The overall focus of this program is aimed at identifying the components of, and the mechanisms for, the processes which maintain the balance between the fluidity and clotting of blood. The components associated with the maintenance of blood fluidity include elements of the plasma, the circulating blood cells, the vascular tissues and their surrounding tissues. The processes responsible for maintaining or altering the fluidity of blood include the coagulation reactions, the pro and anticoagulant functions associated with peripheral blood and vascular cells and the vascular-blood fibrinolytic system. The projects in this Program address, in an integrated fashion, the global reactions associated with each of these processes and their regulation. The fundamental hypothesis is that the properties of the complex multifaceted systems contributing to hemostasis and fibrinolysis are embodied in, and can be deduced from detailed knowledge of the structure, interactions and reactions of the individual components of the systems. The studies focus both upon systems reconstructed from purified components and on natural biomaterials and biosystems, including mechanistic and population studies of thrombophilia. Our strategy is to combine our talents dealing with the molecular and physiological interactions occurring on these biological surfaces and to correlate this knowledge with human health and disease. The program is composed of four projects 1) The Activation of Prothrombin, 2) Venous Thromboembolism: Genes, Risk and Management, 3) Properties of Fibrinolytic Cascade, 4) Regulation of Human Platelet Prothrombinase Activity. An Administrative Core and an Immunology Core support these projects. Overall, these projects and cores are integrated with respect to their purpose and the reagents which they share (natural and recombinant proteins, nucleic acids, synthetic inhibitors, peptide substrates, antibodies and cells) in chemical cellular and epidemiological studies aimed at understanding the processes of human thrombosis and hemostasis. The research proposed extends from fundamental studies of molecular genetics, cell biology and biochemistry to the genetics and mechanisms of the pathology of human thrombotic disease and bleeding disorders. The proposed research program and the historical evidence of past research accomplishments demonstrate that significant interactions, both intellectual and physical, exist between the principal investigators and the laboratories which make this program project grant an effective scientific vehicle.

Public Health Relevance

It is estimated that half the population of the USA and Europe will die of diseases that involve a blood clot. Depending upon the organ affected, the disease will be called a heart attack, stroke or pulmonary embolism but the underlying cause is a clot in a blood vessel. The research in this program aims to develop sufficient knowledge to predict risk and suggest interventional procedures to block blood clots.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL046703-20
Application #
8118189
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Link, Rebecca P
Project Start
1997-09-01
Project End
2013-07-31
Budget Start
2011-08-01
Budget End
2013-07-31
Support Year
20
Fiscal Year
2011
Total Cost
$1,873,190
Indirect Cost
Name
University of Vermont & St Agric College
Department
Biochemistry
Type
Schools of Medicine
DUNS #
066811191
City
Burlington
State
VT
Country
United States
Zip Code
05405
Kusak, Piotr; Czarnecka, Danuta; Gissel, Matthew et al. (2016) Activated factor IX, factor XI and tissue factor identify patients with permanent atrial fibrillation treated with warfarin who are at risk of ischemic stroke. Arch Med Sci 12:1000-1007
Bouchard, Beth A; Chapin, John; Brummel-Ziedins, Kathleen E et al. (2015) Platelets and platelet-derived factor Va confer hemostatic competence in complete factor V deficiency. Blood 125:3647-50
Bouchard, Beth A; Gissel, Matthew T; Whelihan, Matthew F et al. (2014) Platelets do not express the oxidized or reduced forms of tissue factor. Biochim Biophys Acta 1840:1188-93
de Haan, Hugoline G; Bezemer, Irene D; Vossen, Carla Y et al. (2014) Genetic variants in Cell Adhesion Molecule 1 (CADM1): a validation study of a novel endothelial cell venous thrombosis risk factor. Thromb Res 134:1186-92
Undas, A; Brummel-Ziedins, K E; Mann, K G (2014) Anticoagulant effects of statins and their clinical implications. Thromb Haemost 111:392-400
Whelihan, Matthew F; Kiankhooy, Armin; Brummel-Ziedins, Kathleen E (2014) Thrombin generation and fibrin clot formation under hypothermic conditions: an in vitro evaluation of tissue factor initiated whole blood coagulation. J Crit Care 29:24-30
Krudysz-Amblo, Jolanta; Jennings 2nd, Mark E; Knight, Tyler et al. (2013) Disulfide reduction abolishes tissue factor cofactor function. Biochim Biophys Acta 1830:3489-96
Ayombil, F; Abdalla, S; Tracy, P B et al. (2013) Proteolysis of plasma-derived factor V following its endocytosis by megakaryocytes forms the platelet-derived factor V/Va pool. J Thromb Haemost 11:1532-9
Baker, Jason V; Brummel-Ziedins, Kathleen; Neuhaus, Jacqueline et al. (2013) HIV replication alters the composition of extrinsic pathway coagulation factors and increases thrombin generation. J Am Heart Assoc 2:e000264
Wood, Jeremy P; Bunce, Matthew W; Maroney, Susan A et al. (2013) Tissue factor pathway inhibitor-alpha inhibits prothrombinase during the initiation of blood coagulation. Proc Natl Acad Sci U S A 110:17838-43

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