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Koellnberger, Maria (2007): In vivo Analyse der zellulären und molekularen Mechanismen der arteriellen und venösen Thrombose in der Maus. Dissertation, LMU München: Faculty of Veterinary Medicine
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Abstract

In vivo analysis of the cellular and molecular mechanisms in arterial and venous thrombosis in a mouse model The detailed molecular and cellular mechanisms that lead to arterial and venous thrombosis and trigger heart attack and stroke, as well as pulmonary emboli in the case of venous thrombosis, are not yet fully understood. Therefore in the present study, arterial as well as venous thrombi were created in a mouse model in order to analyse the cellular and molecular processes that contribute to arterial and venous thrombosis in vivo. Two thrombosis mouse models (one arterial and one venous) were established. In contrast to existing models, these models include the diverse formation of arterial (endothelial damage) and venous thrombi (stasis with intact endothelium). In addition to histological and electron microscopic analyses intravital microscopy was performed in order to analyse the cellular and molecular phenomena in venous and arterial thrombosis. Wild type animals (C57BL/6J) were compared to genetically modified animals in order to determine the impact of platelets, leukocytes, fibrin and microparticles in both forms of thrombosis. Mice with defective platelet adhesion/aggregation (glycoprotein [GP]IIb-/-) as well as defective leukocyte adhesion (P-Selectin-/-) were used. In addition to investigate the role of the coagulation cascade protein “tissue factor” (TF), the primary initiator of the coagulation cascade, we took advantage of “TF” deficient mice (Low TF, HCV 100). By means of these newly established models, we showed that in arterial thrombosis platelets adhere rapidly, whereas few leukocytes are recruited into the thrombus. In contrast leukocyte adhesion is the prominent initial phenomena in venous thrombosis. The loss of platelet P-Selectin in arterial thrombosis reduced the stability of the thrombus, but had no effect on platelet adhesion and aggregation per se. In contrast the loss of GPIIb led to a complete lack of platelet adhesion and aggregation in arterial thrombosis. In venous thrombosis, P-Selectin-/- mice showed a massive reduction in leukocyte accumulation. The reduced leukocyte adhesion was accompanied by a reduction of the thrombus size 48 hours after stasis. However platelets also appear to contribute to venous thrombosis. While, initially very few platelets adhered to the endothelial cell layer, the loss of GPIIb did reduce thrombus size. Besides cellular mechanisms, the expression of “TF” is essential for venous thrombosis. Accordingly, low TF mice showed a dramatically reduced thrombus size, whereas neither platelet adhesion nor leukocyte adhesion initially is affected by the “TF” defect. Altogether, platelets appear to be the major trigger of arterial thrombosis, whereas venous thrombosis strictly requires the contribution of leukocytes. Together the present study for the first time strikingly points out the diverse cellular and molecular mechanisms that contribute to arterial and venous thrombosis in vivo. Consequently distinct new future strategies for prevention and therapy of both arterial and venous thrombosis are suggested.