Impaired DNase1‐mediated degradation of neutrophil extracellular traps is associated with acute thrombotic microangiopathies

Jiménez-Alcázar, Miguel; Napirei, Markus; Panda, Rachita; Köhler, Elodie C.; Hovinga, Johanna A. Kremer; Mannherz, Hans Georg; Peine, Sven; Renné, Thomas; Lämmle, Bernhard; Fuchs, Tobias A.

doi:10.1111/jth.12796

Cited by 120 publications

(100 citation statements)

References 52 publications

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“…These observations in combination with recent reports of a decreased degradation of neutrophil extracellular traps (NETs) in TMA [10] and increased formation of NETs [11] have suggested a role for NETs in thrombotic microangiopathic disorders. NETs consist of decondensed chromatin covered with antimicrobial proteins/peptides and are released from mainly activated neutrophils in a ROS/NADPH-dependent manner [12,13] .…”

Section: Introductionsupporting

confidence: 57%

Decreased Neutrophil Extracellular Trap Degradation in Shiga Toxin-Associated Haemolytic Uraemic Syndrome

et al. 2016

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Background: Neutrophil extracellular traps (NETs) can stimulate thrombosis, and their degradation is decreased in several autoimmune disorders. It was recently reported that some patients with haemolytic uraemic syndrome (HUS) also fail to degrade NETs and that neutrophils from Shiga toxin-associated HUS are primed to form NETs. Method: We used a well-characterized cohort of 74 thrombotic microangiopathy (TMA) patients, with a subset also providing follow-up samples, and 112 age-matched controls to investigate NET degradation and serum nuclease activity in TMA before, during and after treatment. Results: We identified that in the cohort of TMA patients, 50% of patients with Shiga toxin-associated HUS displayed a decreased ability to degrade NETs. NET degradation correlated with serum nuclease activity, but not with autoantibodies against double-stranded DNA, which has been previously observed in some autoimmune disorders. Further, NET degradation negatively correlated with serum creatinine levels, suggesting that kidney function was negatively impacted by the low NET degradation ability. Conclusions: We revealed that decreased NET degradation is a common feature of Shiga toxin-associated HUS and that it is associated with decreased kidney function in these patients. It remains to be clarified whether improving NET degradation would be beneficial for the patient.

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Section: Introductionsupporting

confidence: 57%

Decreased Neutrophil Extracellular Trap Degradation in Shiga Toxin-Associated Haemolytic Uraemic Syndrome

et al. 2016

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“…123,124 Leukocytes contribute to microvascular thrombosis and disseminated intravascular coagulation (DIC) Microvascular thrombosis involves the development of thrombi in the venules, arterioles, and capillaries. Individuals with thrombotic microangiopathies arising from non-infectious etiologies display evidence of elevated NET markers 125 and impaired DNAse function 126 that may contribute to the acute phase of these disorders. In healthy animals, microvascular thrombosis is evaluated most frequently using chemical or laser-induced endothelial injury models of the cremaster and mesenteric arterioles.…”

Section: Leukocytes Contribute To Arterial Thrombosismentioning

confidence: 99%

The role of leukocytes in thrombosis

Swystun

Liaw

2016

Blood

241

184

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In recent years, the traditional view of the hemostatic system as being regulated by a coagulation factor cascade coupled with platelet activation has been increasingly challenged by new evidence that activation of the immune system strongly influences blood coagulation and pathological thrombus formation. Leukocytes can be induced to express tissue factor and release proinflammatory and procoagulant molecules such as granular enzymes, cytokines, and damage-associated molecular patterns. These mediators can influence all aspects of thrombus formation, including platelet activation and adhesion, and activation of the intrinsic and extrinsic coagulation pathways. Leukocyte-released procoagulant mediators increase systemic thrombogenicity, and leukocytes are actively recruited to the site of thrombus formation through interactions with platelets and endothelial cell adhesion molecules. Additionally, phagocytic leukocytes are involved in fibrinolysis and thrombus resolution, and can regulate clearance of platelets and coagulation factors. Dysregulated activation of leukocyte innate immune functions thus plays a role in pathological thrombus formation. Modulation of the interactions between leukocytes or leukocyte-derived procoagulant materials and the traditional hemostatic system is an attractive target for the development of novel antithrombotic strategies.

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“…3 In at least 1 study, a deficiency in DNAase1 activity in patients presenting with a TMA was responsible for the impaired degradation of NETs. 4 Neutrophils also release nucleosomes during inflammation. The DNA and histones contained on nucleosomes are also prothrombotic, inducing fibrin deposition, platelet aggregation, and adhesion.…”

Section: Tma In the Critically Ill Patient Pathogenesismentioning

confidence: 99%

None of the above: thrombotic microangiopathy beyond TTP and HUS

Masias

Vasu

Cataland

2017

Blood

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Acquired thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS) are appropriately at the top of a clinician’s differential when a patient presents with a clinical picture consistent with an acute thrombotic microangiopathy (TMA). However, there are several additional diagnoses that should be considered in patients presenting with an acute TMA, especially in patients with nondeficient ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) activity (>10%). An increased awareness of drug-induced TMA is also essential because the key to their diagnosis more often is an appropriately detailed medical history to inquire about potential exposures. Widespread inflammation and endothelial damage are central in the pathogenesis of the TMA, with the treatment directed at the underlying disease if possible. TMA presentations in the critically ill, drug-induced TMA, cancer-associated TMA, and hematopoietic transplant–associated TMA (TA-TMA) and their specific treatment, where applicable, will be discussed in this manuscript. A complete assessment of all the potential etiologies for the TMA findings including acquired TTP will allow for a more accurate diagnosis and prevent prolonged or inappropriate treatment with plasma exchange therapy when it is less likely to be successful.

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Impaired DNase1‐mediated degradation of neutrophil extracellular traps is associated with acute thrombotic microangiopathies

Cited by 120 publications

References 52 publications

Decreased Neutrophil Extracellular Trap Degradation in Shiga Toxin-Associated Haemolytic Uraemic Syndrome

Decreased Neutrophil Extracellular Trap Degradation in Shiga Toxin-Associated Haemolytic Uraemic Syndrome

The role of leukocytes in thrombosis

None of the above: thrombotic microangiopathy beyond TTP and HUS

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