Verbatim): The hypothesis underlying this proposal is that cells, rather than proteins, direct the coagulation reactions. Corollaries of this are: 1) the cellular location of the activated coagulation factors determines their function in the coagulation cascade; and 2) specific features of different cell types, such as the presence of specific receptors, determine the anti- and pro-coagulant features of the cells. These studies will use a cell based model system of coagulation we have developed. We have proposed studies that fall within four specific aims.
The first aim examines how the function of activated protein C on endothelial cells is different from its activity on phospholipid vesicles or activated platelets. These studies will use factor V molecules that have cleavage site mutations. We will also look at the ability of factor V and cleaved forms of factor V to act as a cofactor for activated protein C inactivation of factor VIII.
The second aim examines how cellular tissue factor activity is controlled. These studies will look at tissue factor encryption and de-encryption, the role of oxidants in altering cellular tissue factor activity, and the roles of tissue factor pathway inhibitor and anti-thrombin Ill in inactivating the factor VIla/tissue factor complex.
The third aim examines what factors determine the rate and amount of thrombin generated on activated platelets. These studies will examine mechanisms that limit thrombin generation on the platelet surface.
The fourth aim examines how the amount of thrombin generated in the cell-based model correlates with formation of a stable hemostatic clot in vivo? These studies will examine fibrinogen structure and susceptibility to lysis as well as the role of thrombin activatable fibrinolysis inhibitor.
| Hoffman, Maureane; Monroe, Dougald M (2007) Coagulation 2006: a modern view of hemostasis. Hematol Oncol Clin North Am 21:1-11 |
| Monroe, Dougald M; Hoffman, Maureane (2006) What does it take to make the perfect clot? Arterioscler Thromb Vasc Biol 26:41-8 |
| Sauls, Derrick L; Lockhart, Evelyn; Warren, Maria Esteban et al. (2006) Modification of fibrinogen by homocysteine thiolactone increases resistance to fibrinolysis: a potential mechanism of the thrombotic tendency in hyperhomocysteinemia. Biochemistry 45:2480-7 |
| Hoffman, Maureane M; Monroe, Dougald M (2005) Rethinking the coagulation cascade. Curr Hematol Rep 4:391-6 |
| Wolberg, Alisa S; Allen, Geoffrey A; Monroe, Dougald M et al. (2005) High dose factor VIIa improves clot structure and stability in a model of haemophilia B. Br J Haematol 131:645-55 |
| Kempton, Christine L; Hoffman, Maureane; Roberts, Harold R et al. (2005) Platelet heterogeneity: variation in coagulation complexes on platelet subpopulations. Arterioscler Thromb Vasc Biol 25:861-6 |
| Roberts, Harold R; Monroe, Dougald M; Escobar, Miguel A (2004) Current concepts of hemostasis: implications for therapy. Anesthesiology 100:722-30 |
| Roberts, H R (2004) Recombinant factor VIIa: a general hemostatic agent? Yes. J Thromb Haemost 2:1691-4 |
| Wolberg, Alisa S; Meng, Zhi Hong; Monroe 3rd, Dougald M et al. (2004) A systematic evaluation of the effect of temperature on coagulation enzyme activity and platelet function. J Trauma 56:1221-8 |
| Wolberg, Alisa S; Monroe, Dougald M; Roberts, Harold R et al. (2003) Elevated prothrombin results in clots with an altered fiber structure: a possible mechanism of the increased thrombotic risk. Blood 101:3008-13 |
Showing the most recent 10 out of 29 publications
