Incidence and Risk Factors Associated with Thromboembolic Events among Patients with COVID-19 Inpatients: A Retrospective Study

HIGHLIGHTS

• Over a quarter of coronavirus disease-2019 (COVID-19) patients developed thromboembolic events (TEs) despite adequate anticoagulant therapy.

• Factors associated with increased risk of TEs include hypertension (HTN) and ischemic heart disease (IHD); as well as laboratory parameters such as elevated ferritin, lactate dehydrogenase (LDH), and creatinine.

• About four-fifths of COVID-19 patients who developed TEs died.

INTRODUCTION

The COVID-19 is an infectious disease that currently has been declared a global pandemic. A significant issue, particularly in moderate to severe cases of COVID-19, is the prevalence of “severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) coagulopathy”.¹ Also, SARS-CoV-2 coagulopathy has been associated with a higher risk of morbidity and mortality in COVID-19 patients.² The majority of TEs documented in COVID-19 patients is venous thromboembolism (VTE). The inpatient rates of VTE vary widely between 1.7 and 46%, with significant mortality presumptive to be secondary to VTE.³ On the contrary, autopsy studies indicated 71.4% of COVID-19 patients who died exhibited disseminated intravascular coagulation (DIC) compared to 0.6% in survivors.³

Although VTE occurs in less than 5% of patients admitted for infectious respiratory diseases, the incidence is as high as 20% in COVID-19 patients even with adequate thromboprophylaxis.^4,5 According to a meta-analysis,⁶ the pooled incidence rates of pulmonary embolism (PE) and deep vein thrombosis (DVT) in patients with COVID-19 were 16.5 and 14.8%, respectively, while the incidences for both exceeded 20% in patients admitted to the intensive care unit (ICU).⁶ In fact, postmortem studies have reflected classical macrovessel disease and pulmonary microthrombi suggested fatal PE in VTE-related mortality in COVID-19 patients.

Recent reviews have highlighted important procoagulant mechanisms that are upregulated in COVID-19.^7,8 Similarly, many non-specific inflammatory biomarkers are elevated in hospitalized COVID-19 patients, including C-reactive protein (CRP) and erythrocyte sedimentation rates, as well as several procoagulant factors such as von Willebrand factor and factor VIII.^9,10 Likewise, many proinflammatory cytokines are elevated, including tumor necrosis factor-alpha (TNF-α) and interleukin 2R (IL-2R), IL-6, IL-8, and IL-10.58, 59 TNF-α, and IL-6, in particular, are elevated to a degree that differs from bacterial sepsis or influenza.^11,12 The thromboembolic effects of many of these cytokines have been documented, alone or in combination.¹³

Significant predictors of VTE in COVID-19 patients include D-dimer, sepsis-induced coagulopathy scores, lymphocyte count, and prothrombin time (PT). However, such predictors are based on smaller cohorts.³ Moreover, there is inconclusive evidence regarding higher rates of thrombosis and its associated mortality in COVID-19 patients. The extant literature suggests that full-dose anticoagulation therapy reduces VTE and mortality in COVID-19 patients, some authors have found no benefit with prophylactic or therapeutic doses of anticoagulants in the referred patients. Rather, the rate of mortality due to VTE from preemptive therapy since admission was 2.3 times higher.³ This finding raises the dilemma over the beneficial role of anticoagulants. Also, the current literature indicates inconclusive evidence regarding the predictors and outcomes of VTE in COVID-19 patients.^3–6 Therefore, this study aimed to comprehensively assess the prevalence, and risk factors associated with vascular TEs among patients with COVID-19.

MATERIALS AND METHODS

RESULTS

Following confirmation of COVID-19 diagnosis, 56 (27.05%) of the 207 admitted patients developed TEs. The demographic, clinical history, and laboratory parameters in patients with and without TE are presented in Table 1. Overall, 117 (56.52%) of the admitted patients had severe or critical COVID-19 disease requiring ICU admission. Also, 50 (42.70%) of patients with severe or critical COVID-19 disease requiring ICU admission had TE while 67 (57.3) had no TE (p < 0.001).

Table 1 depicted that there were no differences between males and females in terms of TEs (p = 0.561). The mean age-group of the study participants was 54.42 ± 15.01. However, the mean age of patients who experienced TE was significantly more than those who did not experience TE. Table 1 further depicted that the incidences of TE were significantly higher in individuals more than 50 years, suggesting age is a significant predictor of VTE. The analysis of laboratory values showed that the levels of white blood cells (WBC), neutrophil, aspartate transaminase (AST), ferritin, creatinine, and CRP levels were significantly elevated in patients experiencing TE compared to their counterparts who did not experience TE. However, the Hb levels were significantly lower in the former compared to the latter. With regard to comorbidities, the study reflected that the incidences of TE were significantly higher in patients suffering from diabetes, hypertension (HTN), IHD, and chronic kidney disease (CKD). Similarly, Table 1 showed that mortality was significantly higher in those with TE compared to those without TE (80% vs 17.2%, p = 0.001). However, to explore the risk of comorbidities and demographics, ORs were analyzed for the respective variables of TE predisposition (Table 2).

The analysis of the ORs indicated that HTN, IHD, dyspnea, altered consciousness, ICU admission, Hb levels at admission, creatinine levels at admission, and lactate dehydrogenase (LDH) were significantly associated with a higher risk of VTE. The receiver operating characteristic (ROC) analysis was similarly done to estimate the laboratory parameters that could be associated with a higher or lower risk of VTE (Table 3).

Table 3 shows the ROC curve analysis for various laboratory parameters. All the results were found to be statistically significant (p < 0.05) except for the levels of fibrinogen and D-dimer.

Considering the high risk of VTE, the study estimated the extent of TE prophylaxis received by the patients. The various types of anticoagulants used to treat the patients. The most commonly used drug was low molecular weight heparin (LMWH, 47.34%), followed by heparin SC (23.67%), heparin infusion (17.36%), novel anticoagulants (NOAC, 0.48%), warfarin (0.48%), and others (9.18%). We further analyzed the differences in laboratory parameters based on the initiation of anticoagulant therapy (Table 4).

Table 4 shows a comparison between patients (paired analysis) with and without TE before and after the initiation of anticoagulant therapy. The analysis showed that anticoagulant therapy exhibited comparable biochemical parameters between those who experienced VTE and those who did not. However, those with TE had significantly higher levels of lactic acid even after thromboprophylaxis.

DISCUSSION

This study showed that there was a high prevalence of clinically relevant TE in COVID-19 patients who were admitted to the hospital for moderate and severe/critical illness. Despite prophylactic or therapeutic anticoagulants, these complications occurred. The underlying mechanism of TE remains unclear. In the presence of severe hypoxemia, capillaries in the lungs may undergo vasoconstriction, reducing blood flow and causing occlusion of the arteries.¹⁸ In addition, hypoxia induces the activation of hypoxia-inducible factors (HIFs). The hypoxic state induces the activation of hypoxia inducible factor 2α (HIF2α) subunits and decreases hydroxylation, thus inducing or inhibiting many genes, including tissue factor (TF) and plasminogen activator inhibitor-1 (PAI-1). The evidence suggests that obesity-related inflammation and endothelial dysfunction impact severity of COVID-19.¹⁹ This finding suggests that obesity either confounds or interacts with VTE risk factors.

An ideal balance exists between the host coagulation pathway and the fibrinolytic pathway that controls fibrin deposition and maintains the viability of the lung epithelium. The binding of urokinase plasminogen activator (uPA) to urokinase plasminogen activator receptor (uPAR) greatly facilitates fibrinolysis on epithelial surface cells, clearing the lung of abnormal fibrin deposits.²⁰ When this fibrinolytic function is impaired during lung inflammation, the alveolar spaces accumulate abnormal amounts of fibrin that lead to an increase in the procoagulant activity.²⁰

In our study, the majority of COVID-19 patients reporting VTE were males, but there were no differences between males and females in terms of TEs. The most susceptible patients were those aged above 50 years. Our findings are consistent with findings of a previous study which found that patients with COVID-19 who were older and had higher CRP and D-dimer levels had an increased risk of DVT.²¹ Although the VTE and PE risks are higher in COVID-19 patients, such risks are often overestimated.²² However, The VTE incidence in our study was 27% is well aligned with previous studies that showed that VTE incidence was 21% in hospitalized COVID-19 patients and rising to 31% in the subpopulation that admitted to ICU. We found that mortality was higher in VTE patients compared to those who did not experience TE (80% vs 17.2%). In a pooled analysis, mortality rates were 74% higher among adult patients with VTEs compared with those without VTEs (23% vs 13%, respectively). The mortality rates reported in this study were higher than reported by previous studies because we incorporated different cases of TE and not just VTE.

In the present study, 39.1% of obese patients developed VTE. Obesity is associated with a dysfunctional endothelium as a result of an alteration caused by several mechanisms, including low-grade inflammation, generated by either the perivascular adipose tissue (PVAT) or the vasculature itself.²³ Because a dysfunctional endothelium is now widely recognized as a risk factor for cardiovascular events in high-risk patients, this alteration may contribute to increased cardiovascular risk.²³

The most common comorbidity that we found to be present among patients with VTE was HTN followed by diabetes mellitus (DM), IHD, chronic kidney disease (CKD), heart failure (HF), bronchial asthma, and chronic liver disease. This is in line with a previous study where the most common comorbidity was HTN, followed by DM, and IHD.²⁴ The majority of thrombotic events found in our study were among the patients admitted to the ICU (p < 0.01). These findings are in line with a previous study in which a cumulative incidence of arterial or venous thrombosis of 31% was found to be present in COVID-19 patients who had been admitted to ICU.²⁵ Another study found VTE in 35 out of 74 patients admitted to the ICU despite being on thrombosis prophylaxis.²⁰ A probable explanation could be that patients with severe COVID-19 pneumonia can trigger a state of sepsis that in turn can release inflammatory cytokines such as IL-6, IL-8, and TNF-α, among others, that lead to hypercoagulability.²⁵ A study by Yin et al. found higher mortality rates and platelet counts in consecutive patients with severe COVID-19 as compared to non-COVID patients.²⁴ Another alternative hypothesis suggests that the virus causes direct alveolar inflammation, leading to hemostasis activation and vascular thrombosis in the lungs.²⁵

It was found that hospitalized COVID-19 patients, who previously used anticoagulants, were associated with a lower risk of hospital mortality.²⁶ Thus, anticoagulant therapy is an important intervention for ensuring improved prognosis in COVID-19 patients. However, some studies have suggested that the dose of anticoagulants could mediate VTE risk rather than the type of anticoagulant therapy.³

Haybar et al. in their study concluded that thromboprophylaxis should be administered from hospitalization until 7–14 days after discharge, especially for patients with high-risk factors such as a previous history of VTE, active cancer, or BMI above 30.²⁷ According to a meta-analysis, if VTE is identified in COVID-19 patients, therapy with parenteral anticoagulants should be initiated, and once stabilized, patients can be transitioned to oral anticoagulant therapy, which could include either a direct oral anticoagulant (DOAC) or vitamin K antagonist depending on patient-specific variables.²⁸

Several drugs such as heparinoids (heparins or pentasaccharides), vitamin K antagonists, and direct anticoagulants are used in the prophylaxis and treatment of VTE. Besides their anticoagulant properties, heparinoids are also known to have an additional anti‐inflammatory potential that may affect the clinical evolution of people with COVID‐19.²⁹ In our study, the most commonly used anticoagulant was LMWH (47.34%) in both groups (TE and non-TE). Similarly, in a previous study of 449 patients with severe COVID-19, the most commonly used form of heparin was LMWH which was used for 7 days or more.³ The 28-days mortality between heparinized and non-heparinized patients did not show any difference. Middeldorp et al. reported that about 20% of the included COVID-19 patients had VTE in spite of routine thromboprophylaxis with LMWH.⁵ However, it remains to be established whether these results may be translated to Caucasian populations, which seldom develop DIC.³⁰ However, we did not compare prophylactic and higher doses of LMWH for preventing thrombotic events in patients with COVID-19, thus the optimal dose is unknown and is a matter of active debate as reported by previous studies.³¹

The D-dimer represents the activation of coagulation and fibrinolysis pathways and is therefore one of the tests used to detect thrombosis in patients.³² Measuring the level of D-dimer and other coagulation parameters from the early stage of the disease can also be useful in controlling and managing COVID-19 disease. Reported evidence of coagulopathy in COVID-19 patients showed an increased level of D-dimer, LDH, mild to no changes in PT and partial thromboplastin time (PTT), and increased levels of antiphospholipid antibodies.^33,34 In our study, except for fibrinogen and CRP, all the other coagulation parameters showed a statistically significant difference in the VTE group before and after using anticoagulants (p < 0.05). Previously, early-phase COVID-19 infections have been shown to cause leukopenia, lymphocytopenia, elevated CRP, increased D-dimer, prolonged PT, and increased fibrinogen levels.^3,35

Zhou et al. reported that ICU patients had higher median (IQR) D-dimer levels than non-ICU patients did [2400 ng/mL (600–14400) vs 500 (300–800), respectively], and the mortality rate was 18 times higher with D-dimer concentration above 1000 ng/mL upon admission.⁹ In the same way, the increase in the levels of ferritin was reported by many other studies in COVID-19 as being the consequence of the cytokine storm.^11,36,37 The presence of elevated ferritin levels has been linked to thrombosis associated with COVID-19 as opposed to thrombosis without COVID-19.³⁸ Nevertheless, the International Society on Thrombosis and Haemostasis (ISTH) does not recommend screening for VTE based solely on elevated D-dimer levels and maintains that VTE should be diagnosed based on clinical suspicion.³⁹ The present study did not estimate the risk of VTE as a function of mechanical ventilation, which could have helped to assess the effect size of other risk factors in comparison to VTE. This is because one study showed that days on MV significantly increased the risk of VTE in COVID-19 patients. The power of the study was more than 80%.

There are numerous ways in which the COVID-19 pandemic can negatively influence the development of thrombotic and TEs.⁴⁰ COVID-19 has an important implication as it is strongly associated with the development of cytokine storm and thereby exacerbating the systemic inflammatory response and management of patients with severe disease.^41,42 The usefulness of anticoagulants and treatment strategies to overcome coagulation needs to be revisited in the context of COVID-19. Future research is warranted to understand the mechanism operating behind such adverse events and possibly to prevent any untoward events. To clarify the underlying mechanisms of VTE in COVID-19 and to determine the optimal antithrombotic regimens, it is important to conduct longitudinal studies and clinical trials.

CONCLUSION

The prevalence of thrombotic complications in COVID-19 patients is high and contributes significantly to mortality and morbidity. Our study findings indicate that despite anticoagulants, a large number of COVID-19 patients develop serious thrombotic complications. Future studies should explore the dose, duration, and type of anticoagulants with respect to TE incidence and associated clinical outcomes. To clarify the underlying mechanisms of TE in COVID-19 and to determine the optimal antithrombotic regimens, it is important to conduct longitudinal studies and clinical trials.

ETHICAL APPROVAL

The study was conducted after obtaining appropriate permission from the Institutional Review Board (IRB).

AVAILABILITY OF DATA AND MATERIALS

All data will be provided upon request.

ORCID

Wail Abdulhafez Tashkandi https://orcid.org/0000-0003-4932-5407

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