# Project 1: Molecular Impact of VWF on Clinical VWD

> **NIH NIH P01** · VERSITI BLOOD HEALTH, INC. · 2020 · $336,265

## Abstract

Project 1 in the Zimmerman Program for the Biology of VWD (ZPB-VWD) is focused on the Molecular Impact
of VWF on Clinical VWD. It consolidates the two existing cohorts – 1) retrospective PPG cohort previously
diagnosed in the Zimmerman Program for the Molecular and Clinical Biology of VWD and 2) the prospective
R01 cohort recruits. In Aim 1 laboratory studies are done longitudinally on the Type 1, 2, and 3 VWD subjects
as well as the group with reduced VWF levels that we collectively call Low von Willebrand Factor that includes
those that might have been previously labeled as “Mild VWD” with VWF <normal but little or no bleeding.
These may be considered as having a risk factor for bleeding but not a disease. Not only will we study the
changes with time of their laboratory phenotype but also study them with and interim Bleeding Assessment
Score (iBAT) to semiquantitatively assess the amount of “new clinical bleeding” since BATs assess bleeding
but the score saturates and cannot quantify interim bleeding. Additionally, Aim 1 will quantifiably evaluate
potential abnormal binding to new matrix proteins (e.g. myosin) or new functional receptors (e.g. platelet GP
IIb-IIIa (2b3a). In Aim 2 type 2 functional variants will be studied to determine the fidelity of diagnosis (types
2A, 2B, 2M, and 2N) between phenotypic assignments locally to those centrally assigned. Animal models of
type 2 variants have been/will be developed and compared using bleeding and thrombosis testing (tail
bleeding, template bleeding, VenaFlux, and Laser-injury assessment. Aim 3 will include subjects in our
combined cohort who have type 1 or 3 VWD or LVWF and to these existing cohorts add existing, similarly
defined, cohort from Kingston and Dublin but have no VWF mutation and are negative by Array Comparative
Genome Hybridization (aCGH) or Multiplex Ligation-dependent Probe Amplification (MLPA). Within our
cohort, we have at least 3 type 3 VWD subjects with no VWF sequence variant, are negative by aCGH, and
have no anti-VWF antibodies. In addition we have >40 type 1 VWD and >180 LVWF subject samples with
NSV and negative aCGH. Therefore we will first study these type 1 and 3 subjects by whole Genome
Sequencing (WGS) using NGS sequencing in Core B. When individual candidate genes are identified,
sequencing will be performed on the affected (AFM) and unaffected family members (UFM) to ascertain
linkage with phenotype. Candidate SV will then be farmed out to Projects 1-4, based upon whether they are
1) VWF intronic changes (Project 1); 2) involve carbohydrates or carbohydrate receptors (Project 2); 3)
mechanisms outside the VWF coding region (Project 3); or 4) suggest an epigenetic mechanism (Project 4).
For frequent or scientifically unique causes that might be identified, animal models of these will be produced in
Core C and studied in the various projects. Through Project 1 we expect to gain insight into the disease
mechanisms causing VWD and how they affect laboratory and clinic...

## Key facts

- **NIH application ID:** 9891090
- **Project number:** 5P01HL144457-02
- **Recipient organization:** VERSITI BLOOD HEALTH, INC.
- **Principal Investigator:** ROBERT R MONTGOMERY
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $336,265
- **Award type:** 5
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9891090

## Citation

> US National Institutes of Health, RePORTER application 9891090, Project 1: Molecular Impact of VWF on Clinical VWD (5P01HL144457-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9891090. Licensed CC0.

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