title: Mechanisms of enhanced thrombus formation in cerebral microvessels of mice expressing hemoglobin-S.
abstract: The microvasculature assumes an inflammatory and procoagulant state in a variety of different diseases, including sickle cell disease (SCD), which may contribute to the high incidence of ischemic stroke in these patients. This study provides evidence for accelerated thrombus formation in arterioles and venules in the cerebral vasculature of mice that express hemoglobin-S (β(s) mice). Enhanced microvascular thrombosis in β(s) mice was blunted by immunologic or genetic interventions that target tissue factor, endothelial protein C receptor, activated protein C, or thrombin. Platelets from β(s) mice also exhibited enhanced aggregation velocity after stimulation with thrombin but not ADP. Neutropenia also protected against the enhanced thrombosis response in β(s) mice. These results indicate that the cerebral microvasculature is rendered vulnerable to thrombus formation in β(s) mice via a neutrophil-dependent mechanism that is associated with an increased formation of and enhanced platelet sensitivity to thrombin.
authors.affiliation: Wolfson Neuroscience Laboratories, Faculty of Medicine, Imperial College, London, UK. f.gavins@imperial.ac.uk
authors.forename: Felicity N E
authors.initials: FN
authors.lastname: Gavins
authors.forename: Janice
authors.initials: J
authors.lastname: Russell
authors.forename: Elena L
authors.initials: EL
authors.lastname: Senchenkova
authors.forename: Lidiana
authors.initials: L
authors.lastname: De Almeida Paula
authors.forename: Amílcar S
authors.initials: AS
authors.lastname: Damazo
authors.forename: Charles T
authors.initials: CT
authors.lastname: Esmon
authors.forename: Daniel
authors.initials: D
authors.lastname: Kirchhofer
authors.forename: Robert P
authors.initials: RP
authors.lastname: Hebbel
authors.forename: D Neil
authors.initials: DN
authors.lastname: Granger
mesh_terms: D000755:Anemia, Sickle Cell / Q000150:complications / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001792:Blood Platelets / Q000378:metabolism; D016026:Bone Marrow Transplantation; D002536:Cerebral Arteries / Q000378:metabolism*; D004195:Disease Models, Animal; D006451:Hemoglobin, Sickle / Q000235:genetics / Q000378:metabolism*; D020767:Intracranial Thrombosis / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008817:Mice, Mutant Strains; D008833:Microcirculation / Q000502:physiology*; D009504:Neutrophils / Q000378:metabolism; D010974:Platelet Aggregation / Q000502:physiology; D011486:Protein C / Q000378:metabolism; D013917:Thrombin / Q000378:metabolism; D013925:Thromboplastin / Q000378:metabolism
chemical_list: D006451:Hemoglobin, Sickle; D011486:Protein C; D013925:Thromboplastin; D013917:Thrombin