No evidence for tissue factor on platelets

Bouchard, Beth A.; Mann, Kenneth G.; Butenas, Saulius

doi:10.1182/blood-2010-05-285627

Cited by 60 publications

(50 citation statements)

References 10 publications

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“…TF expression in platelets is still a matter of debate. 26,33 Under our experimental conditions, neither a TF-inhibiting antibody nor the absence of FVII reduced the histone-induced enhancement of thrombin generation in PRP, thus ruling out an involvement of endogenous TF. Secretion of the inorganic polymer polyP by activated platelets is an emerging mechanism of clotting activation that sheds new light on the pathophysiological importance of the contact system.…”

Section: Discussionmentioning

confidence: 99%

Extracellular histones promote thrombin generation through platelet-dependent mechanisms: involvement of platelet TLR2 and TLR4

Semeraro

Ammollo

Morrissey

et al. 2011

Blood

732

684

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The release of histones from dying cells is associated with microvascular thrombosis and, because histones activate platelets, this could represent a possible pathogenic mechanism. In the present study, we assessed the influence of histones on the procoagulant potential of human platelets in platelet-rich plasma (PRP) and in purified systems. Histones dose-dependently enhanced thrombin generation in PRP in the absence of any trigger, as evaluated by calibrated automated thrombinography regardless of whether the contact phase was inhibited. Activation of coagulation required the presence of fully activatable platelets and was not ascribable to platelet tissue factor, whereas targeting polyphosphate with phosphatase reduced thrombin generation even when factor XII (FXII) was blocked or absent. In the presence of histones, purified polyphosphate was able to induce thrombin generation in plasma independently of FXII. In purified systems, histones induced platelet aggregation; P-selectin, phosphatidylserine, and FV/Va expression; and prothrombinase activity. Blocking platelet TLR2 and TLR4 with mAbs reduced the percentage of activated platelets and lowered the amount of thrombin generated in PRP. These data show that histone-activated platelets possess a procoagulant phenotype that drives plasma thrombin generation and suggest that TLR2 and TLR4 mediate the activation process. (Blood. 2011;118(7):1952-1961) IntroductionHistones are cationic proteins that associate with DNA in nucleosomes and are involved in chromatin remodeling and regulation of gene transcription. Despite their physiologic nuclear localization, nucleosomes have been found in the circulation of both healthy subjects and patients, where they can be released from dying cells 1 or actively secreted by activated inflammatory cells (neutrophils, basophils, and mast cells) in the form of "extracellular traps," complex structures of DNA strands, histones, and cell-specific granule proteins. 2,3 High blood levels of nucleosomes have been detected in several inflammatory, ischemic, autoimmune, and neoplastic diseases 4 ; in some cases, a correlation with disease severity has been found. 5 Whether extracellular nucleosomes are merely bystanders or active mediators in disease and which role histones play are important emerging questions. Histones are known to possess cytotoxic properties against both microorganisms 6 and eukaryotic cells. 7 Xu et al 8 reported that extracellular histones behave as late mediators of cell damage and organ dysfunction during the hyperinflammatory reaction that characterizes sepsis, as shown by the efficacy of a neutralizing antibody against histone H4 in reducing mortality in several experimental models of murine sepsis. Moreover, direct injection of histones into mice resulted in death with pathologic lesions suggestive of a massive prothrombotic response similar to that found in sepsis, including diffuse microvascular thrombosis, fibrin and platelet deposition in the lung alveoli, and intra-alveolar hemorrhage. Fuchs et al 9 rec...

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Section: Discussionmentioning

confidence: 99%

Extracellular histones promote thrombin generation through platelet-dependent mechanisms: involvement of platelet TLR2 and TLR4

Semeraro

Ammollo

Morrissey

et al. 2011

Blood

732

684

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“…First, the antibody from American Diagnostica that we have been using, and whose specificity was previously questioned, 13 works well also in the hands of Bouchard since, as the authors assert, it is able to recognize the TF expressed on LPS-stimulated THP-1 cells.…”

Section: Functionally Active Platelets Do Express Tissue Factormentioning

confidence: 94%

“…Third, the fact that Bouchard et al do not detect TF in washed activated platelets, 13 even if the antibody works on THP-1 cells, raises the suspicion that the problem lies in platelet preparation. Indeed, particular care should be used to avoid non specific platelet activation.…”

Section: Functionally Active Platelets Do Express Tissue Factormentioning

confidence: 99%

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Response: functionally active platelets do express tissue factor

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Brambilla

Boselli

et al. 2012

Blood

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“…There is much debate surrounding which cells release the most TF-enriched MPs, with monocytes being the leading candidate. [27][28][29] The role of TF-bearing MPs in coagulation and inflammation is a topic of major interest, and a more comprehensive discussion is provided in a separate section later. Finally, soluble TF that lacks the transmembrane domain exhibits procoagulant activity and may incorporate into thrombi.…”

mentioning

confidence: 99%

Cross Talk Pathways Between Coagulation and Inflammation

Foley

Conway

2016

Circulation Research

466

414

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Anatomic pathology studies performed over 150 years ago revealed that excessive activation of coagulation occurs in the setting of inflammation. However, it has taken over a century since these seminal observations were made to delineate the molecular mechanisms by which these systems interact and the extent to which they participate in the pathogenesis of multiple diseases. There is, in fact, extensive cross talk between coagulation and inflammation, whereby activation of one system may amplify activation of the other, a situation that, if unopposed, may result in tissue damage or even multiorgan failure. Characterizing the common triggers and pathways are key for the strategic design of effective therapeutic interventions. In this review, we highlight some of the key molecular interactions, some of which are already showing promise as therapeutic targets for inflammatory and thrombotic disorders. (Circ Res.

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No evidence for tissue factor on platelets

Cited by 60 publications

References 10 publications

Extracellular histones promote thrombin generation through platelet-dependent mechanisms: involvement of platelet TLR2 and TLR4

Extracellular histones promote thrombin generation through platelet-dependent mechanisms: involvement of platelet TLR2 and TLR4

Response: functionally active platelets do express tissue factor

Cross Talk Pathways Between Coagulation and Inflammation

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