School of Biomedical Engineering, McMaster University, Hamilton, ON, Canada;
Blood. 2014 Mar 27;123(13):2102-7. doi: 10.1182/blood-2013-12-540872. Epub 2014 Feb 5.
Central venous catheter thrombosis can cause venous obstruction and pulmonary embolism. To determine the extent to which catheter thrombosis is triggered by the contact or extrinsic pathway of coagulation, we used antisense oligonucleotides (ASOs) to selectively knock down factor (f)XII, fXI, or high-molecular-weight kininogen (HK), key components of the contact pathway, or fVII, which is essential for the extrinsic pathway. Knockdown of contact pathway components prolonged the activated partial thromboplastin time and decreased target protein activity levels by over 90%, whereas fVII knockdown prolonged the prothrombin time and reduced fVII activity to a similar extent. Using a rabbit model of catheter thrombosis, catheters implanted in the jugular vein were assessed daily until they occluded, up to a maximum of 35 days. Compared with control, fXII and fXI ASO treatment prolonged the time to catheter occlusion by 2.2- and 2.3-fold, respectively. In contrast, both HK and fVII knockdown did not significantly prolong the time to occlusion, and dual treatment with fVII- and fXI-directed ASOs produced a time to occlusion similar to that with the fXI ASO alone. These findings suggest that catheter thrombosis is triggered via the contact pathway and identify fXII and fXI as potential targets to attenuate this complication.
中心静脉导管血栓形成可导致静脉阻塞和肺栓塞。为了确定导管血栓形成是由凝血的接触或外在途径引发的程度，我们使用反义寡核苷酸（ASO）选择性地敲低接触途径的关键成分因子（f）XII、fXI 或高分子量激肽原（HK），或 fVII，这对于外在途径是必不可少的。接触途径成分的敲低使活化部分凝血活酶时间延长，并使靶蛋白活性水平降低超过 90%，而 fVII 敲低使凝血酶原时间延长，并使 fVII 活性降低到相似程度。在导管血栓形成的兔模型中，评估植入颈静脉的导管，直到它们闭塞，最长可达 35 天。与对照相比，fXII 和 fXI ASO 治疗使导管闭塞时间分别延长了 2.2 倍和 2.3 倍。相比之下，HK 和 fVII 敲低均未显著延长闭塞时间，而 fVII 和 fXI 双重靶向 ASO 治疗产生的闭塞时间与单独使用 fXI ASO 相似。这些发现表明导管血栓形成是通过接触途径引发的，并确定 fXII 和 fXI 是减轻这种并发症的潜在靶点。
