# Mechanical and biochemical regulation of von Willebrand Factor adhesion in flow

> **NIH NIH K25** · BOSTON CHILDREN'S HOSPITAL · 2020 · $184,205

## Abstract

Von Willebrand factor (VWF) is a long, polymeric blood protein. It adheres to platelets at sites of injury to
form plugs that stops bleeding. The lack or inadequacy of VWF function causes von Willebrand disease, the
most common hereditary bleeding disorder, which affects 1% of the US population. On the other hand, if
platelet plug formation occurs at the wrong time or place, it can lead to thrombosis, which can cut off
circulation, causing a stroke or heart attack. To precisely turn on VWF-platelet adhesion only when injuries are
detected, nature has programmed VWF to sense changes in blood flow and to respond by activating its
adhesion to GPIb, the receptor protein on platelet surface.
 I propose to combine novel microfluidic systems, single-molecule methods and special fluorescence
techniques to improve our understanding of the biochemical and mechanical factors regulating VWF function
by flow. Using advanced techniques that I have developed, we have stretched single VWF multimers by flow
and directly visualized their force-activated conformational transitions and activation for the first time. These
measurements revealed that VWF multimers first elongate and then activate their binding sites for GPIb with
force under flow. Building on this, I will answer three questions related to the mechanical regulation of VWF.
First, I will measure how flow-induced force in VWF regulates its degradation by ADAMTS13 protease. This
degradation process limits the size of VWF to lower the clotting potential of VWF. I will test a “molecular zipper”
binding model, in which one end of the ADAMT13 scarcely binds to the D4-CK domains of globular VWF, with
further binding propagating to the proteolysis site once the A2 domain is unfolded. I will also determine the
amount of ADAMTS13 cleavage in the presence of GPIb or platelets. Second, I will test the hypothesis that
reactive oxygen species (ROS) and cell-free hemoglobin directly integrate with the flow sensing capability of
VWF to regulate its function. I will measure the enhancement of flow-induced VWF adhesion in the presence of
these chemical cues. Third, I will reveal how elongational flow found in ruptured or narrowed blood vessels
activates the adhesion between freely circulating VWF and GPIb to augment thrombosis. I will accomplish
this by combining a high flow-rate cross-slot microfluidic system, a confocal microscope and special
fluorescence techniques to measure the time-dependent response of VWF to changes in elongational flow.
 This proposed work will improve the understanding of VWF regulation by biochemical and mechanical
cues in blood vessels. My quantitative approaches and advanced instrumentation will bring insights from
polymer physics, and advanced single-molecule and fluorescence methods, into the field of hematology. This
study will also give me firsthand experience in biochemistry, molecular biology and hematology, enabling me to
better apply my quantitative and physical training to more ...

## Key facts

- **NIH application ID:** 9898453
- **Project number:** 5K25HL146949-02
- **Recipient organization:** BOSTON CHILDREN'S HOSPITAL
- **Principal Investigator:** Yan Jiang
- **Activity code:** K25 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $184,205
- **Award type:** 5
- **Project period:** 2019-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9898453

## Citation

> US National Institutes of Health, RePORTER application 9898453, Mechanical and biochemical regulation of von Willebrand Factor adhesion in flow (5K25HL146949-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9898453. Licensed CC0.

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