# Hemostasis and Thrombosis: Chemistry, Biology and Physiology

> **NIH NIH P01** · CHILDREN'S HOSP OF PHILADELPHIA · 2022 · $1,637,113

## 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 enzymic function by interactions with membranes and cofactors 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 prothrombinase complex as a paradigm to investigate structural and functional mechanisms deriving
from the membrane-dependent interactions between cofactor, proteinase and substrate in enzyme 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 as unique probes for the macromolecular interactions essential for coagulation
enzyme function and to show the way forward for novel approaches to either interfere with or enhance these
interactions for therapeutic gain. Project 4 (Arruda) investigates the biochemistry of intrinsic Xase with a focus
on characterizing proteinase and cofactor variants with superior function and potential for use as the next
generation of therapeutics in the treatment of hemophilia. The objectives of the four projects will be supported
by an administrative core (Core A), a core that provides support for molecular biology, protein expression and
structural biology (Core B) and a core that supports the program with mouse models of hemostasis and
thrombosis (Core C). Overall, this project applies the expertise of the individual investigators towards
addressing major unanswered questions in hemostasis and thrombosis extending from biochemical insights to
biological function and physiology. 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.

## Key facts

- **NIH application ID:** 10439604
- **Project number:** 5P01HL139420-05
- **Recipient organization:** CHILDREN'S HOSP OF PHILADELPHIA
- **Principal Investigator:** Sriram Krishnaswamy
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $1,637,113
- **Award type:** 5
- **Project period:** 2018-09-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10439604

## Citation

> US National Institutes of Health, RePORTER application 10439604, Hemostasis and Thrombosis: Chemistry, Biology and Physiology (5P01HL139420-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10439604. Licensed CC0.

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