This project evaluates the contribution of contact activation to the progression of vascular device-related blood coagulation and thrombus formation. The research will generate new knowledge supporting the development of novel anticoagulants that lack dose-limiting toxicity, are significantly safer, and cause less bleeding than current drugs while also helping to identify medical conditions that could benefit from the therapeutic use of these contact activation inhibitors. Vascular devices such as stents, hemodialyzers and oxygenators can activate blood and often require the use of systemic antithrombotics to reduce the incidence or severity of device failure and thrombotic events. Currently marketed antithrombotic drugs can help reduce clot formation on vascular devices, but all increase the risk of bleeding. For instance, 30% of severely ill neonates that are treated with extracorporeal membrane oxygenation (ECMO) experience severe bleeding complications, including gastrointestinal, pulmonary and brain hemorrhage, which contribute to the high mortality rate of neonatal ECMO. These and other vascular device-associated thrombotic and treatment-associated bleeding complications signify the unmet medical need to improve the safety and outcome of vascular interventions, including permanent intravascular devices like stents and various forms of temporal extracorporeal organ support (ECOS). This project aims at identifying and characterizing the molecular mechanisms that drive propagation of vascular device surfaces-initiated thrombus formation under flow. Our preliminary data now suggest that coagulation factors (F)XII and XI of the contact activation pathway play important roles in not only the initiation but also the propagation of the thrombotic process. We focus on FXII and FXI because (1) there appears to be a causal relationship between contact activation and vascular device failure, and (2) targeting the contact activation pathway as a therapeutic approach is less likely to have detrimental bleeding side effects for patients.
Each Aim will have 3 subaims that will translate our (A) molecular mechanistic in vitro studies to (B) ex vivo blood flow studies of artificial surface-related thrombus formation and (C) in vivo studies of vascular device-related thrombus propagation in primate models. The potential significance of this translational project is that the knowledge generated will lead to verification of promising, safe, and druggable molecular targets within the contact activation pathway to both prevent and interrupt vascular device-related thrombosis. Our research may ultimately support the rationale for the development of selective contact activation inhibitors that could benefit a large number of patients exposed to vascular interventions and devices.

Public Health Relevance

This project evaluates the contribution of contact activation to the progression of vascular device-related blood clotting. Despite the use of currently available ?blood thinning? drugs, which all have dose-limiting bleeding side effects, local and distal thrombus formation leads to vessel occlusion, causes device failures, and contributes to significant vascular device-associated morbidity and mortality. The research will generate new knowledge supporting the development of novel anticoagulants that are significantly safer, lack dose-limiting toxicity, and cause less bleeding than current drugs while also helping to identify medical conditions that could benefit from the therapeutic use of these contact activation inhibitors.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL144113-01
Application #
9614765
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Kindzelski, Andrei L
Project Start
2018-08-01
Project End
2022-06-30
Budget Start
2018-08-01
Budget End
2019-06-30
Support Year
1
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Oregon Health and Science University
Department
Biomedical Engineering
Type
Schools of Medicine
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239