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.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Hemostasis and Thrombosis Study Section (HT)
Program Officer
Sarkar, Rita
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of North Carolina Chapel Hill
Schools of Medicine
Chapel Hill
United States
Zip Code
Foley, Jonathan H; Walton, Bethany L; Aleman, Maria M et al. (2016) Complement Activation in Arterial and Venous Thrombosis is Mediated by Plasmin. EBioMedicine 5:175-82
Byrnes, James R; Duval, C├ędric; Wang, Yiming et al. (2015) Factor XIIIa-dependent retention of red blood cells in clots is mediated by fibrin ?-chain crosslinking. Blood 126:1940-8
Aleman, Maria M; Holle, Lori A; Stember, Katherine G et al. (2015) Cystamine preparations exhibit anticoagulant activity. PLoS One 10:e0124448
Gebhart, J; Laczkovics, C; Posch, F et al. (2015) Plasma clot properties in patients with a mild-to-moderate bleeding tendency of unknown cause. Ann Hematol 94:1301-10
Krebs, C R; Li, Ling; Wolberg, Alisa S et al. (2015) A portable blood plasma clot micro-elastometry device based on resonant acoustic spectroscopy. Rev Sci Instrum 86:075005
Amin, Chirag; Adam, Soheir; Mooberry, Micah J et al. (2015) Coagulation activation in sickle cell trait: an exploratory study. Br J Haematol 171:638-46
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
Brummel-Ziedins, Kathleen E; Wolberg, Alisa S (2014) Global assays of hemostasis. Curr Opin Hematol 21:395-403
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

Showing the most recent 10 out of 42 publications