REPUBLIC OF THE PHILIPPINES

Department of Education
Region V (Bicol)
Schools Division of Ligao City
BICOL REGIONAL SCIENCE HIGH SCHOOL
Tuburan, Ligao City
TEL: (052) 742- 4205 E-Mail: 301814@deped.gov.ph Website: brshs.depedligaocity.net

Effectiveness of Therapeutic Anticoagulation in COVID-19 Patients:

A Systematic Review

Tyrone Jay M. Almuena

Firdaus-c B. Ibrahim

Dewey Cleighton O. Lansangan

Hannah Joy S. Mariscotes

Hannah Lois L. Maronilla

Andrea Carmela B. Munda

Alliyah Jan L. Salting

Anisha Shen A. Tagum

Inquiries, Investigation, and Immersion

Donna Marichu P. Ramos

December 2022

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Table of Contents

Introduction……………………………………………………..…………………………3

Research Questions…………………………………………………………………5

Significance of the study……………………………………………………………6

Systematic Review Overview

Systematic Review……………………………………………………..…………..7

Definition of terms………………………………………………………………….9

Systematic Review Process…………………………………………….…………10

Methodology

Research Questions and Objectives……………………………………………….11

Preliminary Research and Idea Validation………………………………...……...11

Exclusion and Inclusion Criteria…………………………………………………..12

Search Strategy…………………………………………………………………....12

Data Extraction and Quality Assessment ………………………………………...13

Content Analysis…………………………………………………………....…..13

Manuscript Writing, Revision, and Submission of Script………………………...14

Time Schedule for Research Proposal………………….……….....……………...14

Time Schedule for Systematic Review……………………………………………15

References……………………………………………………………………….……..…16

Appendices

Appendix A: Exclusion and Inclusion Criteria……………………………………19

Appendix B: Risk of Bias for Included Studies………………………...…………20

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Effectiveness of Therapeutic Anticoagulation of COVID-19 Patients:

A Systematic Review

Viral acute infections are associated with a procoagulant state, and the resultant

hypercoagulability may, in severe cases, accelerate, leading to disseminated intravascular

coagulation. The excessive activation of coagulation involves the consumption of platelets and

coagulation factors, which may shift the hyper-coagulant state into a hypocoagulant state (Levi

M., 2018). One example of this is the Coronavirus disease (COVID-19), an infectious disease

caused by the SARS-CoV-2 virus. Approximately one-fifth of the infected individuals develop

severe to critical diseases requiring intensive care support as a cause of pneumonia (Huang C,

Wang Y, Li X et al., 2020). According to recent studies conducted in China, severe COVID-

19 is commonly complicated by coagulopathy with elevated D-dimer; moreover, a pooled

analysis showed that D-dimer values are considerably higher in COVID-19 patients with severe

disease than those without (Yin S. et al., 2020).

According to C. Godino CT and Andrea Scotti (2020), preliminary observations on

anticoagulant therapy appear to be associated with better outcomes in moderate and severe

COVID-19 patients with signs of coagulopathy and in those requiring mechanical ventilation.

The pathophysiology underlying the prothrombotic state elicited by SARS-CoV-2 outlines

possible protective mechanisms of antithrombotic therapy (in primis anticoagulants) for this

viral illness. The indications for antiplatelet/anticoagulant use (prevention, prophylaxis,

therapy) are guided by the clinical context and the COVID-19 severity. Furthermore, medical

therapies are revealed to effectively prevent the effects of the coagulation observed in COVID-

19 patients. Preliminary data on antithrombotic therapy appear to be associated with better

outcomes in moderate and severe COVID-19 patients with signs of coagulopathy (elevated D-

dimer and fibrinogen and low antithrombin levels) and in those requiring mechanical

ventilation. (Klok F, Kruip M., 2020) There is a direct correlation between SARS-CoV-2

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infection and the development of thrombotic events. According to Helmes et al and Fraissé et

al6, respectively, 42.6% and 40% of the individuals under investigation experienced

thrombotic events.

While all coagulation parameters can be affected by COVID-19, there is considerable

variability in the extent of these alterations and their correlation to disease severity and

mortality. Disseminated intravascular coagulation and macrovascular thrombosis, on the other

hand, can also occur in patients with severe COVID-19, which leads to substantial morbidity

and mortality (C. Huang, Y. Wang, et al, 2020). Additionally, a research report by Tang et al.

(2020) showed that 71.4% of patients who died of coronavirus from thrombosis and

hemostasis.

In the systematic review conducted by Gabbai-Armelin et al., it was mentioned that the

clinical characteristics of COVID-19 vary from asymptomatic infections to more severe

conditions. It was also discussed that in mild symptoms, fever, fatigue, cough, sore throat, and

headache are included. In more complicated cases, however, symptoms of pneumonia and

shortness of breath may be observed. Coagulation disorders and thrombotic events have also

been reported in patients with the severe COVID-19 pattern.

According to McBane et al., A key characteristic of COVID-19 has been identified as

the higher risk of thrombosis. Patients with COVID-19 frequently experienced coagulopathy

and thrombotic episodes, and this frequency increased in those with more advanced disease

stages.

In coagulopathy therapy approaches, there is a developing awareness of the pattern of

COVID-19. The result is worse for infected patients with extra risk factors since COVID-19 is

linked to a hypercoagulable state (Miesbach W. & Makris M., 2020). The COVID-19

Treatment Guidelines Panel advises that hospitalized COVID-19 patients continue taking

anticoagulant or antiplatelet therapy unless substantial bleeding occurs, or other

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contraindications are present. While on anticoagulant treatment for Thrombosis, when

diagnostic imaging is not an option, the Panel advises treating COVID-19 individuals who are

highly suspected of having thromboembolic disease with therapeutic anticoagulation.

(Antithrombotic Therapy, 2022). Anticoagulation was linked to decreased mortality and

intubation among hospitalized COVID-19 patients. Therapeutic anticoagulation was linked to

a decreased death rate compared to prophylactic anticoagulation, however this association was

not statistically significant. Thromboembolic illness was frequently found during autopsies.

(Nadkarni G, et al., 2020). In addition, Lazaridis D et al. (2021) discovered Prophylaxis and

higher intensity dosed anticoagulation are linked to increased pulmonary oxygenation, lower

coagulopathy indicators, and decreased mortality in COVID-19 patients despite the low quality

of the studies evaluated. However, Reis S. et al. (2022) state that critically sick patients might

not benefit from therapeutic-dose anticoagulation, although hospitalized, moderately ill

COVID-19 patients might. Major bleeding risks must be considered.

In view of this, the researchers will be conducting a systematic review of the

effectiveness and roles of Therapeutic Anticoagulation in preventing major thrombotic

complications on COVID-19 patients.

Research Questions

The review aims to generate findings on the effectiveness of Therapeutic

Anticoagulation in preventing major thromboembolic complications in COVID-19 patients.

With connection to the primary goal of this review, the researchers aim to provide answers to

the following questions:

1. How effective is therapeutic anticoagulation in preventing major

thromboembolic complications in COVID 19 Patients?

2. What are the roles of therapeutic anticoagulation in preventing major

thromboembolic complications in COVID 19 patients?

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3. What are the effects of screening and evaluation for Venous Thromboembolism

of both Hospitalized and Non-hospitalized Patients?

Significance of the Study

Results of this study will benefit the following:

General Public. This study will give them a deeper understanding of the underlying

thrombotic activities of COVID-19 patients that can enhance the potential effectiveness of the

public health messages.

Public Health Official. Results of this study can also provide feedback on the

alternative implementation of reliable and health value that can be used by the people in the

community.

COVID-19 Patients. Findings of this review can help patients be well aware of

thrombotic events associated with COVID-19 and current treatments available.

Department of Health (DOH). The promotional strategy to mitigate effectiveness of

thrombotic agents against COVID-19 virus to the department's communication response and

increase the population's knowledge of the said virus.

People Suffering from Cardiovascular and Lung Diseases. Since the anticoagulants

aims to decrease the production of blood clots this study can help for the remediation of the

disease.

Health Care Practitioners. This study will be of great help in maximizing the

utilization of local resources, which will lead to socioeconomic development of the community.

Pharmaceutical Industry. To manufacture new medicines and products regarding the

study.

Future Researchers. The result of the study may serve as a reference or provide

information that would be necessary for their studies, project developments, and further

elaboration that will provide an in-depth analysis of the study.

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Systematic Review Overview

Systematic Review

As medical advancements continue to develop, the complexity of the contexts at the

same time makes it more and more challenging to understand. Hence, this systematic review

aims to provide clinical information and will synthesize current and existing data on

anticoagulant effects in COVID-19 patients. It will not, however, seek to create new

knowledge. The research question was patterned with the use of SPIDER method (Sample,

Phenomenon of Interest, Design of Study, Evaluation Type, Research Type) that will aid in the

search of relevant studies. After identifying the specific question to be answered, abstract and

title screening will be done while excluding research in the criteria. After compiling the

included research, the researchers will extract data and summarize obtained knowledge.

Defining Coagulation and Anticoagulants

Preliminary findings on anticoagulant medication seem to be associated with better

outcomes in moderate and severe COVID-19 patients with evidence of coagulopathy and in

those requiring mechanical breathing, according to C Godino and Andrea Scotti (2020). The

potential preventive mechanisms of antithrombotic medication (in particular anticoagulants)

for this viral infection are outlined by the pathophysiology of the prothrombotic state induced

by SARS-CoV-2. The clinical context and the COVID-19 severity serve as a guidance for the

indications for using antiplatelet/anticoagulant medications (prevention, prophylaxis, and

treatment).

Medical therapies are revealed that it effectively prevents the effects of the coagulation

observed in COVID-19 patients. Preliminary data on antithrombotic therapy appear to be

associated with better outcomes in moderate and severe COVID-19 patients with signs of

coagulopathy (elevated D-dimer and fibrinogen and low antithrombin levels) and in those

requiring mechanical ventilation. (Klok F, Kruip M., 2020).

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Mechanism of Coagulation in COVID-19 Virus

When compared to ordinary pneumonia, COVID-19 pneumonia appears to have unique

characteristics. COVID-19 patients clearly exhibit dysregulated uncontrolled host response,

resulting in increased production of various inflammatory cytokines and chemokines. The

release of these molecules causes a macrophage activation syndrome-like picture, which causes

endothelial cells, macrophages, and neutrophils to express tissue factor within the lungs,

causing pulmonary coagulopathy and microvascular thrombosis to begin and worsen. IL-6 is a

major cytokine that is significantly enhanced in severe COVID-19 infection and serves as a

key activator of coagulation by stimulating tissue factor expression and enhancing fibrinogen

and platelet formation. This could explain the considerable disparity in coagulation.

Anticoagulants in COVID-19 Patients

There is proof that hospitalized COVID-19 patients frequently have considerable

infection-related coagulation as well as an elevated risk of microvascular thrombosis,

according to Tan and Wong (2020). Anticoagulants might help in this situation by reducing the

burden of thrombotic disease and coagulation hyperactivity. They might also directly reduce

inflammation, which would help prevent sepsis and the development of coagulation.

Unfractionated and low-molecular-weight heparins in particular are known to exhibit a variety

of non-anticoagulant properties as well as anti-inflammatory effects. Heparins do, in fact,

diminish platelet-neutrophil cross-talk, lower NETosis and the neutrophil response, and

produce less IL-1, IL-6, E-selectin, and ICAM-1. Heparins, an anticoagulant, have been shown

to effectively compete with heparan sulfate, reducing viral attachment and cell infection

(Higgins & u 2020). Therefore, combining this knowledge with the actions of UFH and

LMW—which are all inhibitors of several proteases—the study hypothesizes that this can be

another direct mechanism of heparins to prevent cellular entrance of SARS-CoV2.

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Impact of Anticoagulants in COVID 19 Patients

Cytokines, particularly the interleukin (IL) family, are recognized to play a major role

in inflammation and to have a direct effect on plasma molecules, erythrocytes, and platelets.

(Bester J., Matshailwe C. et al., 2020). Several inflammatory diseases are characterized by

hypercoagulability and poor fibrinolysis. It has been shown that IL-1, IL-6, and IL-8 might

produce hypercoagulation, which results in dispersed fibrin clots. Patients with severe COVID-

19 showed increased IL-6 levels, implying that the hypercoagulation status of COVID-19

patients may be associated to heightened cytokine levels. (Zhou F. Yu T et al., 2020) Other

mechanisms, in addition to anticoagulant and anti-inflammatory qualities, can explain why

heparins are beneficial to COVID-19 patients. Heparins' direct antiviral activity is mediated by

heparan sulfate, a polysaccharide family that is widespread on the cell surface and extracellular

matrix of all species. Heparan sulfate has been shown to act as the first point of interaction

between target cells and a variety of human viruses (including herpesviruses, influenza A virus,

hepatitis C virus, human immunodeficiency virus, and dengue), including SARS-CoV-2.

Definition of terms

Systematic Review. a type of review that uses repeatable methods to find, select, and

synthesize all available evidence. It answers a clearly formulated research question and

explicitly states the methods used to arrive at the answer.

Anticoagulant. It stops the blood from clotting. It will be used in the experiment to

prevent the formation of blood clots of the human blood samples.

COVID-19. Coronavirus disease (COVID-19) is an infectious disease caused by the

SARS-CoV-2 virus. Most people infected with the virus will experience mild to moderate

respiratory illness and recover without requiring special treatment.

Coagulopathy. A condition when the blood's ability to clot (coagulate) is impaired.

This disorder may result in a propensity for prolonged or profuse bleeding (bleeding diathesis).

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Thrombolytic Agents. It works by reducing thrombus formation. Targeting the

components of both arterial and venous thrombi, antithrombotic drugs encompass antiplatelets,

anticoagulants, and fibrinolytic drugs.

Systematic Review Process

Figure 1. Systematic Review Process

The aim of this study is to undertake a thorough analysis of the effectiveness and roles

of therapeutic anticoagulation in preventing significant thrombotic events in COVID-19

patients. This study will formulate research questions using the SPIDER (Sample, Phenomenon

of Interest, Design, Evaluation Type, and Research Type) model. Then, preliminary inquiries

will be asked to ensure that no other study has been evaluated and to validate the current study.

For evaluating the research papers and journals, the researchers will consider exclusion and

inclusion criteria for selecting relevant and related studies that will contribute to the systematic

review. In addition, sites such as PubMed, Embase, Science Direct, Google Scholar, and ERIC

will be utilized in the current study’s approach. Next, Data Extraction and Quality Assessment

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will be performed to guarantee the absence of confounding variables, and this data will be put

into Excel sheets for evaluation.

Since the current systematic review is qualitative study, the researchers will explain the

data through content analysis. Further, due to expected bias and human error, a Systematic

Review Research expert will evaluate and identify errors in the publication. In this approach,

the evaluation and discussion will be more reliable.

Methodology

Research Questions and Objectives

Researchers will conduct a systematic review of the current evidence on the

effectiveness of therapeutic anticoagulation on COVID-19 patients. The review will include

quasi-experimental studies to generate findings on the impact and role of Thrombotic agents in

preventing major thrombotic complications on COVID-19 patients. It will use methods of

qualitative synthesis to combine and interpret the evidence from included studies.

The study intended at responding to the query: What are the roles of Therapeutic

Anticoagulation in preventing major thromboembolic complications in COVID-19 patients?

Based on the SPIDER (Sample, Phenomenon of Interest, Design, Evaluation type, and

Research type) strategy for the systematic review, this question was created, with S (studies

related to therapeutic anticoagulation), PI (therapeutic anticoagulation in COVID-19 patients),

D (a systematic review), E (content analysis in effectiveness and roles of therapeutic

anticoagulation in COVID-19 patients), and R (qualitative analysis).

Preliminary Research and Idea Validation

Online research was done before the actual conduct of the systematic review. The

method was used to determine whether the current study is still relevant and whether no

research has been conducted on it. The researchers began by searching Google Scholar and

PubMed for studies titled "thrombotic activities of COVID-19 patients." While doing so, they

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discovered that patients infected with the COVID-19 virus are prone to coagulation and are at

risk of bleeding. This insight is significant for a deeper understanding of the effects of

thrombolytic agents on COVID-19 patients.

Exclusion and Inclusion Criteria

Exclusion and Inclusion Criteria will be conducted for identifying the study population

in a consistent, reliable, and objective manner.

Exclusive criteria refrain the researchers from bias in conducting the systematic review.

Hence, the criteria include: a) studies in non-human subjects or in vitro studies. b) abstract-

only papers or articles without available full text. c) case reports, case series, and systematic

review studies. d) studies with unreliable, duplicate, overlapping data e) non-English Language

studies.

Inclusive criteria contain information related to the research study and would answer

the research questions. Thus, this includes: a) observational human studies in accordance with

thrombotic activities of COVID-19 patients. b) Scientific articles written in English. c) Studies

published from 2019-2022. d.) Studies associated with thrombotic events in patients diagnosed

with COVID-19.

Search Strategy

A standard search strategy will be used in PubMed, Google Scholar, Embase, ERIC,

and Science Direct then later it will be modified according to each specific database to get the

best relevant results. The basic search strategy will be developed using controlled vocabulary

based on the Medical Subject Headings (MeSH) and on the formulation of the research

questions to identify relevant studies. The following terms will be utilized: Covid-19,

Thrombosis, thrombolytic Agents, Coagulation, and Anticoagulants. The papers will be

selected by the reviewers by evaluating the titles and abstracts. Further, manual elimination

will be conducted to prevent duplication of studies and articles.

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Data Extraction and Quality Assessment

The researchers will pool adjusted and unadjusted data to be used in the analysis of the

review to ensure confounding results. Two impartial reviewers will carry out the process. The

extracted data will then be put into an excel sheet and classified into the study characteristics

and quality assessment. Data in form of graphs and plots shall be extracted utilizing the Web

Plot Digitizer application. The following data will be retrieved from individual studies: a) year

of publication. b) study design c) country conducted. d) sample size. e) control group. f) role

of COVID-19 on thrombosis. g) efficacy of therapeutic anticoagulants in patients diagnosed

with COVID-19. h) main conclusions and outcomes.

To assess the risk of bias, the quality of individual studies will be assessed using an

appropriate quality appraisal tool. 2-3 independent reviewers shall conduct the assessment

using the NIH tool for observational and cross-sectional studies assessment tool (APPENDIX

B) designed for use in systematic reviews. The researchers will categorize each classification

as yes, no, or not applicable. An overall score is computed by summarizing the scores of all the

items, where yes equals one and no and NA = zero. Each publication will be assigned a score

to categorize it as poor, fair, or good research, with a value ranging from 1 to 10.

The results shall determine eligible studies consistent with the standard quality

appraisal for studies reporting on thrombotic events in COVID-19 patients.

Content Analysis

Framework content analysis will be undertaken to distill the key themes of the

reviewed studies. The content analysis of the selected studies suggests that research on

anticoagulation can be categorized into 14 broad dimensions: (i) author; (ii) year of publication;

(iii) type of study; (iv) LoE, Level of evidence according to Oxford Center for Evidence- Based

Medicine; (v) sample size; (vi) mean age; (vii) most frequent comorbidities; (viii) death toll;

(ix) control group; (x) exams performed; (xi) medication; (xii) prognostic factor; (xiii)

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influence of COVID-19 on thrombosis; and (xiv) main conclusions and outcomes. Electronic

databases shall be thoroughly searched in order to locate studies discussing the effects of

anticoagulation on COVID-19 patients. Findings will be synthesized using qualitative content

analysis.

Manuscript writing, Revision, and Submission to a Journal

For writing the four sections: introduction, systematic review overview, methods,

results, discussion and conclusion, the researchers shall send it to a Systematic Review expert

to revise it and choose a suitable journal for the manuscript which fits with considerable impact

factor and fitting field and they will pay attention by reading the author guidelines of journals

before submitting the manuscript.

Plan of Work/Time Schedule for Research Proposal

DATE DELIVERABLES/ACTIVITIES

September 14, 2022 Title Formulation and Research Agenda

September 18, 2022 Research Questions

September 20, 2022 Crafting of Literature Review

October 10, 2022 Revision and Finalization of Research Questions

October 19, 2022 Research and Finding of Review of Related Literature

October 30, 2022 Compilation of Journals, Articles and Research Studies

November 8, 2022 Writing of Introduction

November 14, 2022 Research about Systematic Review

November 22, 2022 Writing Chapter I

November 26, 2022 Finalization of Chapter I

November 28, 2022 Writing of Chapter II

November 30, 2022 Crafting of the Whole Research Proposal

December 1, 2022 Finalization of Research Proposal

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December 5-6, 2022 Research Proposal Defense

Plan of Work/Time Schedule for Systematic Review

DATE DELIVERABLES/ACTIVITIES

December 9 - 15, 2022 Searches for Published and Unpublished Studies

December 10, 2022 Preliminary Research and Idea Validation

December 11, 2022 Pilot Test of Exclusion and Inclusion Criteria

December 12, 2022 Exclusion and Inclusion Assessments

January 9, 2023 Data Extraction and Quality Assessments

January 10 - 12 , 2023 Follow Up of Missing Information

January 13 - 15, 2023 Finding Systematic Review Research Expert

January 16 - 18, 2023 Assessment and Detection of Mistakes in the Paper by a

Systematic Review Research Expert

January 23, 2023 Editing and Finalization of the Systematic Review

January 24, 2023 Analysis

January 25 - 27, 2023 Preparation of Review Report

February 1 - 3, 2023 Keeping the Review Up to Date

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References

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Bendapudi PK, Bornikova L, Gupta S, Leaf DE, Kuter DJ, Rosovsky RP. COVID-19

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Huang, C., Wang, Y., Li, X. et al. (2020, January 24). Clinical features of patients infected

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Yasuda, H., Mayumi, T., & Okano, H. (2022). Efficacy of different anticoagulant doses for

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Appendices

Appendix A. Exclusion and Inclusion Criteria

Exclusion Criteria Inclusion Criteria

a. studies in non-human subjects or in a. observational human studies in

vitro studies. accordance with thrombotic activities

of COVID-19 patients.

b. abstract-only papers or articles b. scientific articles written in English.

without available full text

c. case reports, case series, and c. studies published from 2019-2022.

systematic review studies.

d. studies with unreliable, duplicate, d. studies associated with thrombotic

overlapping data events in patients diagnosed with

COVID-19.

e. non-English Language studies.

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Appendix B. Risk of bias for included studies: NIH Quality Assessment Tool for

Observational Cohort and Cross-sectional Studies

Other (CD, NR,

Criteria Yes No
NA)*

1. Was the research question or objective in this paper clearly stated?

2. Was the study population clearly specified and defined?

3. Was the participation rate of eligible persons at least 50%?

4. Were all the subjects selected or recruited from the same or similar
populations (including the same time period)? Were inclusion and exclusion
criteria for being in the study prespecified and applied uniformly to all
participants?

5. Was a sample size justification, power description, or variance and effect

estimates provided?

6. For the analyses in this paper, were the exposure(s) of interest measured
prior to the outcome(s) being measured?

7. Was the timeframe sufficient so that one could reasonably expect to see an
association between exposure and outcome if it existed?

8. For exposures that can vary in amount or level, did the study examine
different levels of the exposure as related to the outcome (e.g., categories of
exposure, or exposure measured as continuous variable)?

9. Were the exposure measures (independent variables) clearly defined, valid,

reliable, and implemented consistently across all study participants?

10. Was the exposure(s) assessed more than once over time?

11. Were the outcome measures (dependent variables) clearly defined, valid,
reliable, and implemented consistently across all study participants?

12. Were the outcome assessors blinded to the exposure status of participants?

13. Was loss to follow-up after baseline 20% or less?

14. Were key potential confounding variables measured and adjusted

statistically for their impact on the relationship between exposure(s) and
outcome(s)?

Quality Rating (Good, Fair, or Poor)

Rater #1 initials:

Rater #2 initials:

Additional Comments (If POOR, please state why):

*CD, cannot determine; NA, not applicable; NR, not reported

Bicol Regional Science High School:

A school where quality is a habit, and excellence is a lifestyle