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von Willebrand Factor in Traumatic Brain Injury and Associated Coagulopathy

Award Number: R01HL152200
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2020
PERIOD OF PERFORMANCE END DATE: 03/31/2025

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von Willebrand Factor in Traumatic Brain Injury and Associated Coagulopathy - Project Summary Traumatic brain injury is commonly associated with the inability of blood to clot (coagulopathy), resulting in secondary or delayed systemic and intracranial bleeding. Substantial blood loss, hemodilution due to fluid resuscitation, and hypothermia are the most common causes of coagulopathy associated with trauma to the body and limbs and hemorrhagic shock. We have recently demonstrated that an injured brain releases extracellular vesicles (EVs) into circulation. These brain‐derived EVs induce a hypercoagulable state that quickly evolves into consumptive coagulopathy. Extracellular mitochondria (exMTs) are also released into circulation and promote coagulation through the surface‐exposed mitochondrial phospholipid cardiolipin. ExMts also maintain the respiratory activity to generate reactive oxygen species that activate platelets and endothelial cells. These findings demonstrate that TBI induces consumptive coagulopathy that is mechanistically distinct from deficient and dilutional coagulopathy associated with extracranial trauma and hemorrhagic shock. Our recent study further implicates the adhesive ligand von Willebrand factor (VWF) for mediating EV‐induced vascular injury and for activating platelets to propagate coagulopathy in mouse models of traumatic brain injury. These recently findings led us to hypothesize that: 1) brain‐derived EVs released from injured brains stimulate endothelial cells to release hyper‐adhesive VWF multimers that are not timely and sufficiently cleaved by the enzyme ADAMTS13, 2) these hyper‐adhesive VWF multimers facilitate EV‐ induced vascular leakage and propagate EV‐induced coagulopathy, and 3) the hyper‐adhesive activity of VWF can be selectively blocked in acute brain injury without reducing the hemostatic activity of VWF. Here, we propose testing these hypotheses in two specific aims. The first is to study ADAMTS‐13 variants, the VWF A2 domain, and the apoptotic cell‐scavenging molecule Del‐1 for blocking the TBI‐induced hyper‐adhesive activity of VWF to protect mice from developing traumatic brain injury‐induced coagulopathy, and to define the underlying mechanisms of their actions in mouse models. The second is to conduct a cohort study of 120 patients with TBI and trauma controls to determine the clinical relevance of findings from the mouse study. We will analyze patient samples to quantify VWF activity and ADAMTS‐13 cleavage as primary variables and to define platelet activation, plasma levels of EVs and clinical coagulopathy as outcome variables. We will associate primary variables to outcome variables through multivariate analyses to define a causal role of hyper‐adhesive VWF in traumatic brain injury‐induced coagulopathy and to develop new markers for predicting the coagulopathy with focus on VWF hyper‐reactivity and EV clearance. This study is an integral part of our long‐term goal to define the systemic impact of traumatic brain injury and to study a role of the traumatic brain injury‐induced systemic changes in propagating secondary cerebral injury.


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	2023	BLOODWORKS	921 TERRY AVE	SEATTLE	WA	98104	KING	USA	Blood Diseases and Resources Research	000	4	7/30/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $657,939 )
2023	2023	BLOODWORKS	921 TERRY AVE	SEATTLE	WA	98104	KING	USA	Blood Diseases and Resources Research	000	4	3/27/2023	NON-COMPETING CONTINUATION	$657,939
														Subtotal = $657,939

Issue Date FY: 2022 ( Subtotal = $1,115,377 )
2022	2022	BLOODWORKS	921 TERRY AVE	SEATTLE	WA	98104	KING	USA	Blood Diseases and Resources Research	001	3	6/6/2022	SUPPLEMENT FOR EXPANSION	$457,002
2022	2022	BLOODWORKS	921 TERRY AVE	SEATTLE	WA	98104	KING	USA	Blood Diseases and Resources Research	002	3	6/17/2022	NON-COMPETING CONTINUATION	$65,840
2022	2022	BLOODWORKS	921 TERRY AVE	SEATTLE	WA	98104	KING	USA	Blood Diseases and Resources Research	000	3	3/31/2022	NON-COMPETING CONTINUATION	$592,535
														Subtotal = $1,115,377

Issue Date FY: 2021 ( Subtotal = $658,804 )
2021	2021	BLOODWORKS	921 TERRY AVE	SEATTLE	WA	98104	KING	USA	Blood Diseases and Resources Research	000	2	3/11/2021	NON-COMPETING CONTINUATION	$658,804
														Subtotal = $658,804

Issue Date FY: 2020 ( Subtotal = $679,475 )
2020	2020	BLOODWORKS	921 TERRY AVE	SEATTLE	WA	98104	KING	USA	Blood Diseases and Resources Research	000	1	3/26/2020	NEW	$679,475
														Subtotal = $679,475

Grand Total All Awards = $3,111,595

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von Willebrand Factor in Traumatic Brain Injury and Associated Coagulopathy

Award Number: R01HL152200

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/01/2020

PERIOD OF PERFORMANCE END DATE: 03/31/2025

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