 ◽  
Vol 42 (Supplement_1) ◽  
Author(s):  
D Bongiovanni ◽  
M Klug ◽  
O Lazareva ◽  
K Kirmes ◽  
M Biasi ◽  
...  
Keyword(s):  
Single Cell ◽  
Antiplatelet Therapy ◽  
Peripheral Blood ◽  
Therapeutic Targets ◽  
Transmembrane Proteins ◽  
Thrombin Receptor ◽  
Mass Cytometry ◽  
Activation Markers ◽  
Coronary Syndrome ◽  
Custom Made

Abstract Background Reticulated platelets (RPs) are young, hyper-reactive thrombocytes that contain more RNA compared with mature platelets (MPs). The measurement of RPs level in peripheral blood with point-of-care systems is fast, reproducible, and inexpensive. Elevated RPs in peripheral blood predict adverse events in patients with acute and chronic coronary syndrome through unknown mechanisms. Preliminary transcriptome analyses reported an enrichment of pro-thrombotic transcripts. However, proteomic analyses are not available, and the biological features of RPs are largely unknown. Purpose We aimed to perform the largest proteomic characterization of RPs using mass cytometry with single-cell resolution in patients with chronic coronary syndrome (CCS) undergoing dual antiplatelet therapy (DAPT). Methods Thrombocytes from peripheral blood of CCS patients were isolated, prepared for mass cytometry (CyTOF) and stained with a custom-made CyTOF-panel of 20 antibodies targeting important transmembrane proteins (anti-CD9, anti-CD29, anti-CD31, anti-CD36-, anti-CD40, anti-CD41, anti-CD42a, anti-CD42b-, anti-CD47, anti-CD61, anti-CD62P-, anti-CD63, anti-CD69, anti-CD107a, anti-CD154, anti-GPVI, antiGPIIb/GPIIIa complex, anti-Par1, anti-PEAR-1 and the negative control anti-CD3 coupled with different metal isotopes). Two samples were prepared from each donor: one baseline sample (non-stimulated platelets) and one sample stimulated with 10 μM thrombin receptor-activating peptide (TRAP). According to previous experiences and common practice, we detected RPs and MPs based on their RNA content. We analyzed the results with a custom bioinformatic pipeline. Results 13 patients with CCS on DAPT were included in this study. Mass cytometry highlighted an expression heterogeneity of relevant transmembrane proteins in thrombocytes of CCS patients (Figure 1A-B colored according to expression level: from blue-low to red-high). CyTOF detected an upregulation of important transmembrane receptors in RPs compared to MPs in quiescent platelets: GPVI (p&lt;0.0001), PAR-1 (p&lt;0.0001), GPIX (p&lt;0.0001), and GPIbα (p&lt;0.0001, Figure 1C). After TRAP-stimulation, RPs expressed higher levels of the activation markers P-Selectin (p=0.0016) and LAMP-3 (CD63, p&lt;0.0001) compared to MPs confirming RPs hyperactivity (Figure 1D). Conclusion We here describe the first biological proteomic characterization with single-cell resolution of RPs biology in CCS patients. The upregulation of the activation markers P-Selectin and LAMP-3 as well as of specific transmembrane proteins as the collagen receptor GPVI and the thrombin receptor PAR-1 in patients treated with DAPT (schematic overview in Figure 2) provides the first solid biomolecular explanation of RPs hyper-reactivity and involvement in cardiovascular disease. Moreover, these results offer unexplored therapeutic targets to tailor antiplatelet therapy based on platelet protein expression in patients with elevated RPs FUNDunding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): German Center for Cardiovascular Research (DZHK) Figure 1. Platelet expression Figure 2. Schematic overview

scholarly journals Increased Pro-Thrombotic Platelet Activity Associated with Thrombin/PAR1-Dependent Pathway Disorder in Patients with Secondary Progressive Multiple Sclerosis

2020 ◽  
Vol 21 (20) ◽  
pp. 7722
Author(s):  
Angela Dziedzic ◽  
Elzbieta Miller ◽  
Michal Bijak ◽  
Lukasz Przyslo ◽  
Joanna Saluk-Bijak
Keyword(s):  
Multiple Sclerosis ◽  
Mrna Expression ◽  
Platelet Activation ◽  
Blood Platelets ◽  
Surface Expression ◽  
Epidemiological Studies ◽  
Progressive Multiple Sclerosis ◽  
Apolipoprotein A1 ◽  
Platelet Activity ◽  
Activation Markers

Epidemiological studies confirm the high risk of ischemic events in multiple sclerosis (MS) that are associated with increased pro-thrombotic activity of blood platelets. The most potent physiological platelet agonist is thrombin, which activates platelets via cleavage of specific protease-activated receptors (PARs). Our current study is aimed to determine the potential genetics and proteomic abnormalities of PAR1 in both platelets and megakaryocytes, which may have thromboembolic consequences in the course of MS. The obtained results were correlated with the expression level of platelet and megakaryocyte transcripts for APOA1 and A2M genes encoding atherosclerosis biomarkers: apolipoprotein A1 (ApoA1) and α-2-macroglobulin (α2M), respectively. Moreover, PAR1 functionality in MS platelets was assessed by flow cytometry, determining the level of platelet–platelet and platelet–leukocyte aggregates, platelet microparticles and surface expression of P-selectin. As a PAR1 agonist, the synthetic TRAP-6 peptide was used, which made it possible to achieve platelet activation in whole blood without triggering clotting. Comparative analyses showed an elevated level of platelet activation markers in the blood of MS patients compared to controls. The mRNA expression of gene coding α2M was upregulated, whilst ApoA1 was down-regulated, both in platelets and megakaryocytes from MS patients. Furthermore, we observed an increase in both mRNA expression and surface density of PAR1 in platelets and megakaryocytes in MS compared to controls. Both the level of platelet activation markers and PAR1 expression showed a high correlation with the expression of transcripts for APOA1 and A2M genes.

Platelet Activation and Inhibition in Sickle Cell Disease (PAINS) Study

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 5147-5147
Author(s):  
Andrew L. Frelinger ◽  
Joseph A. Jakubowski ◽  
Julie K. Brooks ◽  
Sabrina L. Zayas ◽  
Michelle A. Berny-Lang ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Antiplatelet Therapy ◽  
Platelet Activation ◽  
Healthy Subjects ◽  
Research Funding ◽  
Cell Disease ◽  
Activation Markers ◽  
Circulating Levels

Abstract Abstract 5147 Platelet activation/aggregation in sickle cell disease (SCD) may promote tissue ischemia, suggesting antiplatelet therapy may be useful. However, assessing platelet function and the effect of antiplatelet therapy in blood from SCD patients may be confounded by hemolysis with release of ADP. Here we evaluate levels of platelet activation markers in SCD adolescents vs. normal controls and compare, by multiple methods, the effect of in vitro blockade of the platelet ADP receptor P2Y12 by prasugrel's active metabolite, R-138727. Platelet activation markers in blood from SCD adolescents (n=15) and healthy adults (n=10), and the effect of R-138727 (0. 1 – 10 μM) added in vitro, were evaluated with and without ADP stimulation. Circulating levels of platelet-monocyte and platelet-neutrophil aggregates were significantly higher (p <0. 01) in SCD patients than in healthy controls. R-138727, in a concentration-dependent manner, inhibited platelet function in both SCD patients and healthy subjects as judged by ADP-stimulated light transmission aggregation, VerifyNow P2Y12 assay, multiple electrode aggregometry, and flow cytometric analysis of platelet vasodilator-stimulated phosphoprotein, activated GPIIb-IIIa and P-selectin. The R-138727 IC50s for each assay were not significantly different in SCD vs. healthy subjects. In summary: 1) The high circulating levels of platelet-monocyte and platelet-neutrophil aggregates demonstrate in vivo platelet activation in SCD and may be useful as markers of the in vivo pharmacodynamic efficacy of antiplatelet therapy in SCD. 2) The similar in vitro R-138727 IC50s in SCD and healthy subjects suggest that the prasugrel dose-dependence for platelet inhibition in SCD patients will be similar to that previously observed in healthy subjects. Disclosures: Frelinger: Eli Lilly: Consultancy, Research Funding; Daiichi Sankyo: Research Funding; GLSynthesis: Research Funding. Jakubowski:Eli Lilly: Employment. Heeney:Novartis: Consultancy, Research Funding; Eli Lilly and Company: Research Funding; Pfizer: Consultancy. Michelson:Eli Lilly: Data monitoring committee and idependent external monitor of clinical trials, Research Funding; Takeda: Research Funding; Oxygen Biotherapeutics: Research Funding; Alexion: Research Funding; Omthera: Research Funding.

scholarly journals High Peripheral Blood Circulating BDNF Levels Are Associated with Good Prognosis in CLL Patients; A CXCR-4 Dependent Effect?

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5562-5562
Author(s):  
David Azoulay ◽  
Yair Herishanu ◽  
Mika Shapiro ◽  
Yarden Brenshaft ◽  
Celia Suriu ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
B Cells ◽  
Serum Levels ◽  
Surface Expression ◽  
Independent Effect ◽  
Total Serum ◽  
Healthy Controls ◽  
Disease Prognosis ◽  
And Migration

Abstract Introduction: BDNF is a neuronal growth factor that previously showed to exert survival effect in B cells. The role of BDNF in CLL is unknown. Objectives: To study the circulating levels of BDNF in CLL patients and their association with disease prognosis. We also looked for CXCR-4 as a possible mechanisms underlying BDNF effect in CLL. Design and methods: The total BDNF levels and the levels of the BDNF precursor; proBDNF were quantified in the serum of 36 CLL patients and 5 healthy controls by commercial ELISA kits (DY248 and DY3175 DuoSet, respectively, from R&D Systems, Minneapolis, MN, USA). The patients' BDNF levels were correlated to the disease characteristics and clinical course. mRNA and protein expression of the high affinity receptor for BDNF; TrkB were evaluated by real time PCR and flow cytometry respectively. The effect of BDNF on CXCR4 surface expression and migration of CLL cells towards SDF-1 were studied in-vitro. Results: The total serum levels of BDNF in CLL patients was not statistically different compared to healthy controls (mean±SD; 19.9±15.1ng/ml vs. 10.5±9.5ng/ml respectively, p=0.19). Serum proBDNF levels in both CLL patients and healthy controls were under the detection limit of the kit. Within the CLL group we found higher total BDNF levels in patients with mutated immunoglobulin variable heavy-chain (IGHV) status than in patients with unmutated IGHV (25.2±14.6ng/ml vs. 14.1±13.0 in mutated and unmutated status, respectively, p=0.028). We also found higher serum levels of total BDNF in CLL patients in Binet stage A compared to those with a more advance clinical stage (mean±SD ; 24.5±14.6ng/ml vs. 17.0±16.9 and 10.2±9.6 in A,B and C, respectively, p=0.013). Accordantly, higher BDNF levels were detected in patients who had a clinically stable disease compared to patients who had disease progression and required treatment (23.1±14.7ng/ml vs. 13.4±14.5, respectively, p=0.013). The mRNA levels of the BDNF receptor; TrkB, were twofold lower in CLL cells compared to normal B cells. However, the overall TrkB mRNA transcripts were very low in CLL cells and normal B cells compared to the normalized housekeeping genes of Beta-2-microglobulin and CD19. Likewise, surface expression of TrkB in CLL was undetectable using several commercial monoclonal Abs by flow cytometry. In vitro culture of CLL cells in serum free media for 24h resulted in an increased CXCR4 surface expression and greater apoptosis. Culture of CLL cells in the presence of recombinant BDNF (50ng/ml) resulted in downregulation CXCR-4 surface levels and protection from spontaneous apoptosis, irrespectively of the IGHV mutational status. The effect of BDNF on CXCR4 downregulation was also confirmed at 1h culture as it shows to induce similar effect to SDF-1 (50ng/ml) and additive effect when combined with SDF-1. Finally, possible competition between BDNF and SDF-1 was indicated as pretreatment of CLL cells with BDNF inhibit their migration toward SDF-1. Discussion: Our findings show association between high BDNF levels and favorable disease prognosis in CLL. Undetected TrkB expression in CLL cells is compatible with previous reports showing sequestration of TrkB in normal and malignant B cells and suggests TrkB independent effect of BDNF in CLL. The effect of BDNF on the survival and migration of CLL cells via CXCR-4 needs to be further investigated. Disclosures No relevant conflicts of interest to declare.

scholarly journals Plasmin-Induced Activation of Human Platelets Is Modulated by Thrombospondin-1, Bona Fide Misfolded Proteins and Thiol Isomerases

2020 ◽  
Vol 21 (22) ◽  
pp. 8851
Author(s):  
Claudia Pielsticker ◽  
Martin F. Brodde ◽  
Lisa Raum ◽  
Kerstin Jurk ◽  
Beate E. Kehrel
Keyword(s):  
Platelet Activation ◽  
Surface Expression ◽  
Human Platelets ◽  
Misfolded Proteins ◽  
Tissue Type ◽  
Dependent Manner ◽  
Fibrinogen Binding ◽  
Thrombospondin 1 ◽  
Bona Fide

Inflammatory processes are triggered by the fibrinolytic enzyme plasmin. Tissue-type plasminogen activator, which cleaves plasminogen to plasmin, can be activated by the cross-β-structure of misfolded proteins. Misfolded protein aggregates also represent substrates for plasmin, promoting their degradation, and are potent platelet agonists. However, the regulation of plasmin-mediated platelet activation by misfolded proteins and vice versa is incompletely understood. In this study, we hypothesize that plasmin acts as potent agonist of human platelets in vitro after short-term incubation at room temperature, and that the response to thrombospondin-1 and the bona fide misfolded proteins Eap and SCN−-denatured IgG interfere with plasmin, thereby modulating platelet activation. Plasmin dose-dependently induced CD62P surface expression on, and binding of fibrinogen to, human platelets in the absence/presence of plasma and in citrated whole blood, as analyzed by flow cytometry. Thrombospondin-1 pre-incubated with plasmin enhanced these plasmin-induced platelet responses at low concentration and diminished them at higher dose. Platelet fibrinogen binding was dose-dependently induced by the C-terminal thrombospondin-1 peptide RFYVVMWK, Eap or NaSCN-treated IgG, but diminished in the presence of plasmin. Blocking enzymatically catalyzed thiol-isomerization decreased plasmin-induced platelet responses, suggesting that plasmin activates platelets in a thiol-dependent manner. Thrombospondin-1, depending on the concentration, may act as cofactor or inhibitor of plasmin-induced platelet activation, and plasmin blocks platelet activation induced by misfolded proteins and vice versa, which might be of clinical relevance.

scholarly journals TREM-like transcript 1: a more sensitive marker of platelet activation than P-selectin in humans and mice

2018 ◽  
Vol 2 (16) ◽  
pp. 2072-2078 ◽  
Author(s):  
Christopher W. Smith ◽  
Zaher Raslan ◽  
Lola Parfitt ◽  
Abdullah O. Khan ◽  
Pushpa Patel ◽  
...  
Keyword(s):  
Platelet Activation ◽  
Thrombus Formation ◽  
Surface Expression ◽  
Activated Platelets ◽  
Key Points ◽  
Sensitive Marker

Key Points Platelet activation in vitro results in a more rapid and greater upregulation of TLT-1 surface expression compared with P-selectin. TLT-1 is more rapidly translocated to the surface of activated platelets than P-selectin during thrombus formation in vivo.

Platelet Proinflammatory and Hemostatic Function Is Differentially Regulated in Cystic Fibrosis.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3948-3948
Author(s):  
Alexander Sturm ◽  
Helge Hebestreit ◽  
Ralf Grossmann
Keyword(s):  
Cystic Fibrosis ◽  
Chronic Inflammation ◽  
Platelet Activation ◽  
Platelet Function ◽  
Healthy Controls ◽  
Soluble Cd40 Ligand ◽  
Integrin Αiibβ3 ◽  
Markers Of Inflammation ◽  
Activated Platelets

Abstract Introduction: Platelet function and mechanisms of platelet-leukocyte interactions have been investigated in several vascular und inflammatory disorders. In most studies, platelet activation and an increase of platelet-leukocyte-aggregates (PLA) could be observed. We investigated platelet function in clinically stable patients with cystic fibrosis (CF). Methods: In addition to routine markers of inflammation (e. g. CRP, IgG, ESR) parameters of platelet function were measured in 54 clinically stable CF patients and 55 healthy controls (age range 3 to 41 years): The percentage of P-selectin (CD62P) and PAC-1 (activated integrin αIIbβ3) positive resting and activated platelets (in-vitro activation with the thrombin receptor activating peptide 6) and the number of PLA were determined by flow cytometry. The plasma markers of platelet activation soluble P-selectin (sCD62P) and soluble CD40 ligand (sCD40L) were measured by ELISA. Furthermore, 15 CF patients and 14 healthy controls were investigated to determine CD41a-expression (integrin αIIbβ3) on resting and activated platelets as well as leukocyte expression of P-selectin-glycoprotein ligand 1 (PSGL-1, receptor of CD62P) and integrin αMβ2. Results: Chronic inflammation leads to a decrease of PAC-1-binding to resting and activated platelets. The effects were stronger in patients with higher markers of inflammation. CD41a expression was reduced on in-vitro-activated CF platelets. In contrast, proinflammatory platelet functions remained unchanged (CD62P-expression on resting and activated platelets) or increased (sCD62P, sCD40L, PLA). Leukocyte integrin αMβ2 expression was increased and PSGL-1 expression remained unchanged in CF. Discussion: Platelet function in clinically stable patients with CF is differentially regulated: Chronic inflammation leads to an upregulation of platelet proinflammatory function. In the presence of several procoagulatory mechanisms in inflammation there is a compensatory loss of platelet hemostatic function, shown by the decreased activation and exocytosis of the platelet major integrin αIIbβ3.

Phosphatidylserine-Mediated Platelet Clearance By Endothelium Decreases Platelet Aggregates and Procoagulant Activity in Sepsis

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2538-2538
Author(s):  
Ruishuang Ma ◽  
Xiaoming Wu ◽  
Lixiu Wang ◽  
Lu Zhao ◽  
Yan Zhang ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Platelet Activation ◽  
Conflicts Of Interest ◽  
Disease Process ◽  
Procoagulant Activity ◽  
Activation Markers ◽  
Fibrin Formation ◽  
Activated Platelets

Abstract Introduction: Disorders of coagulation are common in sepsis, with disseminated intravascular coagulation (DIC) occurring in approximately 35 % of severe cases, contributing to microvascular dysfunction and death. Intensive platelet activation in sepsis facilitates platelet aggregation, leading to the formation of microthrombi and platelet depletion. This results in the development of DIC and sepsis-associated thrombocytopenia. Therefore, platelets must be cleared locally and quickly in the early phase of activation. Previous studies mainly focused on the clearance of activated cold-stored and aging platelets as well as platelets in immune-mediated thrombocytopenia. However, platelet activation and their clearance in sepsis are poorly understood. Platelets can form aggregates with leukocytes resulting in leukocyte death, the release of extracellular traps (ETs), increased endothelial permeability, and aggravated thrombosis. This study explored an alternate pathway for platelet disposal mediated by endothelial cells (ECs) through phosphatidylserine (PS) and examined the effect of platelet clearance on procoagulant activity (PCA) in sepsis. Methods: The subjects were septic patients (n=48) and healthy controls (n=48). Platelet engulfment by ECs was observed by electron microscopy, immunofluorescence, or immunochemistry both in vitro and in animal models. The PCA of platelets was measured by clotting time, purified coagulation complex assays, and fibrin formation. Results: Platelets in septic patients demonstrated increased levels of surface activation markers and apoptotic vesicle formation, and also formed aggregates with leukocytes. Activated platelets adhered to and were ultimately digested by ECs in vivo and in vitro. Blocking PS on platelets or integrin on ECs attenuated platelet clearance, resulting in increased platelet count in a mouse model of sepsis (p<0.05). Furthermore, platelet removal by ECs resulted in a corresponding decrease in platelet-leukocyte complex formation and markedly reduced generation of factor Xa and thrombin on platelets (p<0.01). Pretreatment with lactadherin increased phagocytosis of platelets by approximately 2-fold, diminished PCA by 70%, prolonged coagulation time, and attenuated fibrin formation by 50%. A large decline in PS exposure on platelets, associated platelet PCA, and PLA formation is seen in patients in remission, which could be attributed to the elimination of abnormal platelets. Conclusions: Our results suggest that PS-mediated clearance of activated platelets by the endothelium results in an anti-inflammatory, anticoagulant, and antithrombotic effect that contributes to maintaining platelet homeostasis during acute inflammation. Antiplatelet treatment has been suggested as a novel strategy in sepsis, and we speculate that promoting efficient removal of activated and apoptotic platelets could further improve patient outcomes. Therefore, clearance of activated platelets earlier in the disease process could hasten recovery of homeostasis in circulation by eliminating catalytic platforms for the coagulation pathway, protecting blood cells from excessive activation, and restoring their normal function. Endothelium, at least in part, contributes to platelet disposal and may further improve the hypercoagulable status in inflammation. It is noteworthy that PS-mediated and lactadherin-strengthened platelet engulfment may modify coagulopathy, and thus provide a new modality for treatment of septic clotting disorders. Figure 1 Phagocytosis of platelets by endothelial cells in vitro. Figure 1. Phagocytosis of platelets by endothelial cells in vitro. Figure 1 Effect of lactadherin-mediated phagocytosis on procoagulant activity and fibrin formation. Figure 1. Effect of lactadherin-mediated phagocytosis on procoagulant activity and fibrin formation. Disclosures No relevant conflicts of interest to declare.

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