Impaired DNase1-mediated degradation of neutrophil extracellular traps is associated with acute thrombotic microangiopathies
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Impaired DNase1-mediated degradation of neutrophil extracellular traps is associated with acute thrombotic microangiopathies. / 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.
In: J THROMB HAEMOST, Vol. 13, No. 5, 05.2015, p. 732-42.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Impaired DNase1-mediated degradation of neutrophil extracellular traps is associated with acute thrombotic microangiopathies
AU - Jiménez-Alcázar, M
AU - Napirei, M
AU - Panda, R
AU - Köhler, E C
AU - Kremer Hovinga, J A
AU - Mannherz, H G
AU - Peine, S
AU - Renné, T
AU - Lämmle, B
AU - Fuchs, T A
N1 - © 2014 International Society on Thrombosis and Haemostasis.
PY - 2015/5
Y1 - 2015/5
N2 - BACKGROUND: 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.OBJECTIVE: 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.METHODS AND RESULTS: We show that NETs generated in vitro 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.CONCLUSIONS: 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.
AB - BACKGROUND: 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.OBJECTIVE: 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.METHODS AND RESULTS: We show that NETs generated in vitro 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.CONCLUSIONS: 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.
KW - Deoxyribonuclease I
KW - Extracellular Traps
KW - Humans
KW - Hydrolysis
KW - Neutrophils
KW - Thrombotic Microangiopathies
U2 - 10.1111/jth.12796
DO - 10.1111/jth.12796
M3 - SCORING: Journal article
C2 - 25418346
VL - 13
SP - 732
EP - 742
JO - J THROMB HAEMOST
JF - J THROMB HAEMOST
SN - 1538-7933
IS - 5
ER -