Severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2)-induced infection, the cause of coronavirus disease 2019 (COVID-19), is characterized by acute clinical pathologies, including various coagulopathies that may be accompanied by hypercoagulation and platelet hyperactivation. Recently, a new COVID-19 phenotype has been noted in patients after they have ostensibly recovered from acute COVID-19 symptoms. This new syndrome is commonly termed Long COVID/Post-Acute Sequelae of COVID-19 (PASC). Here we refer to it as Long COVID/PASC. Lingering symptoms persist for as much as 6 months (or longer) after acute infection, where COVID-19 survivors complain of recurring fatigue or muscle weakness, being out of breath, sleep difficulties, and anxiety or depression. Given that blood clots can block microcapillaries and thereby inhibit oxygen exchange, we here investigate if the lingering symptoms that individuals with Long COVID/PASC manifest might be due to the presence of persistent circulating plasma microclots that are resistant to fibrinolysis. We use techniques including proteomics and fluorescence microscopy to study plasma samples from healthy individuals, individuals with Type 2 Diabetes Mellitus (T2DM), with acute COVID-19, and those with Long COVID/PASC symptoms. We show that plasma samples from Long COVID/PASC still contain large anomalous (amyloid) deposits (microclots). We also show that these microclots in both acute COVID-19 and Long COVID/PASC plasma samples are resistant to fibrinolysis (compared to plasma from controls and T2DM), even after trypsinisation. After a second trypsinization, the persistent pellet deposits (microclots) were solubilized. We detected various inflammatory molecules that are substantially increased in both the supernatant and trapped in the solubilized pellet deposits of acute COVID-19 and Long COVID/PASC, versus the equivalent volume of fully digested fluid of the control samples and T2DM. Of particular interest was a substantial increase in α(2)-antiplasmin (α2AP), various fibrinogen chains, as well as Serum Amyloid A (SAA) that were trapped in the solubilized fibrinolytic-resistant pellet deposits. Clotting pathologies in both acute COVID-19 infection and in Long COVID/PASC might benefit from following a regime of continued anticlotting therapy to support the fibrinolytic system function.

中文翻译：

---

长期新冠肺炎/COVID-19 急性后遗症 (PASC) 中的持续凝血蛋白病理伴随着抗纤溶酶水平升高

严重急性呼吸综合征冠状病毒 2 (SARS-Cov-2) 引起的感染是 2019 年冠状病毒病 (COVID-19) 的病因，其特点是急性临床病理，包括可能伴有高凝和血小板过度活化的各种凝血病。最近，在表面上从急性 COVID-19 症状中恢复的患者中发现了一种新的 COVID-19 表型。这种新综合征通常被称为“长期新冠肺炎/新冠肺炎 (COVID-19) 急性后遗症”(PASC)。这里我们将其称为 Long COVID/PASC。急性感染后，挥之不去的症状持续长达 6 个月（或更长时间），COVID-19 幸存者抱怨反复疲劳或肌肉无力、呼吸困难、睡眠困难以及焦虑或抑郁。鉴于血凝块可以阻塞微毛细血管，从而抑制氧交换，我们在此调查长效 COVID/PASC 患者表现出的持续症状是否可能是由于存在持续存在的抗纤维蛋白溶解的循环血浆微凝块。我们使用蛋白质组学和荧光显微镜等技术来研究来自健康个体、2 型糖尿病 (T2DM) 患者、急性 COVID-19 患者以及患有长期 COVID/PASC 症状的患者的血浆样本。我们表明，来自 Long COVID/PASC 的血浆样本仍然含有大量异常（淀粉样）沉积物（微凝块）。我们还表明，即使在胰蛋白酶消化后，急性 COVID-19 和长 COVID/PASC 血浆样本中的这些微凝块也能抵抗纤维蛋白溶解（与对照和 T2DM 的血浆相比）。第二次胰蛋白酶消化后，持久的沉淀物（微凝块）被溶解。我们检测到各种炎症分子在上清液中显着增加，并被困在急性 COVID-19 和长 COVID/PASC 的溶解颗粒沉积物中，而与对照样品和 T2DM 的完全消化液体的等效体积相比。特别令人感兴趣的是 α(2)-抗纤溶酶 (α2AP)、各种纤维蛋白原链以及血清淀粉样蛋白 A (SAA) 的大幅增加，这些物质被溶解的抗纤溶颗粒沉积物捕获。急性 COVID-19 感染和长期 COVID/PASC 的凝血病理可能受益于持续的抗凝血治疗方案以支持纤溶系统功能。