Serum angiopoietin 1 level in patients with severe COVID-19: An observational study

Muhammed Turki; Ali A. Kasim

doi:10.12688/f1000research.132827.1

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Research Article

Serum angiopoietin 1 level in patients with severe COVID-19: An observational study

[version 1; peer review: 1 approved with reservations]

Muhammed Turki ¹, Ali A. Kasim¹

PUBLISHED 26 May 2023

Author details Author details

¹ Clinical Laboratory Science, College of Pharmacy, University of Baghdad, Baghdad, Baghdad Governorate, 10011, Iraq

Muhammed Turki
Roles: Conceptualization, Data Curation, Formal Analysis, Methodology, Resources, Visualization, Writing – Original Draft Preparation

Ali A. Kasim
Roles: Conceptualization, Methodology, Software, Supervision, Validation, Visualization, Writing – Review & Editing

OPEN PEER REVIEW

REVIEWER STATUS

This article is included in the Emerging Diseases and Outbreaks gateway.

Abstract

Background: Exocytosis of the endothelial storage granules, Weibel-Palade bodies, upon severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) invasion with the consequent release of P-selectin and Von Willebrand factor, as well as several chemokines, results in hypercoagulability. Angiopoietin-2 is a chemokine stored in Weibel-Palade bodies; it is a context-dependent competitive antagonist of angiopoietin-1. Disruption of the angiopoietin/Tie2 pathway contributes to vascular dyshomeostasis in sepsis. This study aimed to investigate serum levels of angiopoietin-1 in patients with severe coronavirus disease 2019 (COVID-19).
Methods: A total of 85 participants were enrolled in the study and divided into two groups: the first group included 45 patients with severe COVID-19, and the second group included 40 healthy individuals of comparable age and sex to serve as the control group. ELISA was used to measure serum angiopoietin-1 levels.
Results: Serum angiopoietin-1 levels were significantly lower in patients with severe COVID-19 than in control subjects (14.52 (5.56) ng/ml and 30.56 (17.56) ng/ml, respectively; p < 0.001). Moreover, at a cut-off value ≤21.05 ng/ml, serum angiopoietin-1 level had 97.8% sensitivity and 100% specificity in differentiating between severe COVID-19 patients and non-infected individuals (p-value <0.001).
Conclusions: Serum angiopoietin-1 levels were lower in patients with severe COVID-19 than in control subjects, and it has potential to be used as a diagnostic marker for patients with severe COVID-19.

Keywords

Angiopoietin-1, COVID-19, Hypercoagulation, Angiogenesis, Tie2

Corresponding author: Muhammed Turki

Competing interests: No competing interests were disclosed.

Grant information: The author(s) declared that no grants were involved in supporting this work.

Copyright: © 2023 Turki M and A. Kasim A. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

How to cite: Turki M and A. Kasim A. Serum angiopoietin 1 level in patients with severe COVID-19: An observational study [version 1; peer review: 1 approved with reservations]. F1000Research 2023, 12:552 (https://doi.org/10.12688/f1000research.132827.1) First published: 26 May 2023, 12:552 (https://doi.org/10.12688/f1000research.132827.1) Latest published: 26 May 2023, 12:552 (https://doi.org/10.12688/f1000research.132827.1)

Introduction

In 2019, a new coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), caused a contagious disease known as coronavirus disease 2019 (COVID-19). The condition was declared to be a pandemic in March 2020 by the World Health Organization.¹^,² COVID-19 ranges from being asymptomatic in some cases³ to causing mild symptoms in the majority of cases, including fever and upper respiratory and gastrointestinal tract symptoms.⁴^,⁵ However, it can progress to severe cases of pneumonia, multi-organ failure, and, ultimately, death.⁶^–⁸

Akin to other coronaviruses, SARS-CoV-2 uses angiotensin-converting enzyme 2 (ACE2), which is a membrane-bound peptidase, as a gateway to enter the host cells⁹^,¹⁰; ACE2 expression was reported to be correlated with increased viral load in human cell lines¹¹^,¹² as well as rodents.¹³

COVID-19 patients display a state of increased coagulability and thrombotic tendency.¹⁴^,¹⁵ Antithrombotic prophylaxis represents an essential part of the treatment plan to prevent the development of pulmonary embolism and deep vein thrombosis that develop in severe cases or cases with increased d-dimer.¹⁶^–¹⁸ However, despite antithrombotic prophylaxis, approximately 30% of patients with severe COVID-19 admitted to the intensive care unit have developed arterial and venous thrombotic events, increasing the mortality risk in these patients by 5.4 times.¹⁹ Several mechanisms mediate the hypercoagulability of COVID-19 patients.²⁰

Among these mechanisms is the exocytosis of Weibel-Palade bodies from the vascular endothelium upon SARS-CoV-2 invasion.²¹^–²³ Weibel-Palade bodies are endothelial storage granules of mediators involved in inflammation and coagulation, primarily P-selectin and von Willebrand factor.²⁴^,²⁵ Weibel-Palade bodies contain several chemokines.²⁶

Angiopoietins are members of a family of vascular growth factors that play crucial roles in angiogenesis by binding to their physiologic receptors, tyrosine kinase with immunoglobulin-like and epidermal growth factor (EGF)-like domains 1 (Tie-1) and Tie-2, where Tie-2 is the primary receptor. Angiopoietin-1 is primarily produced in pericytes and smooth muscle cells; however, large quantities are produced and released from platelets upon activation.²⁷ It is critical for endothelial cell integrity, survival, migration, and the suppression of inflammatory gene expression.²⁸^,²⁹ Angiopoietin-2, on the other hand, is a context-dependent competitive antagonist of angiopoietin-1, promoting endothelial apoptosis and disrupting vascularization.³⁰ Angiopoietin-2 is a chemokine stored in Weibel-Palade bodies, and its serum level is elevated in patients with severe COVID-19.³¹ Parikh, suggests that disruption of the angiopoietin/Tie2 pathway contributes to vascular dyshomeostasis in sepsis.³²

This study aimed to investigate serum levels of angiopoietin-1 in patients with severe COVID-19.

Methods

Ethical consideration

The ethics committee of the College of Pharmacy, University of Baghdad, approved the research protocol (approval code:112021A) on 5th November 2021. Verbal consent was obtained from all participants after they were informed of the purpose of the study. Verbal consent was obtained because several participants indicated that they were more comfortable in providing verbal consent rather than written consent. The reason given was that the latter might have some element of risk in breaching the anonymity of the participants. When the proposal was submitted to the ethics committee, it included comprehensive information on the study’s purpose and methodology. One of these details was the method of acquiring consent from participants, which was verbal consent recorded on a digital recorder.

Study design

This observational, case-control study compared hospitalized adult patients with severe COVID-19 and healthy control individuals.

Setting

This multicenter study was conducted in Baghdad/Iraq, in the Dar Al Salam, Al Ata’a, and Al Khadymia hospitals, from 10^th November 2021 to June 2022. As both these affiliations (teaching healthcare institutes) and the University of Baghdad are Government Institutions, they have direct official contact to conduct research under continuous supervision.

Variables

The main objective of this study was to compare the serum angiopoietin-1 levels between hospitalized patients with severe COVID-19 and control subjects.

Sample size

G*Power (RRID: SCR_013726) version 3.1.9.7 software estimated the required number of participants. A two-tailed alpha of 0.05, with a confidence interval of 95%, power of 90%, and effect size of 0.80, was used. Therefore, the required sample size was 80 (f). In this research, 85 participants were enrolled, 45 in the COVID-19 group and 40 in the healthy control group.

Eligibility criteria

The COVID-19 participants were adults (20-60 years old) who had severe infection confirmed by positive RT-PCR for SARS-CoV-2 aided by radiological evidence, mainly chest X-ray or computed tomography (CT) scan. The severity was assessed clinically following the National Institute of Health Categorization for severe COVID-19 infection displaying oxygen saturation lower than 94% at room air and sea level with shortness of breath, alongside fever, cough, chest tightness, and pain.³³ While the control group participants were healthy with comparable sex and age to the COVID-19 patients’ group.

Exclusion criteria

Patients with the following conditions were excluded from the study: diabetes mellitus; cardiovascular, hepatic, or renal diseases; those who smoke tobacco; and those on any medication that may interfere with serum angiopoietin-1 levels or measurements.

Bias

Bias was minimized by randomly selecting participants without prior knowledge of the outcome; participants’ enrolment was done in a way that did not favor individuals with high or low exposure to COVID-19. As for the control participants, in addition to their history being taken during sampling, they were asked if they had experienced COVID-19 symptoms previously.

Study procedure

Data regarding diagnosis, tests, case history, and comorbidities were obtained from the patient’s case files and directly from the participants. Blood samples (3 mL) were collected in gel tubes, left to sit for 10–20 min to allow coagulation, and then centrifuged at 3,000 rpm to collect the serum. Eppendorf tubes were used to store the collected serum at -20°C until sample collection was completed. Serum angiopoietin-1 levels were measured using sandwich enzyme-linked immunosorbent assay kits.³⁴

Materials and instruments

Specifications of the human angiopoietin-1 ELISA kit are presented in Table 1.

Table 1. Summary of angiopoietin-1 ELISA kit.

Diagnostic kit	Supplier	Cat. No.	EXP.
Angiopoietin-1 ELISA kit	MyBioSource; USA	MBS264879	6/9/2024

Statistical analysis

SPSS (RRID:SCR_013726) version 25 was used for statistical analysis in this study, and the Shapiro-Wilk test was used to check the distribution uniformity of the data. Continuous variable data were presented as the median and interquartile range (IQR), and the significance of the difference between the groups was analyzed using the Mann-Whitney U test. Percentages and frequencies were used to present categorical variables, and the chi-squared test was used to analyze the significance of differences between the groups. Statistical significance was considered when the p-value was <0.05. Receiver operating characteristic (ROC) curves were used to calculate the area under the curve (AUC), optimal cut-off, sensitivity, and specificity values of serum angiopoietin-1 levels to check their diagnostic potential to differentiate between severe COVID-19 and non-infected individuals.

Results

No significant difference was detected between patients with severe COVID-19 and the control subjects regarding age and sex. Therefore, demographic data are summarized in Table 2.⁴⁵

Table 2. Participant demographic characteristics.

Variables		COVID-19 patients (n=45)	Control (n=40)	p-value
Age, years, median (IQR)		54 (14)	49.50 (15)	0.058
Sex	Female, n (%)	19 (42.2%)	19 (47.5%)	0.253
Sex	Male, n (%)	26 (57.8%)	21 (52.5%)	0.253

Serum angiopoietin-1 level was significantly lower [14.52 (5.56) ng/ml] in the patients with severe COVID-19 than in the control subjects [30.56 (17.56) ng/ml], (p-value <0.001) (Table 3).

Table 3. Serum angiopoietin-1 levels of participants.

Variable	Group	Median	IQR	p-value
Angiopoietin-1 (ng/ml)	COVID-19	14.52	5.56	<0.001*
Angiopoietin-1 (ng/ml)	Control	30.56	17.56	<0.001*

* p<0.05, statistically significant.

Serum angiopoietin-1 levels displayed diagnostic potential in differentiating between patients with severe COVID-19 and non-infected individuals according to the ROC curve (Table 4 and Figure 1).

Table 4. Angiopoietin-1 receiver operating characteristic curve specifications.

Variable	AUC	95% CI	p-value	Cut-off	SN	SP
Angiopoietin-1 (ng/ml)	0.98	0.94-1.00	<0.001*	≤21.05	97.8%	100%

* p<0.05, statistically significant.

Figure 1. Serum angiopoietin-1 ROC curve.

ROC, receiver operating characteristic.

Discussion

COVID-19 was hypothesized to be a vascular disease with endothelial damage or dysfunction, angiogenesis, and hypercoagulation.³⁵ Endothelial cell integrity is crucial for protecting the thrombotic environment and developing inflammation in COVID-19 patients. Disruption of the endothelial thromboprotective role might lead to hypercoagulation, as primarily described in these patients.¹⁴^,¹⁵ In a prospective study, Smadja et al., showed that SARS-CoV-2 infection is accompanied by elevated levels of the soluble endothelial activation markers, namely, soluble E-selectin and angiopoietin-2, in critically ill hospitalized COVID-19 patients.³¹

Angiopoietin-2, a context-dependent competitive antagonist of angiopoietin-1, is an essential regulator of endothelial homeostasis, angiogenesis, and proliferation through the angiopoietin/Tie-2 pathway.³⁰ Elevated serum angiopoietin-2 levels have been reported in patients with sepsis or acute respiratory distress syndrome (ARDS).³⁶ On the other hand, circulating angiopoietin-1 levels have been found to be lower in patients with sepsis-induced multiple organ dysfunction syndrome and to be correlated with the clinical course of the condition.³⁷ Whitney et al., showed that the angiopoietin-2/angiopoietin-1 ratio is higher in septic patients with ARDS than in septic patients without ARDS, which in turn is higher than in the control subjects, suggesting that endothelial dysfunction mediated by alterations in angiopoietins levels is involved in the pathogenesis of ARDS in the course of extrapulmonary sepsis.³⁸

In COVID-19, infected endothelial cells are stimulated to release angiopoietin-2 from the Weibel-Palade bodies. Once in circulation, angiopoietin-2 competitively inhibits angiopoietin-1, disrupting its thromboprotective role.³⁹ Higgins et al., showed that diminished Tie2 signaling develops before overt disseminated intravascular coagulation and that exogenous angiopoietin-1 administration normalizes hypercoagulability in endotoxemic mice. This implies that the angiopoietin-1/Tie2 pathway is central in protecting against microvascular thrombus formation during sepsis, even without inflammation.⁴⁰

In the present study, serum angiopoietin-1 levels were significantly lower in patients with severe COVID-19 than in the control group.

Abou-Arab et al., showed that the serum angiopoietin-2/angiopoietin-1 ratio is significantly higher in critically ill patients than in patients with severe COVID-19. However, serum angiopoietin-1 level was not significantly different between the two groups.⁴¹ Compared to the present study, Abou-Arab et al., did not exclude patients with other comorbidities and did not compare serum angiopoietin-1 levels with healthy controls.⁴¹ Similarly, Vassiliou et al., reported that serum angiopoietin-1 levels were not significantly different between survivors and non-survivors of critically ill COVID-19 patients admitted to the intensive care unit.⁴²

As mentioned earlier, platelets produce and release a significant amount of angiopoietin-1.²⁷ Thrombocytopenia is a common finding in severe COVID-19 infections, and it is associated with poor clinical outcomes.⁴³ Thrombocytopenia in severe COVID-19 conditions was attributed to platelet apoptosis and platelet consumption by incorporation into microthrombi.⁴⁴ Thus, lower serum angiopoietin-1 levels in patients with severe COVID-19 may be a consequence of thrombocytopenia.

In the present study, serum angiopoietin-1 showed good potential as a diagnostic marker to differentiate severe COVID-19 from non-infected individuals, with an AUC of 0.98, 100% specificity, and 97.8% sensitivity at a cut-off value of ≤21.05 ng/ml with a confidence interval of 0.94–1.00. On the other hand, Vassiliou et al., found that the serum angiopoietin-2, an angiopoietin-1 antagonist, is an excellent diagnostic marker to differentiate between severe and critically ill COVID-19 patients with an AUC of 0.86, with 77.3% specificity and 88.9% sensitivity at a cut-off value of ≥4 ng/ml with a confidence interval of 0.72–0.99.⁴² This emphasizes the role of disturbed serum angiopoietin levels during COVID-19.

Limitations

The number of participants in this study was modest; thus, we recommend a future larger-scale prospective study including COVID-19 patients with different severity levels of infection.

Conclusions

Patients with severe COVID-19 have lower serum angiopoietin-1 levels, and serum angiopoietin-1 levels have diagnostic potential for differentiating between patients with severe COVID-19 and non-infected individuals.

Data availability

Underlying data

Zenodo: Measurement of Serum Angiopoietin 1 level in Severe COVID-19 patients: An observational study, https://doi.org/10.5281/zenodo.7747903.⁴⁵

This project contains the following underlying data:

‐ Article data.xlsx (Measurement of Serum Angiopoietin 1 level in Severe COVID-19 patients: An observational study).

Data are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).

Acknowledgments

We express our gratitude to the COVID-19 care units for their support and help with sample collection and to the participants in this study.

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Version 1

VERSION 1 PUBLISHED 26 May 2023

Author details Author details

¹ Clinical Laboratory Science, College of Pharmacy, University of Baghdad, Baghdad, Baghdad Governorate, 10011, Iraq

Muhammed Turki
Roles: Conceptualization, Data Curation, Formal Analysis, Methodology, Resources, Visualization, Writing – Original Draft Preparation

Ali A. Kasim
Roles: Conceptualization, Methodology, Software, Supervision, Validation, Visualization, Writing – Review & Editing

Competing interests

No competing interests were disclosed.

Grant information

The author(s) declared that no grants were involved in supporting this work.

Article Versions (1)

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Published: 26 May 2023, 12:552

https://doi.org/10.12688/f1000research.132827.1

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© 2023 Turki M and A. Kasim A. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Turki M and A. Kasim A. Serum angiopoietin 1 level in patients with severe COVID-19: An observational study [version 1; peer review: 1 approved with reservations] F1000Research 2023, 12:552 (https://doi.org/10.12688/f1000research.132827.1)

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PUBLISHED 26 May 2023

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Reviewer Report 20 Jun 2023

Esra Laloglu, Department of Biochemistry, Faculty of Medicine, Ataturk University, Erzurum, Erzurum, Turkey

Approved with Reservations

https://doi.org/10.5256/f1000research.145779.r175833

In the abstract: "Serum angiopoietin-1 levels were lower in patients with severe COVID-19 than in control subjects,” You used the same sentence in the result part, this sentence is suitable for the result part.

In the abstract: "Serum angiopoietin-1 levels were lower in patients with severe COVID-19 than in control subjects,” You used the same sentence in the result part, this sentence is suitable for the result part.
Specify the reference you used to calculate the sample size.
Has pcr been done for healthy people, can they be asymptomatic Covid 19?
Please, write important laboratory parameters of patients. I would like to see the correlation between the laboratory results of the patients and ANG 1, especially, is the relationship between D dimer, PT, PTT, INR, Fibrinogen, thrombocyte level and ANG 1 significant?
Do patients have comorbidities that will affect ANG 1 level?
Have you ever had a COVID 19 patient who developed arterial or venous thromboembolism, and if so, wıll you compare the ANG1 level of those with and without thromboembolism?
In Conclusion: “Patients with severe COVID-19 have lower serum angiopoietin-1 levels, and serum angiopoietin-1 levels have diagnostic potential for differentiating between patients with severe COVID-19 and non-infected individuals”.

In order to say ANG 1 is a diagnostic marker, necessary laboratory studies must be done, this is a very definite statement, a sentence containing probability must be written (for example ”may be”).

Is the work clearly and accurately presented and does it cite the current literature?

Yes
Is the study design appropriate and is the work technically sound?

Yes
Are sufficient details of methods and analysis provided to allow replication by others?

Yes
If applicable, is the statistical analysis and its interpretation appropriate?

Yes
Are all the source data underlying the results available to ensure full reproducibility?

Yes
Are the conclusions drawn adequately supported by the results?

Yes

Competing Interests: No competing interests were disclosed.

Reviewer Expertise: Medical Biochemistry

I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above.

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Esra Laloglu, Ataturk University, Erzurum, Turkey

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20 Jun 2023 | for Version 1

Esra Laloglu, Department of Biochemistry, Faculty of Medicine, Ataturk University, Erzurum, Erzurum, Turkey

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Approved With Reservations

In the abstract: "Serum angiopoietin-1 levels were lower in patients with severe COVID-19 than in control subjects,” You used the same sentence in the result part, this sentence is suitable for the result part.
Specify the reference you used to calculate the sample size.
Has pcr been done for healthy people, can they be asymptomatic Covid 19?
Please, write important laboratory parameters of patients. I would like to see the correlation between the laboratory results of the patients and ANG 1, especially, is the relationship between D dimer, PT, PTT, INR, Fibrinogen, thrombocyte level and ANG 1 significant?
Do patients have comorbidities that will affect ANG 1 level?
Have you ever had a COVID 19 patient who developed arterial or venous thromboembolism, and if so, wıll you compare the ANG1 level of those with and without thromboembolism?
In Conclusion: “Patients with severe COVID-19 have lower serum angiopoietin-1 levels, and serum angiopoietin-1 levels have diagnostic potential for differentiating between patients with severe COVID-19 and non-infected individuals”.

In order to say ANG 1 is a diagnostic marker, necessary laboratory studies must be done, this is a very definite statement, a sentence containing probability must be written (for example ”may be”).

Is the work clearly and accurately presented and does it cite the current literature?

Yes
Is the study design appropriate and is the work technically sound?

Yes
Are sufficient details of methods and analysis provided to allow replication by others?

Yes
If applicable, is the statistical analysis and its interpretation appropriate?

Yes
Are all the source data underlying the results available to ensure full reproducibility?

Yes
Are the conclusions drawn adequately supported by the results?

Yes

Competing Interests

No competing interests were disclosed.

Reviewer Expertise

Medical Biochemistry

I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above.

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Serum angiopoietin 1 level in patients with severe COVID-19: An observational study

Abstract

Keywords

Introduction

Methods

Ethical consideration

Study design

Setting

Variables

Sample size

Eligibility criteria

Exclusion criteria

Bias

Study procedure

Materials and instruments

Table 1. Summary of angiopoietin-1 ELISA kit.

Statistical analysis

Results

Table 2. Participant demographic characteristics.

Table 3. Serum angiopoietin-1 levels of participants.

Table 4. Angiopoietin-1 receiver operating characteristic curve specifications.

Figure 1. Serum angiopoietin-1 ROC curve.

Discussion

Limitations

Conclusions

Data availability

Underlying data

Acknowledgments

References

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