title: Inflammation induces hemorrhage in thrombocytopenia.
abstract: The role of platelets in hemostasis is to produce a plug to arrest bleeding. During thrombocytopenia, spontaneous bleeding is seen in some patients but not in others; the reason for this is unknown. Here, we subjected thrombocytopenic mice to models of dermatitis, stroke, and lung inflammation. The mice showed massive hemorrhage that was limited to the area of inflammation and was not observed in uninflamed thrombocytopenic mice. Endotoxin-induced lung inflammation during thrombocytopenia triggered substantial intra-alveolar hemorrhage leading to profound anemia and respiratory distress. By imaging the cutaneous Arthus reaction through a skin window, we observed in real time the loss of vascular integrity and the kinetics of skin hemorrhage in thrombocytopenic mice. Bleeding-observed mostly from venules-occurred as early as 20 minutes after challenge, pointing to a continuous need for platelets to maintain vascular integrity in inflamed microcirculation. Inflammatory hemorrhage was not seen in genetically engineered mice lacking major platelet adhesion receptors or their activators (alphaIIbbeta3, glycoprotein Ibalpha [GPIbalpha], GPVI, and calcium and diacylglycerol-regulated guanine nucleotide exchange factor I [CalDAG-GEFI]), thus indicating that firm platelet adhesion was not necessary for their supporting role. While platelets were previously shown to promote endothelial activation and recruitment of inflammatory cells, they also appear indispensable to maintain vascular integrity in inflamed tissue. Based on our observations, we propose that inflammation may cause life-threatening hemorrhage during thrombocytopenia.
authors.affiliation: Immune Disease Institute, Harvard Medical School, Boston, MA, USA.
authors.forename: Tobias
authors.initials: T
authors.lastname: Goerge
authors.forename: Benoit
authors.initials: B
authors.lastname: Ho-Tin-Noe
authors.forename: Carla
authors.initials: C
authors.lastname: Carbo
authors.forename: Charaf
authors.initials: C
authors.lastname: Benarafa
authors.forename: Eileen
authors.initials: E
authors.lastname: Remold-O'Donnell
authors.forename: Bing-Qiao
authors.initials: BQ
authors.lastname: Zhao
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Cifuni
authors.forename: Denisa D
authors.initials: DD
authors.lastname: Wagner
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000502:physiology; D002199:Capillary Permeability; D006470:Hemorrhage / Q000209:etiology*; D007249:Inflammation / Q000150:complications*; D051379:Mice; D010973:Platelet Adhesiveness; D013921:Thrombocytopenia / Q000150:complications* / Q000473:pathology