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Neutrophil α-defensins promote thrombosis in vivo by altering fibrin formation, structure, and stability.

Authors
  • Abu-Fanne, Rami1
  • Stepanova, Victoria2
  • Litvinov, Rustem I3, 4
  • Abdeen, Suhair1
  • Bdeir, Khalil2
  • Higazi, Mohamed1
  • Maraga, Emad1
  • Nagaswami, Chandrasekaran3
  • Mukhitov, Alexander R3
  • Weisel, John W3
  • Cines, Douglas B2
  • Higazi, Abd Al-Roof1, 2
  • 1 Department of Clinical Biochemistry, Hadassah-Hebrew University, Jerusalem, Israel. , (Israel)
  • 2 Department of Pathology and Laboratory Medicine and.
  • 3 Department of Cell and Developmental Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA; and.
  • 4 Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Russia.
Type
Published Article
Journal
Blood
Publisher
American Society of Hematology
Publication Date
Jan 31, 2019
Volume
133
Issue
5
Pages
481–493
Identifiers
DOI: 10.1182/blood-2018-07-861237
PMID: 30442678
Source
Medline
Language
English
License
Unknown

Abstract

Inflammation and thrombosis are integrated, mutually reinforcing processes, but the interregulatory mechanisms are incompletely defined. Here, we examined the contribution of α-defensins (α-defs), antimicrobial proteins released from activated human neutrophils, on clot formation in vitro and in vivo. Activation of the intrinsic pathway of coagulation stimulates release of α-defs from neutrophils. α-Defs accelerate fibrin polymerization, increase fiber density and branching, incorporate into nascent fibrin clots, and impede fibrinolysis in vitro. Transgenic mice (Def++) expressing human α-Def-1 developed larger, occlusive, neutrophil-rich clots after partial inferior vena cava (IVC) ligation than those that formed in wild-type (WT) mice. IVC thrombi extracted from Def++ mice were composed of a fibrin meshwork that was denser and contained a higher proportion of tightly packed compressed polyhedral erythrocytes than those that developed in WT mice. Def++ mice were resistant to thromboprophylaxis with heparin. Inhibiting activation of the intrinsic pathway of coagulation, bone marrow transplantation from WT mice or provision of colchicine to Def++ mice to inhibit neutrophil degranulation decreased plasma levels of α-defs, caused a phenotypic reversion characterized by smaller thrombi comparable to those formed in WT mice, and restored responsiveness to heparin. These data identify α-defs as a potentially important and tractable link between innate immunity and thrombosis. © 2019 by The American Society of Hematology.

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