ThromboForce · Platelet tractions through the Glycoprotein (GP) GPIb receptor as a potential marker for platelet reactivity

Platelet tractions through the Glycoprotein (GP) GPIb receptor as a potential marker for platelet reactivity

Problem addressed: Blood platelets bind to injured sites of blood vessels and aggregate there to stop bleeding. Platelet adhesion and aggregation is an active biomechanical process controlled by platelet biochemistry and signalling. When this process goes out of control, it can result in thrombosis, heart attack, or stroke. Clinical platelet function tests however do not directly address platelet biomechanics. There is thus a need for new assays that can measure how firmly platelets bind to specific components of the vascular bed, and a need to better understand what platelet signalling pathways are modulated by mechanotransduction through the respective adhesion receptors. The initial anchoring of a platelet is mediated by the binding of glycoprotein (GP) Ib receptors on its surface to the protein von Willebrand factor (vWF) that gets immobilized at injured vessel walls. Based on the mechanical force applied through this linkage, the platelet decides whether to bind firmly and aggregate or whether to let go. Recent research has revealed GPIb’s mechanotransduction properties, yet the consequences for platelet biomechanics are not well understood. Societal importance: Platelet-mediated thrombosis is a leading cause of mortality and disability in the European Union. Platelet function tests so far have not been able to guide the treatment of patients to prevent cardiovascular events. The current ‘one dose fits all’ strategy is opposed by a substantial variability in the patients’ responses to anti-platelet medication. New insights into fundamental platelet biology and novel assays to measure platelet function are needed to develop better diagnostics for personalizing treatment. The aim of ThromboForce was to directly measure the mechanical forces that single platelets apply when they bind to vWF. The main objectives were to i) Establish and optimize a platform for measuring contractile forces of single adhering platelets with high throughput. ii) Test whether GPIb expression levels affect platelet adhesion forces. iii) Validate the platform using clinical samples from patients with established cardiovascular disease on antiplatelet therapy. Conclusions: The action successfully established traction force measurements of single platelets using a newly developed experimental platform and custom software. Platelet traction forces systematically depended on adhesion protein identity, adhesion receptor numbers, and myosin activity. Correlations between traction forces and the more readily available cytoskeletal morphology of spread platelets were established. Preliminary clinical data were obtained from a small number of stroke patients. The results provide new insights into platelet mechanobiology. The established technology helped to establish new collaborations within the platelet scientific community.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз