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Platelets are essential players in thrombosis and haemostasis, as they ‘survey’ the integrity of the vascular system. After vascular injury, platelets are recruited to the exposed subendothelial extracellular matrix that triggers platelet activation to seal wound sites by the formation of a haemostatic plug, thereby preventing excessive bleeding. However, if thrombus formation is uncontrolled under pathological conditions, itmay lead to irreversible vessel occlusion and to lifethreatening acute ischaemic disease states, such as myocardial infarction or stroke.1 Platelet activation and subsequent thrombus growth involve receptor–ligand interactions, signaling molecules and cytoskeletal proteins which regulate the cellular mechanotransduction. In vitro flow chamber systems combined with wholeblood fromgeneticallymodifiedmice or incubatedwith inhibitors have significantly contributed to a better understanding of the function of platelet proteins in the thrombotic process under shear conditions. Most researchers have analysed their generated real-time movies or off-line images semi-automatically or manually for surface coverage by platelet thrombi (83%), thrombus volume (78%) and the number of adhered platelets (56%).2 However, while this method includingdata evaluationhas beenusedprimarily to characterize the role of platelet proteins in thrombus formation, the mechanobiology of platelets in this complex environment had been addressed and understood insufficiently. In this issue, Tunströmer et al introduce and take advantage of a new computational tool which enables quantitative analysis of platelet intra-thrombus movements.3 For this purpose, the authors further developed their in-house image processing script, which has enabled quantification of positional information of individual platelets within a thrombus so far.4 They used the acquired positional information of each platelet to track thousands of platelets in a thrombus at the same time and to measure thrombus contraction.3 For this, 5%ofplateletswere labelledwith aplatelet-specific antibody and annexin Vwas added towhole blood tomeasure pro-coagulant, phosphatidylserinepositiveplatelets. Thesamples were either left untreated or incubated with blocking antibodies against glycoprotein (GP) IIb/IIIa and GPIbα, or inhibitors blocking P2Y12 or thromboxane production. Then, bloodwasperfused in a custom-madeflowchamber at 400 s-1 over a collagen strip. The authors were able to show how the panel of inhibitors affected thrombus architecture, platelet intra-thrombusmovements and thrombus contraction.3More specifically, total platelet accumulationwas decreased but the ratio of pro-coagulant platelets to total platelet numbers increased in the presence of inhibitors, particularly when the receptors GPIIb/IIIa and GPIbα were blocked. Platelet movements were dramatically shorter for all samples incubated with inhibitors in contrast to control sample. Furthermore, the authors investigated whether the relative platelet position in a thrombus is a determinant of platelet movement. Platelet movement trajectories were longer and velocity was increased on the outer edge of the thrombus compared with platelets in the thrombus core. Interestingly, a support vector machine regression approach revealed that initially platelets contracted to small aggregates, which then conjoined to larger aggregates, and finally moved in a homogeneous way towards the centre of the thrombus. The contractile component of platelets strongly contributed to thrombus contraction and was reduced in the presence of inhibitors. Finally, the authors could show that thrombus contraction increased during the first 800 seconds of thrombus formation.3 Overall, this big set of data supports and conclusively explains the spatial and functional heterogeneity of a thrombus5,6 with respect to the contractile properties.3 This advanced analysis tool will be powerful to obtain observerindependent information of thousands of platelets within a

No Escape—A Novel Tool to Quantify Platelet Intra-Thrombus Movements