Platelet secretion is crucial to prevent bleeding in the ischemic brain but not in the inflamed skin or lung in mice

TY - JOUR

T1 - Platelet secretion is crucial to prevent bleeding in the ischemic brain but not in the inflamed skin or lung in mice

AU - Deppermann, Carsten

AU - Kraft, Peter

AU - Volz, Julia

AU - Schuhmann, Michael K

AU - Beck, Sarah

AU - Wolf, Karen

AU - Stegner, David

AU - Stoll, Guido

AU - Nieswandt, Bernhard

N1 - © 2017 by The American Society of Hematology.

PY - 2017/3/23

Y1 - 2017/3/23

N2 - Platelets maintain hemostasis after injury, but also during inflammation. Recent studies have shown that platelets prevent inflammatory bleeding through (hem) immunoreceptor tyrosine-based activation motif-dependent mechanisms irrespective of aggregation during skin and lung inflammation. Although the exact mechanisms underlying this process remain unknown, it was speculated that mediators released from platelet granules might be involved. Maintaining cerebral hemostasis during stroke treatment is of high clinical relevance because hemorrhage may aggravate the disease state and increase mortality. Although it was shown that platelets help maintain hemostasis in the ischemic brain, their exact contribution remains ill defined. Here we show that Unc13d -/- /Nbeal2 -/- mice, which lack platelet α- and dense-granule secretion, show no signs of hemorrhage in models of skin or lung inflammation. In stark contrast, lack of platelet granule release resulted in impaired hemostasis in the ischemic brain after transient middle cerebral artery occlusion leading to increased intracranial hemorrhage and mortality. Our results reveal for the first time that platelet granule constituents are essential for maintenance of hemostasis during thrombo-inflammatory brain infarction but not experimental inflammation of the skin or lung, thereby uncovering vascular bed-specific differences in the prevention of inflammatory bleeding.

AB - Platelets maintain hemostasis after injury, but also during inflammation. Recent studies have shown that platelets prevent inflammatory bleeding through (hem) immunoreceptor tyrosine-based activation motif-dependent mechanisms irrespective of aggregation during skin and lung inflammation. Although the exact mechanisms underlying this process remain unknown, it was speculated that mediators released from platelet granules might be involved. Maintaining cerebral hemostasis during stroke treatment is of high clinical relevance because hemorrhage may aggravate the disease state and increase mortality. Although it was shown that platelets help maintain hemostasis in the ischemic brain, their exact contribution remains ill defined. Here we show that Unc13d -/- /Nbeal2 -/- mice, which lack platelet α- and dense-granule secretion, show no signs of hemorrhage in models of skin or lung inflammation. In stark contrast, lack of platelet granule release resulted in impaired hemostasis in the ischemic brain after transient middle cerebral artery occlusion leading to increased intracranial hemorrhage and mortality. Our results reveal for the first time that platelet granule constituents are essential for maintenance of hemostasis during thrombo-inflammatory brain infarction but not experimental inflammation of the skin or lung, thereby uncovering vascular bed-specific differences in the prevention of inflammatory bleeding.

KW - Animals

KW - Blood Platelets/metabolism

KW - Brain Ischemia/blood

KW - Cerebral Hemorrhage/blood

KW - Hemorrhage/pathology

KW - Hemostasis

KW - Infarction, Middle Cerebral Artery

KW - Inflammation/blood

KW - Lung/pathology

KW - Mice

KW - Secretory Vesicles/physiology

KW - Skin/pathology

U2 - 10.1182/blood-2016-12-750711

DO - 10.1182/blood-2016-12-750711

M3 - SCORING: Journal article

C2 - 28077416

VL - 129

SP - 1702

EP - 1706

JO - BLOOD

JF - BLOOD

SN - 0006-4971

IS - 12

ER -