Circulating Von Willebrand factor and high molecular weight multimers as markers of endothelial injury predict COVID-19 in-hospital mortality,Angiogenesis

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Circulating Von Willebrand factor and high molecular weight multimers as markers of endothelial injury predict COVID-19 in-hospital mortality
Angiogenesis ( IF 9.8 ) Pub Date : 2021-01-15 , DOI: 10.1007/s10456-020-09762-6
Aurélien Philippe ₁ , Richard Chocron ₂ , Nicolas Gendron ₁ , Olivier Bory ₃ , Agathe Beauvais ₃ , Nicolas Peron ₄ , Lina Khider ₅ , Coralie L Guerin ₆ , Guillaume Goudot ₅ , Françoise Levasseur ₇ , Christophe Peronino ₁ , Jerome Duchemin ₈ , Julie Brichet ₁ , Elise Sourdeau ₉ , Florence Desvard ₁ , Sébastien Bertil ₁ , Frédéric Pene ₁₀ , Cherifa Cheurfa ₁₁ , Tali-Anne Szwebel ₁₂ , Benjamin Planquette ₁₃ , Nadia Rivet ₁ , Georges Jourdi ₁₄ , Caroline Hauw-Berlemont ₄ , Bertrand Hermann ₄ , Pascale Gaussem ₁ , Tristan Mirault ₁₅ , Benjamin Terrier ₁₆ , Olivier Sanchez ₁₃ , Jean-Luc Diehl ₁₇ , Michaela Fontenay ₁₈ , David M Smadja ₁

Affiliation

Université de Paris, Innovative Therapies in Haemostasis, INSERM, 75006 Paris, France, Hematology Department and Biosurgical Research Lab (Carpentier Foundation), Assistance Publique Hôpitaux de Paris. Centre-Université de Paris (APHP.CUP), 20 rue Leblanc, 75015, Paris, France.
Université de Paris, PARCC, INSERM, Emergency Department, Assistance Publique - Hôpitaux de Paris-Centre (APHP-CUP), 75015, Paris, France.
Université de Paris, Emergency department, Assistance Publique - Hôpitaux de Paris-Centre (APHP-CUP), 75015, Paris, France.
Université de Paris, Assistance Publique - Hôpitaux de Paris-Centre (APHP-CUP), 75015, Paris, France.
Université de Paris, Vascular Medicine Department and Biosurgical Research Lab (Carpentier Foundation), Assistance Publique Hôpitaux de Paris-Centre (APHP-CUP), 75015, Paris, France.
Université de Paris, Innovative Therapies in Haemostasis, INSERM, 75006 Paris, France, Curie Institute, Cytometry department, 75006, Paris, France.
Université de Paris, Institut Cochin, INSERM, 75014, Paris, France.
Hematology Department, Assistance Publique-Hôpitaux de Paris. Centre-Université de Paris (AP-HP.CUP), Cochin Hospital, 75014, Paris, France.
Emergency department, Assistance Publique-Hôpitaux de Paris.Centre-Université de Paris (AP-HP.CUP), Hôtel-Dieu Hospital, 75014, Paris, France.
Intensive Care Medicine and Reanimation Department, Assistance Publique-Hôpitaux de Paris.Centre-Université de Paris (AP-HP.CUP), Cochin Hospital, 75014, Paris, France.
Anaesthesia, Intensive Care and Perioperative Medicine Department, GHU AP-HP, Centre - Université de Paris - Cochin Hospital, 75014, Paris, France.
Internal Medicine Department, AP-HP.Centre - Université de Paris - Cochin Hospital, 75014, Paris, France.
Université de Paris, Innovative Therapies in Haemostasis, INSERM, 75006 Paris, France, Respiratory Medicine Department and Biosurgical Research Lab (Carpentier Foundation), Assistance Publique - Hôpitaux de Paris-Centre (APHP-CUP), 75015, Paris, France.
Université de Paris, Innovative Therapies in Haemostasis, INSERM, 75006 Paris, France, Hematology Department Assistance Publique Hôpitaux de Paris.Centre-Université de Paris (APHP-CUP), 75014, Paris, France.
Université de Paris, PARCC, INSERM, 75015 Paris, France, Vascular medicine department, Assistance Publique - Hôpitaux de Paris-Centre (APHP-CUP), 75015, Paris, France.
Université de Paris, PARCC, INSERM U970, 75015 Paris, France, Internal Medicine Department, AH-HP-Centre Université de Paris (CUP), 75014, Paris, France.
Université de Paris, Innovative Therapies in Haemostasis, INSERM, 75006 Paris, France, Intensive Care Unit and Biosurgical Research Lab (Carpentier Foundation), Assistance Publique - Hôpitaux de Paris-Centre (APHP-CUP), 75015, Paris, France.
Université de Paris, Institut Cochin, INSERM, 75014 Paris, France, Hematology Department Assistance Publique Hôpitaux de Paris. Centre-Université de Paris (APHP-CUP), Cochin Hospital, 75014, Paris, France.

Background

Coronavirus disease 2019 (COVID-19) is a respiratory disease associated with endotheliitis and microthrombosis.

Objectives

To correlate endothelial dysfunction to in-hospital mortality in a bi-centric cohort of COVID-19 adult patients.

Methods

Consecutive ambulatory and hospitalized patients with laboratory-confirmed COVID-19 were enrolled. A panel of endothelial biomarkers and von Willebrand factor (VWF) multimers were measured in each patient ≤ 48 h following admission.

Results

Study enrolled 208 COVID-19 patients of whom 23 were mild outpatients and 189 patients hospitalized after admission. Most of endothelial biomarkers tested were found increased in the 89 critical patients transferred to intensive care unit. However, only von Willebrand factor antigen (VWF:Ag) scaled according to clinical severity, with levels significantly higher in critical patients (median 507%, IQR 428–596) compared to non-critical patients (288%, 230–350, p < 0.0001) or COVID-19 outpatients (144%, 133–198, p = 0.007). Moreover, VWF high molecular weight multimers (HMWM) were significantly higher in critical patients (median ratio 1.18, IQR 0.86–1.09) compared to non-critical patients (0.96, 1.04–1.39, p < 0.001). Among all endothelial biomarkers measured, ROC curve analysis identified a VWF:Ag cut-off of 423% as the best predictor for in-hospital mortality. The accuracy of VWF:Ag was further confirmed in a Kaplan–Meier estimator analysis and a Cox proportional Hazard model adjusted on age, BMI, C-reactive protein and d-dimer levels.

Conclusion

VWF:Ag is a relevant predictive factor for in-hospital mortality in COVID-19 patients. More than a biomarker, we hypothesize that VWF, including excess of HMWM forms, drives microthrombosis in COVID-19.

中文翻译：

循环血管性血友病因子和高分子量多聚体作为内皮损伤标志物可预测 COVID-19 住院死亡率

背景

2019 年冠状病毒病 (COVID-19) 是一种与内皮炎和微血栓形成相关的呼吸道疾病。

目标

在 COVID-19 成年患者的双中心队列中，将内皮功能障碍与住院死亡率相关联。

方法

连续招募了实验室确诊的 COVID-19 的门诊和住院患者。在每位患者入院后 48 小时内测量一组内皮生物标志物和血管性血友病因子 (VWF) 多聚体。

结果

研究招募了 208 名 COVID-19 患者，其中 23 名是轻度门诊患者，189 名患者入院后住院。在转移到重症监护病房的 89 名危重患者中，检测到的大多数内皮生物标志物都有所增加。然而，只有血管性血友病因子抗原 (VWF:Ag) 根据临床严重程度进行了调整，与非危重患者相比，危重患者的水平显着更高（中位数 507%，IQR 428–596）（288%，230–350，p < 0.0001) 或 COVID-19 门诊患者 (144%, 133–198, p = 0.007)。此外，与非危重患者（0.96、1.04-1.39、p < 0.001)。在所有测量的内皮生物标志物中，ROC 曲线分析确定了 423% 的 VWF:Ag 截止值是院内死亡率的最佳预测指标。VWF:Ag 的准确性在 Kaplan-Meier 估计分析和根据年龄、BMI、C 反应蛋白和d-二聚体水平调整的 Cox 比例危险模型中得到进一步证实。