Gentium SpA, Villa Guardia, Como, Italy.
Clin Appl Thromb Hemost. 2012 Jan-Feb;18(1):79-86. doi: 10.1177/1076029611412367. Epub 2011 Jul 6.
Patients with multiple myeloma (MM) are at relatively high risk of developing thromboembolic events such deep venous thrombosis (DVT) where thalidomide therapy has been identified to increase this risk. Defibrotide (DF), a polydisperse oligonucleotide, showed previously to counteract the alterations in endothelial cells (ECs) induced by lipopolysaccharide. It prompts us to investigate the impact of thalidomide on ECs and whether DF modulates changes in fibrinolysis induced by thalidomide. In this in vitro study, MM by itself alters the profibrinolytic potential of ECs decreasing the tissue plasminogen activator (t-PA) and increasing the plasminogen activator inhibitor 1 (PAI-1) levels which is potentiated by thalidomide. Defibrotide was able to counteract these effects. Additionally, DF upregulated the t-PA and downregulated PAI-1 gene expression modulated by thalidomide. Defibrotide also protects ECs from thalidomide-mediated cell death without interfering with its antitumor effects. These findings support DF clinical use for the prevention of DVT induced by immunomodulatory drugs.
多发性骨髓瘤（MM）患者发生血栓栓塞事件（如深静脉血栓形成）的风险相对较高，而沙利度胺治疗已被确定会增加这种风险。地拉罗司（DF）是一种多分散的寡核苷酸，先前已被证明可对抗脂多糖诱导的内皮细胞（EC）的改变。这促使我们研究沙利度胺对 EC 的影响，以及 DF 是否调节沙利度胺诱导的纤维蛋白溶解变化。在这项体外研究中，MM 本身改变了 EC 的纤维蛋白溶解前体潜能，降低了组织型纤溶酶原激活物（t-PA）水平，增加了纤溶酶原激活物抑制剂 1（PAI-1）水平，而沙利度胺则增强了这种作用。DF 能够对抗这些作用。此外，DF 还上调了沙利度胺调节的 t-PA 和下调了 PAI-1 基因表达。DF 还可以防止 EC 因沙利度胺介导的细胞死亡，而不干扰其抗肿瘤作用。这些发现支持 DF 用于预防免疫调节药物引起的 DVT 的临床应用。
