In IBD patients there are quantitative, morphological and qualitative alterations in platelet characteristic. Thrombocytosis and IBD have been first correlated in 1968 [
83] and it is now well established that trombocytosis is related to disease activity and severity [
84]. Thrombocytosis is considered a non specific response to inflammation which may occur in chronic inflammatory conditions other than IBD [
25], but it has also been proposed that thrombocytosis in UC and CD may reflect an aberration in thrombopoiesis induced by greater plasma levels of thrombopoietin and IL6, which are involved in megakaryocytes maturation process [
85]. On the other hand, platelets in IBD patients have smaller mean corpuscular volume (MCV) than in controls [
86], and platelet MCV seems to be smaller during active phases of the disease as compared to remission [
56]. MCV has also been demonstrated to be inversely proportional to some inflammation markers levels such as C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) so that this has been proposed as a marker of disease activity [
87]. It has been hypothesized that during active disease platelet agglomerates (platelet-platelet, platelet-leukocyte, platelet-endothelium) - that are found to be elevated in IBD patients [
88] - mainly involve younger platelets with a higher MCV and consequently that would relatively increase the circulating amount of older and smaller platelets [
89]. Moreover, platelets in IBD seem to circulate in a chronic activated status and to be more reactive and more sensitive to activation induced by pro-aggregating agents. First of all, platelets have been demonstrated to aggregate in vitro in over 30% of IBD patients, independently of disease severity, compared to none of the healthy controls [
90]. This was thought to be a consequence of the inflammatory condition but it has subsequently been demonstrated that platelet aggregates are found in IBD patients but not in other inflammatory diseases, thus being a specific characteristic of IBD [
91]. The same author found an increase in surface and serum platelet activation markers such as P-selectin, GP53 and beta-thromboglobulin (beta-TG), whose increase was independent from disease activity so suggesting that once stimulated, platelets may remain chronically activated even during remission phases of the disease [
25,
91]. In the recent years another piece has come to partially complete the picture. In fact, in CD and UC patients high values - up to 4 times greater than healthy controls - of the surface CD40 ligand (CD40L), an activation markers that allows platelets to interact with a broad of immune and non immune cells with pro inflammatory consequences [
25,
92], and that acts as an inducer of the TF mediated coagulation cascade [
36] have been detected. Together with its increase on the platelet surface, even the soluble form of CD40L (sCD40L) in IBD patients serum is increased - almost 15 fold compared to controls - as released by such platelets [
93]. High levels of sCD40L have been associated with an increased risk of TE [
55]. Others reported that in vitro activated platelets may directly increase CD40L expression in intestinal endothelial cells favoring their interaction with numerous immune cells and sustaining chronic inflammation [
94]. Recent data reported an increased expression of CD40/CD40L in the intestinal epithelial cells, in particular in samples from inflamed ileal and colonic mucosa from CD and UC patients, whereas that increase was not found in uninvolved intestinal segments [
95]. This finding provide, for the first time, a piece of evidence of the interaction between activated platelets and IBD affected intestinal mucosa via the CD40/CD40L pathway [
56]. That leads to a key point: platelets could themselves act as inflammatory cells and enhance the inflammatory process in IBD mucosa. One of the first suggestion of the platelet role in intestinal inflammation came from the finding of capillary microthrombi in the mucosa of IBD patients, independently of the severity of inflammation. Those findings were consistently absent in healthy subjects [
96]. It has then been suggested that platelet activation occurs in the intestinal mucosa because of the finding of greater platelet aggregates in the mesenteric blood of CD patients [
97]. This process has recently been reproduced in vitro using human intestinal microvascular endothelial cells (HIMEC) exposed to IL-1beta to mimic IBD endothelial changes [
25,
93]. Activated CD40L positive platelets are then thought to enhance themselves intestinal inflammation by the interaction with CD40 positive microvascular endothelium in the intestinal mucosa. That is thought to be the trigger to up-regulation of endothelial IL8 production and adhesion molecule expression (as ICAM-1 and VCAM-1) on the endothelium surface, leading to inflammatory cell, specifically T-cell, recruitment and inflammatory response amplification [
25].