Sepsis-associated Microthrombus Formation: Processing and Secretion of von-Willebrand Factor Cleaving Protease
Acronym: ADAMTS13
Principal Investigator: Michael Ekaney
Scientific Advisor: PD Dr. RA Claus
Research Area: D Sepsis related Organ Failure
Project Number: D1.9
Duration: 01.05.2011 - 30.04.2014
Module: PhD Fellowship
The Problem
Reduced ADAMTS13 is a hallmark of sepsis-associated coagulopathy with increased ULVWF-platelet aggregation and deposition of microthrombi. In this project, we investigate events of endothelial dysfunction affecting ADAMTS13 synthesis and activity in septic conditions.
Results so far
We hypothesized that extracellular histones released during sepsis are triggers of endothelial dysfunction. In a clinical setting, we have shown that histones are significantly elevated through out the course of sepsis and are found associated with thrombocytopenia and renal dysfunction. Patients who received APC treatment showed a decrease in histone levels. In a cell specific approach, we observed a dose dependent decrease in cell viability after histone stimulation and APC conciliated effects. LDH release was also dose dependently increased. Real-time Impedance response of HMEC-1 cells after stimulation with histones decreased and APC non-responsive to this effect. We also found that ADAMTS13 transcription markedly declined after 24h in the presence of proinflammatory cytokines, LPS and septic serum while septic patients who received APC showed an increase in ADAMTS13 activity.
Contact
Tel. +49 (0)3641 - 9 32 58 60
Universitätsklinikum Jena
AG Molekulare Mechanismen des Organversagens
Forschungszentrum Lobeda
Erlanger Allee 101
07747 Jena