By Rafat Abonour, MD
2008-12-09
During today’s Special Symposium on the Basic Science of Hemostasis and Thrombosis, five renowned individuals will present data on the complex role of platelets and their close friend, the endothelial cell, in several diseases.
First, Yacine Boulaftali, from the INSERM in Paris, will present data that may change our approach to platelets’ role in thrombosis and hemostasis. Why not recruit platelets to stop thrombosis? Protease nexin-1 (PN-1) inhibits the plasminogen activators of both plasmin and thrombin. PN-1 is barely detectable in plasma but is expressed by platelets. These investigators have characterized platelet PN-1 localization and function in human and mouse platelets. Their results establish for the first time that platelet PN-1 possesses efficient anticoagulant and antithrombotic properties and may be an important regulator in the initiation of thrombosis.
Dr. Paul Kubes from the University of Calgary, Canada, will discuss how platelets trap bacteria in sepsis. Platelets express Toll-like receptors, specifically TLR4. Lipopolysachharide (LPS) binds these TLR4-inducing platelets to more avidly bind fibrinogen as well as adherent neutrophils. LPS-induced neutrophil-platelet interaction leads to supra-activation of the neutrophils and the release of web-like structures consisting of DNA previously termed neutrophil extracellular traps (NETs). The NETs are full of proteases and other anti-microbial molecules that effectively trap and kill bacteria. However, how to prevent the associated injury of surrounding endothelium is a different story.
Dr. Scott L. Diamond from the University of Pennsylvania will present his work on studying the dynamics of thrombus buildup in blood vessels. He developed novel approaches to measurement of thrombus formation and the contribution of platelets and tissue factor to the process. The authors have been able to determine sub-micromolar determinants of tissue factor concentration during flow conditions that are efficient in promoting thrombus formation. Similar determinations are also shown for ADP-induced platelet aggregation. This work exemplifies development of novel technology in aiding our understanding of macromolecular associations during thrombus formation.
Dr. Leslie V. Parise, from the University of North Carolina, will explain how platelets are involved in immune response and inflammation. Platelets contain high amounts of certain inflammatory mediators, including CD40 ligand (CD40L). Platelet activation leads to the exposure of CD40L on the cell surface, which is then released as a soluble fragment (sCD40L). CD40L after binding to CD40 leads to increased adhesion receptor expression on endothelial cells, B-cell proliferation, and tissue factor (TF) expression. In addition, CD40L binds to GPIIb-IIIa on platelets, induces platelet activation, and promotes thrombosis. Dr. Parise’s group studied a mouse model for sickle cell anemia in which platelet activation and chronic inflammation contribute to the disease process. They noted that platelet-derived sCD40L is significantly elevated, biologically active, and likely to be a major contributor to the inflammatory response in sickle cell anemia.
Lastly, Dr. Berend Isermann, from the University of Heidelberg, Germany, will discuss the role of endothelial cell injury in microvascular diabetic complications. This group studied the association of diabetic microvascular complications with markers of endothelial dysfunction such as soluble thrombomodulin (TM). They demonstrated a reduction of TM expression in renal glomeruli, which results in impaired activation of protein C (PC). Diabetic mice with elevated plasma levels of activated PC were protected against both diabetic nephropathy and neuropathy by inhibiting endothelial cells and podocytes. It seems that microvascular complications of diabetes are mostly related to the toxic effect of hyperglycemia on the endothelial cells.
This special session will be begin at 7:30 a.m. in 2009-2011-2022-2024 – West.
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