Secrets of platelet exocytosis – what do we really know about platelet secretion mechanisms?

Golebiewska, Ewelina M.; Poole, Alastair W.

doi:10.1111/bjh.12682

Cited by 51 publications

(43 citation statements)

References 117 publications

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“…Upon activation by extracellular matrix components or soluble agonists, platelet α-granules release hundreds of different types of active molecules, which further activate platelets and thus participate in a series of responses to aggravate the inflammatory damage in sepsis. Platelet α-granule contents include coagulation proteins (e.g., fibrinogen), protease inhibitors (e.g., plasminogen activator inhibitor-1), growth factors (e.g., PDGF), soluble adhesion molecules (e.g., vWF), and membrane adhesion molecules (e.g., P-selectin) [11]. Platelet α-granule heterogeneity and differential release possibly account for opposing actions of physiological and pathological correlates in sepsis [37].…”

Section: Discussionmentioning

confidence: 99%

“…It have been identified that SNAREs and SNARE accessory proteins control the process of α-granule secretion [11,35]. Known VAMP8, syntaxin2 and SNAP23 are highlighted by reports showing enrichment at sites of platelet membrane fusion [36].…”

Section: Corm-2 Regulates Snares Complex Assembly In Lps-stimulated Pmentioning

confidence: 99%

“…During sepsis, lipopolysaccharides (LPS) and inflammatory cytokines (e.g.,TNF-α) accelerate the activation of platelets, which further leads to the formation of micro-thrombi in the capillaries [4,9]. Meanwhile, activated platelets promote α-granules secretion and release plenty of functional proteins, such as P-selectin, platelet derived growth factor (PDGF), tissue inhibitor of metalloproteinases (TIMP), matrix metalloproteinases (MMP) and so on, which as secondary activators aggravate the inflammatory damage in sepsis [10,11].…”

Section: Introductionmentioning

confidence: 99%

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WITHDRAWN: "Exogenous carbon monoxide suppresses LPS-induced platelet SNAREs complex assembly and Î±-granule exocytosis via integrin Î±IIbÎ²3-mediated PKCÎ¸/Munc18a pathway"

Zhuang¹,

Song²,

Liu³

et al. 2018

Oncotarget

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Activation of coagulation occurs in sepsis and contributes to the development of thrombosis. Platelet α-granule exocytosis plays an important role in septic coagulation abnormalities. The present study aimed to investigate the effects and the underlying mechanisms of exogenous carbon monoxide, carbon monoxide-releasing molecules II (CORM-2)-liberated CO, on suppressing platelet α-granule exocytosis in sepsis. It was shown that CORM-2 weakened α-granule membrane fusion with platelet plasma membrane and attenuated α-granule contents exocytosis in LPS-Induced platelet. Further studies revealed that CORM-2 suppressed the expression of integrin αIIbβ 3 in platelets stimulated by LPS. This was accompanied by a decrease in production and phosphorylation of PKCθ and Munc18a, SNAREs complex assembly and subsequently platelet α-granule exocytosis. Taken together, we suggested that the potential mechanism of suppressive effect of CORM-2 on LPS-induced platelet SNAREs complex assembly and α-Granule Exocytosis might involve integrin αIIbβ 3 -mediated PKCθ/ Munc18a pathway activation.

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Section: Discussionmentioning

confidence: 99%

Section: Corm-2 Regulates Snares Complex Assembly In Lps-stimulated Pmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

WITHDRAWN: "Exogenous carbon monoxide suppresses LPS-induced platelet SNAREs complex assembly and Î±-granule exocytosis via integrin Î±IIbÎ²3-mediated PKCÎ¸/Munc18a pathway"

Zhuang¹,

Song²,

Liu³

et al. 2018

Oncotarget

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“…The most well-characterized aspects of platelets are the roles they play in hemostasis and thrombosis, but they have also been implicated in processes such as inflammation and the migration of cancer cells [1-3]. …”

Section: Introductionmentioning

confidence: 99%

Cytoskeleton dynamics in drug-treated platelets

Finkenstaedt-Quinn

Haynes

2015

Anal Bioanal Chem

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Platelet activation is a key process in blood clot formation. During activation, platelets go through both chemical and physical changes, including secretion of chemical messengers and cellular shape change. Platelet shape change is mediated by the two major cytoskeletal elements in platelets, the actin matrix and microtubule ring. Most studies to date have evaluated these structures qualitatively, whereas this paper aims to provide a quantitative method of examining changes in these structures by fluorescently labeling the element of interest and performing single cell image analysis. The method described herein tracks the diameter of the microtubule ring and the circumference of the actin matrix as they change over time. Platelets were incubated with a series of drugs that interact with tubulin or actin, and the platelets were observed for variation in shape change dynamics throughout the activation process. Differences in shape change mechanics due to drug incubation were observable in each case.

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“…Platelets store cargo in granular stores called α-granules (alpha granules), δ-granules (dense granules) and lysosomal granules, containing different sets of hemostatically active ingredients that are released upon activation by a calcium-dependent exocytotic mechanism (Golebiewska and Poole, 2013). As the physiological relevance of lysosomal release is currently unclear, only dense granules and alpha granules will be described in this section.…”

Section: Granule Releasementioning

confidence: 99%

Studies on interfaces between primary and secondary hemostasis

Boknäs¹

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Our conceptual understanding of hemostasis is still heavily influenced by outdated experimental models wherein the hemostatic activity of platelets and coagulation factors are understood and studied in isolation. Although perhaps convenient for researchers and clinicians, this reductionist view is negated by an ever increasing body of evidence pointing towards an intimate relationship between the two phases of hemostasis, marked by strong interdependence. In this thesis, I have focused on factual and proposed interfaces between primary and secondary hemostasis, and on how these interfaces can be studied.In my first project, we zoomed in on the mechanisms behind the wellknown phenomenon of thrombin-induced platelet activation, an important event linking secondary to primary hemostasis. In our study, we examined how thrombin makes use of certain domains for high-affinity binding to substrates, called exosite I and II, to activate platelets via PAR4. We show that thrombin-induced platelet activation via PAR4 is critically dependent on exosite II, and that blockage of exosite II with different substances virtually eliminates PAR4 activation. Apart from providing new insights into the mechanisms by which thrombin activates PAR4, these results expand our knowledge of the antithrombotic actions of various endogenous proteins such as members of the serpin superfamily, which inhibit interactions with exosite II. Additionally, we show that inhibition of exosite II could be a feasible pharmacological strategy for achieving selective blockade of PAR4.In my second project, we examined the controversial issue of whether platelets can initiate the coagulation cascade by means of contact activation, a hypothesis which, if true, could provide a direct link between primary and secondary hemostasis. In contrast to previous results, our findings falsify this hypothesis, and show that some of the erroneous conclusions drawn from earlier studies can be explained by inappropriate experimental models unsuitable for the study of platelet-coagulation interfaces.My third project comprised an assessment of the methodological difficulties encountered when trying to measure the ability of platelets to initiate secondary hemostasis by the release of microparticles expressing tissue factor. Our study shows that the functional assays available for this purpose are highly susceptible to error caused by artificial contact activation. These results could help to improve the methodology of future research and thus pave the way for new insights into the roles of tissue factor-bearing microparticles in the pathophysiology of various thrombotic disorders.From a personal perspective, my PhD project has been a fascinating scientific odyssey into the largely unexplored interfaces between primary and secondary hemostasis. Looking forward, my ambition is to continue our work exploring platelet-coagulation interactions and to translate these insights into clinically meaningful information, which may someday improve treatments of patients with bleedi...

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Secrets of platelet exocytosis – what do we really know about platelet secretion mechanisms?

Cited by 51 publications

References 117 publications

WITHDRAWN: "Exogenous carbon monoxide suppresses LPS-induced platelet SNAREs complex assembly and Î±-granule exocytosis via integrin Î±IIbÎ²3-mediated PKCÎ¸/Munc18a pathway"

WITHDRAWN: "Exogenous carbon monoxide suppresses LPS-induced platelet SNAREs complex assembly and Î±-granule exocytosis via integrin Î±IIbÎ²3-mediated PKCÎ¸/Munc18a pathway"

Cytoskeleton dynamics in drug-treated platelets

Studies on interfaces between primary and secondary hemostasis

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