Department of Haematology, Mater Misericordiae University Hospital, Dublin, Ireland.
UCD Conway SPHERE Research Group, University College Dublin, Dublin, Ireland.
J Thromb Haemost. 2022 Apr;20(4):1008-1014. doi: 10.1111/jth.15660. Epub 2022 Feb 13.
Hypercoagulability and endothelial dysfunction are hallmarks of coronavirus disease 2019 (COVID-19) and appear to predict disease severity. A high incidence of thrombosis despite thromboprophylaxis is reported in patients with moderate to severe COVID-19. Recent randomized clinical trials suggest that therapeutic-intensity heparin confers a survival benefit in moderate-severity COVID-19 compared to standard-intensity heparin, potentially by harnessing heparin-mediated endothelial-stabilizing and anti-inflammatory effects.
We hypothesized that patients with moderate-severity COVID-19 exhibit enhanced hypercoagulability despite standard-intensity thromboprophylaxis with low molecular weight heparin (LMWH) compared to non-COVID-19 hospitalized patients.
Patients with moderate COVID-19 and a control group (severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2]-negative hospitalized patients) receiving LMWH thromboprophylaxis were recruited. Markers of endothelial damage and plasma thrombin generation parameters were assessed.
Tissue plasminogen activator levels were significantly increased in the COVID-19 group (8.3 ± 4.4 vs. 4.9 ± 2.4 ng/ml; P = .02) compared to non-COVID-19-hospitalized patients. Despite thromboprophylaxis, mean endogenous thrombin potential was significantly increased among COVID-19 patients (1929 ± 448 vs. 1528 ± 460.8 nM*min; P = .04) but lag time to thrombin generation was significantly prolonged (8.1 ± 1.8 vs. 6.2 ± 1.8 mins; P = .02). While tissue factor pathway inhibitor (TFPI) levels were similar in both groups, in the presence of an inhibitory anti-TFPI antibody, the difference in lag time between the groups was abrogated.
Collectively, these data demonstrate that COVID-19 of moderate severity is associated with increased plasma thrombin generation and endothelial damage, and that hypercoagulability persists despite standard LMWH thromboprophylaxis. These findings may be of clinical interest given recent clinical trial data which suggest escalated heparin dosing in non-severe COVID-19 may be associated with improved clinical outcomes.
高凝状态和内皮功能障碍是 2019 年冠状病毒病（COVID-19）的标志，似乎可预测疾病的严重程度。尽管对中度至重度 COVID-19 患者进行了预防性抗凝治疗，但仍有报道称血栓形成的发生率较高。最近的随机临床试验表明，与标准强度肝素相比，治疗强度肝素可使中重度 COVID-19 患者的生存率提高，这可能是通过利用肝素介导的稳定内皮和抗炎作用实现的。
我们假设，与非 COVID-19 住院患者相比，即使接受标准强度低分子肝素（LMWH）预防性抗凝治疗，中重度 COVID-19 患者仍存在增强的高凝状态。
招募了中重度 COVID-19 患者和对照组（严重急性呼吸综合征冠状病毒 2[SARS-CoV-2]阴性住院患者），他们均接受 LMWH 预防性抗凝治疗。评估了内皮损伤标志物和血浆凝血酶生成参数。
COVID-19 组组织型纤溶酶原激活物水平明显升高（8.3±4.4 vs. 4.9±2.4ng/ml；P=0.02）。尽管进行了预防性抗凝治疗，但 COVID-19 患者的平均内源性凝血酶潜力显著增加（1929±448 vs. 1528±460.8 nM*min；P=0.04），但凝血酶生成的延迟时间明显延长（8.1±1.8 vs. 6.2±1.8 分钟；P=0.02）。虽然两组的组织因子途径抑制剂（TFPI）水平相似，但在存在抑制性抗 TFPI 抗体的情况下，两组之间的延迟时间差异消失。
总的来说，这些数据表明，中度严重的 COVID-19 与血浆凝血酶生成和内皮损伤增加有关，并且尽管进行了标准的 LMWH 预防性抗凝治疗，但高凝状态仍然存在。鉴于最近的临床试验数据表明，在非严重 COVID-19 中增加肝素剂量可能与改善临床结局相关，这些发现可能具有临床意义。
