# Protein S Regulates Blood Coagulation by Inhibiting Factor IXa

> **NIH NIH R01** · LSU HEALTH SCIENCES CENTER · 2022 · $628,112

## Abstract

Protein S (PS), a plasma anticoagulant, is vital for the maintenance of hemostasis.
Deficiencies or abnormalities in PS can lead to thrombotic conditions such as pulmonary
embolism, deep vein thrombosis, and acute small blood vessel coagulation. PS is a non-
enzymatic cofactor for Activated Protein C and for Tissue Factor Pathway Inhibitor. Recently,
we discovered that PS inhibits procoagulant FIXa. This significant finding likely explains the
thrombotic pathology associated with PS deficiency. Thus, we seek to derive a complete
understanding of the interaction between FIXa and PS and to establish the explicit importance
of the PS-FIXa interaction, exclusive of PS interactions with APC and TFPI. Identification of the
biochemical details of PS-FIXa interaction will enable development a small derivative of PS that
could treat individuals who have excess FIXa activity (and excess blood clotting) and PS
deficiencies or abnormalities.
 We have pinpointed the PS binding site to FIXa’s heparin-binding site and identified HBE
residues necessary for PS-FIXa binding. We have established that the Gla and EGF domains of
FIXa contribute to the stability of the interaction with PS, and we discovered that the isolated
Laminin G1+2 domains of PS are effective inhibitors of FIXa.
 For this project, we will use the following in vivo and in vitro approaches to achieve a
thorough understanding of the interaction of PS with FIXa: (1) Confirm PS domains required for
FIXa inhibition, (2) Identify PS residues required for FIXa inhibition, and (3) Define the in vivo
interaction of FIXa with PS LG domains and single-site LG domain mutants. The molecular and
biochemical knowledge obtained from this study will provide the basis for creation of a PS-
derived FIXa-inhibiting molecule for the treatment of thrombotic conditions caused by PS
deficiency or upregulation of FIXa.

## Key facts

- **NIH application ID:** 10422368
- **Project number:** 1R01HL163018-01
- **Recipient organization:** LSU HEALTH SCIENCES CENTER
- **Principal Investigator:** Rinku Majumder
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $628,112
- **Award type:** 1
- **Project period:** 2022-05-05 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10422368

## Citation

> US National Institutes of Health, RePORTER application 10422368, Protein S Regulates Blood Coagulation by Inhibiting Factor IXa (1R01HL163018-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10422368. Licensed CC0.

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