Thrombosis and Atherosclerosis Research Institute, McMaster University, Hamilton, Canada.
Department of Medical Sciences, McMaster University, Hamilton, Canada.
J Thromb Haemost. 2016 Jan;14(1):143-52. doi: 10.1111/jth.13182. Epub 2016 Jan 4.
ESSENTIALS: Does thrombus stability alter the presentation of venous thromboembolism and do anticoagulants alter this? In a murine model, we imaged a femoral vein thrombus and quantified emboli in the pulmonary arteries. Dabigatran decreases thrombus stability via factor XIII increasing embolization and pulmonary emboli. This cautions against the unapproved use of dabigatran for acute initial treatment of deep vein thrombosis.
Venous thromboembolism (VTE) is a collective term for deep vein thrombosis (DVT) and pulmonary embolism (PE). Thrombus instability possibly contributes to progression of DVT to PE, and direct thrombin inhibitors (DTIs) may alter this.
To develop a model to assess thrombus stability and its link to PE burden, and identify whether DTIs, in contrast to low-molecular-weight heparin (LMWH), alter this correlation.
Twelve minutes after ferric chloride-induced thrombus formation in the femoral vein of female mice, saline, dalteparin (LMWH) or dabigatran (DTI) was administered. Thrombus size and embolic events breaking off from the thrombus were quantified before treatment and at 10-min intervals after treatment for 2 h using intravital videomicroscopy. Lungs were stained for the presence of PE.
Thrombus size was similar over time and between treatment groups. Total and large embolic events and pulmonary emboli were highest after treatment with dabigatran. Variations in amounts of pulmonary embolic events were not attributed to variations in thrombus size. Large embolic events correlated with the number of emboli per lung slice independent of treatment. Embolization in factor XIII deficient (FXIII(-/-) ) saline-treated mice was greater than that in wild-type (WT) saline-treated mice, but was similar to WT dabigatran-treated mice.
We have developed a mouse model of VTE that can quantify emboli and correlate this with PE burden. Consistent with clinical data, dabigatran, a DTI, acutely decreases thrombus stability and increases PE burden compared with LMWH or saline, which is a FXIII-dependent effect.
建立一种评估血栓稳定性及其与 PE 负荷关系的模型，并确定直接凝血酶抑制剂（DTI）是否与低分子肝素（LMWH）不同，改变这种相关性。
在雌性小鼠股静脉内形成血栓后 12 分钟，给予生理盐水、达肝素（LMWH）或达比加群（DTI）。使用活体显微镜在治疗前和治疗后 10 分钟间隔 2 小时内定量测量血栓大小和从血栓上脱落的栓塞事件。用肺染色来确定是否存在 PE。
血栓大小随时间和治疗组之间没有差异。在用达比加群治疗后，总栓塞事件和大栓塞事件以及肺栓塞的数量最高。栓塞事件的变化与血栓大小无关。大栓塞事件与每肺切片的栓塞数量相关，与治疗无关。在 FXIII 缺陷（FXIII(-/-)）生理盐水治疗的小鼠中，栓塞的数量大于在野生型（WT）生理盐水治疗的小鼠中，但与 WT 达比加群治疗的小鼠相似。
我们已经开发出一种可以定量栓塞并将其与 PE 负担相关联的 VTE 小鼠模型。与临床数据一致，达比加群，一种 DTI，与 LMWH 或生理盐水相比，急性降低血栓稳定性并增加 PE 负担，这是一种依赖 FXIII 的效应。
