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 Table of Contents  
Year : 2023  |  Volume : 15  |  Issue : 1  |  Page : 97-104

Factors of venous thromboembolism among COVID-19 patients

1 Centre for Quality Management of Medicines, Faculty of Pharmacy, University Kebangsaan Malaysia, Kuala Lumpur; Department of Pharmacy, Hospital Sultanah Aminah, Johor Bahru, Malaysia
2 Centre for Quality Management of Medicines, Faculty of Pharmacy, University Kebangsaan Malaysia, Kuala Lumpur, Malaysia

Date of Submission27-Jan-2023
Date of Decision08-Mar-2023
Date of Acceptance10-Mar-2023
Date of Web Publication31-Mar-2023

Correspondence Address:
Farida Islahudin
Faculty of Pharmacy, University Kebangsaan Malaysia, Jalan Raja Muda Abdul Aziz, Kuala Lumpur 50300
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ajprhc.ajprhc_13_23

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Context: Anticoagulants are used to prevent and treat venous thromboembolism (VTE), such as deep-vein thrombosis (DVT) and pulmonary embolism (PE) in COVID-19 for better outcomes. Aim: This study aims to explore clinical outcomes and factors affecting VTE among COVID-19 patients. Settings and Design: The study design involved a retrospective cohort study. Study Methods: Hospitalized COVID-19 patients in a tertiary hospital prescribed subcutaneous (SC) anticoagulants were included. Statistical Analysis Used: Multiple logistic regression was performed to determine factors affecting VTE among subjects. Results: A total of 450 patients were included. Types of anticoagulants include fondaparinux (n = 114, 38.1%), enoxaparin (n = 113, 37.8%), and heparin (n = 72, 24.1%). 423 (94.0%) patients were discharged well, 27 (6.0%) patients were admitted to the intensive care unit (ICU). The primary outcome was the prevalence of VTE, which occurred in 19.3% (n = 87) patients, with 80 (92.0%) reporting DVT and 7 (8.0%) reporting PE. The secondary outcome, which was the average length of hospital stay was 9.9 (±4.7) days. Factors of VTE occurrence were likely in patients not prescribed SC anticoagulants compared to those prescribed with SC anticoagulants (adjusted odds ratio [aOR] 54.330, 95% confidence interval [CI]: 7.086, 416.526), treatment with fondaparinux compared to heparin (aOR 2.502, 95% CI: 1.175, 5.327), and less likely in those discharged well compared to patients in the ICU (aOR 0.139, 95% CI: 0.053, 0.361). Conclusions: Careful monitoring is required to reduce VTE risk in COVID-19 patients.

Keywords: Anticoagulants, COVID-19, effectiveness, pattern use, venous thromboembolism

How to cite this article:
Low LF, Islahudin F, Saffian SM. Factors of venous thromboembolism among COVID-19 patients. Asian J Pharm Res Health Care 2023;15:97-104

How to cite this URL:
Low LF, Islahudin F, Saffian SM. Factors of venous thromboembolism among COVID-19 patients. Asian J Pharm Res Health Care [serial online] 2023 [cited 2023 Jun 8];15:97-104. Available from: http://www.ajprhc.com/text.asp?2023/15/1/97/373370

  Introduction Top

Since 2019, COVID-19 has caused a worldwide pandemic affecting more than 3.8 million deaths globally.[1] Severe COVID-19 infection causes a significant impact on multiple organ systems leading to increase in morbidity and mortality.[2] One of the complications related to COVID-19 is the occurrence of venous thromboembolism (VTE) such as deep-vein thrombosis (DVT) and pulmonary embolism (PE). Approximately one-third of patients, in the intensive care unit (ICU), have reported high rates of VTE even though anticoagulants are prescribed prophylactically, leading to an increased mortality rate.[3] Among these, it is reported that out of the 15.6% VTE observed in the ICU, 6.2% were identified as PE and 9.4% as DVT.[4] VTE has also been reported among non-ICU patients, although to a lesser extent.[5]

COVID-19 mortality is mainly attributed to hypoxemia secondary to acute respiratory distress syndrome in view of thromboembolic formation.[5] The thromboembolic event in COVID-19 patients is triggered by an endothelial injury, stasis, and hypercoagulable state, causing coagulation abnormalities. Clinical evidence strongly proves direct invasion of the virus SARS-CoV-2 into the endothelial cells causing cell injury.[6],[7] Significant changes in circulating prothrombotic factors in severely infected COVID-19 patients occur to increase the risk of coagulation, which is evident in an increased factor VIII, fibrinogen, circulating prothrombotic microparticles, neutrophil extracellular traps, and ultimately hyperviscosity.[8]

Management of thrombotic complications in COVID-19 is with the use of anticoagulants to decrease hypercoagulability and thromboembolic events.[9] In hospitalized COVID-19 patients, both injection and oral anticoagulants are used to treat VTE. The selection of different anticoagulants used for thromboprophylaxis is based on the risk stratification of each infected COVID-19 patient.[10] The prophylactic dose of anticoagulants is usually significantly lower than the therapeutic dose for thromboembolism. Among the commonly injected anticoagulants used are heparin and low-molecular-weight heparins (LMWHs), which have been clinically proven for its preventive effect on VTE.[11] LMWHs have led to a shorter hospital stay compared to those who are left untreated among COVID-19 patients.[12] On the other hand, transfer rates to ICU have also significantly and clinically reduced among COVID-19 patients treated with LMWH.[12] Treatment with anticoagulants has also provided a better prognosis and outcome among COVID-19 patients with comorbidities such as diabetes mellitus and hypertension, as well as in decreasing mortality of sepsis-induced coagulopathy.[12],[13]

In view of the various types of anticoagulants available for the management of VTE, their use has increased significantly since COVID-19. Nevertheless, anticoagulant therapy can cause adverse events such as bleeding. Despite this, there are limited data on the pattern of use of these anticoagulants among COVID-19 patients. In addition, some patients are warranted the use of oral anticoagulants once they are discharged, which requires close monitoring of patients to ensure efficacy and safety. Therefore, this study aims to identify clinical outcomes and factors affecting VTE among COVID-19 patients.

  Methodology Top

Study type and design

This was a retrospective cohort study among hospitalized COVID-19 patients admitted in a tertiary hospital. Adult patients that were confirmed positive for COVID-19 based on a polymerase chain reaction test, admitted into the hospital and prescribed subcutaneous (SC) anticoagulants were included in the study. Patients with incomplete data were excluded. The list of patients was collected and randomized using a random generator.

Ethical approval

The study protocol was approved by the Medical Research Ethics Committee, Malaysia (NMRR-21–1790-61304 [IIR]) and the Universiti Kebangsaan Malaysia Research Ethic Committee (JEP–2022-501). This study was conducted in compliance with the Declaration of Helsinki and the Malaysian Good Clinical Practice Guideline.

Sample size

The sample size was calculated as previously described based on hospitalized COVID-19 patients.[14] The total number of COVID-19 patients until January 2022 was 42,843 cases. Patients that are hospitalized and diagnosed as stage 3 and above are prescribed anticoagulants based on the Ministry of Health Malaysia COVID-19 guideline.[15] Therefore, based on previous reports, approximately 28.1% of COVID-19 patients are hospitalized, of which stages 3 and above would require SC anticoagulants.[16] The sample size required is, therefore, 381 patients. Nevertheless, the sample size targeted was 400 patients to allow for the exclusion of incomplete data.

Data collection

Patient data were collected using a standardized for based on patient medical records. The form was divided into three sections. The 1st section was the sociodemographic data which were age, gender, and ethnicity. The 2nd section included the clinical characteristics of the patients, which were body mass index (BMI), COVID-19 disease stages, comorbidities, pregnancy and obesity, thrombotic event, length of hospital stay, discharge type, and bleeding occurrence. Medication details were collected in the 3rd section, which included the usage and types of SC anticoagulants prescribed, characteristics of SC anticoagulants prescribed, types of oral anticoagulants, usage and types of oral antiplatelet, as well as pattern use of both intravenous and oral medication.

Clinical outcomes

In this study, the primary outcome was the incidence of VTE, and secondary outcomes were: (i) Length of hospital stay; (ii) Types of patient discharged; (iii) Hemorrhagic events, and (iv) Factors affecting VTE occurrence.

Data analysis

Data analysis was performed using SPSS version 28 (IBM Corp, Armonk, NY, USA). Descriptive analysis was performed with categorical data presented as frequencies and percentages, while numerical data were presented as mean and standard deviation. The Chi-square test was used to determine the association between categorical data. Fisher's exact test was applied if the assumptions of the Chi-squared test were not met. A Mann–Whitney or Kruskal–Wallis test was used to compare means between two or more groups of continuous data. Simple and multiple logistic regression was performed on all variables to determine factors affecting VTE among subjects. Factors with a P < 0.05 in the multiple logistic regressions were considered significant.

  Results Top

[Table 1] demonstrates the demographic characteristics of the study population. A total of 450 patients were included in the study, of which 423 (94.0%) patients were admitted into medical wards and the remaining 27 (6.0%) patients were in the ICU. The age range of the study population was between 11 and 92 years old, with the majority being female (n = 304, 67.6%) and Malay (n = 359, 79.8%). The average BMI among the subjects was 31.01 ± 7.78. Patients were mostly diagnosed with category 3 COVID-19 (n = 285, 63.3%). The common comorbidities presented were obesity (n = 233, 51.8%) and hypertension (n = 194, 43.2%).
Table 1: Demographic and clinical characteristics of the study population (n=450)

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[Table 2] depicts the medication characteristic of the study population. A total of 432 (96%) have been prescribed medication for the management of COVID-19. SC anticoagulants were included in 299 patients for VTE prophylaxis only (n = 273, 91.3%) or both prophylaxis and treatment of thrombotic events (n = 26, 8.7%). SC fondaparinux was the most prescribed anticoagulant (n = 114, 38.1%). It was demonstrated that oral anticoagulants and antiplatelets were occasionally used. The most common oral anticoagulant was warfarin (n = 2, 33.3%) and rivaroxaban (n = 2, 33.3%) while the most common antiplatelet was aspirin/glycine tablets (n = 42, 77.8%).
Table 2: Medication characteristics of the study population (n=450)

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The primary outcome of the study, which was prevalence of VTE events was 19.3% (n = 87) of the study population; with 80 (92.0%) patients diagnosed with DVT and 7 (8.0%) diagnosed with PE [Table 3]. The secondary outcomes, length of hospital stay, patient discharged well, and hemorrhagic events, were also analyzed. The average length of hospital stay was 9.87 (±4.73) days. Of the total study population (n = 450), 423 (94.0%) were discharged well, with 27 (6.0%) patients stratified into ICU-level care. Hemorrhagic complications after SC anticoagulants were classified into gastrointestinal bleeding, intracerebral bleeding, and major ischemic events in the study population. No hemorrhagic event occurred with the use of SC anticoagulants in both prophylaxis and treatment among the study population.
Table 3: Overall outcome of the study population (n=450)

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Simple and multiple logistic regressions were performed to determine the factors affecting the occurrence of VTE events in the study population in [Table 4]. Patients were deemed to have VTE if they had either DVT or PE. From the simple logistic regression, variables such as stage of COVID-19 disease, obesity, whether prescribed SC anticoagulant, SC anticoagulant used for VTE prophylaxis and types of discharge were included in the multiple logistic regression (P < 0.25). In the multiple logistic regression, the risk of VTE was significant in patients not prescribed with SC anticoagulants that showed 54.3 times more likely to have a VTE (adjusted odds ratio [aOR] 54.330, 95% confidence interval [CI]: 7.086, 416.526) compared to those prescribed with SC anticoagulants, treatment with fondaparinux was 2.5 times more likely to have VTE compared to heparin (aOR 2.502, 95% CI: 1.175, 5.327), while those discharged well were 0.13 times likely to have a VTE compared to patients in the ICU (aOR 0.139, 95% CI: 0.053, 0.361).
Table 4: Factors associated with venous thromboembolism among the study population (n=450)

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  Discussion Top

VTE among COVID-19 patients is characterized by thrombocytopenia, remarkably high serum D-dimer levels, pro-inflammatory cytokines, and prolongation of prothrombin time that can prompt coagulopathy development such as DVT and PE, which greatly contributes to the morbidity and mortality of the disease.[17] The prevalence of VTE has been varied, with studies showing that 20%–23.9% of hospitalized patients reporting an incident of DVT or PE,[18],[19] similar to the 19.3% VTE in the current work. Postmortem discovery of COVID-19 patients has also revealed microangiopathy, alveolar capillary microthrombi, and different degree of endothelial injury, further emphasizing the importance of anticoagulants in the management of COVID-19 infection.[19] Therefore, hospitalized COVID-19 patients should receive pharmacological VTE prophylaxis with anticoagulants unless contraindicated, to reduce thrombotic complications.[20]

Factors associated with VTE were patients with COVID-19 disease without prescribed SC anticoagulant. According to preliminary evidence, most of the COVID-19 patients would exhibit a sort of mild infection of the disease.[21] However, there have been reports of a disproportionate prevalence of abnormal coagulation tests and VTE in non-ICU COVID-19 patients compared to those admitted to ICU.[22],[23] Moreover, some of the patients who suffered severe VTE episodes were young people without established risk factors.[24] Current work observed that among the COVID-19 patients, only those who were not prescribed with SC anticoagulants, which could have led to a higher risk of VTE event. An earlier study suggested that VTE may be an early complication of COVID-19, given that 50% of VTE episodes were identified within 24 h of hospital admission.[23]

Although anticoagulants have reportedly decreased COVID-19 patients' mortality, evidence on the effectiveness of SC anticoagulants on prophylaxis of VTE has been varied, with the current work demonstrating higher VTE risk in those on fondaparinux. Fondaparinux, a new class of synthetic antithrombotic agents, has often been used to reduce the risk of VTE, with patients clinically demonstrated to have a lower risk of VTE.[24],[25],[26] The incidences of VTE were also significantly decreased with the use of fondaparinux in recent work.[27] However, other studies have reported no difference between fondaparinux and enoxaparin, indicating that the effectiveness of a single daily dose of fondaparinux was comparable with twice-daily dose of enoxaparin in the management of recurrent VTE.[26],[28] In the absence of contraindications, several studies recommend using fondaparinux or LMWH as VTE prophylaxis for anticoagulation in acutely unwell and critically ill patients.[29] On the other hand, unfractionated heparin is commonly recommended for the treatment of VTE in the ICU because of its quick onset of action and lack of known interactions with any of the investigational COVID-19 medications.[25] Despite this, current findings suggest closer monitoring of the use of fondaparinux to ensure risks of VTE are minimized.

Patients that were discharged well were noted to have lower risks of VTE in the current work, compared to ICU patients. There is strong and growing evidence that various factors among patients with COVID-19 may significantly lead to a higher risk of VTE, leading to poorer outcomes such as ICU admissions, similar to the current work. Among factors that predispose ICU COVID-19 patients at a high risk of VTE include age, obesity, a history of prior VTE either personally or within the family, and pregnancy.[20],[21] Immobility, in addition to comorbidities and other serious infections, has also been reported to lead to VTE in ICU COVID-19 patients,[20] compared to those not admitted into the ICU.

In the current work, the lack of SC anticoagulant use as well as the type of SC anticoagulants were factors of VTE that could have led to ICU admissions. Despite the lack of ability to determine cause and effect in these types of studies, close monitoring of patients not on SC anticoagulants should be warranted. However, as with all studies, a few limitations were identified. First, the study is constrained by the small sample size; thus, larger studies should be conducted involving other tertiary hospitals. Furthermore, the results of the current study cannot be used to infer causality. Other medications taken by the patients should also be screened thoroughly as interactions between medications or herbal medicines may also occur, which could reduce the effectiveness or increased bleeding SC anticoagulants used in these patients.[30] As such generalizability of the study should be done with caution.

  Conclusions Top

Patients with COVID-19 infection, that are not treated with SC anticoagulants or those treated with fondaparinux had a higher risk of VTE and risk of ICU admissions. In view of the potential VTE, early treatment is necessary, even in the absence of clinical signs. In order to reduce morbidity, VTE prophylaxis should be administered to all hospitalized COVID-19 patients as soon as is practical unless contraindicated.

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Conflicts of interest

There are no conflicts of interest.

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  [Table 1], [Table 2], [Table 3], [Table 4]


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