title: A shear gradient-dependent platelet aggregation mechanism drives thrombus formation.
abstract: Platelet aggregation at sites of vascular injury is essential for hemostasis and arterial thrombosis. It has long been assumed that platelet aggregation and thrombus growth are initiated by soluble agonists generated at sites of vascular injury. By using high-resolution intravital imaging techniques and hydrodynamic analyses, we show that platelet aggregation is primarily driven by changes in blood flow parameters (rheology), with soluble agonists having a secondary role, stabilizing formed aggregates. We find that in response to vascular injury, thrombi initially develop through the progressive stabilization of discoid platelet aggregates. Analysis of blood flow dynamics revealed that discoid platelets preferentially adhere in low-shear zones at the downstream face of forming thrombi, with stabilization of aggregates dependent on the dynamic restructuring of membrane tethers. These findings provide insight into the prothrombotic effects of disturbed blood flow parameters and suggest a fundamental reinterpretation of the mechanisms driving platelet aggregation and thrombus growth.
authors.affiliation: The Australian Centre for Blood Diseases, Monash University, Alfred Medical Research and Educational Precinct, Melbourne, Victoria, Australia.
authors.forename: Warwick S
authors.initials: WS
authors.lastname: Nesbitt
authors.forename: Erik
authors.initials: E
authors.lastname: Westein
authors.forename: Francisco Javier
authors.initials: FJ
authors.lastname: Tovar-Lopez
authors.forename: Elham
authors.initials: E
authors.lastname: Tolouei
authors.forename: Arnan
authors.initials: A
authors.lastname: Mitchell
authors.forename: Jia
authors.initials: J
authors.lastname: Fu
authors.forename: Josie
authors.initials: J
authors.lastname: Carberry
authors.forename: Andreas
authors.initials: A
authors.lastname: Fouras
authors.forename: Shaun P
authors.initials: SP
authors.lastname: Jackson
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000166:cytology / Q000378:metabolism; D002448:Cell Adhesion; D006439:Hemodynamics; D007091:Image Processing, Computer-Assisted; D051379:Mice; D010974:Platelet Aggregation; D013927:Thrombosis / Q000473:pathology*