Fatal Hemostatic Complications in Artificial Lungs: From Understanding to Prevention - Understanding of Shear-Induced Clotting Mechanisms for Prevention of Thrombosis

• Applicants: Professor Dr.-Ing. Lars Krenkel; Professorin Dr. Karla Lehle; Privatdozent Dr. Thomas Müller
• Subject Area: Medical Physics, Biomedical Technology ; Biomaterials ; Immunology ; Fluid Mechanics
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 447721607

Background: Artificial lungs (extracorporeal and future implantable) have a common problem – significant thromboembolic effects and a high risk of bleeding complications. Long-term use and implantation is currently impossible. In this project we will analyze current extracorporeal membrane oxygenation (ECMO) systems to get a fundamental understanding of the biological responses caused after blood contact with artificial surfaces and due to non-physiological or adverse flow-patterns within the devices (pump head and oxygenator). Objectives: Extensive detailed clinical data from the EMCO database of our certified ECMO center in Regensburg should be used to show the influence of different systems and regimes (VA vs VV) on the development of thrombocytopenia, bleeding or thrombus formation and coagulation disorders. We postulate that platelets as well as inflammatory cells (especially neutrophils) are responsible for serious hemostatic complications that cause thrombus formation in the oxygenator. We therefore want to analyze the cell-cell interactions and cellular functions in the thrombi in order to identify new biomarkers for the early prediction of system failures. Indicators of shear stress-induced thrombus formation are the elongated von Willebrand factor (vWF), accumulated/activated platelets and leukocytes, and NET formation (neutrophil extracellular traps). NETs are extracellular DNA networks that are released by activated neutrophils in the course of a cell death program (NETose) and can initiate thrombosis via platelet binding. The localization and the histological examination of the thrombi in the pump heads should make it possible to identify high local shear forces and to correlate them with the thrombus characteristics. A spatially high-resolution micro-CT system is used to locate thrombi in the oxygenators. The additional identification of non-physiological flow conditions within the "bioincompatible" system will enable a correlation with the cellular reactions. Finally, proposals for an optimized system design in combination with the introduction of therapeutic options based on the new knowledge of cellular interactions to maintain the hemostaseological balance are developed. Knowledge gain: We expect new knowledge on the role of platelets and neutrophils in combination with e.g. vWF and activated platelets in the development of clots. Specific components in organized or growing clots may bring new insights into the clinical development and pathology of thrombosis and provides new perspectives for therapeutic advances in the future. The knowledge about the real flow dynamics within the native/used oxygenators, the elucidation of cellular responses after contact with the oxygenator, and the localization of the clots within high or low flow regions of the oxygenator will allow the definition of new designs of the device and new therapeutic strategies towards an implantable artificial lung.

• DFG Programme: Priority Programmes
• Subproject of: SPP 2014: Towards an Implantable Lung