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Regulation of coagulation and thrombosis by C1 inhibitor

Award Number: R01HL171042
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2025
PERIOD OF PERFORMANCE END DATE: 07/31/2029

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Regulation of coagulation and thrombosis by C1 inhibitor - PROJECT SUMMARY Venous thromboembolism is a leading cause of morbidity and mortality in the United States. The contact pathway of coagulation plays an important role in the pathogenesis of venous thromboembolism. However, there are few studies on regulation of this pathway by endogenous anticoagulants. C1 inhibitor is a multifunctional serine protease inhibitor that functions as a major endogenous inhibitor of kallikrein, factor XII and factor XI. Patients with a congenital deficiency in C1 inhibitor suffer from a rare episodic swelling disorder called Hereditary Angioedema. Critically, patients with Hereditary Angioedema have evidence of increased systemic activation of coagulation. We recently reported that Hereditary Angioedema is associated with a significantly increased risk of venous thromboembolism in a small case-control study. Further, we have found that Hereditary Angioedema patient plasmas support significantly increased contact pathway-mediated coagulation. Importantly, this phenotype could be recapitulated in C1 inhibitor deficient mice that model key aspects of Hereditary Angioedema. Our preliminary data indicates that aberrant contact pathway-mediated coagulation and enhanced venous thrombosis observed in C1-inhibitor deficient mice can be rescued by select anticoagulant interventions. Additional preliminary data indicates that exogenous C1 inhibitor effectively reduces contact pathway-mediated coagulation and venous thrombosis in C1 inhibitor replete settings. Our central hypothesis is that C1 inhibitor prevents venous thrombosis through inhibition of contact pathway-mediated coagulation. In Aim 1 of this proposal, we will evaluate the molecular mechanism by which endogenous C1 inhibitor regulates coagulation and venous thrombosis in mice using substrate selective C1 inhibitor variants and an arsenal of pharmacological inhibitors. In Aim 2, we will evaluate the impact of C1INH deficiency on coagulation and thrombosis in patients with Hereditary Angioedema using patient samples and a large-scale epidemiological dataset. In Aim 3, we will evaluate the therapeutic potential of exogenous C1 inhibitor in mouse models of thrombosis. The work proposed will provide new insights into the anticoagulant activity of endogenous C1 inhibitor and the potential of exogenous C1 inhibitor to serve as a novel hemostasis sparing anticoagulant.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $788,721 )
2025	2025	BETH ISRAEL DEACONESS MEDICAL CENTER, INC.	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Blood Diseases and Resources Research	001	2	8/19/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$788,721
2025	2024	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Blood Diseases and Resources Research	000	1	8/19/2025	NEW	$0
														Subtotal = $788,721

Issue Date FY: 2024 ( Subtotal = $685,884 )
2024	2024	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Blood Diseases and Resources Research	001	1	8/28/2024	NEW	$0
2024	2024	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Blood Diseases and Resources Research	000	1	8/20/2024	NEW	$685,884
														Subtotal = $685,884

Grand Total All Awards = $1,474,605

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Regulation of coagulation and thrombosis by C1 inhibitor

Award Number: R01HL171042

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 08/01/2025

PERIOD OF PERFORMANCE END DATE: 07/31/2029

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