Hemostasis; vitamin K-dependent protein; Inflammation; Gas6; Protein S
Calzavarini Sara, Prince-Eladnani Raja, Saller François, Bologna Luca, Burnier Laurent, Brisset Anne C., Quarroz Claudia, Reina Caro Maria Desiré, Ermolayev Vladimir, Matsumura Yasuhiro, Fernández José A., Hackeng Tilman M., Griffin John H., Angelillo-Scherrer Anne (2020), Platelet protein S limits venous but not arterial thrombosis propensity by controlling coagulation in the thrombus, in Blood
, 135(22), 1969-1982.
Calzavarini Sara, Brodard Justine, Quarroz Claudia, Maire Livia, Nützi Raphael, Jankovic Jovana, Rotondo Laura C., Giabbani Evelyne, Fiedler Georg Martin, Nagler Michael, Angelillo-Scherrer Anne (2019), Thrombin generation measurement using the ST Genesia Thrombin Generation System in a cohort of healthy adults: Normal values and variability, in Research and Practice in Thrombosis and Haemostasis
, 3(4), 758-768.
Schnegg‐Kaufmann Annatina, Calzavarini Sara, Limacher Andreas, Mean Marie, Righini Marc, Staub Daniel, Beer Juerg‐Hans, Frauchiger Beat, Osterwalder Joseph, Kucher Nils, Matter Christian M., Husmann Marc, Banyai Martin, Aschwanden Markus, Mazzolai Lucia, Hugli Oliver, Nagler Michael, Daskalakis Michael, Rodondi Nicolas, Aujesky Drahomir, Angelillo‐Scherrer Anne (2019), A high Gas6 level in plasma predicts venous thromboembolism recurrence, major bleeding and mortality in the elderly: a prospective multicenter cohort study, in Journal of Thrombosis and Haemostasis
, 17(2), 306-318.
Caversaccio Nathalie I., Reina Caro Maria D., Prince Raja, Müller Martin, Lewis Clayton S., Bogdanov Vladimir Y., Dufour Jean-François, Angelillo-Scherrer Anne (2018), Alternatively spliced tissue factor levels are elevated in the plasma of patients with chronic liver diseases, in European Journal of Gastroenterology & Hepatology
, 30(12), 1470-1475.
Prince Raja, Bologna Luca, Manetti Mirko, Melchiorre Daniela, Rosa Irene, Dewarrat Natacha, Suardi Silvia, Amini Poorya, Fernández José A., Burnier Laurent, Quarroz Claudia, Reina Caro Maria Desiré, Matsumura Yasuhiro, Kremer Hovinga Johanna A., Griffin John H., Simon Hans-Uwe, Ibba-Manneschi Lidia, Saller François, Calzavarini Sara, Angelillo-Scherrer Anne (2018), Targeting anticoagulant protein S to improve hemostasis in hemophilia, in Blood
, 131(12), 1360-1371.
1.1BackgroundWe intend to further study the role of protein S (Pros) and growth arrest-specific gene 6 (Gas6), their mechanism of action and the possible therapeutic use of Pros/Gas6 agonists or antagonists in medically important -often lifethreatening- conditions such as bleeding, thrombosis and inflammation. Both Pros and Gas6 belong to the vitamin K-dependent protein family. Apart from a gamma-carboxyglutamic acid-domain interaction with phospholipid membranes, Pros and Gas6 also bind to the receptor tyrosine kinases Tyro3, Axl and Mer (or TAM receptors) by their carboxy-terminal globular domains. Pros is an important natural anticoagulant. This is evidenced by the fact that homozygous PROS1 deficiency promotes dramatic clinical manifestations including disseminated intravascular coagulation and purpura fulminans that, if untreated, are incompatible with life. Heterozygous patients deficient in PROS1 have an increased risk of thromboembolic events. Gas6 is redundant for normal homeostasis but critical for stress-responses. Therefore, inactivation of Gas6 does not cause life-threatening developmental defects, but modulates the severity of disease related phenotypes. We generated and studied different models of Pros1 deficient mice as well as Gas6 deficient mice bringing consistent insights into the role of Pros/Gas6 in hemostasis and inflammation. One important part of our pre-clinical studies of these last 3 years allowed us to demonstrate that targeting anticoagulant Pros is a valuable approach for hemophilia therapy. 1.2Specific aims(1) To further investigate the regulation of the hemostatic balance by Pros; (2) to study further the role of Pros/Gas6 in inflammation especially in its relationship with hemostasis/thrombosis and in anemia of chronic diseases, (3) to investigate patients with a defect in Gas6 or TAM receptors and develop Pros/Gas6 agonists or antagonists for therapy.1.3Project descriptionIn the first part of the project, we will use different approaches to circumvent the embryonically lethal phenotype of Pros1-/- mice. We will generate mice with total deficiency in Pros1 but expressing high levels of activated protein C (APChigh mice) or low tissue factor (TF) levels or no factor XI (F11) or XII (F12). The viability and prothrombic/bleeding phenotype of the latter mice will be investigated. Conditional Pros1 knockout mice will also allow us to specifically repress Pros expression in various tissues. The effect of this tissue-specific reduced expression on the APChigh, low TF as well as F11 or F12 deficiency phenotypes will be investigated. We would also study mice lacking both Pros1 and Tfpi to determine to which extent the double knockout phenotype differs from that of both single knockouts. Another interesting subject implying modifications of the hemostatic balance is the chronic liver diseases (CLD). We will therefore apply models of CLD to our transgenic mice. Better understanding the pathophysiology of hemostasis in CLD will allow us to propose diagnostic tests capable to predict bleeding/thrombosis in patients with this disease. In addition, such approach may allow us to identify therapeutic targets. The second part of the project will be dedicated to the continuation of the study of the role of Pros/Gas6 pathways in inflammation in relationship with hemostasis in conditions where histones and neutrophil extracellular traps (NETs) are also involved. Besides, we will further investigate the anemia of chronic diseases in this context and the potential role of Pros/Gas6 in iron metabolism.The third part of the project aims at identifying and study patients with defects in Gas6 and TAM receptors and to develop Pros/Gas6 agonists or antagonists for therapy.1.4Expected value of the proposed projectWe aim at a better understanding of Pros/Gas6 pathways in mechanisms of hemostasis, thrombosis and inflammation. Perspectives include clinical trials implying Pros/Gas6 agonists or antagonists to treat human diseases such as bleeding disorders, thrombosis or sepsis. More specifically, collaborative work with industry will be set up to go head and concretely evaluate Pros targeting for hemophilia treatment.