When a blood vessel ruptures, a hemostatic clot, consisting mainly of platelets and fibrin, is formed to restrict the loss of blood. Physiological blood clotting is highly regulated, but a pathological clot (thrombus) may form within a vessel and restrict blood flow to organs or clot pieces (emboli) can detach and be carried to the lungs, causing a life-threatening complication called pulmonary embolism. Also, clots are formed in coronary arteries, causing heart attacks, and in brain vessels, causing ischemic strokes. The high morbidity and mortality rates (about 900,000 incidences and 300,000 deaths annually just from venous thromboembolic disease) underscore the biomedical importance of studying processes limiting clot formation. However, the mechanisms stopping clot growth are poorly understood. In particular, current models of thrombus development do not address how structure of fibrin network (FNW) affect spatial-temporal evolution of blood coagulation factors and the interplay between FNW and platelets under flow conditions limiting blood clot growth. This proposal combines development of 3D Multiscale Blood Clot Modeling Environment (MBCME-3D) and coupling MBCME-3D simulations and specifically designed experiments using optical tweezers and microfluidic chambers, to study two specific roles that a FNW plays in regulating blood clot growth: 1) impeding protein transport;and 2) mediating platelet-FNW binding kinetics under physiological or pathological conditions. This will result in detailed examination of the common clinical scenario of increasing blood shear in response to partial obstruction and narrowing of the vessel lumen, which is considered a critically important component, affecting both the generation of fibrin and binding of platelets, mechanisms limiting blood clot growth. Better understanding of the structure and properties as well as the mechanisms of clot growth and its limitations under blood flow will help physicians to estimate risk of thrombotic disease for an individual patient by identifying critical values of parameters o processes regulating thrombogenesis. Additionally, the generalized MBCME-3D will be able to simulate in detail motion of biological cells and proteins in the fluid environment in the presence of porous biogels at the micro- and mesoscale which will contribute to the development of a variety of predictive multiscale computational models for biomedical research.

Public Health Relevance

Thrombosis is a major cause of death in the developed world and results from the growth of thrombi (blood clots forming within blood vessels) that restricts blood flow to vital organs. The proposal integrates multiscale modeling and experiments to examine a novel hypothesis related to the role of fibrin networks in processes halting thrombus growth. This will help physicians to estimate risk of thrombotic disease for an individual patient by identifying critical values of parameters of processes regulating thrombogenesis.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project--Cooperative Agreements (U01)
Project #
1U01HL116330-01A1
Application #
8744538
Study Section
Special Emphasis Panel (ZEB1)
Program Officer
Lee, Albert
Project Start
2014-07-25
Project End
2019-06-30
Budget Start
2014-07-25
Budget End
2015-06-30
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Notre Dame
Department
Biostatistics & Other Math Sci
Type
Schools of Arts and Sciences
DUNS #
City
Notre Dame
State
IN
Country
United States
Zip Code
46556
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