# Hemostasis and Thrombosis: Chemistry, Biology and Physiology

> **NIH NIH P01** · CHILDREN'S HOSP OF PHILADELPHIA · 2024 · $3,045,975

## Abstract

Overall Program-Abstract
Blood coagulation derives from a series of specific proteolytic activation reactions that are catalyzed with
narrow and defined specificity by trypsin-like serine proteinases. In several instances, these proteinases
function in membrane assembled enzyme complexes. Distinctive protein substrate specificities and the
modulation of function by interactions with membranes, cofactors and ligands are hallmarks of the proteolytic
reactions of blood coagulation. There are major gaps in the current understanding of the molecular bases for
these unique features that underlie the function of the hemostatic reactions. This program proposes an
integrated approach focused on the modulation of enzymic function and specificity that uniquely arises from
macromolecular interactions that underlie the action of the hemostatic enzymes. Project 1 (Krishnaswamy)
uses the constituents of the prothrombinase complex as a paradigm to investigate functional and structural
mechanisms underlying regulation of zymogen, proteinase and cofactor function. Project 2 (Camire) will
investigate molecular mechanisms at play in the conversion of factor V to the cofactor, factor Va and the
surprising new biological insights that these mechanisms reveal. Project 3 (Sullenger) employs RNA aptamers
in a unique inhibitor strategy that combines specific aptamers targeting exosites linked to active site ligands to
form potent and readily reversible bivalent EXosite-ACTive site (EXACT) inhibitors to modulate coagulation
reactions for therapeutic gain. Project 4 (Samelson-Jones) is an ESI-led project that investigates mechanisms
underlying the structural correlates of IXa and VIIIa function to develop novel approaches for the treatment of
hemophilia B or to improve approaches for hemophilia A treatment by gene therapy. The objectives of the five
projects will be supported by an administrative core (Core A) and a core that provides support for molecular
biology, protein expression and structural biology (Core B). Overall, this project applies the expertise of the
individual investigators towards addressing major unanswered questions in hemostasis and thrombosis
extending from biochemical and structural insights, to biological function and the translation of of these insights
to the treatment of disease. The proposed approaches will provide new insights into the chemistry and biology
of the blood coagulation reactions with implications for an understanding of normal hemostasis and thrombosis
and the treatment of clotting or bleeding disorders.

## Key facts

- **NIH application ID:** 10768826
- **Project number:** 2P01HL139420-06
- **Recipient organization:** CHILDREN'S HOSP OF PHILADELPHIA
- **Principal Investigator:** Sriram Krishnaswamy
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $3,045,975
- **Award type:** 2
- **Project period:** 2018-09-01 → 2029-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10768826

## Citation

> US National Institutes of Health, RePORTER application 10768826, Hemostasis and Thrombosis: Chemistry, Biology and Physiology (2P01HL139420-06). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10768826. Licensed CC0.

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