Adenoviral vectors do not induce, inhibit, or potentiate human platelet aggregation.
Adenoviruses are commonly used as vectors in human clinical gene therapy trials. High doses of intravenous adenovirus vectors have been associated with development of thrombocytopenia of undetermined origin. Viral internalization requires the presence cell surface integrins, alpha(v)beta(3) or alpha(v)beta(5), that can blind ligands with a arginine-glycine-aspartic acid (RGD) sequence. This sequence is found in the adenovirus penton base. Platelets express the alpha(v)beta(3) integrin and other integrins that bind the RGD sequence of ligands such as fibrinogen, laminin, vitronectin, and von Willebrand factor (vWF). Platelet aggregation is mediated, in part, by the binding of the RGD sequence of fibrinogen to a platelet surface integrin, glycoprotein IIb/IIIa (GP IIb/IIIa). We investigated whether adenovirus particles could interfere with or potentiate agonist-induced platelet aggregation. Incubation of platelet-rich plasma with adenovirus under stirred conditions did not promote spontaneous aggregation. The addition of physiological platelet agonists, ADP, collagen, or epinephrine, induced platelet aggregation. However, the presence of adenovirus in a wide range of concentrations did not inhibit or potentiate agonist-induced aggregation. These results suggest that the adenovirus-associated thrombocytopenia observed in vivo is independent of a direct effect of the virus on platelet aggregation.
Eggerman
Thomas L
TL
Division of Cellular and Gene Therapy, Office of Therapeutics Research and Review, FDA, Bethesda, MD 20892, USA.
Mondoro
Traci Heath
TH
Lozier
Jay N
JN
Vostal
Jaroslav G
JG
D000244:Adenosine Diphosphate / Q000494:pharmacology; D000260:Adenoviruses, Human / Q000235:genetics*; D000322:Adrenergic Agonists / Q000494:pharmacology; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D003094:Collagen / Q000494:pharmacology; D004837:Epinephrine / Q000494:pharmacology; D005164:Factor IX / Q000378:metabolism; D005822:Genetic Vectors / Q000494:pharmacology*; D006801:Humans; D016023:Integrins / Q000378:metabolism; D010974:Platelet Aggregation / Q000187:drug effects* / Q000502:physiology
D000322:Adrenergic Agonists; D016023:Integrins; D000244:Adenosine Diphosphate; D005164:Factor IX; D003094:Collagen; D004837:Epinephrine