Neb Holger, Talbot Steven R, Ruskowski Katharina, Brkic Djurdjina, Sonntagbauer Michael, Adam Elisabeth H, von Knethen Andreas, Zacharowski Kai, Heinicke Ulrike
Department of Anesthesiology, Intensive Care Medicine and Pain Therapy, University Hospital Frankfurt, Goethe University, Frankfurt am Main, Germany.
Institute for Laboratory Animal Science, Hannover Medical School, Hannover, Germany.
Shock. 2022 Dec 1;58(6):514-523. doi: 10.1097/SHK.0000000000002021. Epub 2022 Oct 31.
Background: Severe progression of coronavirus disease 2019 (COVID-19) causes respiratory failure and critical illness. Recently, COVID-19 has been associated with heparanase (HPSE)-induced endothelial barrier dysfunction and inflammation, so called endothelitis, and therapeutic treatment with heparin or low-molecular-weight heparin (LMWH) targeting HPSE has been postulated. Because, up to this date, clinicians are unable to measure the severity of endothelitis, which can lead to multiorgan failure and concomitant death, we investigated plasma levels of HPSE and heparin-binding protein (HBP) in COVID-19 intensive care patients to render a possible link between endothelitis and these plasma parameters. Therefore, a prospective prolonged cohort study was conducted, including 47 COVID-19 patients from the intensive care unit. Plasma levels of HPSE, and HBP were measured daily by enzyme-linked immunosorbent assay in survivors (n = 35) and nonsurvivors (n = 12) of COVID-19 from admission until discharge or death. All patients were either treated with heparin or LMWH, aiming for an activated partial thromboplastin time of ≥60 seconds or an anti-Xa level of >0.8 IU/mL using enoxaparin, depending on the clinical status of the patient (patients with extracorporeal membrane oxygenation or >0.1 μg/kg/min noradrenaline received heparin, all others enoxaparin). Results: We found significantly higher plasma levels of HPSE and HBP in survivors and nonsurvivors of COVID-19, compared with healthy controls. Still, interestingly, plasma HPSE levels were significantly higher ( P < 0.001) in survivors compared with nonsurvivors of COVID-19. In contrast, plasma HBP levels were significantly reduced ( P < 0.001) in survivors compared with nonsurvivors of COVID-19. Furthermore, when patients received heparin, they had significantly lower HPSE ( P = 2.22 e - 16) and significantly higher HBP ( P = 0.00013) plasma levels as when they received LMWH. Conclusion: Our results demonstrated that patients, who recover from COVID-19-induced vascular and pulmonary damage and were discharged from the intensive care unit, have significantly higher plasma HPSE level than patients who succumb to COVID-19. Therefore, HPSE is not suitable as marker for disease severity in COVID-19 but maybe as marker for patient's recovery. In addition, patients receiving therapeutic heparin treatment displayed significantly lower heparanse plasma level than upon therapeutic treatment with LMWH.
2019冠状病毒病（COVID-19）的严重进展会导致呼吸衰竭和危重症。最近，COVID-19与乙酰肝素酶（HPSE）诱导的内皮屏障功能障碍和炎症（即所谓的内皮炎）有关，因此有人提出用肝素或低分子量肝素（LMWH）针对HPSE进行治疗。由于迄今为止临床医生无法测量内皮炎的严重程度，而内皮炎会导致多器官功能衰竭并伴随死亡，我们对COVID-19重症监护患者的血浆HPSE和肝素结合蛋白（HBP）水平进行了研究，以确定内皮炎与这些血浆参数之间可能存在的联系。因此，我们进行了一项前瞻性长期队列研究，纳入了47名来自重症监护病房的COVID-19患者。从入院到出院或死亡，每天通过酶联免疫吸附测定法测量COVID-19幸存者（n = 35）和非幸存者（n = 十二）的血浆HPSE和HBP水平。所有患者均接受肝素或LMWH治疗，根据患者的临床状况，使用依诺肝素时目标是活化部分凝血活酶时间≥60秒或抗Xa水平>0.8 IU/mL（接受体外膜肺氧合或去甲肾上腺素>0.1μg/kg/min的患者接受肝素治疗，其他所有患者接受依诺肝素治疗）。结果：我们发现，与健康对照相比，COVID-19幸存者和非幸存者的血浆HPSE和HBP水平显著更高。然而，有趣的是，COVID-19幸存者的血浆HPSE水平显著高于非幸存者（P < 0.001）。相反，COVID-19幸存者的血浆HBP水平与非幸存者相比显著降低（P < 0.001）。此外，与接受LMWH治疗时相比，患者接受肝素治疗时的血浆HPSE水平显著更低（P = 2.22 e - 16），而血浆HBP水平显著更高（P = 0.00013）。结论：我们的结果表明，从COVID-19引起的血管和肺部损伤中康复并从重症监护病房出院的患者，其血浆HPSE水平显著高于死于COVID-19的患者。因此，HPSE不适宜作为COVID-19疾病严重程度的标志物，但可能作为患者康复的标志物。此外，接受肝素治疗的患者其血浆乙酰肝素酶水平显著低于接受LMWH治疗的患者。
