An absence of platelet activation following thalidomide treatment in vitro or in vivo
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Jianlin Qiao1,2,3,*, Yulu Wu1,*, Xiaoqing Wu1,*, Yun Liu1, Xiaoqian Li2, Wen Ju1,2,3, Kunming Qi2, Depeng Li2, Elizabeth E. Gardiner4, Robert K. Andrews5, Lingyu Zeng1,3, Kailin Xu1,2,3
1Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China
2Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
3Key Laboratory of Bone Marrow Stem Cell, Jiangsu Province, Xuzhou, China
4Department of Cancer Biology and Therapeutics, John Curtin School of Medical Research, Australian National University, Canberra, Australia
5Australian Centre for Blood Diseases, Monash University, Melbourne, Australia
*These authors contributed equally to this work
Kailin Xu, email: firstname.lastname@example.org
Lingyu Zeng, email: email@example.com
Keywords: thalidomide, platelet activation, blood coagulation, thrombosis, multiple myeloma
Received: January 20, 2017 Accepted: March 01, 2017 Published: March 15, 2017
Increased risk of thromboembolism and platelet hyperreactivity has been reported in patients receiving thalidomide therapy. Whether thalidomide induces platelet activation directly or through other factors remains unclear. The aim of this study was to evaluate the effect of thalidomide on platelet activation under resting conditions in vitro and in vivo. Isolated human or mouse platelets were treated with different concentrations of thalidomide (10, 50 and 100 μg/ml) for 60 min at 37°C followed by analysis of platelet surface expression of platelet receptors GPIbα, GPVI, αIIbβ3 and P-selectin, and PAC-1 or fibrinogen binding, by flow cytometry and collagen- or ADP-induced platelet aggregation. In addition, thalidomide (200 mg/kg) was intraperitoneally injected into mice for analysis of the effect of thalidomide on platelet activation in vivo. No increased expression of P-selectin, PAC-1 or fibrinogen binding was observed in either human and mouse platelets after thalidomide treatment in vitro for 60 min at 37oC. Thalidomide treatment also did not affect expression of GPIbα, GPVI or αIIbβ3, nor did it affect collagen- or ADP-induced platelet aggregation at threshold concentrations. However, while mice injected with thalidomide displayed no increased surface expression of platelet P-selectin or αIIbβ3, there was a significantly shortened tail bleeding time, thrombin time, prothrombin time together with higher levels of Factor IX and fibrinogen. In conclusion, thalidomide at therapeutic doses does not directly induce platelet activation under resting conditions in vitro or in vivo, but results in increased procoagulant activity, which could explain the thalidomide-dependent prothrombotic tendency in patients.
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