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Blood, 15 May 2008, Vol. 111, No. 10, pp. 4958-4964.
Prepublished online as a Blood First Edition Paper on February 6, 2008; DOI 10.1182/blood-2007-11-123620.
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Submitted November 13, 2007
Accepted January 17, 2008
Inflammation induces hemorrhage in thrombocytopenia
Tobias Goerge, Benoit Ho-Tin-Noe, Carla Carbo, Charaf Benarafa, Eileen Remold-O'Donnell, Bing-Qiao Zhao, Stephen M Cifuni, and Denisa D. Wagner*
Immune Disease Institute, Boston, MA, United States
Department of Pathology, Harvard Medical School, Boston, MA, United States
Servei d'Hemoterapia-Hemostasia, Hospital Clinic, Universitat de Barcelona, Barcelona, Spain
Department of Pediatrics, Harvard Medical School, Boston, MA, United States
* Corresponding author; email: wagner{at}cbr.med.harvard.edu.
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 intraalveolar 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 – mostly observed 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 ( IIb 3, GPIb, GPVI, and 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.
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