An Unexpected Villain in Venous Thromboembolism?
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Venous thromboembolism (VTE), encompassing deep vein thrombosis and pulmonary embolism, is a major clinical problem, and its pharmacological prevention incurs a high cost to healthcare systems. With an annual incidence of 1 to 2 per 1000 person-years, it affects ≤600 000 individuals per year in the United States alone and carries a substantial case fatality of 10% to 30% at 1 month.1 Despite well-documented risk factors, the pathogenesis of VTE remains incompletely understood. Historically, it is thought to result from a combination of Virchow’s triad, namely, vascular wall injury, flow stasis, and hypercoagulability. Although this serves as a useful conceptual framework and led to the development of preventative strategies and therapeutics, significant side effects (bleeding rate of ≤8%)2 remain a major clinical problem and call for a better understanding of the pathophysiology of VTE. Ponomaryov et al3 now report on a potential new cellular player of this disease.
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Over the last decade, the importance of inflammation in venous thrombosis has been increasingly appreciated. It was found that neutrophils release neutrophil extracellular traps, a lattice of DNA, histone, and proteins (eg, elastase, myeloperoxidase, and cathepsin G), that function as a scaffold to facilitate the interactions between platelets, von Willebrand factor, and coagulation factors (Figure).4 Individual components of neutrophil extracellular traps can also promote thrombosis. For example, serine proteases including neutrophil elastase inactivate tissue factor pathway inhibitor and extracellular histones promote the generation of thrombin (Figure).5 Importantly, these experimental studies were corroborated with clinical data. Indeed, neutrophil extracellular traps were found in the organizing phase of human venous thrombi,6 and elevated levels of circulating nucleosomes and markers of neutrophil activation were associated with an increased risk of deep vein thrombosis.7 Similarly, experimental studies have shown that …