Neutrophil α-defensins promote thrombosis in vivo by altering fibrin formation, structure, and stability
| Autor: | Chandrasekaran Nagaswami, Khalil Bdeir, Alexander R. Mukhitov, Mohamed Higazi, Abd Al-Roof Higazi, Emad Maraga, John W. Weisel, Rustem I. Litvinov, Suhair Abdeen, Rami Abu-Fanne, Douglas B. Cines, Victoria Stepanova |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
medicine.medical_treatment Immunology Inflammation 030204 cardiovascular system & hematology Biochemistry Inferior vena cava Fibrin 03 medical and health sciences 0302 clinical medicine In vivo Fibrinolysis medicine biology Chemistry Cell Biology Hematology Heparin Cell biology 030104 developmental biology medicine.vein Coagulation Neutrophil degranulation biology.protein medicine.symptom medicine.drug |
| Zdroj: | Blood. 133:481-493 |
| ISSN: | 1528-0020 0006-4971 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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