A. Brill

Asaga

Becattini

Brighton

Brill

Brinkmann

D. D. Wagner

Hemmers

Hirahashi

J. Hu

K. Martinod

Leshner

M. Demers

M. Gallant

Massberg

Pinsky

Raskob

Rohrbach

S. L. Wong

Saffarzadeh

T. A. Fuchs

Thevenaz

Urban

Vossenaar

Wakefield

Y. Wang

Yipp


            Deep vein thrombosis and pulmonary embolism are major health problems associated with high mortality. Recently, DNA-based neutrophil extracellular traps (NETs) resulting from the release of decondensed chromatin, were found to be part of the thrombus scaffold and to promote coagulation. However, the significance of nuclear decondensation and NET generation in thrombosis is largely unknown. To address this, we adopted a stenosis model of deep vein thrombosis and analyzed venous thrombi in peptidylarginine deiminase 4 (PAD4)-deficient mice that cannot citrullinate histones, a process required for chromatin decondensation and NET formation. Intriguingly, less than 10% of
            
              PAD4
              −/−
            
            mice produced a thrombus 48 h after inferior vena cava stenosis whereas 90% of wild-type mice did. Neutrophils were abundantly present in thrombi formed in both groups, whereas extracellular citrullinated histones were seen only in thrombi from wild-type mice. Bone marrow chimera experiments indicated that PAD4 in hematopoietic cells was the source of the prothrombotic effect in deep vein thrombosis. Thrombosis could be rescued by infusion of wild-type neutrophils, suggesting that neutrophil PAD4 was important and sufficient. Endothelial activation and platelet aggregation were normal in
            
              PAD4
              −/−
            
            mice, as was hemostatic potential determined by bleeding time and platelet plug formation after venous injury. Our results show that PAD4-mediated chromatin decondensation in the neutrophil is crucial for pathological venous thrombosis and present neutrophil activation and PAD4 as potential drug targets for deep vein thrombosis.
          </jats:p

Kimberly Martinod

Melanie Demers

Tobias A. Fuchs

Siu Ling Wong

Alexander Brill

Maureen Gallant

Jing Hu

Yanming Wang

Denisa D. Wagner

Crossref

Proceedings of the National Academy of Sciences

Neutrophil histone modification by peptidylarginine deiminase 4 is critical for deep vein thrombosis in mice

Neutrophil histone modification by peptidylarginine deiminase 4 is critical for deep vein thrombosis in mice

Abstract

Similar works

Full text

Available Versions

Crossref