The role of NETs and thrombosis in different disease states
The therapeutic potential of inhibiting NETs in various pathological conditions is elucidated in a scientific discourse by Dr Martinod. Dr Martinod’s research primarily delves into the PAD4 molecule’s involvement in the early stages of NET formation, offering a promising target for drug intervention. These drugs, currently undergoing preclinical development through in vitro and animal studies, aim to modulate the activity of the PAD4 enzyme.
Citrullinated histones, a byproduct of PAD4 enzymatic activity, emerge as a potential biomarker, exhibiting elevated levels in several thrombotic diseases. The anticipation surrounding the imminent future stems from the prospective impact of inhibiting NETs.
Dr Martinod’s investigation encompasses a comprehensive examination of NETs’ binding targets in thrombosis, including activated platelets, various coagulation factors, red blood cells, and the scaffold of thrombus growth. Notably, the study utilizing genetically modified mice lacking the PAD4 enzyme reveals a diminished thrombus formation, elucidating the enzyme’s pivotal role.
While NETs play a crucial role in neutralizing bacteria, their potential impact on infections warrants investigation. Notably, in a mouse model of endocarditis, where infected blood clots at the heart valve are mimicked, the role of NETs in either promoting thrombosis or combating infection is explored. Surprisingly, targeting NETs showed no discernible effect. Further scrutiny revealed that coagulation of Staphylococcus aureus bacteria formed a fibrin barrier, hindering neutrophils’ entry for releasing NETs. Genetic mutation preventing this staphylocoagulation underscored the importance of NETs in fighting bacterial infection, implicating the bacteria in thrombosis.
Future endeavors involve evaluating the efficacy of NET formation inhibitors in human diseases, and transitioning candidate drugs from preclinical stages to clinical studies. A deeper comprehension of the conditions and contributing factors that elevate NET levels to a prothrombotic extent may provide valuable insights for identifying patients suitable for targeted NET inhibition.
Reference:
Martinod K. NETs and Thrombosis in Different Disease States
With the educational support of:
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