Division of Thoracic Surgery, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada; Latner Thoracic Surgery Research Laboratories, Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada.
Coagulation Laboratory, University Health Network, Toronto, Ontario, Canada.
Semin Thorac Cardiovasc Surg. 2022 Spring;34(1):315-323. doi: 10.1053/j.semtcvs.2021.03.042. Epub 2021 May 10.
Pulmonary endarterectomy (PEA) is the main treatment for chronic thromboembolic pulmonary hypertension (CTEPH). Postoperative unfractionated heparin dosing can be monitored by activated partial thromboplastin time (APTT) or by anti-factor Xa activity (anti-Xa). In pseudo heparin resistance, APTT response to heparin is blunted due to elevated Factor VIII (FVIII) which can underestimate anticoagulation. We examined possible pseudo heparin resistance after PEA and assessed the impact of FVIII. APTT response to heparin before and after operation was determined in 13 PEA patients anticoagulated with unfractionated heparin. APTT and anti-Xa concordance was analyzed from paired postoperative samples, and antithrombin, fibrinogen and FVIII levels were measured. Single-cell RNA sequencing was used to characterize FVIII gene expression in PEA specimens of 5 patients. APTT response to heparin was blunted after PEA. APTT and anti-Xa were discordant in 36% of postoperative samples and most common discordant patterns were subtherapeutic APTT with therapeutic (16%) or supratherapeutic (11%) anti-Xa. Overall, APTT underestimated anticoagulation relative to anti-Xa in one-third of the samples. FVIII levels were elevated before surgery, increased substantially 1 and 3 days (median 4.32 IU/mL) after PEA, and were higher in discordant than concordant samples. Single-cell RNA sequencing showed FVIII gene expression in PEA specimen endothelial cells. Pseudo heparin resistance is common after PEA likely due to highly elevated postoperative FVIII levels indicating that anti-Xa reflects postoperative heparinization better than APTT in these patients. FVIII production by the pulmonary artery endothelium may participate in local prothrombotic processes important for CTEPH pathogenesis.
肺动脉内膜切除术（PEA）是治疗慢性血栓栓塞性肺动脉高压（CTEPH）的主要方法。术后未分馏肝素的剂量可以通过激活部分凝血活酶时间（APTT）或抗因子 Xa 活性（抗-Xa）来监测。在假性肝素抵抗中，由于因子 VIII（FVIII）升高导致肝素对 APTT 的反应减弱，这可能会低估抗凝作用。我们检查了 PEA 后可能出现的假性肝素抵抗，并评估了 FVIII 的影响。在接受未分馏肝素抗凝的 13 例 PEA 患者中，测定了手术前后肝素对 APTT 的反应。分析了配对术后样本中 APTT 和抗-Xa 的一致性，并测量了抗凝血酶、纤维蛋白原和 FVIII 水平。使用单细胞 RNA 测序来描述 5 例 PEA 标本中 FVIII 基因的表达。PEA 后肝素对 APTT 的反应减弱。36%的术后样本中 APTT 和抗-Xa 不一致，最常见的不一致模式是治疗性 APTT 伴治疗性（16%）或超治疗性（11%）抗-Xa。总体而言，三分之一的样本中 APTT 相对于抗-Xa 低估了抗凝作用。手术前 FVIII 水平升高，PEA 后 1 天和 3 天（中位数 4.32IU/mL）显著升高，在不一致样本中高于一致样本。单细胞 RNA 测序显示 PEA 标本内皮细胞中 FVIII 基因的表达。PEA 后假性肝素抵抗很常见，可能是由于术后 FVIII 水平显著升高，表明在这些患者中，抗-Xa 比 APTT 更能反映术后肝素化。肺动脉内皮细胞产生的 FVIII 可能参与了 CTEPH 发病机制中重要的局部促血栓形成过程。
