Project 4. Platelet accumulation is both a hallmark of hemostasis and a contributor to heart attacks and strokes. Previous studies have focused on identifying individual signaling molecules that support platelet activation. Here we attempt a paradigm shift, first, by approaching platelet activation and the hemostatic response as the product of the global platelet signaling network rather than any one pathway, and, second, by linking testable ideas about the function of that network to real time observations of platelet activation in vivo and in vitro. We and others have shown that hemostatic thrombi have a characteristic structure in which a core of fully-activated platelets is overlaid with an unstable shell of less-activated platelets. We have recently extended this model by showing that the core and shell are regulated by different elements of the platelet signaling network and demonstrating that increased packing density in the core affects thrombin distribution, contact-dependent signaling and the influx of plasma-borne molecules. The proposed studies will build upon this background, merging mechanism-driven and observational approaches to determine how thrombus structure evolves define its relationship the platelet signaling network.
In Aim #1 we will use intravital confocal and multi-photon microscopy to compare platelet activation in the micro- and macro-vasculature. Dyslipidemia will be used to study the impact of acquired disorders of platelet reactivity.
In Aim #2 we will use human platelets, transgenic mouse lines and pharmacologic agents to examine the relationships between the platelet signaling network and thrombus structure.
In Aim #3 we will focus on contact-dependent signaling events between platelets, testing the novel hypothesis that these events are segregated spatially and temporally into pathways that either promote or restrain the thrombus core. Through these aims, we hope to define the mechanisms that drive thrombus formation, account for differences in the clinical impact and bleeding risk associated with different antiplatelet agents, and show how pathological conditions can subvert normal responses by their impact on the platelet signaling network

Public Health Relevance

Platelet activation is part of the normal response to vascular injury, producing a plug that limits blood loss. Thrombosis occurs when platelets are activated inappropriately, blocking blood flow and damaging tissues such as the heart and brain. The goal of this project is to better understand the molecular basis of platelet activation and translate that understanding into improved methods to prevent thrombosis..

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
Project #
Application #
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Pennsylvania
United States
Zip Code
Fong, Karen P; Zhu, Hua; Span, Lisa M et al. (2016) Directly Activating the Integrin αIIbβ3 Initiates Outside-In Signaling by Causing αIIbβ3 Clustering. J Biol Chem 291:11706-16
Litvinov, Rustem I; Farrell, David H; Weisel, John W et al. (2016) The Platelet Integrin αIIbβ3 Differentially Interacts with Fibrin Versus Fibrinogen. J Biol Chem 291:7858-67
Bennett, Joel S (2016) Shedding New Light on the Platelet Storage Lesion. Arterioscler Thromb Vasc Biol 36:1715-6
Fuentes, Rudy E; Zaitsev, Sergei; Ahn, Hyun Sook et al. (2016) A chimeric platelet-targeted urokinase prodrug selectively blocks new thrombus formation. J Clin Invest 126:483-94
Armstead, William M; Riley, John; Yarovoi, Serge et al. (2016) Tissue-Type Plasminogen Activator-A296-299 Prevents Impairment of Cerebral Autoregulation After Stroke Through Lipoprotein-Related Receptor-Dependent Increase in cAMP and p38. Stroke 47:2096-102
Welsh, John D; Muthard, Ryan W; Stalker, Timothy J et al. (2016) A systems approach to hemostasis: 4. How hemostatic thrombi limit the loss of plasma-borne molecules from the microvasculature. Blood 127:1598-605
Sayani, Farzana A; Abrams, Charles S (2015) How I treat refractory thrombotic thrombocytopenic purpura. Blood 125:3860-7
Meng, Ronghua; Wu, Jie; Harper, Dawn C et al. (2015) Defective release of α granule and lysosome contents from platelets in mouse Hermansky-Pudlak syndrome models. Blood 125:1623-32
Ma, Peisong; Ou, Kristy; Sinnamon, Andrew J et al. (2015) Modulating platelet reactivity through control of RGS18 availability. Blood 126:2611-20
Muthard, Ryan W; Welsh, John D; Brass, Lawrence F et al. (2015) Fibrin, γ'-fibrinogen, and transclot pressure gradient control hemostatic clot growth during human blood flow over a collagen/tissue factor wound. Arterioscler Thromb Vasc Biol 35:645-54

Showing the most recent 10 out of 265 publications