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Blood, 1 April 2007, Vol. 109, No. 7, pp. 2832-2839.
Prepublished online as a Blood First Edition Paper on December 5, 2006; DOI 10.1182/blood-2006-06-032524.
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Submitted June 29, 2006
Accepted November 13, 2006
Adenovirus-induced thrombocytopenia: The role of von Willebrand factor and P-selectin in mediating accelerated platelet clearance
Maha Othman, Andrea Labelle, Ian Mazzetti, Hisham S. Elbatarny, and David Lillicrap*
Dept of Pathology & Molecular Medicine, Queen's University, Kingston, Canada
Dept of Pharmacology & Toxicology, Queen's University, Kingston, Canada
* Corresponding author; email: lillicrap{at}cliff.path.queensu.ca.
Thrombocytopenia has been consistently reported following the administration of adenoviral gene transfer vectors. The mechanism underlying this phenomenon is currently unknown. In this study, we have assessed the influence of von Willebrand Factor (VWF) and P-selectin on the clearance of platelets following adenovirus administration. In mice, thrombocytopenia occurs between 5 and 24 hours after adenovirus delivery. The virus activates platelets and induces platelet-leukocyte aggregate formation. There is an associated increase in platelet and leukocyte-derived microparticles. Adenovirus-induced endothelial cell activation was shown by VCAM-1 expression on virus-treated, cultured endothelial cells and by the release of ultra-large molecular weight multimers of VWF within 1-2 hours of virus administration with an accompanying elevation of endothelial microparticles. In contrast, VWF KO mice did not show significant thrombocytopenia post-adenovirus administration. We have also shown that adenovirus interferes with adhesion of platelets to a fibronectin-coated surface and flow cytometry revealed the presence of the CAR receptor on the platelet surface. We conclude that VWF and P-selectin are critically involved in a complex platelet-leukocyte-endothelial interplay, resulting in platelet activation and accelerated platelet clearance following adenovirus administration.
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