TY - JOUR
T1 - Mechanisms of enhanced thrombus formation in cerebral microvessels of mice expressing hemoglobin-S
AU - Gavins, Felicity N E
AU - Russell, Janice
AU - Senchenkova, Elena L.
AU - De Almeida Paula, Lidiana
AU - Damazo, Amílcar S.
AU - Esmon, Charles T.
AU - Kirchhofer, Daniel
AU - Hebbel, Robert P.
AU - Granger, D. Neil
PY - 2011/4/14
Y1 - 2011/4/14
N2 - 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 (βs mice). Enhanced microvascular thrombosis in βs mice was blunted by immunologic or genetic interventions that target tissue factor, endothelial protein C receptor, activated protein C, or thrombin. Platelets from βs mice also exhibited enhanced aggregation velocity after stimulation with thrombin but not ADP. Neutropenia also protected against the enhanced thrombosis response in βs mice. These results indicate that the cerebral microvasculature is rendered vulnerable to thrombus formation in |5s mice via a neutrophil-dependent mechanism that is associated with an increased formation of and enhanced platelet sensitivity to thrombin.
AB - 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 (βs mice). Enhanced microvascular thrombosis in βs mice was blunted by immunologic or genetic interventions that target tissue factor, endothelial protein C receptor, activated protein C, or thrombin. Platelets from βs mice also exhibited enhanced aggregation velocity after stimulation with thrombin but not ADP. Neutropenia also protected against the enhanced thrombosis response in βs mice. These results indicate that the cerebral microvasculature is rendered vulnerable to thrombus formation in |5s mice via a neutrophil-dependent mechanism that is associated with an increased formation of and enhanced platelet sensitivity to thrombin.
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U2 - 10.1182/blood-2010-08-301366
DO - 10.1182/blood-2010-08-301366
M3 - Article
C2 - 21304105
AN - SCOPUS:79954620292
SN - 0006-4971
VL - 117
SP - 4125
EP - 4133
JO - Blood
JF - Blood
IS - 15
ER -