Advertisement

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

Rami Abu-Fanne, Victoria Stepanova, Rustem I. Litvinov, Suhair Abdeen, Khalil Bdeir, Mohamed Higazi, Emad Maraga, Chandrasekaran Nagaswami, Alexander R. Mukhitov, John W. Weisel, Douglas B. Cines and Abd Al-Roof Higazi

Key points

  • α-defensins accelerate fibrin polymerization, increase fiber density and branching and impede tPA-mediated fibrinolysis in vitro.

  • Transgenic mice expressing human α-defensin-1 developed larger and more occlusive venous clots resistant to heparin and fibrinolysis.

Abstract

Inflammation and thrombosis are integrated, mutually reinforcing processes, but the inter-regulatory 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 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 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 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.

  • Submitted July 3, 2018.
  • Accepted October 17, 2018.