Universiẗat, Diss., 2007--Giessen.

Thesis (doctoral)--Lund University, 1997. / Added t.p. with thesis statement inserted. Includes bibliographical references.

Thesis (doctoral)--Lund University, 1997. / Added t.p. with thesis statement inserted. Includes bibliographical references.

A Research Report submitted to the Faculty of Medicine, University of the Witwatersrand, in part fulfilment of the requirements for the degree of Master of Medicine in the branch of Haematology Johannesburg, October 1997 / Venous thromboembolic disease is a common health problem. It contributes considerably to morbidity as well as to mortality. Thrombosis usually occurs due to an underlying risk factor which may be environmental or genetic in origin. The recently described activated Protein C (APC) resistance is the commonest cause of familial thrombophilia documented to date. The molecular lesion is a single point mutation in the factor V (FV) gene which abolishes a cleavage site whereby it is normally inactivated by APC. This defect, termed the FV Leiden mutation, is highly prevalent in normal Caucasian populations. Although it would appear to have arisen due to a founder effect, there is a paucity of data concerning non-Caucasian populations. / IT2018

The endothelial protein C receptor (EPCR) binds to protein C (PC) and increases the rate of activated protein C (APC) generation by the thrombin-thrombomodulin (TM) complex. APC exerts anticoagulant, anti-inflammatory, and cytoprotective effects, which are EPCR-dependent. The thrombin-TM complex is also a potent activator of thrombin activable fibrinolysis inhibitor (TAFI), leading to impaired clot lysis. Mutations and polymorphisms identified in the EPCR gene, which can affect the efficiency of PC activation, have been associated with an increased risk of thrombosis. In this thesis we investigate the impact of impaired PC binding to EPCR on coagulation, inflammation, and fibrinolysis using novel in vitro and in vivo models. Using a murine model that harbours a variant of EPCR that does not bind PC (R84A), we demonstrate that upon thrombotic challenge, there is an increase in thrombin generation and fibrin deposition in the lungs. Upon inflammatory challenge, impaired PC/EPCR interactions also result in increased thrombin generation and increased neutrophil infiltration into the lungs. Using cells that express TM and a human variant of EPCR that does not bind PC (R96C), we demonstrate that clot lysis is delayed in normal plasma independent of TAFI activation, suggesting PC and TAFI do not compete for activation by the thrombin-TM complex. In contrast, delayed clot lysis in plasma deficient of PC is a result of greater TAFI activation by the thrombin-TM complex. Taken together, impairment of the PC pathway contributes to thrombosis through pro-coagulant, pro-inflammatory and anti-fibrinolytic mechanisms. Interestingly, mice with EPCR variant R84A, develop bone marrow failure and splenomegaly, revealing a novel role for EPCR in the bone marrow. Taken together, PC/EPCR interactions regulate the coagulation, inflammation, and fibrinolytic pathways, which may have a significant impact on maintaining hematopoietic homeostasis. / Thesis / Doctor of Philosophy (PhD) / Under normal conditions, blood is maintained in a fluid state. Upon injury or infection, the blood begins to form a clot to prevent bleeding. Once bleeding has stopped the clot is dissolved and blood regains its fluid state. The formation of a blood clot is a serious and potentially life threatening disease. A blood clot formed inside a blood vessel can block the flow of blood through the circulation, leading to organ damage. Approximately 50% of blood clots are caused by known genetic or environmental factors, leaving 50% of blood clots caused by unknown factors. In this thesis we investigate the unknown factors that contribute to blood clotting. In patients who have experienced blood clots with no known cause, we have identified genetic mutations in a blood vessel wall protein, known as the endothelial protein C receptor (EPCR) that renders it non-functional. We demonstrate both in vitro and in vivo that non-functional EPCR not only leads to the formation of a blood clot but also delays the removal of the blood clot. Our in vivo studies have also revealed a previously unknown role for EPCR in the bone marrow, likely through its effects on blood coagulation. Taken together, loss of EPCR function contributes to the development of clot formation and likely impacts other organ systems.

Thesis (Ph.D.)--University of Nebraska-Lincoln, 2010. / Title from title screen (site viewed July 6, 2010). PDF text: vi, 166 p. : ill. (some col.) ; 4 Mb. UMI publication number: AAT 3398196 . Includes bibliographical references. Also available in microfilm and microfiche formats.

No description available.

Zugl.: Giessen, Universiẗat, Diss., 2008.

Zugl.: Jena, Univ., Diss., 2006 u.d.T.: Hagel, Stefan: Protein-C- und Antithrombin-III-Aktivität / Hergestellt on demand

Zugl.: Berlin, Freie Universiẗat, Diss., 2009.