When platelets encounter a damaged vessel wall they rapidly respond by shape change, secretion and aggregation. Platelets perform this job under rapid flowing conditions, which is continuously present in the circulation. Dysfunction of the platelets may result in changes in their adhesive properties and eventually lead to bleeding or thrombotic complications. Our general goal is to increase our understanding how platelet adhesion responses are regulated, and more specific, from rheological perspective, what processes take place within the fine structure of the platelet that define the formation of a stable thrombus when platelets adhere under natural flow conditions. To this end we use state-of-the-art imaging methods such as reflection interference contrast microscopy, immuno electron microscopy, and EM tomography. We have established that platelets roll and tether on immobilized vWF before becoming irreversibly attached. Platelet tethering is the result of transient formation of discrete adhesion points (DAPs) that connect the cytoskeleton with GPIb, the receptor for VWF. DAPs are also the starting point of long membrane tethers that are pulled out of the platelet body (Fig 1). The formation of membrane tethers is a requirement to slow down the platelets under fast flowing conditions and to promote multiple interactions with substrate and other platelets to form a stable thrombus. Due to shear stress tethers severe and travel further in the circulation thereby acting as potent pro-coagulant devices (microparticles). In a similar fashion shearing forces may also promote severing of unstable aggregates and induce occlusion of vital blood vessels elsewhere in the circulation.
Aim
To clarify the complex mechanisms of platelet adhesive properties, microparticle formation, and thrombus stability under fast flowing conditions, in particular with respect to the role of the cytoskeleton.
References:
Armin J Reininger, Harry F.G. Heijnen, Hannah Schumann, Hanno M Specht, Wolfgang Schramm, and Zaverio M Ruggeri. Mechanism of platelet adhesion to von Willebrand factor and microparticle formation under high shear stress. 2006. Blood; 107:3537-3545.