RESEARCH AND RELATED Other Project Information 6. PROJECT SUMMARY/ABSTRACT Following injury, tissue factor (TF)-bearing cells are exposed to the blood, triggering blood clot formation. Blood clots are stabilized by a web-like network of fibrin, which protects the clot from the rigors of flowing blood. Fibrin also has immunological functions during infection and contributes to wound healing. Studies have shown that abnormalities in the formation or quality (structure and/or stability) of the fibrin network are an established, independent risk factor for abnormal blood clots (thrombosis and/or bleeding). We and others have shown that different cells determine fibrin quality via their procoagulant activity and receptor expression. Interestingly, both cellular procoagulant activity and receptors produce fibrin that is denser and more stable near the cell than further away from the cell surface. We hypothesize that the spatial location of thrombin generation influences clot structure and stability. We will use laser scanning confocal microscopy to characterize activities that regulate fibrin clot structure proximal and distal to the site of clotting initiation. We will specifically investigate the roles of cell stimulation, cellular and circulating tissue factor, soluble clotting factors, and cell receptors in determining clot structure. We will use passive and magnetically-driven microbead techniques and microscopy to examine how vascular cells modulate fibrin network permeability, mechanical strength, and resistance to fibrinolysis. Finally, we will use transmission electron microscopy to compare fibrin structure in clots formed under different shear rates on freshly-excised human vessels. We anticipate our data will show how different hemostatic and prothrombotic mechanisms contribute to clot structure and stability in static and low shear conditions. These mechanisms may be specific targets for preventing intravascular thrombosis and/or embolism.

Public Health Relevance

RESEARCH AND RELATED Other Project Information 7. PROJECT NARRATIVE Inappropriate blood clot formation (thrombosis) is the leading cause of death and disability in the Western world. Understanding the mechanisms leading to thrombosis is critical in order to develop approaches for preventing this devastating disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL094740-04
Application #
8277904
Study Section
Hemostasis and Thrombosis Study Section (HT)
Program Officer
Sarkar, Rita
Project Start
2009-09-10
Project End
2014-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
4
Fiscal Year
2012
Total Cost
$325,850
Indirect Cost
$103,100
Name
University of North Carolina Chapel Hill
Department
Pathology
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Snow, S J; Cheng, W; Wolberg, A S et al. (2014) Air pollution upregulates endothelial cell procoagulant activity via ultrafine particle-induced oxidant signaling and tissue factor expression. Toxicol Sci 140:83-93
Aleman, Maria M; Byrnes, James R; Wang, Jian-Guo et al. (2014) Factor XIII activity mediates red blood cell retention in venous thrombi. J Clin Invest 124:3590-600
Walton, B L; Getz, T M; Bergmeier, W et al. (2014) The fibrinogen ?A/?' isoform does not promote acute arterial thrombosis in mice. J Thromb Haemost 12:680-9
Zucker, M; Seligsohn, U; Salomon, O et al. (2014) Abnormal plasma clot structure and stability distinguish bleeding risk in patients with severe factor XI deficiency. J Thromb Haemost 12:1121-30
Aleman, Maria M; Walton, Bethany L; Byrnes, James R et al. (2014) Fibrinogen and red blood cells in venous thrombosis. Thromb Res 133 Suppl 1:S38-40
Aleman, Maria M; Wolberg, Alisa S (2013) Tick spit shines a light on the initiation of coagulation. Circulation 128:203-5
Aleman, Maria M; Walton, Bethany L; Byrnes, James R et al. (2013) Elevated prothrombin promotes venous, but not arterial, thrombosis in mice. Arterioscler Thromb Vasc Biol 33:1829-36
Wu, Gongting; Krebs, Charles R; Lin, Feng-Chang et al. (2013) High sensitivity micro-elastometry: applications in blood coagulopathy. Ann Biomed Eng 41:2120-9
Wolberg, Alisa S; Aleman, Maria M; Leiderman, Karin et al. (2012) Procoagulant activity in hemostasis and thrombosis: Virchow's triad revisited. Anesth Analg 114:275-85
Wang, Jian-Guo; Geddings, Julia E; Aleman, Maria M et al. (2012) Tumor-derived tissue factor activates coagulation and enhances thrombosis in a mouse xenograft model of human pancreatic cancer. Blood 119:5543-52

Showing the most recent 10 out of 16 publications