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New approaches to the pathophysiology, diagnosis and management of heparin-induced thrombocytopenia

Award Number: R01HL158932
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/25/2026
PERIOD OF PERFORMANCE END DATE: 07/31/2027

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New approaches to the pathophysiology, diagnosis and management of heparin-induced thrombocytopenia - PROJECT SUMMARY/ABSTRACT Heparin-induced thrombocytopenia (HIT) is a severe, antibody (ab)-mediated prothrombotic syndrome with high morbidity and mortality. The biochemical basis of the distinction between “pathogenic” platelet-activating antibodies and “benign” non-activating HIT antibodies is not well understood. This results in significant diagnostic challenges and in excessive use of non-heparin alternative anticoagulation that have worse bleeding profiles than heparin. Outcomes in HIT are suboptimal despite current therapy with direct thrombin inhibitors: One-third of affected patients develop thrombosis and one in ten patients dies. The proposed studies will explore key unanswered questions in areas of HIT pathophysiology, diagnosis, and treatment. For Aim 1, we hypothesize the existence of multiple functional classes of HIT antibodies: (1) Pathogenic antibodies that recognize PF4-treated platelets with or without reactivity to PF4-heparin complexes, and (2) Benign abs that recognize PF4-heparin but not platelets treated with PF4. We will identify and characterize these antibody classes by chromatography-based isolation from patient samples and will generate novel HIT monoclonal antibodies in each of these functional classes. Generated monoclonal antibodies will be tested for pathogenicity in a HIT mouse model and results will be correlated with their serologic characteristics. Obtaining and processing normal donor platelets is a major challenge that limits the availability of functional “gold standard” testing in HIT. In Aim 2, we will develop a rapid HIT diagnostic test using the patient’s own platelets treated with PF4/heparin. This will facilitate “in-hospital” HIT diagnosis leading to early detection of this condition. Currently used non-heparin alternative anticoagulants do not address the most proximal event in HIT: Activation of platelets by HIT antibodies. Given this, breakthrough thrombosis is frequently seen in patients under treatment and so is unintended bleeding caused by the potent non-heparin anticoagulants used. In Aim 3, we will use platelet-derived and synthetic chondroitin sulfates of various sulfation levels and saccharide lengths to evaluate their ability to inhibit HIT-antibody mediated platelet activation in vitro and to ameliorate thrombocytopenia in a HIT murine model. In Aim 1, we expect to successfully separate and characterize multiple functional classes of HIT antibodies which will suggest new ways to selectively detect only the pathogenic ones. Developing and optimizing a diagnostic method using the patient’s own platelets in Aim 2 will transform platelet-activation based HIT testing by moving it from the reference laboratory environment to the in-hospital setting. Finally, studies described in Aim 3 will introduce a new class of therapeutics in HIT, chondroitin sulfates, that will prevent thrombosis, but unlike current therapies, will not increase the risk of bleeding. In summary, we anticipate that all three aims of this proposal will lead to a significant impact on pathophysiology, diagnosis, and treatment of HIT.


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: 2026 ( Subtotal = $0 )
2026	2025	MAYO CLINIC ARIZONA	13400 E SHEA BLVD	SCOTTSDALE	AZ	85259	MARICOPA	USA	Blood Diseases and Resources Research	002	6	6/15/2026	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2026	2025	MAYO CLINIC ARIZONA	13400 E SHEA BLVD	SCOTTSDALE	AZ	85259	MARICOPA	USA	Blood Diseases and Resources Research	001	6	6/1/2026	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$249,258
2026	2025	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Blood Diseases and Resources Research	000	5	5/20/2026	NON-COMPETING CONTINUATION	-$249,258
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $397,500 )
2025	2025	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Blood Diseases and Resources Research	000	5	8/13/2025	NON-COMPETING CONTINUATION	$397,500
														Subtotal = $397,500

Issue Date FY: 2024 ( Subtotal = $397,500 )
2024	2024	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Blood Diseases and Resources Research	000	4	7/22/2024	NON-COMPETING CONTINUATION	$397,500
														Subtotal = $397,500

Issue Date FY: 2023 ( Subtotal = $397,500 )
2023	2023	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Blood Diseases and Resources Research	000	3	8/8/2023	NON-COMPETING CONTINUATION	$397,500
														Subtotal = $397,500

Issue Date FY: 2022 ( Subtotal = $397,500 )
2022	2022	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Blood Diseases and Resources Research	001	2	8/2/2022	NON-COMPETING CONTINUATION	$397,500
2022	2021	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Cardiovascular Diseases Research	000	1	10/19/2021	NEW	$0
														Subtotal = $397,500

Issue Date FY: 2021 ( Subtotal = $397,500 )
2021	2021	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Cardiovascular Diseases Research	000	1	8/15/2021	NEW	$397,500
														Subtotal = $397,500

Grand Total All Awards = $1,987,500

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New approaches to the pathophysiology, diagnosis and management of heparin-induced thrombocytopenia

Award Number: R01HL158932

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/25/2026

PERIOD OF PERFORMANCE END DATE: 07/31/2027

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