# An integrated mass spectrometry approach to study heparin structure-bioactivity

> **NIH NIH R01** · UNIVERSITY OF MASSACHUSETTS AMHERST · 2024 · $422,502

## Abstract

PROJECT SUMMARY
Heparin is arguably the most versatile biopolymer, capable of interacting with and modulating the behavior of an
impressive variety of biomolecules even outside of its native environment (mast cell granules). A large fraction
of heparin interactome in the human body are key players in a variety of physiological processes (including
several pathologies) and are considered high-value therapeutic targets, although at present antithrombin
remains the only protein whose interaction with heparin has been successfully exploited in medicine. Successful
exploitation of heparin’s unique versatility for other therapeutic purposes critically depends on the ability to
characterize its interactions with relevant proteins; however, specific molecular mechanisms remain elusive
outside of the very few extensively studied systems. In the previous period of support, we developed powerful
analytical tools capable of providing information on protein/heparin interactions at the whole molecule level, as
well as identifying specific structural motifs within highly heterogeneous heparin macromolecules that enable
their association with specific proteins. Building upon this success, we now propose to focus our inquiry on
understanding the molecular mechanisms underlying etiology of heparin-induced thrombocytopenia (HIT), a
serious (and potentially fatal) immune disorder affecting up to 5% of patients receiving heparin as an
anticoagulant. Despite the central role played by heparin in formation of antigenic aggregates that may lead to
development of HIT, relatively little is known about the specific molecular mechanisms governing these
interactions. This not only creates a tremendous challenge vis-a-vis the ability to design efficient anti-HIT
therapeutic strategies, but also prevents a reliable prognosis of the occurrence of this pathology. Recognizing
the importance of multiple factors that may modulate interaction of heparin with relevant proteins (mostly platelet
factor 4, PF4), we will use a multi-level strategy to study the mechanism of PF4/heparin association, architecture
of these aggregates and specific features that make them immunogenic and trigger the onset of HIT. The work
will be carried out in close collaboration with the Hematology team at McMaster University Health Centre headed
by Dr. I. Nazy, a leading expert in the field of thrombocytopenia and thrombosis. This knowledge will catalyze
efforts to develop reliable diagnostic and prognostic tools for HIT, and will be critical for designing safe and
effective therapeutic intervention strategies.

## Key facts

- **NIH application ID:** 10756459
- **Project number:** 5R01GM112666-08
- **Recipient organization:** UNIVERSITY OF MASSACHUSETTS AMHERST
- **Principal Investigator:** IGOR A KALTASHOV
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $422,502
- **Award type:** 5
- **Project period:** 2016-04-01 → 2025-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10756459

## Citation

> US National Institutes of Health, RePORTER application 10756459, An integrated mass spectrometry approach to study heparin structure-bioactivity (5R01GM112666-08). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10756459. Licensed CC0.

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