# A systems approach to hemostasis and thrombosis

> **NIH NIH P01** · UNIVERSITY OF PENNSYLVANIA · 2022 · $551,372

## Abstract

Project 3 Abstract
Platelet activation is critical for hemostasis and a contributing factor in thrombosis. Although recent studies have
highlighted roles for platelets in diverse processes, the rapid accumulation of large numbers of platelets remains
the hallmark of hemostasis and arterial thrombosis, and is the major focus of this project. Our recent studies in
the mouse microvasculature show that the hemostatic response to small injuries produces a relatively simple
structure in which a core of fully-activated platelets is overlaid by a shell of less-activated platelets. Dense
packing in the core acts as a molecular trap, establishing an environment in which diffusion replaces convection.
This structure allows thrombin and other agonists to form overlapping gradients that produce regional differences
in platelet activation and fibrin distribution. Recognizing that transport is regulated by platelet packing density is
a paradigm shift, suggesting that platelet procoagulant activity arises from forming a sheltered environment and
not just from phospholipid exposure. We believe that this concept is key to understanding the impact of
antiplatelet agents and the events of arterial thrombosis. Testing it calls for scaling up to larger injuries in larger
vessels, and for extending our analysis from mice to humans and from hemostasis to thrombosis, all with a
hybrid experimental and computational approach that integrates with and supports the other projects in this PPG.
Aim #1 will examine the spatial and temporal distribution of platelet activation at high resolution, measure
transport in the gaps between platelets, and examine the hemostatic response in large arteries and veins. The
initial results show a more complex architecture with regions of greater and lesser platelet activation and packing
density, and large differences between the luminal and abluminal surfaces. Our subcontract with Brian Storrie at
the University of Arkansas will allow 3-dimensional reconstruction of larger hemostatic thrombi at the sub-micron
level. In collaboration with Project 4 we will examine the impact of sepsis and systemic inflammation on platelet
function in vivo and support studies on the impact of the PF4-directed antibody, KKO. Studies with µ- and m-
calpain deficient mice will support work in Project 2, but also be part of understanding the role of clot retraction
in limiting transport through larger hemostatic structures. Aim #2 will examine the mechanisms that shape the
hemostatic plug, testing the hypothesis that hemostatic structure requires tight regulation of the extent of platelet
activation and the delivery of platelet cargoes deep within the hemostatic mass. Studies on NBEAL2-/- (gray
platelet syndrome) mice and the “empty a-granule” mice developed in Project 1 will allow us to examine the role
of secretion on hemostatic plug architecture. Aim #3 will determine whether the ordered hemostatic structure
that we have observed in mice applies to humans, and...

## Key facts

- **NIH application ID:** 10434811
- **Project number:** 5P01HL146373-03
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** LAWRENCE F BRASS
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $551,372
- **Award type:** 5
- **Project period:** 2020-05-10 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10434811

## Citation

> US National Institutes of Health, RePORTER application 10434811, A systems approach to hemostasis and thrombosis (5P01HL146373-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10434811. Licensed CC0.

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