Blood coagulation parameter abnormalities in hospitalized patients with confirmed COVID-19 in Ethiopia

Shambel Araya; Mintesnot Aragaw Mamo; Yakob Gebregziabher Tsegay; Asegdew Atlaw; Aschalew Aytenew; Abebe Hordofa; Abebe Edao Negeso; Moges Wordofa; Tirhas Niguse; Mahlet Cheru; Zemenu Tamir

doi:10.1371/journal.pone.0252939

. 2021 Jun 21;16(6):e0252939. doi: 10.1371/journal.pone.0252939

Blood coagulation parameter abnormalities in hospitalized patients with confirmed COVID-19 in Ethiopia

Shambel Araya ^1,^2,^*, Mintesnot Aragaw Mamo ^1,², Yakob Gebregziabher Tsegay ^3,⁴, Asegdew Atlaw ², Aschalew Aytenew ², Abebe Hordofa ², Abebe Edao Negeso ¹, Moges Wordofa ¹, Tirhas Niguse ¹, Mahlet Cheru ¹, Zemenu Tamir ¹

Editor: Elizabeth S Mayne⁵

¹Department of Medical Laboratory Sciences, College of Health Sciences, Addis Ababa University, Addis Ababa, Ethiopia

²Department of Medical Laboratory, Millennium COVID-19 Treatment and Care Centre, St. Paual Millennium Medical College, Addis Ababa, Ethiopia

³Department of Medical Biotechnology, Institute of Biotechnology, University of Gondar, Gondar, Ethiopia

⁴Department of Research and Development Center, College of Health Sciences, Defense University, Addis Ababa, Ethiopia

⁵University of Witwatersrand/NHLS, SOUTH AFRICA

Competing Interests: The authors have declared that no competing interests exist.

^✉

* E-mail: shambelaraya8@gmail.com

Roles

Shambel Araya: Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Software, Supervision, Validation, Visualization, Writing – original draft, Writing – review & editing

Mintesnot Aragaw Mamo: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Resources, Software, Validation, Visualization, Writing – review & editing

Yakob Gebregziabher Tsegay: Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Resources, Software, Supervision, Validation, Visualization, Writing – review & editing

Asegdew Atlaw: Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Resources, Software, Supervision, Validation, Visualization, Writing – review & editing

Aschalew Aytenew: Conceptualization, Data curation, Formal analysis, Funding acquisition, Methodology, Resources, Software, Supervision, Visualization, Writing – original draft, Writing – review & editing

Abebe Hordofa: Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Resources, Software, Supervision, Validation, Visualization, Writing – review & editing

Abebe Edao Negeso: Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Software, Validation, Visualization, Writing – original draft, Writing – review & editing

Moges Wordofa: Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Resources, Software, Validation, Visualization, Writing – review & editing

Tirhas Niguse: Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Software, Supervision, Validation, Visualization, Writing – original draft, Writing – review & editing

Mahlet Cheru: Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Resources, Software, Validation, Visualization, Writing – review & editing

Zemenu Tamir: Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Resources, Software, Supervision, Validation, Visualization, Writing – original draft, Writing – review & editing

Elizabeth S Mayne: Editor

PMCID: PMC8216564 PMID: 34153056

Abstract

Background

Coagulopathy and thromboembolic events are among the complications of Corona Virus disease 2019 (COVID-19). Abnormal coagulation parameters in COVID-19 patients are important prognostic factors of disease severity. The aim of this study was to analyze coagulation profiles of hospitalized COVID-19 patients in Addis Ababa, Ethiopia.

Methods

This prospective cross-sectional study was conducted among 455 Covid-19 patients admitted at Millennium COVID-19 care and treatment center, Addis Ababa, Ethiopia from July 1- October 23, 2020. Prothrombin Time (PT), Activated Partial Thromboplastin Time (APTT) and International normalized ratio (INR) were determined on HUMACLOT DUE PLUS® coagulation analyzer (Wiesbaden, Germany). In all statistical analysis of results, p<0.05 was defined as statistically significant.

Result

A prolonged prothrombin time was found in 46.8% of study participants with COVID-19 and a prolonged prothrombin time and elevated INR in 53.3% of study subjects with severe and 51% of critically COVID patients. Thrombocytopenia was detected in 22.1% of COVID-19 patients. 50.5% and 51.3% of COVID-19 patients older than 55 years had thrombocytopenia and prolonged APTT respectively.

Conclusion

In this study, prolonged prothrombin time and elevated INR were detected in more than 50% of severe and critical COVID-19 patients. Thrombocytopenia and prolonged APTT were dominant in COVID-19 patients older than 55 years. Thus, we recommend emphasis to be given for monitoring of platelet count, PT, APTT and INR in hospitalized and admitted COVID-19 patients.

Introduction

Coronavirus disease 2019 (COVID-19) is caused by a novel beta corona virus called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [1]. COVID-19 has become a pandemic that has affected the global population. As of November 8, 2020, there have been more than 49 million confirmed cases of COVID-19 and more than 1.2 million deaths, reported to World Health organization (WHO). Similarly, there have been 99,204 confirmed cases of COVID-19 with 1,518 deaths in Ethiopia [2].

The severity of COVID-19 infection ranges considerably from asymptomatic to life threatening, with lung injury being the main clinical manifestation. Most of the patients have a favorable prognosis, but some rapidly progress to severe respiratory distress syndrome, coagulation dysfunction and multiple organ failures [3, 4]. Although the pathophysiology and the underlining mechanisms of clinical manifestations remain unclear, thrombo inflammation and cytokine storm are clearly established components in Severe Acute Respiratory Distress Syndrome (SARS) of COVID-19 [5–8].

Coagulopathy and abnormal coagulation parameters were indicated among the most significant biomarkers of poor prognosis in COVID-19 patients [9–11]. A retrospective cohort study conducted in Spain Madrid demonstrated that COVID-19 non-survivors had significantly lower prothrombin time, abnormal coagulation parameters such as prolonged PT, APTT, higher D- dimer and higher fibrinogen levels compared to survivors indicating coagulation parameters could be an efficient measure for predicting the prognosis of patients with SARS COV-2 [7] and used as guiding clinical management. Similarly, Long et al. has reported that occurrence of coagulation dysfunction is more likely in severe and critically ill patients. The study also showed that D-dimer and prothrombin time could be considered as main indicators in predicting the mortality of COVID-19 patients [3]. Many studies have also demonstrated the increased occurrence of intravascular disseminated coagulopathy (DIC) in patients with COVID-19 [12, 13]. The result of blood coagulation profiles in COVID-19 patients can also guide management decisions and improve outcomes [12, 14].

Moreover, routine coagulation parameter tests results could potentially be utilized in symptomatic patients in resource limited settings with inadequate access to COVID-19 RT-PCR, as in Ethiopia, to raise suspension of this infection. However, data on coagulation profiles among Ethiopian COVID-19 patients is not readily available. Thus, the aim of this study was to determine the coagulation profile of COVID-19 patients admitted at Millennium COVID-19 treatment center, Addis Ababa, Ethiopia.

Methods

Ethical consideration

Ethical clearance was obtained and approved by Addis Ababa University College of Health Sciences, department of Medical Laboratory Sciences research ethics review committee (DRERC/538/20/MLS) and it was in accordance with the principles of the Helsinki II declaration. Laboratory test results were communicated to the responsible clinicians working at COVID-19 care and treatment center. Written informed consent was obtained from the study participants. All the personal identifying information obtained from the study participants were kept confidential.

Study population

In this study, we have included 455 consecutive patients with confirmed SARS-CoV-2 infection admitted to Millennium COVID-19 treatment center, Addis Ababa, Ethiopia from July 1- October 23, 2020. The treatment center is the first referral center for COVID-19 patients in Ethiopia, since May 02, 2020. None of the study participants were receiving anticoagulant medications before blood drawing. Diagnosis of SARS-CoV-2 infection was made with real time RT-PCR.

Sample collection and coagulation profile analysis

Laboratory analysis

Venous bloods were collected by professional nurses working in the COVID-19 care and treatment center: 5 mL in EDTA and 3 mL in 3.2% sodium citrated anti-coagulated tube for analysis of coagulation parameters. The samples for coagulation profile tests were collected at hospital admission. The prothrombin time (PT), activated partial prothrombin time (APTT), and international normalized ratio (INR) were analyzed using HUMACLOT DUE PLUS^® coagulation analyzer (Wiesbaden ^®, Germany). Platelet count was performed using UniCel® DxH 800 Coulter®Cellular Analysis System (Beckman Coulter ^®, Inc. 4300 N. Harbor Blvd. Fullerton, CA 92835). The coagulation parameters were compared with the manufacturer cut off normal range of PT = 11.7‐15 seconds, APTT = 23.8‐37.9 seconds, INR = 1.0‐1.2 and PLT = 159-386/μ.l. The coagulation parameters above the cut off value were considered as a prolonged and thrombocytopenia in the case of lower than cut off value for platelets. All laboratory tests and interpretation were done following the manufacturers’ recommendation and standard operating procedures set out by the center.

Statistical analysis

Statistical Package for the Social Sciences (SPSS) software version 25.0 (SPSS^® Inc., Chicago, IL, USA) was used for statistical analysis. Chi-square test was used to determine association among categorical variables. The quantitative data were expressed as Mean ± SD. P value < 0.05 was considered as statistically significant.

Results

Socio-demographic and clinical characteristics of study participants

In this study, 455 patients diagnosed with COVID-19 were included. Among the study participants, 289 (63.5%) were males. The study participants were between the age of 4 and 90 years with a mean of 49.9 ±18.3 years. From the total 455 study subjects, there were 297 mild cases, 90 severe cases, and 68 critical cases based on disease severity of COVID-19 (Table 1).

Table 1. Socio-demographic characteristics of study participants.

Variables		Frequency	Percent
Gender	Male	289	63.5%
Gender	Female	166	36.5%
Age group	0–18 years	15	3.2%
	18–35 years	101	22.1%
	36–55 years	158	34.7%
	>55 years	181	39.7%
Disease severity	Moderate	297	65.2%
	Severe	90	19.8%
	Critical	68	15%

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The median time from the disease onset to admission was 4 days (2–8 days). Severe and critical groups showed differences in sex ratio and age distribution. In severe (36.6%) and critical groups (48.5%), were elderly males of the age of >55 years old (Table 2).

Table 2. Socio-demographic characteristics and disease severity of COVID-19 patients.

Variables		Disease Severity			P-value
Variables		Moderate, n (%)	Severe, n (%)	Critical, n (%)
Age (year)	0–18, n = 15	10(66.7)	4(26.7)	1(6.7)	0.283
	18–35, n = 101	65(64.35)	22(21.78)	14(13.8)
	36–55, n = 158	107(67.7)	31(19.6)	20(12.65)
	>55, n = 181	115(63.5)	33(18.2)	33(8.2)
Sex	Male, n = 289	187(64.7)	56(19.3)	46(15.9)	0.045
Sex	Female, n = 166	110(66.2)	34(20.4)	22(13.2)	0.045

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Magnitude of coagulation abnormalities

In this study, 209 COVID-19 patients (46%) showed prolonged PT and elevated INR values. Among those study participants with prolonged PT, 51.3% were above 55 years of age. Prolonged PT values were demonstrated more frequently among males (49.8%) than females (41%) and this difference was statistically significant (P = 0.045). Similarly, 51.4% and 53.3% of ICU (critical) and severe patients had prolonged PT values. Notably, prolonged APTT values were found among 43.1% of individuals, and from these 47%, 45% and 41% were among ICU (critical), severe and moderate patients, respectively. 57.2% of female patients had prolonged APTT; and 51.3% of patients aged older than 55 years had a prolonged APTT.

Thrombocytopenia was detected in 22.1% (101 out of 455) study subjects. 50.5% (50 out of 99) patients aged older than 55 years had thrombocytopenia and the occurrence was higher among male (23.8%) than female (18%) ICU patients (Table 3).

Table 3. Result of coagulation parameters in patients with severe COVID-19 according to different variables.

Coagulation parameters		Variables
		Age				Sex		Disease severity
		0–18 n(%)	19–35 n(%)	36–55 n(%)	>55 n(%)	Male n(%)	Female n(%)	Moderate n(%)	Severe n(%)	Critical n(%)
PT	High n = 213	9(4.2)	50(23.47)	61(28.6)	93(43.6)	144(67.6)	69(32.4)	130(61)	48(22.5)	35(16.4)
	Normal n = 220	6(2.7)	45(20.45)	89(40.4)	80(36.3)	131(59.5)	89(40.4)	149(67.7)	40(18.1)	31(14.1)
	Low = 22	0	6(27.2)	8(36.3)	8(36.3)	14(63.6)	8(36.3)	18(81)	2(9)	2(9)
*APTT*	High = 196	6(3)	46(23.4)	68(34.7)	76(38.77)	101(51.5)	95(48.5)	115(58.67)	41(21)	42(21.4)
	Normal n = 193	6(3.1)	38(19.7)	70(36.2)	79(41)	136(70.4)	57(29.5)	137(71)	36(18.6)	21(10.8)
	Low n = 66	3(4.5)	17(25.7)	20(30.3)	26(39.3)	52(78.7)	14(21)	45(68)	13(19.7)	5(7.5)
*PLT*	High n = 65	4(6.1)	11(17)	24(37)	26(40)	43(66)	22(33.8)	39(60)	8(12.3)	8(12.3)
	Normal n = 289	8(3)	70(24.2)	105(36.3)	105(36.3)	175(60.8)	114(39)	214(74)	44(15)	31(10.6)
	Low n = 101	3(2.9)	20(20)	28(27.7)	50(49.5)	69(69.70	30(30.3)	33(32)	38(37.6)	30(29.7)
*INR*	High n = 210	9(4.2)	50(24.7)	60(28.5)	91(43.3)	141(67)	69(32.8)	127(60.4)	50(23.8)	33(15.7)
	Normal = 224	5(2.2)	44(19.6)	93(41.5)	82(36.6)	115(51)	75(33.4)	113(50.4)	45(20)	32(14.2)
	Low n = 21	1(4.7)	7(33.3)	5(23.8)	8(38)	14(66.6)	7(33.3)	15(71)	3(14.5)	3(14.5)

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PLT = platelet; PT = prothrombin time; APTT = activated partial thromboplastin time; INR = international normalized ratio.

Discussion

The COVID-19 pandemic had a major impact on health care globally. COVID-19 has already caused >1.2 million deaths worldwide and more than 1400 in Ethiopia as of October 30,2020 according to WHO report [15]. Coagulation abnormalities are frequent in COVID-19 patients and are associated with poor prognosis and reduced survival [7]. The dysregulation of coagulation associated with hypercoagulability manifests as venous and arterial thrombosis and multiorgan dysfunction [16] which are poor prognostic markers [13, 14, 17–19]. Previous studies indicated that the coagulopathy in patients hospitalized with COVID-19 is characterized by increases in coagulation parameters such as PT, APTT and INR [20, 21].

Patients with serious infection are more likely to have COVID-19 associated coagulopathy than patients with a mild infection [21, 22]. In this recent study, prolonged PT, APTT and INR were more frequent among severe and critical COVID-19 patients. Similarly, studies also reported that thrombotic complications are common among COVID-19 patients admitted to intensive care unit (ICU) [22–24].

Treatment of the underlying condition is suggested to be paramount in coagulopathies. It is shown that bleeding is not common clinical manifestation in COVID-19 infections despite abnormal coagulation parameters [23, 24] and supportive care including blood product transfusion should be individualized in COVID -19 patients [25, 26]. Laboratory findings alone should not be taken as basis for instituting blood transfusion therapy, rather it should be reserved for those who are bleeding, requires an invasive procedure, or who are otherwise at high risk for bleeding complications [26, 27].

Published studies indicate that COVID-19 is associated with a hyper-coagulable state. Venous thromboembolism (VTE) and arterial thrombosis ranging from 15% to 30% were found in critically ill patients with COVID-19 and about 7% in those admitted to medical wards [28–30]. Abnormal thrombosis of different medical devices, deep vein thrombosis and multiple thrombi in the vessels of the lungs, kidneys and other organs at autopsy of patients who died of Covid-19 have been reported serving as the impetus behind guidelines [9, 29] which support the use of therapeutic doses of heparin or low-molecular-weight heparin instead of prophylactic doses in critically ill COVID-19 patients [12, 26, 31]. In the current study, thrombocytopenia was observed more frequently among males (23.8%) than females (19.8%) and older people (27.6%). Severe (42.68%) and critical (42%) patients also more frequently had thrombocytopenia and this was in line with studies conducted in different countries [20, 22, 32, 33]. Thrombocytopenia, defined as platelet count less than 100×10⁹ cells/L were independently associated with COVID-19 severity [34]. Studies suggest that routine coagulation test results are markers of disease severity and assist in management decision. In critically ill patients, thrombocytopenia correlates with multi-organ failure and death, and a decline in platelet count, even in the absence of overt thrombocytopenia, portends a worse outcome [9, 12, 13]. In patients who are not bleeding, there is no evidence that correction of laboratory parameters with blood products improves outcomes. Replacement might worsen disseminated thrombosis and further deplete scarce blood products [28, 35].

Many studies reported that coagulopathy associated with COVID-19 is characterized by thrombocytopenia, prolongation of the prothrombin time, high levels of D-dimer, and elevated levels of fibrinogen, factor VIII, and von Willebrand factor [3, 11, 16]. Published studies indicate that COVID-19-associated coagulopathy is characterized by a decreased platelet count [9, 36–38] and a cytokine storm with an extreme hyper-coagulable state. Even though the reason for this life-threatening condition is not known, this might be due to an uncontrolled hyper-inflammatory response without previous immunity [39, 40].

Conclusion

In this study, prolonged prothrombin time and high INR were found among severe and critical COVID-19 patients. Thrombocytopenia and prolonged clotting time assay were dominant in COVID-19 patients older than 55 years. Thus, we recommend emphasis to be given for monitoring of platelet count, PT, APTT and INR in hospitalized COVID-19 patients management.

Data Availability

All relevant data are within the manuscript.

Funding Statement

The author(s) received no specific funding for this work.

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PLoS One. doi: 10.1371/journal.pone.0252939.r001

Decision Letter 0

Elizabeth S Mayne

18 Dec 2020

PONE-D-20-35898

Blood coagulation parameter abnormalities among patients with confirmed COVID-19 in Ethiopia

PLOS ONE

Dear Dr. Araya,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

This is an important and timely paper to consider the abnormalities of haematological parameters in an African context and in COVID-19 disease. There are, however, unfortunately significant numbers of typographical errors and word omissions which make the sense of the paper difficult to follow in some cases. For example, the authors refer to a "prolonged" but do not indicate which parameter. There are, in addition, a number of references which need to be included (especially in the discussion).

Please submit your revised manuscript by Jan 31 2021 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

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We look forward to receiving your revised manuscript.

Kind regards,

Elizabeth S. Mayne, M.D.

Academic Editor

PLOS ONE

Additional Editor Comments:

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2. Thank you for submitting the above manuscript to PLOS ONE. During our internal evaluation of the manuscript, we found significant text overlap in the Discussion, Abstract, and other sections, between your submission and the following previously published works:

- https://applications.emro.who.int/emhj/v26/09/1020-3397-2020-2609-999-1004-eng.pdf

- https://www.hematology.org/COVID-19/COVID-19-and-coagulopathy

- https://pubmed.ncbi.nlm.nih.gov/32702124/

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

**********

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: No

Reviewer #2: Yes

**********

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Reviewer #1: This study is a simple evaluation of coagulation parameters that occur durning covid. The authors detected an increase in the prothrombin time and a decrease in the platelet count which correlated with the severity of infection. It is interesting and is worthy of publication

Reviewer #2: The study is relevant in the African context and will assist in the management of COVID patients in this often under resourced environment. The article however requires review of the English grammar.

**********

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Attachment

Submitted filename: PONE-D-20-35898_reviewer SL.pdf

Click here for additional data file.^{(778.4KB, pdf)}

PLoS One. 2021 Jun 21;16(6):e0252939. doi: 10.1371/journal.pone.0252939.r002

Author response to Decision Letter 0

11 Jan 2021

Cover letter

Shambel Araya

Addis Ababa University

Addis Ababa, Ethiopia

Email: shambelaraya8@gmail.com

Date: January 1, 2021

To: PLOS ONE Journal

Dear Editorial:

We are glad to write this response that our paper entitled “Blood coagulation parameter abnormalities among patients with confirmed COVID-19 in Ethiopia” (Submission ID: PONE-D-20-35898) has been requested to review for publication in PLOS ONE journal. We are pleased to have an opportunity to make our paper revised and we have greatly appreciated the reviewers’ and editor’s comments and suggestions were very helpful overall. In revising the paper, we have carefully considered reviewers’ and editor’s comments and suggestions on our revised submission. As instructed, we have attempted to succinctly explain changes made in reaction to all comments and reply to each comment in point-by-point fashion as follows:

Response to Editor’s comments

Additional Editor comments

Comment. “This is an important and timely paper to consider the abnormalities of haematological parameters in an African context and in COVID-19 disease. There are, however, unfortunately significant numbers of typographical errors and word omissions which make the sense of the paper difficult to follow in some cases. For example, the authors refer to a "prolonged" but do not indicate which parameter. There are, in addition, a number of references which need to be included (especially in the discussion).”

Response: As suggested by the editor we thoroughly went through the manuscript and revised the typographical, grammatical, editorial, and word omissions.

Journal requirements

When submitting your revision, we need you to address these additional requirements.

Comment #1. “Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming.”

Response #1: we strictly followed PLOS ONE's style requirements during preparation and revision of our manuscript as suggested by the editor.

Comment #2. “Thank you for submitting the above manuscript to PLOS ONE. During our internal evaluation of the manuscript, we found significant text overlap in the Discussion, Abstract, and other sections, between your submission and the following previously published works:

- https://applications.emro.who.int/emhj/v26/09/1020-3397-2020-2609-999-1004-eng.pdf

- https://www.hematology.org/COVID-19/COVID-19-and-coagulopathy

- https://pubmed.ncbi.nlm.nih.gov/32702124/

Response #2. As per the suggestion of the editor, we have revised different sections of manuscript to reduce text overlap with the mentioned previous studies and cite the utilized sources as follows:

• Abstract, Background section: ‘Infection with corona virus disease 2019 (COVID-19) could be complicated with coagulopathy and high risk of thromboembolic events.’ Revised as “Coagulopathy and thromboembolic events are among the complications of Corona Virus disease 2019 (COVID-19).”

• Abstract, conclusion section: ‘We found an abnormal pattern of coagulation parameters and association of advanced age and co-morbidities with a high rate of mortality in severe COVID-19 patients, which should be taken into consideration in their hospital management.

Revised as “In this study, prolonged prothrombin time and high INR were found among severe and critical COVID-19 patients. Thrombocytopenia and prolonged APTT were dominant in COVID-19 patients older than 55 years. Thus, we recommend emphasis to be given for monitoring of platelet count, PT, APTT and INR in hospitalized COVID-19 patients management.”

• Discussion part first paragraph: ‘COVID-19, which is caused by SARS-CoV-2, has spread across the globe. Although most patients recover within 1 to 3 weeks, COVID-19 has already caused >1.2 million deaths worldwide and more than 1400 in Ethiopia as of October 30,2020 according to WHO report (15). Dysregulation of coagulation produces a coagulopathy associated with hyper coagulability as evidenced by venous and arterial thrombosis and multi-organ dysfunction. Up to 20% of affected patients require hospitalization, and the mortality rate in such patients is high (16, 17). Coagulopathy is one of the most significant prognostic factors in patients with COVID-19 and is associated with increased mortality and admission to critical care (14, 18). Most commonly observed coagulopathy in patients hospitalized with COVID-19 (COVID-19-associated coagulopathy) is characterized by increased coagulation parameters like PT, APTT and INR levels (19, 20).’

Revised as “The COVID-19 pandemic has brought major impact on health care globally. It has already caused >1.2 million deaths worldwide and more than 1400 in Ethiopia as of October 30,2020 according to WHO report(15). Coagulation abnormalities are indicated as frequent findings in COVID-19 patients and associated with poor prognosis and survival(7). Similarly, it is also indicated that coagulopathy which is resulted due to dysregulation of coagulation and associated with hypercoagulability as evidenced by venous and arterial thrombosis and multiorgan dysfunction(16); is one of the most significant prognostic factors in patients with COVID-19 and associated with increased hospitalization, admission to critical care, and mortality(14, 17-19). Previous studies indicated that coagulopathy in patients hospitalized with COVID-19 is characterized by increase in coagulation parameters such as PT, APTT and INR levels(20, 21).”

• Discussion part 3rd Paragraph: “As for all coagulopathies, treatment of the underlying condition is paramount. Experience to date suggests that COVID-19 infection infrequently leads to bleeding despite abnormal coagulation parameters (23,24). Supportive care including blood product transfusion should be individualized (24, 25). Blood component therapy should not be instituted on the basis of laboratory results alone, but reserved for those who are bleeding requires an invasive procedure, or who are otherwise at high risk for bleeding complications (25).”

Revised as “Treatment of the underlying condition is suggested to be paramount in coagulopathies. It is shown that bleeding is not common clinical manifestation in COVID-19 infections despite abnormal coagulation parameters (23,24). Along these, it is suggested that supportive care including blood product transfusion should be individualized in COVID -19 patients (25, 26). Laboratory findings alone should not be taken as basis for instituting blood transfusion therapy, rather it should be reserved for those who are bleeding, require an invasive procedure, or who are otherwise at high risk for bleeding complications(26, 27)”

Discussion part 4th Paragraph: “Considerable evidence indicates that COVID-19 is associated with a hyper-coagulable state. Thus, despite anticoagulant thrombo-prophylaxis, different studies have reported that rates of venous thromboembolism (VTE) and arterial thrombosis ranging from 15% to 30% in critically ill patients with COVID-19 and ∼7% in those admitted to medical wards (26-28). Clotting of access catheters, dialysis membranes, and extracorporeal circuits has also been reported. Furthermore, in patients dying from COVID-19, autopsy studies reveal unsuspected deep vein thrombosis and multiple thrombi in the vessels of the lungs, kidneys, and other organs (9, 27). These findings have prompted some clinicians to use treatment doses of heparin or low- molecular-weight heparin instead of prophylactic doses in critically ill COVID-19 patients (12,25, 29).

Revised as “Evidences indicate that COVID-19 is associated with a hyper-coagulable state. Venous thromboembolism (VTE) and arterial thrombosis ranging from 15% to 30% were found in critically ill patients with COVID-19 and about 7% in those admitted to medical wards (28-30). Clotting is reported from different medical devices used, deep vein thrombosis and multiple thrombi in the vessels of the lungs, kidneys and other organs from autopsy of patients died of Covid-19 (9, 29). These indicate clinicians to use therapeutic doses of heparin or low-molecular-weight heparin instead of prophylactic doses in critically ill COVID-19 patients (12, 26, 31).

• Conclusion part: “We recommend monitoring platelet count, PT, APTT and INR. Worsening of these parameters indicates progressive severity of COVID-19 infection and predicts that more aggressive critical care will be needed; experimental therapies for COVID-19 infection might be considered in this setting. Improvement of coagulation parameters along with improving clinical condition provides confidence that stepping down of aggressive treatment may be appropriate.”

Comment #3. “Please state whether you validated the questionnaire prior to testing on study participants. Please provide details regarding the validation group within the methods section.”

Response #3. Not applicable. We did not used questionnaire in this study.

Comment #4. We note that you have indicated that data from this study are available upon request. PLOS only allows data to be available upon request if there are legal or ethical restrictions on sharing data publicly. For information on unacceptable data access restrictions, please see http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions.

Response #4. All the available data were included in the manuscript.

Comment #5. ” PLOS requires an ORCID iD for the corresponding author in Editorial Manager on papers submitted after December 6th, 2016. Please ensure that you have an ORCID iD and that it is validated in Editorial Manager. To do this, go to ‘Update my Information’ (in the upper left-hand corner of the main menu), and click on the Fetch/Validate link next to the ORCID field. This will take you to the ORCID site and allow you to create a new iD or authenticate a pre-existing iD in Editorial Manager. Please see the following video for instructions on linking an ORCID iD to your Editorial Manager account: https://www.youtube.com/watch?v=_xcclfuvtxQ”

Response #5. “Already linked”

Comment #6. “Please amend the manuscript submission data (via Edit Submission) to include author Moges Wordofa.”

Response #6. Comment accepted and author included

Comment #7. “We note you have included a table to which you do not refer in the text of your manuscript. Please ensure that you refer to Table 1 in your text; if accepted, production will need this reference to link the reader to the Table.”

Response #7. Comment accepted and corrected accordingly.

Response to comments and suggestions inserted in the PDF format Manuscript

Comment # 1: in the abstract section. A prolonged (insert analytical parameter that was prolonged) was present in 48.8% of study subjects with COVID-19?

Response 1: Parameter inserted and and revised as “A prolonged prothrombin time was found among 46.8% of study subjects with COVID-19”

Comment # 2: In the abstract section. The comment to remove the interpretation and conclusion.

Response #2. Comment accepted and modified accordingly.

Comment #3. On Title. “Blood coagulation parameter abnormalities among in hospitalized patients with confirmed COVID-19 in Ethiopia”

Response #3: Accepted and modified as: “Blood coagulation parameter abnormalities in hospitalized patients with confirmed COVID-19 in Ethiopia”

Comment#4: in the abstract, method part: ‘…were estimated by auto analyzer.” ‘Which parameter?’.

Response to #5. Although the comment was to indicate which parameter, since the parameter are already mentioned we perceived it as to mean which auto analyzer and inserted the specific analyzer used as_”…..HUMACLOT DUE PLUS coagulation analyzer (Wiesbaden, Germany)”

Comment #6. In the introduction part. “ ….WHO. Write out abbreviation in full the first time it is used”.

Response #6. Corrected as suggested. …..World Health Organization(WHO).

Comment #7. In the laboratory analysis part, “…HUMACLOT DUE PLUS.. Insert trademark symbol e.g. R or TM.”

Response #7. Accepted and modified as “…HUMACLOT DUE PLUS coagulation analyzer (Wiesbaden, Germany)

Comment #8. In the laboratory analysis part, “…Beckman coulter DxH 600 automated hematology analyzer.. Insert trademark symbol e.g. R or TM.”

Response #8. Accepted and modified as “…Beckman coulter DxH 600 automated hematology analyzer

Comment #9. “Thrombocytopenia and abnormal coagulation parameters (PT, APTT and INR) could be considered as important indicators of COVID-19 disease severity. This statement belongs in the discussion section of the article.”

Response # 9: Accepted and removed as suggested.

Comment #10. In discussion part. ‘Thrombocytopenia, defined as platelet count less than 100×10⁹ cells per L were independently associated with severity. Insert reference.’

Response #10: Comment accepted; reference inserted as suggested. “Thrombocytopenia, defined as platelet count less than 100×10⁹cells/L were independently associated with COVID-19 severity(34)”

Comment 11. Discussion Part. “As many studies reported that the coagulopathy associated with COVID-19 is characterized by thrombocytopenia, prolongation of the prothrombin time, high levels of D-dimer, and elevated levels of fibrinogen, factor VIII, and von Willebrand factor. Insert reference”

Response #11. Comment accepted; reference inserted as suggested. “Many studies reported that coagulopathy associated with COVID-19 is characterized by thrombocytopenia, prolongation of the prothrombin time, high levels of D-dimer, and elevated levels of fibrinogen, factor VIII, and von Willebrand factor(3, 11, 16).”

Comment #12. Conclusion part. “We recommend monitoring platelet count, PT, APTT and INR. ...in patients hospitalized COVID-19 patients.

Response #12. Comment accepted and modified as “We recommend monitoring platelet count, PT, APTT and INR in hospitalized COVID-19 patients.”

Looking forward to hearing from you. Thank you again for your consideration!

Sincerely,

Shambel Araya (BSc, MSc)

Corresponding author

PLoS One. doi: 10.1371/journal.pone.0252939.r003

Decision Letter 1

Elizabeth S Mayne

31 Mar 2021

PONE-D-20-35898R1

Blood coagulation parameter abnormalities in hospitalized patients with confirmed COVID-19 in Ethiopia

PLOS ONE

Dear Dr. Araya,

==============================

Although both reviewers were happy that their concerns were addressed, there are some minor predominantly typographical and grammatical errors.

Please review attached reviews.

==============================

Please submit your revised manuscript by May 15 2021 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Elizabeth S. Mayne, M.D.

Academic Editor

PLOS ONE

Journal Requirements:

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #2: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #2: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

Reviewer #2: Yes

**********

6. Review Comments to the Author

Reviewer #2: The study adds to local knowledge of the clinical manifestations and outcomes in patients with COVID and has the potential to assist with clinical decisions. Various final changes have been recommended as indicated on the uploaded edited article.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #2: No

Attachment

Submitted filename: PONE-D-20-35898_R1_reviewer SL 23_01_2021.pdf

Click here for additional data file.^{(1.5MB, pdf)}

PLoS One. 2021 Jun 21;16(6):e0252939. doi: 10.1371/journal.pone.0252939.r004

Author response to Decision Letter 1

2 Apr 2021

Cover letter

Shambel Araya

Addis Ababa University

Addis Ababa, Ethiopia

Email: shambelaraya8@gmail.com

Date: April, 2021

To: PLOS ONE Journal

Dear Editorial:

We are glad to write this response that our research article entitled “Blood coagulation parameter abnormalities among patients with confirmed COVID-19 in Ethiopia” (Submission ID: PONE-D-20-35898R1) has been requested to review for publication in PLOS ONE journal. We are pleased to have an opportunity to make our paper revised and we have greatly appreciated the reviewers’ and editor’s comments and suggestions were very helpful overall. In revising the paper, we have carefully considered reviewers’ and editor’s comments and suggestions on our revised submission. As instructed, we have attempted to succinctly explain changes made in reaction to all comments and reply to each comment in point-by-point fashion as follows:

Response to comments and suggestions inserted in the PDF format of the Manuscript

� Comment 1: Abstract, methods section: “...Estimated by...” was replaced by “...determined on...” as per your suggestion in line 34

� Comment 2: Abstract, Result section: “among” is replaced with ‘in’ in line 36

� Comment 3: Abstract, Result section: “…Prolonged prothrombin time and high INR were seen among 53.3% severe and 51% critical 38 patients with COVID-19 manifestation…. Thrombocytopenia was detected in 22.1% of COVID-19 39 patients” has replaced with… and a prolonged prothrombin time and elevated INR with 53.3% of study subjects with severe and 51 % of critically COVID patients…” in line 37-39

� Comment 4: abstract, conclusion section. In this study, prolonged prothrombin time and high INR were found among severe and critical COVID-19 patients.

Revised: In this study, prolonged prothrombin time and high INR were detected in 50% of severe and critical COVID-19 patients

� Comment: abstract, conclusion section. Delete management

Response: Accepted and deleted in line 45

� Comment 6: Introduction section. Replace showed with demonstrated that

Response: Accepted and replaced

� Comment 7: …Introduction section. coagulation parameters could be an efficient measure for improving the clinical management and predicting the prognosis of patients with SARS COV-2(7)…

Revised: …coagulation parameters could be an efficient measure for predicting the prognosis of patients with SARS COV-2(7) and guiding management…

� Comment 8: Introduction section: Accepted and modified as follow

“Different studies also support that COVID-19 patients are at high risk of developing disseminated intravascular coagulation (12, 13). It is also indicated that comparison of reports from various populations related to the clinical course, outcome of COVID-19 and blood coagulation profile in these patients are necessary to help the management and treatment of the disease (12, 14). Moreover, this routine coagulation parameter tests could be used as potential indicators for COVID-19 in individuals having typical clinical manifestations that would be inputs for prompt patient management especially in resource limited settings where the high-tech gold standard RT-PCR is not widely available, like Ethiopia”

Revised: Several studies have also demonstrated the increased occurrence of intravascular disseminated coagulopathy (DIC) in patients with COVID-19 (12, 13). The result of blood coagulation parameters in COVID-19 can also guide management decisions and improve outcomes (12, 14).

Comment8: Introduction section Replace “…find out…” with “...Determine…”

Response: accepted and replaced as per your suggestion

� Comment 9: Delete “and” in line 88

� Line 92: Replace “…of…” with “…for…”

� Line 94: Replace “…Was taking…” with “…were receiving…”

� Line 95: Change “According to” in to “…with…”

Response: Accepted and modified accordingly

Comment 10: Methods, laboratory section.

Eight milliliters of venous blood were collected by professional nurses working in the treatment center: five milliliters in EDTA for platelet count, three milliliters in 3.2% sodium citrated

Revised: Venous bloods were collected by professional nurses working in the treatment center: 5 mL in EDTA and 3 mL in 3.2% sodium citrated

� Comment 11: Insert trade mark for each instruments and software’s

Response: accepted and inserted as follow in line 99-102

� Comment12: remove Addis Ababa, Ethiopia, 2020 from table 1

Response: Deleted as per your suggestion

� Comment 13: Result section line 120-122 “Severe and critical groups showed differences in sex ratio and age distribution. In severe and critical groups, majority were males and elderly (Table 2).”

Revised: Severe and critical groups showed differences in sex ratio and age distribution. In severe (36.6%) and critical groups (48.5%), were elderly males of the age of >55 years old. y (Table 2).

� Comment 14: result section table 3: remove “…admitted to Millennium COVID-19 treatment center Addis Ababa, Ethiopia…”

Response: accepted and removed table heading

� Comment 15: Result section line 127-129, rewrite “Prolonged PT value was found among males (49.8%) than females (41%) and it has a significant association with gender (P = 0.045).”

Revised: accepted and modified as “Prolonged PT values were demonstrated more frequently among males (49.8%) than females (41%) and this difference was significantly different (P = 0.045).”

Comment 16: replace study subjects with individuals

Response accepted and replaced in line 130

� Comment 16 result section line 135-136: rearrange “…patients aged older than 55 years had thrombocytopenia. Thrombocytopenia was higher among…” in to

Revised: modified as “…patients aged older than 55 years had thrombocytopenia and the occurrence was higher among…”

� Comment 17: insert “…Result of …” in table 3 heading

Response: accepted and modified as follow “Result of coagulation parameters in patients with severe COVID-19 according to different variables”

Comment 18: Discussion section: Replace “…had brought…” with “...had a…”

Delete indicated as

Remove findings

� Comment 19: Rearrange the paragraph as below for “Coagulation abnormalities are indicated as frequent findings in COVID-19 patients and associated with poor prognosis and survival(7). Similarly, it is also indicated that coagulopathy which is resulted due to dysregulation of coagulation and associated with hypercoagulability as evidenced by venous and arterial thrombosis and multiorgan dysfunction (16); is one of the most significant prognostic factors in patients with COVID-19 and is associated with increased hospitalization, admission to critical care, and mortality”

Response: accepted

Revised: Coagulation abnormalities are frequent in COVID-19 patients and are associated with poor prognosis and reduced survival(7). Dysregulation of coagulation and associated with hypercoagulability in patients with COVID manifest as venous and arterial thrombosis and multiorgan dysfunction (16); which are poor prognostic markers resulting in increased mortality and hospitalization and ICU admission

� Comment 20: discussion section

Line 151: remove “…levels...”

Line 153 insert “…more frequent…”

Line 153: remove “…than moderate ones…”

Line 159: replace “… alongside these, it is suggested that…” with “and”

Line 164: replace “…Evidence…” with “…published studies…”

Response: Accepted and modified as per your suggestion

Line 167: replace “…clotting is reported from…” with “…Abnormal thrombosis of…”

Line 167-170: rewrite it as follow for “…Clotting is reported from different medical devices used, deep vein thrombosis and multiple thrombi in the vessels of the lungs, kidneys and other organs from autopsy of patients died of Covid-19 (9, 29). These indicate clinicians to use…”

Response: Accepted and rephrase as follow

Revised: “…Abnormal thrombosis of different medical devices, deep vein thrombosis and multiple thrombi in the vessels of the lungs, kidneys and other organs at autopsy of patients who died of Covid-19 have been reported serving as the impetus behind guidelines (9, 29)which support the use…”

Line 173-175: rewrite it as follow for “Studies across suggested that routine coagulation tests can be considered as a significant marker to help clinicians assess prognosis and severity of patients with COVID-19…”

Response: Accepted and rephrase as follow

Revised: (34). “...Studies suggest that routine coagulation test results are markers of disease severity and assist in management decision…”

Line 184: Insert “… in critically ill non-COVID patients…”

Response: accepted

Line 186-189: rephrase the sentence “COVID-19-associated coagulopathy is however unique with a much-decreased platelet count (9, 36-38)”

Revised: Published studies support that COVID-19-associated coagulopathy is characterized by a decreased platelet count (9, 36-38).

Dear all, we are very grateful for your valuable comments and for your time

Looking forward to hearing from you. Thank you again for your consideration!

Sincerely,

Shambel Araya (BSc, MSc, PhD fellow)

PLoS One. doi: 10.1371/journal.pone.0252939.r005

Decision Letter 2

Elizabeth S Mayne

26 Apr 2021

PONE-D-20-35898R2

Blood coagulation parameter abnormalities in hospitalized patients with confirmed COVID-19 in Ethiopia

PLOS ONE

Dear Dr. Araya,

==============================

The reviewer felt that the manuscript was substantially improved but there are still a number of grammatical and typographical errors that should be corrected. Again, it is recommended that the manuscript is reviewed by a native English language speaker.

==============================

Please submit your revised manuscript by Jun 10 2021 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

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We look forward to receiving your revised manuscript.

Kind regards,

Elizabeth S. Mayne, M.D.

Academic Editor

PLOS ONE

Journal Requirements:

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

Reviewer #2: (No Response)

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #2: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

Reviewer #2: Yes

**********

6. Review Comments to the Author

Reviewer #2: The article provides information pertaining to the coagulation abnormalities in the local African context that could potentially assist with the treatment of patients with COVID and improve outcomes.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

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PLoS One. 2021 Jun 21;16(6):e0252939. doi: 10.1371/journal.pone.0252939.r006

Author response to Decision Letter 2

5 May 2021

General Comments

Dear reviewers and editors

� We have carefully consider your comments and we have incorporated all your comments and recommendations

� The manuscript have also reviewed by a native English language speaker

Specific comments

� Comment 1: Abstract, background section:

� “Thus”, “taken as” and “COVID-19” was removed as per your suggestion in line 28 & 29

� Comment 2: Abstract, method section:

� Insert trade mark: inserted

� Remove tests and replace it with statistical analysis results: accepted and replaced

� Comment 3: Result section: “with” is replaced with ‘in’ in line

� Comment 4: abstract, conclusion section.

� Replace “around” with “more than”

� Comment5: Introduction section:

Dear editor and reviewers, all comments and suggestions given in introduction section were accepted and amended accordingly

� Remove “heavily” in line 52

� Replace 49,578, 490 with “more than 1.4 million” in line 53

� Insert with lung injury in line 56

� Remove and critical cases with

� Comment 6: method section:

Dear editor and reviewers, all comments and suggestions given in method section were accepted and amended accordingly

� Insert “personal identifying” in line 87: accepted and inserted

� Delete “time”, “its” in line 107 and 108

� Replace Platelet with platelets in line 108

� Comment 6: Result section:

Dear editor and reviewers, all comments and suggestions given in result section were accepted and amended accordingly

� Delete Y in line 126

� Delete N=455 in table 1

� Replace “higher” with “elevated”

� Move heading of table 3 to the top

� Comment 6: Discussion section:

Dear editor and reviewers, all comments and suggestions given in discussion section were accepted and amended accordingly

� Replace “and” with “is” in line 153

� Replace in “patients with COVID” with “and” in line 151

� Delete “resulting in increased mortality and hospitalization and ICU admission” in line 153

� Change manifest in to manifests and increase in to increases

� Delete “(9.5%-47%)” in line 160

� Insert “More frequently” in line 176 and 177

� Rephrase the sentences from line 188-193

Before: The degree of coagulation abnormalities in critically ill non-COVID patients correlates with disease severity and predict the risk of thrombosis, the need for ventilator support, and mortality. Published studies support that COVID-19-associated coagulopathy is characterized by a decreased platelet count (9, 36-38). Patients with critical COVID-19 infection and a cytokine storm have an extreme hyper-coagulable state.

Modified: Published studies indicate that COVID-19-associated coagulopathy is characterized by a decreased platelet count (9, 36-38)and a cytokine storm with an extreme hyper-coagulable state.

� Comment 6: Discussion section:

� Replace “APTT” with “clotting time assays”

Response: Dear editors and reviewers all of the above listed comments, recommendations and suggestions are accepted, replaced and corrected and we thank you very much for your valuable comments & time.

Looking forward to hearing from you. Thank you again for your consideration!

Sincerely,

Shambel Araya (BSc, MSc, PhD fellow)

PLoS One. doi: 10.1371/journal.pone.0252939.r007

Decision Letter 3

Elizabeth S Mayne

26 May 2021

Blood coagulation parameter abnormalities in hospitalized patients with confirmed COVID-19 in Ethiopia

PONE-D-20-35898R3

Dear Dr. Araya,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Elizabeth S. Mayne, M.D.

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

Reviewer #2: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #2: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

Reviewer #2: Yes

**********

6. Review Comments to the Author

Reviewer #2: The information contained in the article will add to much needed local African data pertaining to COVID-19 and assist in appropriate care of patients in order to improve clinical outcomes.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #2: No

Attachment

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PLoS One. doi: 10.1371/journal.pone.0252939.r008

Acceptance letter

Elizabeth S Mayne

28 May 2021

PONE-D-20-35898R3

Blood coagulation parameter abnormalities in hospitalized patients with confirmed COVID-19 in Ethiopia

Dear Dr. Araya:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

If we can help with anything else, please email us at plosone@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Elizabeth S. Mayne

Academic Editor

PLOS ONE

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

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Data Availability Statement

All relevant data are within the manuscript.

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PERMALINK

Blood coagulation parameter abnormalities in hospitalized patients with confirmed COVID-19 in Ethiopia

Shambel Araya

Mintesnot Aragaw Mamo

Yakob Gebregziabher Tsegay

Asegdew Atlaw

Aschalew Aytenew

Abebe Hordofa

Abebe Edao Negeso

Moges Wordofa

Tirhas Niguse

Mahlet Cheru

Zemenu Tamir

Roles

Abstract

Background

Methods

Result

Conclusion

Introduction

Methods

Ethical consideration

Study population

Sample collection and coagulation profile analysis

Laboratory analysis

Statistical analysis

Results

Socio-demographic and clinical characteristics of study participants

Table 1. Socio-demographic characteristics of study participants.

Table 2. Socio-demographic characteristics and disease severity of COVID-19 patients.

Magnitude of coagulation abnormalities

Table 3. Result of coagulation parameters in patients with severe COVID-19 according to different variables.

Discussion

Conclusion

Data Availability

Funding Statement

References

Decision Letter 0

Elizabeth S Mayne

Roles

Author response to Decision Letter 0

Decision Letter 1

Elizabeth S Mayne

Roles

Author response to Decision Letter 1

Decision Letter 2

Elizabeth S Mayne

Roles

Author response to Decision Letter 2

Decision Letter 3

Elizabeth S Mayne

Roles

Acceptance letter

Elizabeth S Mayne

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