Impaired DNase1‐mediated degradation of neutrophil extracellular traps is associated with acute thrombotic microangiopathies. (13th April 2015)

• Record Type: Journal Article
• Authors: Jiménez‐Alcázar, M.; Napirei, M.; Panda, R.; Köhler, E. C.; Kremer Hovinga, J. A.; Mannherz, H. G.; Peine, S.; Renné, T.; Lämmle, B.; Fuchs, T. A.
• Is Part Of: Journal of thrombosis and haemostasis. Volume 13:Number 5(2015:May)
• Page Start: 732
• Page End: 742
• Publication Date: 2015-04-13
• Subjects: Thrombosis -- Periodicals; Hemostasis -- Periodicals; Blood coagulation disorders -- Periodicals; 616.1
• DOI: 10.1111/jth.12796
• Languages: English
• ISSNs: 1538-7933

Abstract

<abstract abstract-type="main" id="jth12796-abs-0001"> <title>Summary</title> <sec id="jth12796-sec-0001" sec-type="section"> <title>Background</title> <p>Acute thrombotic microangiopathies (TMAs) are characterized by excessive microvascular thrombosis and are associated with markers of neutrophil extracellular traps (NETs) in plasma. NETs are composed of DNA fibers and promote thrombus formation through the activation of platelets and clotting factors.</p> </sec> <sec id="jth12796-sec-0002" sec-type="section"> <title>Objective</title> <p>The efficient removal of NETs may be required to prevent excessive thrombosis such as in TMAs. To test this hypothesis, we investigated whether TMAs are associated with a defect in the degradation of NETs.</p> </sec> <sec id="jth12796-sec-0003" sec-type="section"> <title>Methods and Results</title> <p>We show that NETs generated <italic>in vitro</italic> were efficiently degraded by plasma from healthy donors. However, NETs remained stable after exposure to plasma from TMA patients. The inability to degrade NETs was linked to a reduced DNase activity in TMA plasma. Plasma DNase1 was required for efficient NET degradation and TMA plasma showed decreased levels of this enzyme. Supplementation of TMA plasma with recombinant human DNase1 restored NET‐degradation activity.</p> </sec> <sec id="jth12796-sec-0004" sec-type="section"> <title>Conclusions</title> <p>Our data indicate that DNase1‐mediated degradation of NETs is impaired in patients with TMAs. The role of plasma DNases in thrombosis is, as of yet, poorly understood. Reduced plasma DNase1 activity may cause the persistence of pro‐thrombotic NETs and thus promote microvascular thrombosis in TMA patients.</p> </sec> </abstract>