Predictive factors of pulmonary embolism in intensive care unit hospitalized patients with coronavirus disease (COVID-19) infection

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RESEARCH ARTICLE

Hippokratia 2025, 29(1): 13-19

Papasarantou A1, Tsikrika S2, Sotiropoulou Z1, Koukaki E1, Bakakos A1, Bartziokas K3, Vontetsianos A1, Zaneli S1, Anagnostopoulou C1, Pontikis K1, Bourikou M1, Rovina N1, Bakakos P1, Papaioannou AI1
11st Respiratory Department, Medical School, National and Kapodistrian University of Athens,
2Respiratory Medicine Emergency Department “Sotiria” Chest Hospital, Athens
3Pulmonologist, Private Sector, Trikala
Greece

Abstract

Aims: Pulmonary embolism is the most severe complication of the severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) infection. In this study, we aimed to evaluate the prognostic value of PE in patients admitted to the intensive care unit (ICU) and identify factors associated with an increased risk of thromboembolic disease in this population.

Methods: We conducted a retrospective case-control study collecting data regarding patients with severe coronavirus disease who were hospitalized in the ICU between September 2020 and January 2022, using the online platform of “Sotiria” Hospital. The diagnosis of thromboembolic disease was based either on a computed tomography pulmonary angiogram or on a positive triplex of the lower extremities.

Results: The study included 297 patients, of whom 33 had pulmonary embolism (PE). Patients with PE required a longer hospital stay, both overall and in the intensive care unit (ICU), higher oxygen concentrations, and had elevated levels of C-reactive protein, D-dimers, and lactate dehydrogenase (LDH) compared to patients without PE. Specifically, the p-values for hospital stay duration, oxygen concentrations, C-reactive protein, D-dimers, and LDH were 0.031, 0.023, 0.02, 0.03, and 0.04, respectively. Patients with cardiovascular comorbidities did not exhibit a significantly higher incidence of pulmonary embolism. Finally, the survival of patients with and without pulmonary embolism hospitalized in the ICU due to SARS-Cov-2 infection did not differ significantly.

Conclusion: In patients with severe SARS-Cov 2 infection admitted to the ICU, pulmonary embolism presence was associated with elevated D-dimer and lactate dehydrogenase levels, greater need for mechanical ventilation, more frequent occurrence of sepsis, barotrauma, and fungal infections, and prolonged ICU stay.
A better understanding of the pathophysiological mechanisms of thrombosis and its correlation with laboratory data is useful for the early recognition of PE in these patients. HIPPOKRATIA 2025, 29 (1):13-19.

Keywords: Pulmonary embolism, thromboembolic disease, intensive care unit, coronavirus disease, COVID-19 infection, severe acute respiratory syndrome coronavirus 2, SARS‑CoV‑2, complication, prognostic value, C-reactive protein, D-dimers, lactate dehydrogenase

Corresponding author: Assistant Professor, Andriana I. Papaioannou, 1st  Respiratory Department, Medical School, National and Kapodistrian University of Athens, “Sotiria” Chest Hospital, Athens, Greece, e-mail: papaioannouandriana@gmail.com

Introduction

The severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) virus, responsible for coronavirus disease (COVID-19), emerged in Wuhan, China, in December 2019 and quickly spread worldwide, leading to a pandemic. While most cases present mild flu-like symptoms, severe infections can cause pneumonia and acute respiratory distress, often requiring intensive care unit (ICU) support1. The complexity of severe cases and the strain on healthcare systems highlight the need to study hospitalized patients to improve future ICU care2.

Coronavirus infection is associated with an increased risk of thrombotic complications. Macrovascular episodes and in situ thrombosis have been reported both during acute illness and several weeks afterward. Thromboembolic disease is the most common of these thrombotic complications, with its incidence ranging around 30 % in critically ill patients3. In a Dutch study4 with 184 COVID-19 patients hospitalized in the ICU, approximately half developed pulmonary embolism, and it was found that these patients had a five times greater risk of death compared to patients without pulmonary embolism. Various pathophysiological mechanisms contribute to the creation of a prothrombotic state. These mechanisms include i) activation of the complement system, ii) macrophage activation syndrome and hyperferritinemia, iii) disruption of the renin-angiotensin-aldosterone system, iv) antiphospholipid syndrome, and v) immune-driven thrombotic mechanisms5.

This study aimed to compare the clinical and laboratory characteristics, hospitalization duration, and outcomes of patients admitted to the intensive care unit for severe SARS-CoV-2 infection, based on the presence of pulmonary embolism and assess its potential prognostic value on disease outcome.

Materials and Methods

Study design

We conducted a retrospective case-control study collecting data regarding patients with severe COVID-19 who were hospitalized in the 1st ICU department of the National and Kapodistrian University of Athens in “Sotiria” Chest Hospital in Athens, Greece between September 2020 and January 2022. Patients’ characteristics were recorded using the online platform of the patient’s electronic medical records. All patient characteristics, including demographics, comorbidities, laboratory values, type and duration of treatment, and disease severity according to the APACHE score and duration of hospitalization (from the day of admission to the hospital to the day of discharge), were recorded. Among laboratory tests, the cut-off value for D-Dimers was 0.05 μg/dl, while the age-adjusted value was used for patients over 50 years of age6. It should be noted that patients’ data included in the current study has partially already been used in a previous publication7. The study was approved by the hospital’s Ethics Committee (protocol No 17676, date: 14/06/2024), and we conducted the research work in full compliance with the Declaration of Helsinki, keeping all data of participating patients anonymous. 

Study Population

The study included 297 out of 317 consecutive patients admitted to the ICU for severe COVID-19. The flow chart of the study participants is presented in Figure 1. All patients had a confirmed SARS-CoV-2 infection using reverse transcription polymerase chain reaction test. We included patients with a fully available medical history and laboratory data in the electronic record system used in the ICU (Siemens Medical Solutions) and excluded patients with missing data.

Figure 1: Flow chart of this retrospective case-control study’s 297 enrolled subjects.

Calculation of the Charlson comorbidity index and APACHE score

In all patients, we calculated the Charlson comorbidity index (CCI)8 and the APACHE II score9 within the first 24 hours from admission to the ICU. We estimated CCI using data from the patient’s electronic medical records and the electronic medical prescription archives, including the specific ICD-10 diagnoses for each condition. CCI is a score that assesses many comorbidities, with higher scores being predictors of increased mortality.

The APACHE II score was based on each patient’s vital signs upon admission and the results of laboratory tests on the same day. All information was also available in their electronic medical records9. All laboratory tests were performed in the central laboratory of the “Sotiria” Chest Diseases Hospital.

Diagnosis of pulmonary embolism

In all patients, pulmonary embolism was confirmed either by computed tomography (CT) pulmonary angiogram (CTPA) or indirectly based on present clinical signs combined with a positive ultrasound of the lower limb veins. Pulmonary embolism evaluation was performed upon ICU admission and was established on the D-dimer levels and the pre-test probability for pulmonary embolism according to the Wells score10. The CT scans were performed using either a SomatonHiQ or a Somaton Plus scanner optima CT540 and were evaluated by experienced radiologists, and the findings consistent with pulmonary embolism were recorded and provided as a report.

Study endpoints

The primary objective was to evaluate the clinical features and laboratory results of patients with severe COVID-19 who developed pulmonary embolism and compare them to those without the condition. The secondary aim was to assess the potential prognostic effect of pulmonary embolism on overall disease outcomes.

Statistical analysis

We checked the normality of distributions with the Kolmogorov-Smirnov test. Data are presented as numbers with percentages in brackets for categorical variables, mean ± standard deviation for normally distributed, and median with interquartile range in brackets for skewed numerical variables. We conducted group comparisons utilizing the chi-square test for categorical variables, while we applied the unpaired t-test and Mann-Whitney U-test for normally distributed and skewed numerical data, respectively. We considered a p-value <0.05 as statistically significant and performed all analyses using the IBM SPSS Statistics for Windows, Version 23.0 (IBM Corp., Armonk, NY, USA). We used Kaplan-Meier estimates to visualize and describe the effect of categorical variables. 

Results

Comparison of severe COVID-19 patients with and without pulmonary embolism

We included data from 297 patients (29 % females) in this study, out of whom 166 participants (57.4 %) required intubation and mechanical ventilatory support, and pulmonary embolism was present in 33 patients (11.1 %). Patients with no indication for a therapeutic dose of anticoagulation therapy received prophylactic therapy, either low molecular weight heparin or fondaparinux, during their hospitalization. Compared to patients without pulmonary embolism, patients with pulmonary embolism required more frequent intubation and mechanical ventilation (75.8 % vs 52.3 %, p =0.01) and had higher levels of C-reactive protein (CRP; mg/dl) [13.07 (6.68, 20.7) vs 9 (3.90, 13.92), p =0.02], D-dimers (μg/dl) [1.92 (0.88, 4.32) vs 0.97 (0.56, 1.82), p <0.001] and lactate dehydrogenase (LDH; IU/L) [467 (376, 638) vs 406 (310, 512), p =0.004] on admission, and had a more extended hospital stay both overall [44 (24, 74.5) vs 25 (17, 39), p <0.001] and in the ICU [32 (10, 71) vs 10 (6, 20), p <0.001]. Additionally, patients with pulmonary embolism exhibited a significantly higher incidence of septic episodes (51.5 % vs 28.4 %, p =0.007), barotrauma (33.3 % vs 11.7 %, p <0.001), and fungal infections (18.2 % vs 6.1 %, p =0.024) compared to those without pulmonary embolism. These complications were more frequent in patients who required mechanical ventilation, further indicating an association between prolonged ICU stay, critical illness, and thromboembolic events.

Interestingly, the incidence of diabetes mellitus was lower in patients with pulmonary embolism (9.1 %) compared to those without (24.2 %), p =0.049. In contrast, no significant correlation was found between pulmonary embolism and either cardiovascular or respiratory comorbidities among the recorded data. Furthermore, treatment with monoclonal antibodies against interleukin 6 (IL-6) did not appear to reduce thromboembolic events in this cohort.

It is important to highlight that no significant association was found between pulmonary embolism and either cardiovascular or respiratory diseases among the recorded comorbidities. Demographic and clinical characteristics of the study participants are shown in Table 1.

Effect of pulmonary embolism on mortality of patients with severe COVID-19

In total, 78/297 patients died during their stay in ICU from severe COVID-19 complications (mortality rate 26.3 %). Mortality rates were similar in patients with pulmonary embolism (8/33, 24.2 %) and those without pulmonary embolism (70/264, 26.5 %). No significant difference was observed in mortality among patients with severe COVID-19 with or without pulmonary embolism admitted in the ICU (p =0.890) (Log Rank Test). The Kaplan-Meier survival curves in the two study groups are shown in Figure 2.

Figure 2: Kaplan Meier curve for intensive care unit survival in patients with severe COVID-19 according to the presence or absence of pulmonary embolism.
PE: pulmonary embolism.

Discussion

In this study, we concluded that patients with severe COVID-19 infection and concurrent pulmonary embolism had elevated D-dimer levels (using age-adjusted cut-off values) and serum LDH. At the same time, the incidence of diabetes mellitus was lower. Additionally, those who developed thromboembolic events had a longer hospital stay before the onset of pulmonary embolism, required more intensive ventilatory support, and experienced complications such as sepsis, fungal infections, and barotrauma more frequently. A notable limitation in our study is that CTPA did not confirm all cases of pulmonary embolism, which could have led to potential misclassification and an underestimation or overestimation of pulmonary embolism incidence. Future studies with systematic imaging protocols are needed to define better the true prevalence of pulmonary embolism in critically ill COVID-19 patients.

In COVID-19, lung regions with a low ventilation/perfusion ratio are the leading cause of hypoxemia. Furthermore, consolidated lung regions provoking right-to-left shunting also play a considerable role. Pulmonary embolism causes hypoxia and respiratory alkalosis due to ventilation-perfusion mismatch and increased dead space in patients who are not intubated11. In mechanically ventilated patients, pulmonary embolism leads to significant lung perfusion defects and, as a result, CO2 retention may occur, causing respiratory acidosis11.

In our study, the incidence of pulmonary embolism was significantly higher in patients on mechanical ventilation than those receiving oxygen therapy with a Venturi mask or undergoing non-invasive mechanical ventilation, which agrees with previous studies12. It is known that mechanical ventilation reduces venous return by creating flow stasis and prolongs the period of patient immobilization, which is a situation that predisposes patients to thromboembolic disease. Hypoxemia is common in COVID-19 lung disease. The occurrence of pulmonary embolism in combination with potential parenchymal damage induced by COVID-19 may further impair oxygenation, increasing the need for invasive respiratory support13.

A retrospective multicenter study14 conducted in seven hospitals in Italy aimed to study the predictors of pulmonary embolism in patients with SARS-COV-2 infection and to compare survival with patients without thromboembolic disease. The results indicated that pulmonary embolism is a common complication in this population and that these patients have a significantly increased mortality14. These results contradict the current study’s results indicating that for patients with severe disease admitted to the ICU, mortality is not increased.

In patients with pulmonary embolism, the white blood cell count did not significantly increase compared to those without; however, there was a trend towards a difference, with the p-value at 0.06. In contrast, we recorded substantially higher CRP levels in patients with pulmonary embolism (p =0.002), indicating a slight difference in leukocyte count, with higher levels observed in patients with pulmonary embolism. We expect the hyperinflammatory state in severe SARS-COV-2 infection manifesting with pulmonary embolism would also increase leukocyte count. Several studies have reported that leukocytes in patients with COVID-19 and pulmonary embolism were elevated compared to those without embolism15,16. A possible explanation for the lack of a significant difference in this study might be the fact that we recorded laboratory data at the time of ICU admission and not at the time of the thromboembolic event. Furthermore, irrespective of the severity of the infection and the development of a hyperinflammatory state, it has been suggested that extensive endothelial dysfunction of the pulmonary capillary endothelium, caused either directly by the virus or by the immune-directed inflammatory response, leads to microvascular dysfunction and thus to thrombosis. Therefore, in this way, even milder infections can lead to the development of thromboembolic complications17. Elevated CRP levels have been identified as a significant prognostic marker in patients with COVID-19, particularly concerning pulmonary embolism development. A previous study reported that higher CRP levels were associated with an increased risk of PE in COVID-19 patients. Specifically, the C-reactive protein to lymphocyte ratio (CLR) was highlighted as a predictive factor, with elevated CLR correlating with higher mortality rates18. Another study has shown similar findings, indicating that elevated CRP levels upon ICU admission predict unfavorable outcomes in COVID-19 patients, underscoring the importance of CRP as a biomarker for disease severity and potential complications, including thromboembolic events like pulmonary embolism19.

Finally, given the effect of the hyperinflammatory syndrome of SARS-COV-2 on the development of a hypercoagulable state, it is expected that the CRP value would be significantly increased in patients with pulmonary embolism compared to patients without as it was found in our study.

As anticipated, D-dimers significantly increased in patients with pulmonary embolism (p <0.01). D-dimers are fibrin degradation products and are widely used as a predictive marker of pulmonary embolism in both COVID-19 and non-COVID-19 patients. Furthermore, this marker is closely associated with the severity of SARS-COV-2 infection and the associated hypercoagulable state20. However, since the predictive value of this biomarker using the commonly used cut-off point for non-COVID-19 patients remains unclear, more studies are needed to determine the sensitivity and specificity of D-dimers levels in predicting pulmonary embolism in patients with SARS-COV-2 infection.

Notably, among comorbidities, neither cardiovascular nor respiratory diseases were associated with an increased incidence of pulmonary embolism. However, congestive heart failure and respiratory failure are considered intermediate risk factors for the development of thromboembolic disease. The paradox in our study was that diabetes mellitus was less frequent among patients with pulmonary embolism than those without. However, the short number of patients with diabetes mellitus in the group of patients with pulmonary embolism makes the value of this observation quite poor.

Treatment with monoclonal antibodies and, remarkably, antibodies against IL-6 was proposed to reduce the risk of thrombotic complications21. The rationale lies in the fact that SARS-Cov-2 infection leads to the activation of the innate immune system and the generation of a hyperinflammatory state. Immune cell activation leads to excessive cytokine secretion, including tumor necrosis factor-alpha, IL-2, IL-6, IL-8, and IL-10. IL-6 was particularly elevated in SARS-COV-2 infection compared to bacterial infections. IL-6 is associated with increased levels of fibrinogen. In addition, it has been shown to reduce the function of natural killer cells, resulting in prolonged interaction between innate and acquired immunity cells, excessive activation of macrophages (macrophage activation syndrome), and ultimately, a vicious cycle of cytokine production, haemophagocytosis, and multiorgan failure. This syndrome is associated with increased hypercoagulability22. Tocilizumab is an anti-IL-6monoclonal antibody that could theoretically lower the risk of thromboembolic events by reducing the hyperinflammatory state. Our results are similar to those of other studies showing that despite reducing inflammatory indices, treatment with tocilizumab did not reduce thrombotic events21.

Our study found that hospital stay duration in the ICU was much longer in patients with pulmonary embolism than in those without. The prolonged length of hospitalization is associated with longer patient immobilization and increased risk of complications including central venous catheter-related thrombosis. All of these factors predispose to the development of thromboembolic disease.

The LDH value was significantly increased in patients with pulmonary embolism. The role of LDH as a predictive marker for severe SARS-COV-2 disease has been described in several studies. LDH is an enzyme found in the cytoplasm of cells of many tissues, mainly in the myocardium, kidneys, lungs, liver, and muscles. In these tissues, it catalyzes the conversion of lactic acid to pyruvate in the glycolysis. In situations of tissue destruction, this enzyme is released into the circulation23. A study that included 123 participants from May to July 2021 showed that this enzyme was significantly increased in patients with severe COVID-19 disease as opposed to patients with mild disease23. Therefore, although this enzyme is an independent risk factor for worsening COVID-19 disease and the increase is non-specific in COVID-19 patients, increased levels should raise a strong suspicion of hepatic lung and muscle injury. This study indicated that LDH can be used as a predictor of thromboembolic disease in patients with severe COVID-19 hospitalized in the ICU23.

We also found an increased incidence of septic episodes in patients with pulmonary embolism (p <0.007). Both COVID-19 infection and ICU hospitalization increase the risk of septic shock. Administration of vasoconstrictors is an independent risk factor for thromboembolism, and this is explained by the reduced absorption of subcutaneously administered heparin24. It is known that vascular endothelium has physiological antithrombotic properties. In cases of sepsis there is increased expression of tissue factor while endocytosis and the release of thrombodulin into the circulation lead to a decrease in the expression of this anticoagulant and subsequently reduced activation of protein C (the binding of thrombin to thrombodulin leads to activation of protein C)24.

Additionally, it appeared that patients with SARS-COV-2 infection and pulmonary embolism also had a higher incidence of fungal infections. In a study conducted at the “Sotiria” Hospital with a total of 178 patients with COVID-19 infection, 19 of them developed fungal infection. These patients were younger, had on admission to the ICU a lower ratio of arterial partial pressure of oxygen to the fraction of inspiratory oxygen concentration (PaO2/FiO2), had longer length of stay in the unit, longer duration of mechanical ventilation, received dexamethasone more frequently and underwent more frequent exoneration7. Some of these factors also significantly increase in patients with pulmonary embolism. Therefore, this study indicates that fungal infection presence may increase the risk for thromboembolic disease.

This study has several limitations that should be acknowledged. Firstly, the evaluation of pulmonary embolism took place at the time of the ICU admission. As a retrospective case-control study, it is inherently susceptible to selection bias, as cases and controls were identified based on available data, which may not fully represent all patients with similar clinical characteristics. Additionally, recall bias is a concern, as the study relies on recorded medical data rather than prospective observation, potentially leading to inaccuracies. The study design also limits our ability to establish temporality, as it is difficult to determine whether certain factors preceded the development of pulmonary embolism or were consequences of the disease process. Furthermore, no measurement of the degree of lung parenchyma involvement was performed. Moreover, confounding variables may affect our findings, as not all potential influencing factors could be accounted for despite statistical adjustments. The study is also limited in its ability to analyze rare exposures, as case-control studies are more suited for studying rare outcomes rather than uncommon risk factors. Furthermore, survivor bias may have influenced our results, as patients who died before a diagnosis of pulmonary embolism could be underrepresented. Another limitation is that mortality was only assessed during hospitalization and not beyond hospital discharge, which could have provided a more comprehensive evaluation of the long-term impact of pulmonary embolism in these patients. Moreover, data collection occurred only during ICU admission, meaning that changes in laboratory parameters and clinical progression over time were not assessed. Lastly, a lack of valid exclusion of pulmonary embolism in patients classified as not having the condition since a CTPA was not performed in all cases, while in some cases pulmonary embolism was based on the clinical signs in combination with a positive triplex of the lower extremities, may have led to misclassification and potential under- or overestimation of its true incidence. Future prospective studies incorporating systematic CTPA screening may provide more robust data on pulmonary embolism’s true incidence and impact in critically ill COVID-19 patients. 

Conclusion

In patients with severe SARS-CoV-2 infection admitted to the ICU, pulmonary embolism was more frequently observed in those with elevated D-dimer and lactate LDH levels, greater need for mechanical ventilation, as well as sepsis, barotrauma, and fungal infections, and prolonged ICU stay.

Since both ICU hospitalization and SARS-COV-2 infection increase the risk of thromboembolic events, it was deemed appropriate to study the association of pulmonary embolism with mortality in these patients. In addition, understanding the pathophysiological mechanisms of thrombosis and the correlation with comorbidities and laboratory data is helpful for early recognition of pulmonary embolism in patients with SARS-COV-2 hospitalized in the ICU. 

Conflicts of interest

Authors declare no conflicts of interest.

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