Reply to: "Circulating platelet derived microparticles are not increased in patients with cirrhosis".

To the Editor:We thank Dr. Rautou et al. for their interest in our Snapshotreview (in which we sought to summarizethe important role thatplatelets play in mediating coagulation and thrombosis inpatients with cirrhosis) [1]. We proposed that microparticlescould have important effects on coagulation and thrombosis inthese clinical settings. We mentioned the possibility of circulat-ing cell-derived, and by inference (given the current state of theﬁeld), platelet microparticles as possible mediators of inﬂamma-tion. Rautou and colleagues correctly point out that they andother groups have recently published data in this area [2].Inacute and chronic liver diseases, circulating microparticle levelshave consistently been shown to be increased, albeit previousstudies have shown variable levels of platelet-derived micropar-ticles in these settings [3–7]. Importantly, Rautou et al. also foundthat ‘‘the severity of cirrhosis and systemic inﬂammation were majordeterminants of the levels of leuko-endothelial and hepatocytemicroparticles’’ [2]. Speciﬁcally, after correcting for the circulatingconcentrations of platelets, the levels of platelet-derived micro-particles in this study are lower in cirrhotic patients when com-pared to controls [2]. Other investigators have suggestedincreased levels of platelet microparticles in cirrhosis [3] or thatno differences are associated with increasing levels of hepaticﬁbrosis [6].The origins of circulating microparticles, whether platelet-derived or not, remain a point of contention. In truth, this is aﬁeld in evolution where critical elements of methodology areyet to be determined. For example, Rautou et al. and other groupshave measured static microparticle levels. It is not clear if suchstatic values are pathophysiologically relevant, in relation to agiven stimulus, or whether the rapidity of changes in concentra-tion levels and ﬂuxes over time are more important [5]. Nor is itclear whether determination of CD41 labeling is sufﬁcient todescribe platelet versus megakaryocyte-derived microparticles– in either health or disease states [8–10]. While Rautou et al. uti-lize CD41 as a marker of platelet microparticles, the article thatwe had cited utilized the related marker CD61 to measure plate-let microparticles and infer that these may vary with inﬂamma-tory insults as during and after an alcoholic binge [3].Finally, Rautou et al. suggest tissue factor expressing micro-particles may be more relevant as prothrombotic mediators inliver disease and not platelet microparticles per se. Tissue factorexpression, typically thought to be distinct from platelet-derivedmicroparticles, can be readily found co-expressed with CD41 inplasma microparticles using whole blood analyses and modiﬁedtechniques [8]. Clearly, microparticles can co-express a varietyof surface proteins (e.g., CD39), likely with unique biologicalproperties depending on both source and target interaction[11]. Further, one might speculate that microparticles from plate-lets and other cellular sources could function as transport anddelivery systems for bioactive molecules in vivo, participatingnot only in hemostasis and thrombosis but also in inﬂammation,angiogenesis, tissue remodeling, and cellular transformation [11].As this ﬁeld matures and more data is available, the contro-versies that uncertainty brings will likely settle. Future studiesare needed to understand the respective roles of static/dynamicchanges in concentrations, to standardize methodology for thequantiﬁcation process and to delineate not only the absolute lev-els but also, importantly, any qualitative differences in micropar-ticle populations.Conﬂict of interestThe authors declared that they do not have anything to discloseregarding funding or conﬂict of interest with respect to thismanuscript.References