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Characterization of an isoform specific anticoagulant function of TFPI-alpha

Award Number: R01HL068835
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2002
PERIOD OF PERFORMANCE END DATE: 03/31/2024

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Characterization of an isoform specific anticoagulant function of TFPI-alpha - Abstract Tissue factor pathway inhibitor (TFPI) is an essential anticoagulant protein. Decreased plasma TFPI is associated with venous and arterial thrombosis, and pharmaceutical agents that block TFPI activity are being developed to treat patients with hemophilia. TFPI is an alternatively spliced protein and all isoforms are capable of inhibiting tissue factor (TF)-initiated blood coagulation. Our laboratory identified TFPIβ as the primary isoform on endothelium, while TFPIα is the primary isoform within platelets. Using murine model systems, we demonstrated that platelet TFPIα limits thrombus growth following vascular injury and weakens the hemostatic response in hemophilia. These results suggested that TFPIα has a specific anticoagulant activity that is not performed by TFPIβ. We recognized that the basic C-terminal region of TFPIα and the basic region of the FV B-domain have striking homology, and sought to define how TFPIα may specifically interact with FV/FVa. Our biochemical studies described how TFPIα effectively inhibits prothrombinase assembled with forms of FVa that retain the acidic region of the FV B-domain, such as that activated by FXa or found within platelets, but not with forms of FVa that have the entire B-domain removed, such as that activated by thrombin. During the previous funding period, we have worked to further characterize the TFPIα-FV interaction, finding that TFPIα has reduced ability to inhibit prothrombinase assembled with FV Leiden (FVL) and that the LIKT amino acids within the TFPIα C-terminus are required for inhibitory activity, but do not contribute to the affinity of TFPIα for FVa. We also generated several new murine models to investigate the physiological role of the TFPIα-FV interaction in vivo. Preliminary findings indicate that altering the TFPIα-FV interaction by modulating expression of TFPIα or FV in platelets dramatically alters embryonic survival of TFPI-K1 null mice. Additionally, we found that a transgene over-expressing hyperactivatable mouse protein C alters embryonic survival of TFPI-K1 null mice. Some of the surviving mice live to adulthood, but then often develop severe hydrocephalus. The proposed aims are designed to further pursue these intriguing preliminary findings to define TFPI- associated biology during embryonic development. Aim 1 will examine how altering expression of TFPIα and FV, in general or specifically within platelets, modulates embryonic development. Aim 2 will characterize murine brain and how TFPI deficiency modulates its development. Inhibition of prothrombinase by TFPIα is a recently recognized anticoagulant mechanism not performed by any other human protein. Therefore, it is anticipated that the results of the proposed experiments will describe the pathophysiology of coagulation and the coagulation-mediated cellular signaling developmental processes modulated by TFPI.


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 = $0 )
2025	2022	VERSITI WISCONSIN, INC.	638 N 18TH ST	MILWAUKEE	WI	53233	MILWAUKEE	USA	Blood Diseases and Resources Research	000	16	2/13/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $763,919 )
2024	2024	VERSITI WISCONSIN, INC.	638 N 18TH ST	MILWAUKEE	WI	53233	MILWAUKEE	USA	Blood Diseases and Resources Research	000	17	6/4/2024	COMPETING CONTINUATION	$763,919
														Subtotal = $763,919

Issue Date FY: 2022 ( Subtotal = $745,219 )
2022	2022	VERSITI WISCONSIN, INC.	638 N 18TH ST	MILWAUKEE	WI	53233	MILWAUKEE	USA	Blood Diseases and Resources Research	000	16	4/2/2022	NON-COMPETING CONTINUATION	$670,694
2022	2022	VERSITI WISCONSIN, INC.	638 N 18TH ST	MILWAUKEE	WI	53233	MILWAUKEE	USA	Blood Diseases and Resources Research	001	16	6/13/2022	NON-COMPETING CONTINUATION	$74,525
														Subtotal = $745,219

Issue Date FY: 2021 ( Subtotal = $756,244 )
2021	2021	VERSITI WISCONSIN, INC.	638 N 18TH ST	MILWAUKEE	WI	53233	MILWAUKEE	USA	Blood Diseases and Resources Research	000	15	3/31/2021	NON-COMPETING CONTINUATION	$756,244
														Subtotal = $756,244

Issue Date FY: 2020 ( Subtotal = $775,764 )
2020	2020	VERSITI WISCONSIN, INC.	638 N 18TH ST	MILWAUKEE	WI	53233	MILWAUKEE	USA	Blood Diseases and Resources Research	000	14	3/30/2020	NON-COMPETING CONTINUATION	$775,764
														Subtotal = $775,764

Issue Date FY: 2019 ( Subtotal = $808,152 )
2019	2019	VERSITI WISCONSIN, INC.	638 N 18TH ST	MILWAUKEE	WI	53233	MILWAUKEE	USA	Cardiovascular Diseases Research	002	13	4/3/2019	COMPETING CONTINUATION	$0
2019	2019	VERSITI WISCONSIN, INC.	638 N 18TH ST	MILWAUKEE	WI	53233	MILWAUKEE	USA	Cardiovascular Diseases Research	001	13	3/26/2019	COMPETING CONTINUATION	$808,152
2019	2018	VERSITI WISCONSIN, INC.	638 N 18TH ST	MILWAUKEE	WI	53233	MILWAUKEE	USA	Blood Diseases and Resources Research	000	12	3/25/2019	NON-COMPETING CONTINUATION	$0
2019	2018	VERSITI WISCONSIN, INC.	638 N 18TH ST	MILWAUKEE	WI	53233	MILWAUKEE	USA	Blood Diseases and Resources Research	003	12	7/31/2019	NON-COMPETING CONTINUATION	$0
														Subtotal = $808,152

Issue Date FY: 2018 ( Subtotal = $422,194 )
2018	2018	BLOODCENTER OF WISCONSIN, INC.	638 N 18TH ST	MILWAUKEE	WI	53233	MILWAUKEE	USA	Blood Diseases and Resources Research	000	12	12/1/2017	NON-COMPETING CONTINUATION	$413,749
2018	2018	BLOODCENTER OF WISCONSIN, INC.	638 N 18TH ST	MILWAUKEE	WI	53233	MILWAUKEE	USA	Blood Diseases and Resources Research	001	12	5/21/2018	NON-COMPETING CONTINUATION	$8,445
														Subtotal = $422,194

Issue Date FY: 2017 ( Subtotal = $422,194 )
2017	2017	BLOODCENTER OF WISCONSIN, INC.	638 N 18TH ST	MILWAUKEE	WI	53233	MILWAUKEE	USA	Blood Diseases and Resources Research	000	11	11/24/2016	NON-COMPETING CONTINUATION	$422,194
														Subtotal = $422,194

Issue Date FY: 2016 ( Subtotal = $417,500 )
2016	2016	BLOOD CENTER OF SOUTHEASTERN WISCONSIN, INC	P.O. BOX 2178	MILWAUKEE	WI	53201	MILWAUKEE	USA	Blood Diseases and Resources Research	000	10	1/11/2016	NON-COMPETING CONTINUATION	$411,237
2016	2016	BLOOD CENTER OF SOUTHEASTERN WISCONSIN, INC	P.O. BOX 2178	MILWAUKEE	WI	53201	MILWAUKEE	USA	Blood Diseases and Resources Research	001	10	2/12/2016	NON-COMPETING CONTINUATION	$6,263
														Subtotal = $417,500

Issue Date FY: 2015 ( Subtotal = $417,500 )
2015	2015	BLOOD CENTER OF SOUTHEASTERN WISCONSIN, INC	P.O. BOX 2178	MILWAUKEE	WI	53201	MILWAUKEE	USA	Blood Diseases and Resources Research	000	9	12/19/2014	COMPETING CONTINUATION	$417,500
														Subtotal = $417,500

Issue Date FY: 2012 ( Subtotal = $363,083 )
2012	2012	BLOOD CENTER OF SOUTHEASTERN WISCONSIN, INC	P.O. BOX 2178	MILWAUKEE	WI	53201	MILWAUKEE	USA	Blood Diseases and Resources Research	001	8	4/21/2012	NON-COMPETING CONTINUATION	$36,309
2012	2012	BLOOD CENTER OF SOUTHEASTERN WISCONSIN, INC	P.O. BOX 2178	MILWAUKEE	WI	53201	MILWAUKEE	USA	Blood Diseases and Resources Research	000	8	12/30/2011	NON-COMPETING CONTINUATION	$326,774
														Subtotal = $363,083

Issue Date FY: 2011 ( Subtotal = $366,750 )
2011	2011	BLOOD CENTER OF SOUTHEASTERN WISCONSIN, INC	P.O. BOX 2178	MILWAUKEE	WI	53201	MILWAUKEE	USA	Blood Diseases and Resources Research	000	7	12/20/2010	NON-COMPETING CONTINUATION	$366,750
														Subtotal = $366,750

Issue Date FY: 2010 ( Subtotal = $366,750 )
2010	2010	BLOOD CENTER OF SOUTHEASTERN WISCONSIN, INC	P.O. BOX 2178	MILWAUKEE	WI	53201	MILWAUKEE	USA	Blood Diseases and Resources Research	000	6	12/18/2009	NON-COMPETING CONTINUATION	$366,750
														Subtotal = $366,750

Issue Date FY: 2009 ( Subtotal = $386,962 )
2009	2009	BLOOD CENTER OF SOUTHEASTERN WISCONSIN, INC	P.O. BOX 2178	MILWAUKEE	WI	53201	MILWAUKEE	USA	Blood Diseases and Resources Research	000	5	12/31/2008	COMPETING CONTINUATION	$360,000
2009	2009	BLOOD CENTER OF SOUTHEASTERN WISCONSIN, INC	P.O. BOX 2178	MILWAUKEE	WI	53201	MILWAUKEE	USA	Blood Diseases and Resources Research	001	5	2/6/2009	COMPETING CONTINUATION	$6,750
2009	2009	BLOOD CENTER OF SOUTHEASTERN WISCONSIN, INC	P.O. BOX 2178	MILWAUKEE	WI	53201	MILWAUKEE	USA	Trans-NIH Recovery Act Research Support	002	5	6/3/2009	SUPPLEMENT FOR EXPANSION	$20,212
														Subtotal = $386,962

Issue Date FY: 2005 ( Subtotal = $405,135 )
2005	2005	BLOOD CENTER OF SOUTHEASTERN WISCONSIN, INC	PO BOX 2178, 638 N 18TH STREET	MILWAUKEE	WI	53201	MILWAUKEE	USA	Blood Diseases and Resources Research	000	4	8/8/2005	NON-COMPETING CONTINUATION	$405,135
														Subtotal = $405,135

Issue Date FY: 2004 ( Subtotal = $482,251 )
2004	2004	BLOOD CENTER OF SOUTHEASTERN WISCONSIN, INC	PO BOX 2178, 638 N 18TH STREET	MILWAUKEE	WI	53201	MILWAUKEE	USA	Blood Diseases and Resources Research	000	3	8/27/2004	NON-COMPETING CONTINUATION	$396,404
2004	2004	BLOOD CENTER OF SOUTHEASTERN WISCONSIN, INC	PO BOX 2178, 638 N 18TH STREET	MILWAUKEE	WI	53201	MILWAUKEE	USA	Blood Diseases and Resources Research	001	2	12/15/2003	SUPPLEMENT FOR EXPANSION	$85,847
														Subtotal = $482,251

Issue Date FY: 2003 ( Subtotal = $231,984 )
2003	2003	BLOOD CENTER OF SOUTHEASTERN WISCONSIN, INC	PO BOX 2178, 638 N 18TH STREET	MILWAUKEE	WI	53201	MILWAUKEE	USA	Blood Diseases and Resources Research	000	2	8/18/2003	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$231,984
														Subtotal = $231,984

Issue Date FY: 2002 ( Subtotal = $217,700 )
2002	2002	UNIVERSITY OF TENNESSEE CENTER FOR THE HEALTH SCIENCES	62 SOUTH DUNLAP STREET	MEMPHIS	TN	38103	SHELBY	USA	Blood Diseases and Resources Research	000	1	9/30/2002	NEW	$217,700
														Subtotal = $217,700

Grand Total All Awards = $8,349,301

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Characterization of an isoform specific anticoagulant function of TFPI-alpha

Award Number: R01HL068835

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/01/2002

PERIOD OF PERFORMANCE END DATE: 03/31/2024

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