| First Author | Abu-Fanne R | Year | 2019 |
| Journal | Blood | Volume | 133 |
| Issue | 5 | Pages | 481-493 |
| PubMed ID | 30442678 | Mgi Jnum | J:273062 |
| Mgi Id | MGI:6284913 | Doi | 10.1182/blood-2018-07-861237 |
| Citation | Abu-Fanne R, et al. (2019) Neutrophil alpha-defensins promote thrombosis in vivo by altering fibrin formation, structure, and stability. Blood 133(5):481-493 |
| abstractText | Inflammation and thrombosis are integrated, mutually reinforcing processes, but the interregulatory mechanisms are incompletely defined. Here, we examined the contribution of alpha-defensins (alpha-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 alpha-defs from neutrophils. alpha-Defs accelerate fibrin polymerization, increase fiber density and branching, incorporate into nascent fibrin clots, and impede fibrinolysis in vitro. Transgenic mice (Def(++)) expressing human alpha-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 alpha-defs, caused a phenotypic reversion characterized by smaller thrombi comparable to those formed in WT mice, and restored responsiveness to heparin. These data identify alpha-defs as a potentially important and tractable link between innate immunity and thrombosis. |
