Influence of thromboembolic events in the prognosis of COVID-19 hospitalized patients. Results from a cross sectional study.

BACKGROUND: COVID-19 may predispose to both venous and arterial thromboembolism event (TEE). Reports on the prevalence and prognosis of thrombotic complications are still emerging.
OBJECTIVE: To describe the rate of TEE complications and its influence in the prognosis of hospitalized patients with COVID-19 after a cross-sectional study.
METHODS: We evaluated the prevalence of TEE and its relationship with in-hospital death among hospitalized patients with COVID-19 who were admitted between 1st March to 20th April 2020 in a multicentric network of sixteen Hospitals in Spain. TEE was defined by the occurrence of venous thromboembolism (VTE), acute ischemic stroke (AIS), systemic arterial embolism or myocardial infarction (MI).
RESULTS: We studied 1737 patients with proven COVID-19 infection of whom 276 died (15.9%). TEE were presented in 64 (3.7%) patients: 49 (76.6%) patients had a VTE, 8 (12.5%) patients had MI, 6 (9.4%%) patients had AIS, and one (1.5%) patient a thrombosis of portal vein. TEE patients exhibited a diffuse profile: older, high levels of D-dimer protein and a tendency of lower levels of prothrombin. The multivariate regression models, confirmed the association between in-hospital death and age (odds ratio [OR] 1.12 [95% CI 1.10-1.14], p<0.001), diabetes (OR 1.49 [95% CI 1.04-2.13], p = 0.029), chronic obstructive pulmonary disease (OR 1.61 [95% CI 1.03-2.53], p = 0.039), ICU care (OR 9.39 [95% CI 5.69-15.51], p<0.001), and TTE (OR 2.24 [95% CI 1.17-4.29], p = 0.015).
CONCLUSIONS: Special attention is needed among hospitalized COVID-19 patients with TTE and other comorbidities as they have an increased risk of in-hospital death.

Introduction

The coronavirus disease of 2019 (COVID-19) is a viral illness caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) that is now considered a pandemic by the World Health Organization [1-3]. Although, initial efforts have been focused on the diagnosis and treatment of severe pneumonia with vital compromise [1, 3], a spectrum of extra respiratory symptoms and signs generated by the infection itself have been verified. Among those symptoms, we can stand out that COVID-19 infection might predispose patients to thrombotic disease, both in the venous and arterial circulations mediated by inflammation, endothelial dysfunction, thrombin generation, platelet activation and stasis [4, 5]. Recently, it was reported a 31% prevalence of thrombotic complications in ICU patients with COVID-19 infections in Dutch intensive care units [6]. Coagulopathy and over disseminated intravascular coagulation appear to be associated with high mortality rates. Among the coagulation parameters, D-dimer elevation was the strongest independent predictor of mortality [7], and high levels of D-dimer have been observed in patients admitted to intensive care units [1]. Non-survivors have shown significantly higher levels of plasma D-dimers and fibrin degradation products, increased prothrombin times and activated partial thromboplastin times compared to survivors [8]. Moreover, the metallopeptidase enzyme of angiotensinogen converter 2 (ACE2), identified as the cellular receptor for the coronavirus, is expressed in alveolar epithelial cells and in endothelial cells [9]. The prothrombotic predisposition seems to be developed more intensely from the tenth day of infection [10], and it would also be related to the inflammatory effect of the COVID-19 infection.

The relationship between inflammation and ischemic episodes is already described [11, 12] and COVID-19 associated ischemic strokes are more severe with worse functional outcome and higher mortality than non-COVID-19 ischemic strokes patients [13, 14]. COVID-19 has a number of important cardiovascular implications [15-17]. There is a high prevalence of cardiovascular disease among patients with COVID-19 and acute cardiac injury is commonly observed in severe cases. Patients with prior risk factors are at higher risk for adverse events from COVID- 19 and worse prognosis [18, 19].

Here, we evaluated the prevalence of thromboembolism event (TEE) in all COVID-19 patients admitted to the network of 16 Hospitals in Spain (HM Hospitals). The influence of the composite outcome in the risk of death during the admission was also determined.

Material and methods

Data source

This is a cohort study based on anonymized clinical dataset provided by HM Hospitales, which includes sixteen hospitals from all over Spain (HM Delfos, HM Sant Jordi, HM nens, HM modelo, HM Belén, HM Rosaleda, HM la esperanza, HM San Francisco, HM regla, HM Madird, HM Montepríncipe, HM Torrelodones, HM Sanchinarro, HM Nuevo Belén, HM Puerta del Sur and HM Vallés), with detailed hospital admission information for COVID-19 patients from March 1st to April 20th 2020. Database was accessed by the research on August 2020. Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines were applied [20].

Study participants

A dedicated electronic medical record data extraction protocol was developed to identify all patients with confirmed COVID-19 (defined as a positive SARS-CoV2 reverse-transcriptase polymerase chain reaction test by nasopharyngeal/oropharyngeal swab or sputum specimen). Patients whose age was under 18 years were excluded (n = 11) (Fig 1). We retrieved the primary International Classification of Diseases (ICD10, 10th Revision, Clinical Modification) codes for each patient. For the selected patients, clinical characteristics, demographic variables, admission at ICU, laboratory determinations, coexisting conditions and vascular risk factors based on ICD10 were collected for further analysis. Patients without ICD10 codification were also excluded (n = 131) (Fig 1).

Fig 1

Patients flowchart.

The primary outcome was the occurrence of TEE defined by venous thromboembolism (VTE), acute ischemic stroke (AIS), systemic arterial embolism or myocardial infarction. The relationship of TEE with the endpoint of in-hospital discharged or exitus was also evaluated.

Data analysis

Categorical variables were presented as numbers and percentages and continuous variables as mean and standard deviation if they were normally distributed or median and interquartile range if they were not normally distributed. Variables related to the composite outcome and death were identified. We compared means for continuous variables by using independent group t-tests when the data was normally distributed; otherwise, we used the Mann-Whitney test. Proportions for categorical variables were compared using the chi-square (χ2) test. Fisher’s exact test was used in the analysis of contingency when the sample sizes were small. Multivariate logistic regression analysis was used to identify predictors of death, in which variables showing p≤0.10 on a univariate testing were included. Forward selection model with likelihood ratio (LR) was used, first demographic and clinical characteristics (model 1) were added and vital signs (model 2) were added afterwards, to analyze the single best improvement of the model. All the tests were 2-sided and were run at a statistical significance level of p≤0.05. Data was analyzed using SPSS Statistics software, version 20 (IBM SPSS, Chicago, IL, USA).

The study was approved by the Ethics committee of the HM Hospitals (approval number 20.03.1573-GHM).and adhered to the policy for protection of human subjects according to Declaration of Helsinki. As the information was obtained from a de-identified public database written informed consent for our specific study from all study participants was not needed. The data were analyzed anonymously.

Results

A total of 1737 patients (Fig 1) were included in the current analysis, all of them were COVID-19 positive. Of those, 64 (3.7%) patients had a TEE: 49 (76.6%) patients had a VTE, 8 (12.5%) patients had an acute ischemic heart disease event, 6 (9.4%%) patients had an AIS, and one (1.5%) patient a thrombosis of portal vein. Median time from admission to discharge was 7 (interquartile range [IQR], 4.0–10.0) days. The main diagnosis at admission was pneumonia or respiratory symptoms present in 1606 (92.5%) patients. Hypertension was the main vascular risk factor presented in 647 (37.2%) patients. 117 (6.7%) patients required intensive care. 276 patients died after hospital’s admission, corresponding to an in-hospital mortality rate of 15.9%. Median time until death was 5.0 days (IQR 3.0–9.0) days.

Variables associated with thromboembolic events

Dataset was clustered by the absence/presence of TEE (Table 1). The group of TEE was characterized by older patients (mean age 68.9 [standard deviation, SD:14.0] vs. 65.3 [SD:16.7] years, p = 0.097). TEE patients had signicantly less pneumonia or respiratory symptoms at admission than non-TEE patients. (75.0% versus 93.1%, p<0.001). Mortality risk during admission was significant higher in TEE patients than in non-TEE patients (29.7% [95% CI 18.5–40.9] vs. 15.4% [95% CI 13.7–17.1], p = 0.002). No descriptive variables nor previous coexisting conditions or vascular risk factors were significantly associated with TEE. D-dimer levels were significantly higher among TEE patients than in non-TEE patients (median 6679.0 [IQR 661.0–11297.0] vs. 742.5 [IQR 425.0–1496.0] ng/mL, p = 0.009); and prothrombin time showed a lower tendency in TEE patients (median 12.6 [IQR 11.9–13.2] vs. 13.3 [IQR 12.4–14.6] seconds, p = 0.056) (Table 1).

Table 1

Description and frequency of baseline characteristics, comorbidity, clinical, laboratory variables in patients with thromboembolic events.

		All	Non-TEE	TEE	p-valuea
n (%)		1737	1673 (96.3)	64 (3.7)	-
Age, mean (SD), years		65.5 (16.7)	65.3 (16.7)	68.9 (14.0)	0.097
Sex female		686 (39.5)	660 (39.5)	26 (40.6)	0.850
Hypertension		647 (37.2)	622 (37.2)	25 (39.1)	0.760
Diabetes		263 (15.1)	255 (15.2)	8 (12.5)	0.548
Hyperlipidemia		390 (22.5)	376 (22.5)	14 (21.9)	0.910
Chronic kidney disease		64 (3.7)	63 (3.8)	1 (1.6)	0.358
Congestive heart failure		38 (2.2)	35 (2.1)	3 (4.7)	0.164
Atrial fibrillation		72 (4.1)	70 (4.2)	2 (3.1)	0.677
Previous ischemic heart disease		91 (5.2)	89 (5.3)	2 (3.1)	0.439
Previous cerebrovascular disease		15 (0.9)	14 (0.8)	1 (1.6)	0.538
Pneumonia or respiratory symptoms		1606 (92.5)	1558 (93.1)	48 (75.0)	<0.001
Chronic obstructive pulmonary disease		119 (6.9)	112 (6.7)	7 (10.9)	0.187
Ex-smoker		258 (14.9)	246 (14.7)	12 (18.8)	0.372
Current smoker		52 (3.0)	50 (3.0)	2 (3.1)	0.950
Management
ICU admission		117 (6.7)	110 (6.6)	7 (10.9)	0.172
Days of hospitalization, median (IQR)		7.0 (4.0–10.0)	7.0 (4.0–10.0)	7.5 (4.0–13.0)	0.118
Death		276 (15.9)	257 (15.4)	19 (29.7)	0.002
Vital signs
Systolic blood pressure, mean (SD) mmHg	N = 1099	131.5 (21.5)	131.4 (21.4)	132.2 (22.3)	0.799
Diastolic blood pressure, mean (SD) mmHg	N = 1104	76.5 (33.0)	76.4 (33.6)	78.6 (14.2)	0.643
Oxygen saturation, mean (SD)	N = 1385	92.3 (7.0)	92.3 (7.0)	91.4 (7.4)	0.357
Laboratory determinations
D-dimer, median (IQR) ng/mL	N = 257	822.5 (450.5–1745.5)	742.5 (425.0–1496.0)	6679.0 (661.0–11297.0)	0.009
Alanine aminotransferase, median (IQR) U/L	N = 277	28.2 (17.0–49.0)	27.1 (17.0–46.7)	37.0 (23.8–67.1)	0.343
Aspartate aminotransferase, median (IQR) U/L	N = 284	34.0 (23.8–57.1)	33.0 (23.3–56.3)	43.5 (25.0–78.2)	0.265
Creatinine, median (IQR) mg/dL	N = 304	0.9 (0.7–1.1)	0.9 (0.7–1.1)	0.8 (0.7–0.9)	0.232
Hemoglobin, median (IQR) g/dL	N = 297	13.6 (12.2–14.8)	13.7 (12.5–14.8)	14.1 (11.6–15.9)	0.696
Leukocytes, median (IQR) x10e3/μL	N = 308	6.6 (5.0–9.5)	6.4 (4.9–8.9)	6.8 (5.0–9.1)	0.857
Neutrophil count, median (IQR) x10e3/μL	N = 308	4.8 (3.3–7.6)	4.6 (3.3–7.1)	4.9 (3.3–7.6)	0.772
Platelet count, median (IQR) x103 per uL	N = 302	218.5 (168.3–299.5)	214.0 (165.5–301.0)	240.0 (209.5–271.5)	0.493
C reactive protein, median (IQR) mg/dl	N = 288	61.8 (24.2–118.6)	60.3 (22.9–122.2)	89.5 (33.0–135.7)	0.279
Prothrombin time, median (IQR) s	N = 259	13.2 (12.3–14.5)	13.3 (12.4–14.6)	12.6 (11.9–13.2)	0.056

Values are presented as n (%) or mean ± SD unless otherwise stated. Statistically significant results are highlighted in bold. Abbreviations: Non-TEE: non-thromboembolic event. TEE: thromboembolic event. Reference ranges are as follows: d-dimer, 0 to 500 ng per milliliter; alanine aminotransferase (ALT), U/L <33–41; aspartate aminotransferase (AST), U/L <33–41; creatinine, mg/dL (0.7–1.2) mg/dL (0.5–0.9); hemoglobin, g/dL (12.3–15.3) (14.0–17.5); leukocytes, x10e3/μL (4.4–11.3); neutrophil count, x10e3/μL (1.5–7.5); platelet count, 150,000 to 450,000 per cubic microliter; C reactive protein, mg/L <5; prothrombin time, 9.9 to 14.2 seconds.

Abbreviations: SD, standard deviation; IQR, interquartile range; ICU, intensive care unit.

Associations of in-hospital mortality

Non-survivor patients were significantly older than survivor patients (mean 80.7 [SD 9.7] vs. 62.6 [SD 9.7] years, p<0.001). A higher prevalence of risk factors was also presence in the group of non-survivors: hypertension (51.8% vs. 34.5%, p<0.001), diabetes mellitus (25% vs. 13.3%, p<0.001), hyperlipidemia (27.2% vs. 21.6%, p = 0.040), chronic kidney disease (8.7% vs. 2.7%, p<0.001), congestive heart failure (4.7% vs. 1.7%, p = 0.002), chronic obstructive pulmonary disease (15.6% vs. 5.2%, p<0.001), and atrial fibrillation (8.3%) (Table 2). Mortality was higher in patients initially admitted to intensive care unit than in conventional units (16.3% vs. 4.9%, p<0.001).

Table 2

Demographic and clinical findings among COVID-19 patients with thromboembolic events, stratified by mortality.

		All	Survivors	Non survivors	p-valuea
n (%)		1737	1461 (84.1)	276 (15.9)	-
Age, mean (SD) years		65.5 (16.7)	62.6 (16.2)	80.7 (9.7)	<0.001
Sex female		686 (39.5)	589 (40.3)	97 (35.1)	0.107
Hypertension		647 (37.2)	504 (34.5)	143 (51.8)	<0.001
Diabetes		263 (15.1)	194 (13.3)	69 (25.0)	<0.001
Hyperlipidemia		390 (22.5)	315 (21.6)	75 (27.2)	0.040
Chronic kidney disease		64 (3.7)	40 (2.7)	24 (8.7)	<0.001
Congestive heart failure		38 (2.2)	25 (1.7)	13 (4.7)	0.002
Atrial fibrillation		72 (4.1)	49 (3.4)	23 (8.3)	<0.001
Previous ischemic heart disease		91 (5.2)	61 (4.2)	30 (10.9)	<0.001
Previous cerebrovascular disease		15 (0.9)	10 (0.7)	5 (1.8)	0.063
Pneumonia or respiratory symptoms		1606 (92.5)	1353 (92.6)	253 (91.7)	0.587
Chronic obstructive pulmonary disease		119 (6.9)	76 (5.2)	43 (15.6)	<0.001
Ex-smoker		258 (14.9)	213 (14.6)	45 (16.3)	0.460
Current smoker		52 (3.0)	45 (3.1)	7 (2.5)	0.627
Management
ICU care		117 (6.7)	72 (4.9)	45 (16.3)	<0.001
Days of hospitalization, median (IQR)		7.0 (4.0–10.0)	7.0 (4.0–10.0)	5.0 (3.0–9.0)	<0.001
Thromboembolism Event		64 (3.7)	45 (3.1)	19 (6.9)	0.002
Venous thromboembolism		49 (2.8)	35 (2.4)	14 (5.1)	0.014
Acute ischemic stroke		6 (0.3)	3 (0.2)	3 (1.1)	0.022
Acute ischemic heart disease		8 (0.5)	5 (0.3)	3 (1.1)	0.094
Vital signs
Systolic blood pressure, mean (SD) mmHg	N = 1099	131.5 (21.5)	131.9 (20.4)	129.8 (25.9)	<0.001
Diastolic blood pressure, mean (SD) mmHg	N = 1104	76.5 (33.0)	77.6 (35.7)	71.3 (14.2)	0.242
Oxygen saturation, mean (SD)	N = 1385	92.3 (7.1)	93.4 (5.3)	86.2 (11.4)	0.018
Laboratory determinations
D-dimer, median (IQR) ng/mL	N = 257	822.5 (450.5–1745.5)	690.0 (403.0–1217.0)	3321.0 (1003.5–6526.0)	<0.001
Alanine aminotransferase, median (IQR) U/L	N = 277	28.2 (17.0–49.0)	27.4 (17.7–46.9)	26.1 (15.5–51.1)	0.816
Aspartate aminotransferase, median (IQR) U/L	N = 284	34.0 (23.8–57.1)	31.0 (22.8–51.9)	46.2 (25.9–65.1)	0.007
Creatinine, median (IQR) mg/dL	N = 304	0.9 (0.7–1.1)	0.8 (0.7–1.0)	1.0 (0.8–1.7)	0.001
Hemoglobin, median (IQR) g/dL	N = 297	13.6 (12.2–14.8)	13.9 (12.6–14.9)	12.7 (11.8–13.8)	0.001
Leukocytes count, median (IQR) x10e3/μL	N = 308	6.6 (5.0–9.5)	6.1 (4.9–8.5)	8.4 (5.7–10.8)	0.001
Neutrophil count, median (IQR) x10e3/μL	N = 308	4.8 (3.3–7.6)	4.4 (3.2–6.4)	7.3 (4.1–11.1)	<0.001
Platelets count, median (IQR) x103 per uL	N = 302	218.5 (168.3–299.5)	224.5 (171.0–311.0)	185.0 (141.0–240.0)	0.002
C reactive protein, median (IQR) mg/dl	N = 288	61.8 (24.2–118.6)	54.5 (21.7–107.7)	129.7 (48.2–238.9)	<0.001
Prothrombin time, median (IQR) seconds	N = 259	13.2 (12.3–14.5)	13.2 (12.3–14.5)	13.8 (12.8–15.2)	0.039

Values are presented as n (%) or mean ± SD unless otherwise stated. Statistically significant results are highlighted in bold. Reference ranges are as follows: d-dimer, 0 to 500 ng per milliliter; alanine aminotransferase (ALT), U/L <33–41; aspartate aminotransferase (AST), U/L <33–41; creatinine, mg/dL (0.7–1.2) mg/dL (0.5–0.9); hemoglobin, g/dL (12.3–15.3) (14.0–17.5); leukocytes, x10e3/μL (4.4–11.3); neutrophil count, x10e3/μL (1.5–7.5); platelet count, 150,000 to 450,000 per cubic microliter; C reactive protein, mg/L <5; prothrombin time, 9.9 to 14.2 seconds.

Abbreviations: SD, standard deviation; IQR, interquartile range; ICU, intensive care unit.

Monitored vital signs were also altered in non-survivor patients. Basal systolic blood pressure (mean 129.8 [SD 25.9] vs. 131.9 [SD 20.4] mmHg, p<0.001) and oxygen saturation (mean 86.2% [SD 11.4] vs. 93.4% [SD 5.3], p = 0.018) were significantly reduced in non-survivor patients.

The thrombotic profile of non-survivor patients was characterized by elevated levels of d-dimer (median 3321.0 [IQR 1003.5–6526.0] vs. 690.0 [IQR 403.0–1217.0] ng/mL, p<0.001), and prolonged prothrombin time suggesting coagulopathy (median 13.8 [IQR 12.8–15.2] vs. 13.2 [IQR 12.3–14.5] seconds, p = 0.039). The influence of inflammation and immune response was showed by elevated levels of c-reactive protein (median 129.7 [IQR 48.2–238.9] vs. 54.5 [IQR 21.7–107.7] mg/dl, p<0.001) and higher counts of leukocytes (median 8.4 [IQR 5.7–10.8] vs. 6.1 [IQR 4.9–8.5] x10e3/uL, p = 0.001) and neurotrophils (median 7.3 [IQR 4.1–11.1] vs. 4.4 [3.2–6.4] x10e3/uL, p<0.001) among non-survivor patients. Finally, hemoglobin (median 12.7 [IQR 11.8–13.8] vs. 13.9 [IQR 12.6–14.9] g/dL, p = 0.001) and platelets (median 185.0 [IQR 141.0–240.0] vs. 224.5 [IQR 171.0–311.0] x10e3/uL, p = 0.002) counts were decreased in non-survivor patients (Table 2).

The multivariate regression models confirmed the association between in-hospital death and age (odds ratio [OR] 1.12 [95% CI 1.10–1.14], p<0.001), diabetes (OR 1.49 [95% CI 1.04–2.13], p = 0.029), chronic obstructive pulmonary disease (OR 1.61 [95% CI 1.03–2.53], p = 0.039), ICU care (OR 9.39 [95% CI 5.69–15.51], p<0.001), and thromboembolism presence (OR 2.24 [95% CI 1.17–4.29], p = 0.015). In addition, basal systolic blood pressure (OR 0.98 [95% CI 0.98–0.99], p<0.001) and basal oxygen saturation (OR 0.90 [95% CI 0.88–0.93], p<0.001) were inversely related to the risk of in-hospital mortality (Table 3).

Table 3

Multivariate analysis and adjusted logistic regression for predictors of death.

Variables	Model 1		Model 2
	OR (CI 95%)	p-value	OR (CI 95%)	p-value
Age	1.12 (1.10–1.14)	<0.001	1.12 (1.09–1.14)	<0.001
Diabetes	1.49 (1.04–2.13)	0.029	2.04 (1.28–3.25)	0.003
Chronic obstructive pulmonary disease	1.61 (1.03–2.53)	0.039	1.81 (1.00–3.27)	0.049
ICU care	9.40 (5.69–15.51)	<0.001	4.86 (2.34–10.08)	<0.001
Thromboembolism	2.24 (1.17–4.29)	0.015	2.46 (1.11–5.45)	0.027
Systolic blood pressure	-	-	0.98 (0.98–0.99)	<0.001
Oxygen saturation	-	-	0.90 (0.88–0.93)	<0.001

Multivariate analysis exploring the predictors of death in COVID-19 patients. Statistically significant results are highlighted in bold. Abbreviations: OR: odds ratio; CI: confidence interval.

Discussion

Our results showed a deleterious effect of TEE, age, diabetes mellitus, and COPD in in-hospital mortality among COVID-19 patients (Table 3). Previous reports identified both the relationship of COVID-19 infection and TEE [5, 6, 21–23] and the increased risk of death among TEE patients [24]. However, most of them have been limited in size and focused on patients with severe disease hospitalized in intensive care units. These aspects could explain the significantly lower observed TEE risk in our investigation than in others. We have confirmed the association of D-dimer levels and TEE events [24]. In initial reports of COVID-19 infection, D-dimers levels and prolonged prothrombin time have defined a coagulation disorder associated with COVID-19 infection severity [1]. In line with this hypothesis, recent autopsy studies identified extensive extracellular fibrin deposition and the presence of fibrin thrombi within small vessels and capillaries of the lungs [25-27]. As in our study, VTE is the most described thrombotic complication [6, 28]. COVID-19 infection was also associated with hyperviscocity, which could explain anticoagulation failures [29]. Moreover, in cases of sepsis the overproduction of proinflammatory cytokines can cause microvasculature and endothelial dysfunction, which could trigger hemostatic cascade [30]. In addition, the prothrombotic effect of COVID-19 infection might be related with the risk of developing acute coronary syndrome, that increases on acute infections like influenza epidemics [31-33] due to the increment of myocardial demands triggered by infections [34]. Also, there is an evidence of increasing in-hospital mortality among patients with myocardial injury associated with elevated troponin T levels [35, 36]. As well, a direct viral infection of vascular endothelium and myocardium is possible [37, 38]. Stroke mechanisms include hypercoagulability and cardioembolic stroke of cited virus-related with cardiac injury [10]. The absence of association between general risk factors for TEE in our cohort was similar with previous studies [6, 39].

As in other respiratory viral infections [31, 40], we observed that old patients [7, 41, 42] and COPD [43] were associated with a higher risk of poor outcomes or death. Recent data indicate that diabetes is an important risk factor for unfavorable outcome in COVID-19 patients. However, most of the studies described a small number of cases [7, 19, 42]. Our investigation included enough patients to demonstrated independent predictive value of this risk factor on mortality. This relationship could be partially explained because diabetic patients are predisposed to a hyper-inflammatory and pro-coagulant state [44]. COVID-19 infection could cause pleiotropic alterations of glucose metabolism due to direct effect on angiotensin-converting enzyme 2 (ACE2) receptors of pancreatic beta cells [45].

Our study has some important limitations as well. First, the retrospective nature of the study might constraint the dataset. Second, we analyzed data supplied by HM Hospitales and it would have been beneficial to perform a revision of the electronic medical records of the included patients, concretely the TEE group to refine some of the variables and get a deeper description. Third, information of previous treatments like anticoagulants or antiplatelet agents was not available. Fourth, we were not able to evaluate a relevant cofounder such as the motivation of hospitalization (clinical or surgical). These limitations avoid us making a recommendation of thrombosis prophylaxis although, due to the large number of patients included we considered that our sample is representative of a larger population. A recent meta-analysis concluded that there is currently insufficient evidence to determine the risks and benefits of prophylactic anticoagulants for people hospitalized with COVID-19 [46].

In conclusion, the analysis of this multicenter retrospective observational dataset of COVID-19 patients confirmed some of the previous observations related with TEE in COVID-19 patients. The prevalence of TEE was not negligible. In addition, patients who develop TEE such as patients with other comorbidities as diabetes, COPD, and older patients had worse prognosis than patient without TEE or theses comorbidities.

STROBE statement—checklist of items that should be included in reports of cohort studies.

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26 Mar 2021

PONE-D-21-03654

Influence of thromboembolic events in the prognosis of COVID-19 hospitalized patients

PLOS ONE

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Reviewers' comments:

Reviewer's Responses to Questions

Review Comments to the Author

Reviewer #1: I appreciated the asking for a peer review report, and I give kind regards for the whole work. All my comments and suggestions are intending to improve the quality of the work.

Specific comments

page 1, title. The authors should follow the journal recommendations about manuscript format (https://journals.plos.org/plosone/s/submission-guidelines) and follow the STROBE checklist when formatting your text. For instance, from what I could see, it is a non-randomized observational study, but it was not clearly stated in the title and the abstract.

Is there a registration number to be reported? If yes, please provide the number here.

Additionally, submitting the fulfilled STROBE checklist accompanying your manuscript is highly recommended.

pages1-2 financial disclosure. The authors state that 'The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.' but there is no detail about the received found. Please provide the details (Initials of the authors who received each award / Grant numbers awarded to each author / The full name of each funder / URL of each funder website) as required by the journal.

Page 3, ethics statement. the authors state that 'HM Hospital ethics comittee' but there is no detail about ethics statement. Please, provide details (Give the name of the institutional review board or ethics committee that approved the study / • Include the approval number and/or a statement indicating approval of this research / • Indicate the form of consent obtained (written/oral) or the reason that consent was not obtained (e.g. the data were analyzed anonymously)) as required by the journal.

Page 8, keywords. The authors have used some mesh terms (https://www.ncbi.nlm.nih.gov/mesh/) as 'COVID-19'. However, I suggest using other Mesh terms in the keywords section to improve the article indexing and citation, such as 'venous thrombosis' instead of deep vein thrombosis and 'thrombosis' instead of thromboembolic disease.

page 8. abbreviations. Please, could you explain the exact differences between composite thromboembolic outcome and thromboembolism event terms? I believe that they are very similar and could be merged in a unique term.

pages9, abstract. the abstract text should reflect the same information as the full text; for instance, the methods used should be described here and not only the primary outcome of interest (incidence of TEE). Besides, the conclusion should primarily answer your objectives and not make inferences or recommendations. Please, amend your conclusions.

page 12, methods. The authors state that the main objective was to determine the composite outcome incidence, but there is no description of follow-up time. To establish an incidence, you must follow the cohort for some time and preferable report the results as a risk ratio. However, you did not report the time of follow-up. In truth, it seems that it was a cross-sectional study that used a de-identified database. If you performed a cross-sectional study, you could not report any incidence data, only prevalence. Please, clarify your methods.

page 14, line 155. Please clarify if the numbers are correct: 48 participants represent 75%?

Page 14, results. please, could you explain the difference between composite thromboembolic outcome and thromboembolism event terms? Please, see my comments on page 8 above. The authors describe a median time (7 days) until discharge, but there was 15.9% mortality. What was the time until death?

page 18, discussion. The authors did not evaluate relevant confounders such as the motivation of hospitalization (clinical or surgical), the previous use of anticoagulants or antiplatelet agents, the need and the dose of used anticoagulants the participants during hospitalization. Although all hospitalized patient should undergo a checklist verification about the necessity of thrombosis prophylaxis, you can not make this general recommendation for all people with COVID-19, based on your evidence. Besides, there is a lack of evidence for anticoagulant therapy in people hospitalized with COVID-19 (please see https://pubmed.ncbi.nlm.nih.gov/33502773/). Please amend your last sentence.

page 18, conclusion. Clinical decision making should be done under a synthesis of the best available evidence and an evaluation of this evidence's certainty. An observational study that did not evaluate previous and current anticoagulation without a specific follow-up period does not allow you to make any recommendation regarding 'thrombosis prophylaxis in related patients. The conclusion should primarily answer your objectives and not make inferences or recommendations. Please revise your conclusions to strict answer your objectives, as the good scientific practice recommends.

Reviewer #2: Well written article. The incidence of thrombotic events in critically ill COVID-19 infected patients is markedly high as compared to critically ill non-COVID-19 infected patients is markedly high. While the venous thromboses appear in proliferation of publications, the data about the incidence of arterial and capillary thromboses are still scant. While the authors have addressed most of the points accurately in their manuscript, I have a few concerns

Minor Points:

# This is a thoughtful and intriguing study, however, many studies published during this pandemic talk about thromboses in COVID infected patients. How is this study different from the rest of them?? or what is it, in this study that separates and distinguishes it from the already published literature has not been made clear by the authors.

# 'Results' section of this manuscripts gives statistics of the study in very fine details. However, it becomes difficult to maintain the flow while reading - if simplified further, maybe by adding a couple of paragraphs, will be a good addition to this paper.

# Please mention the inclusion and exclusion criteria clearly in the material and methods section.

# A flowchart depicting the study population, excluded and included patients will be a good addition to this paper

# Line no. 49 - 'Emerging' will be a better word than 'on going' in this place

In conclusion, this is an interesting study. If worked on the above points, it will only add to its quality

Reviewer #3: Formal comment:

Formal comment to Franciscoet al.: Influence of thromboembolic events in the prognosis of COVID-19 hospitalized patients.

Chun-yi Wang,MB, Wen Wen,MB, Jie Ni,MB, Jing-jie Jiang,MB, Ming-Wei Wang,MD,PhD*,Guofan Chen,MD,PhD*

Affiliated Hospital of Hangzhou Normal University , Hangzhou,310015,China

Chun-yi Wang and Wen Wen contributed equally to this work

*Corresponding Author: Ming-Wei Wang; E-mail: wmw990556@163.com;Guofan Chen,E-mail: 495086736@qq.com

Author Contributions

Writing–original draft: Chun-yi Wang,Wen Wen,Jie Ni and Jing-jie Jiang.

Writing–review & editing: Ming-wei Wang and Guofan Chen.

We read with great interest an article published in PLoS ONE titled “Influence of thromboembolic events in the prognosis of COVID-19 sickened patients.” [1] On the basis of a study conducted among patients with COVID-19 at 16 hospitals in Spain, the authors concluded that COVID-19 patients experiencing thrombotic events had significantly poorer prognoses than those without thrombotic events. They also confirmed higher mortality rates in patients who have developed complications COVID-19 than those without thrombotic events.

Although the author strengthened the correlation between thrombotic events and prognosis in patients through this study and proved the need for clinical thrombotic prevention and antithrombotic treatment, several points need to be considered in the interpretation of the presented results. Composite thromboembolic outcome (CTE) was defined as arterial thromboembolic complications and venous thromboembolic complications by the author.

Venous thromboembolism (VTE), clinically manifested as deep vein thrombosis or pulmonary embolism, is the third most common acute cardiovascular syndrome after myocardial infarction and stroke worldwide [2]. Endothelial injury, hypercoagulability, and blood stasis (Virchow factors) are the three risk factors for thrombosis. Infection is a common trigger for VTE. Acute infection was assigned 1 point under the Padua Prediction Score [3].

In our meta-analysis, we concluded that the prognosis of patients with VTE was significantly worse than that of patients without thrombus; moreover, the disease was more severe in patients with VTE than in those without thrombus [4], which was consistent with the results of the author's study.

A meta-analysis by Tan BK et al. mentioned that patients with severe COVID-19 had a higher risk of VTE on admission. A certain risk of arterial embolization was present, but relevant data remained inadequate [5].

However, our study mainly focused on VTE and did not include the outcome of arterial thrombotic events in patients with COVID-19. McBane RD 2nd argued that most reports focused on VTE, and few studies provided the incidence of arterial thrombotic events, which varied from 2% to 5% [6]. Fournier M et al. also analyzed arterial thrombosis, but the prevalence remained relatively low [7].

The prevalence of arterial thrombotic events (acute ischemic stroke, systemic arterial embolism, and myocardial infarction) considered by the authors was low. CTE was mentioned in 64 cases, but 76.6% of them were VTE [1].

Arterial thrombus formation generally occurs because of certain underlying diseases or certain inducements or risk factors. For instance, acute thrombotic events may occur with coronary stents after percutaneous transluminal coronary intervention for acute myocardial infarction. However, acute arterial embolism occurs because as a “foreign body,” the stent induces platelet aggregation. The origin of arterial thrombosis is thus difficult to determine.

Therefore, whether the authors ignore arterial thrombotic events and only consider studying venous thrombosis has to be determined. On the basis of the present study, the correlation between arterial thrombosis and venous thrombosis in patients with COVID-19 may be separately studied. Regardless of the aforementioned point, we agree with the author's view that patients with COVID-19 experiencing thrombotic events have poor prognoses and increased mortality. Therefore, during clinical treatment, antithrombotic therapy should be administered in patients with COVID-19.

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Reviewer #1: Yes: Ronald Luiz Gomes Flumignan, MD, PhD

Reviewer #2: No

Reviewer #3: Yes: Mingwei Wang

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9 May 2021

Dear Aleksandar R. Zivkovic,

Thank you for giving us the opportunity to resubmit a revised draft of our manuscript titled “Influence of thromboembolic events in the prognosis of COVID-19 hospitalized patients” to your prestigious journal Plos One. We appreciate the time and effort that you and the reviewers have dedicated to providing your valuable feedback on our manuscript. We are grateful to the reviewers for their insightful comments on the paper. We have been able to incorporate changes to reflect most of the suggestions from the reviewers. We have highlighted the changes within the manuscript using track changes.

Here is a point-by-point response to the editors and reviewers’ comments.

Responses to Academic Editor

Comment 1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at

https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and

https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf

Response: We have reviewed PLOS ONE’s style requirements to improve the original submission.

Comment 2. Thank you for stating in the text of your manuscript "The study was approved by the Ethics committee of the HM Hospitals and adhered to the policy for protection of human subjects according to Declaration of Helsinki. As the information was obtained from a de-identified public database written informed consent from all study participants was not needed."

Please also add this information to your ethics statement in the online submission form.

Response: We have considered editor’s comment

Comment 3. Thank you for providing the date(s) when patient medical information was initially recorded.

Please also include the date(s) on which your research team accessed the databases/records to obtain the retrospective data used in your study.

Response: We have addressed the editor’s comment in the new version of the manuscript.

Comment 4. In your Methods section, please provide additional information about the participant selection method and the demographic details of your participants. Please ensure you have provided sufficient details to replicate the analyses such as:

a) a list of the sixteen hospitals that make up the HM Hospitales

b) description of any inclusion/exclusion criteria that were applied to participant selection (e.g., ICD10 codes, characteristics, age, etc.)

c) a statement as to whether your sample can be considered representative of a larger population

Response: We have addressed the editor’s comments in the new version of the manuscript. We have listed all HM hospitals. We have clarified that patients under 18 years old were excluded. In addition, patients without ICD10 codification were also excluded (n=131). We add an statement in the discussion section highlighting that our sample could be considered representative of a larger population.

Comment 5. Thank you for stating in your financial disclosure:

'The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.'

At this time, please address the following queries:

- Please clarify the sources of funding (financial or material support) for your study. List the grants or organizations that supported your study, including funding received from your institution.

- State what role the funders took in the study. If the funders had no role in your study, please state: “The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.”

- If any authors received a salary from any of your funders, please state which authors and which funders.

- If you did not receive any funding for this study, please state: “The authors received no specific funding for this work.”

- Please include your amended statements within your cover letter; we will change the online submission form on your behalf.

Response: We have add information about the founding in the new version of the manuscript. We confirm that we received no specific funding for this work.

Comment 6. 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.

Response: We have reviewed all cites. We confirm that no retracted article has been added in the bibliography of the new version of the article.

Responses to Reviewer #1

I appreciated the asking for a peer review report, and I give kind regards for the whole work. All my comments and

suggestions are intending to improve the quality of the work.

Response: We appreciate the time and effort that you have dedicated to providing your valuable feedback on our manuscript.

Comment 1

page 1, title. The authors should follow the journal recommendations about manuscript format (https://journals.plos.org/plosone/s/submission-guidelines) and follow the STROBE checklist when formatting your text. For instance, from what I could see, it is a non-randomized observational study, but it was not clearly stated in the title and the abstract.

Is there a registration number to be reported? If yes, please provide the number here.

Additionally, submitting the fulfilled STROBE checklist accompanying your manuscript is highly recommended.

Response: We have taken into account reviewer 1 comment in the new version of the manuscript. We clarify that is a study based on a cross sectional study in the title and in the abstract. We have added a fulfilled STROBE checklist.

Comment 2

pages1-2 financial disclosure. The authors state that 'The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.' but there is no detail about the received found. Please provide the details (Initials of the authors who received each award / Grant numbers awarded to each author / The full name of each funder / URL of each funder website) as required by the journal.

Response: We have clarified this point in the new version of the manuscript. We confirm that we received no specific funding for this work.

Comment 3

Page 3, ethics statement. the authors state that 'HM Hospital ethics comittee' but there is no detail about ethics statement. Please, provide details (Give the name of the institutional review board or ethics committee that approved the study / • Include the approval number and/or a statement indicating approval of this research / • Indicate the form of consent obtained (written/oral) or the reason that consent was not obtained (e.g. the data were analyzed anonymously)) as required by the journal.

Response: We have taken into account reviewer 1 comment in the new version of the manuscript. The study was approved by the Ethics committee of the HM Hospitals (approval number 20.03.1573-GHM).and adhered to the policy for protection of human subjects according to Declaration of Helsinki. As the information was obtained from a de-identified public database written informed consent for our specific study from all study participants was not needed. The data were analyzed anonymously.

Comment 4

Page 8, keywords. The authors have used some mesh terms (https://www.ncbi.nlm.nih.gov/mesh/) as 'COVID-19'. However, I suggest using other Mesh terms in the keywords section to improve the article indexing and citation, such as 'venous thrombosis' instead of deep vein thrombosis and 'thrombosis' instead of thromboembolic disease.

Response: We have taken into account reviewer 1 comment in the new version of the manuscript.

Comment 5

page 8. abbreviations. Please, could you explain the exact differences between composite thromboembolic outcome and thromboembolism event terms? I believe that they are very similar and could be merged in a unique term.

Response: We have taken into account reviewer 1 comment in the new version of the manuscript. We use only one term in the new version of the manuscript.

Comment 6

pages9, abstract. the abstract text should reflect the same information as the full text; for instance, the methods used should be described here and not only the primary outcome of interest (incidence of TEE). Besides, the conclusion should primarily answer your objectives and not make inferences or recommendations. Please, amend your conclusions.

Response: We have taken into account reviewer 1 comment in the new version of the manuscript.

Comment 7

page 12, methods. The authors state that the main objective was to determine the composite outcome incidence, but there is no description of follow-up time. To establish an incidence, you must follow the cohort for some time and preferable report the results as a risk ratio. However, you did not report the time of follow-up. In truth, it seems that it was a cross-sectional study that used a de-identified database. If you performed a cross-sectional study, you could not report any incidence data, only prevalence. Please, clarify your methods.

Response: We have taken into account reviewer 1 comment in the new version of the manuscript. We confirm that we did a cross-sectional study that used a de-identified database. We recognize that we could no offer information about incidence.

Comment 8

page 14, line 155. Please clarify if the numbers are correct: 48 participants represent 75%?

Response: We have taken into account reviewer 1 comment in the new version of the manuscript. We have clarified that these 48 participants represented 75.0% of the 64 TEE patients

Comment 9

Page 14, results. please, could you explain the difference between composite thromboembolic outcome and thromboembolism event terms? Please, see my comments on page 8 above. The authors describe a median time (7 days) until discharge, but there was 15.9% mortality. What was the time until death?

Response: We have taken into account reviewer 1 comment in the new version of the manuscript. We agree with reviewer 1 that is better to use one term. Median time until death was 5.0 days (IQR 3.0-9.0) days. We have added this information in the new version of the manuscript.

Comment 10

page 18, discussion. The authors did not evaluate relevant confounders such as the motivation of hospitalization (clinical or surgical), the previous use of anticoagulants or antiplatelet agents, the need and the dose of used anticoagulants the participants during hospitalization. Although all hospitalized patient should undergo a checklist verification about the necessity of thrombosis prophylaxis, you can not make this general recommendation for all people with COVID-19, based on your evidence. Besides, there is a lack of evidence for anticoagulant therapy in people hospitalized with COVID-19 (please see https://pubmed.ncbi.nlm.nih.gov//). Please amend your last sentence.

Response: We have considered reviewer 1 comment in the new version of the manuscript. We have added the limitations highlighted in the discussion. We have avoided a general recommendation for all people with COVID-19 infection. We have amended our previous last sentence in the new version of the manuscript.

Comment 11

page 18, conclusion. Clinical decision making should be done under a synthesis of the best available evidence and an evaluation of this evidence's certainty. An observational study that did not evaluate previous and current anticoagulation without a specific follow-up period does not allow you to make any recommendation regarding 'thrombosis prophylaxis in related patients. The conclusion should primarily answer your objectives and not make inferences or recommendations. Please revise your conclusions to strict answer your objectives, as the good scientific practice recommends.

Response: We have taken into account reviewer 1 comment in the new version of the manuscript.

“In conclusion, the analysis of this multicenter retrospective observational dataset of COVID-19 patients confirmed some of the previous observations related with TEE in COVID-19 patients. The prevalence of TEE was not negligible. In addition, patients who develop TEE such as patients with other comorbidities as diabetes, COPD, and older patients had worse prognosis than patient without TEE or theses comorbidities.”

Responses to Reviewer #2

Reviewer #2: Well written article. The incidence of thrombotic events in critically ill COVID-19 infected patients is markedly high as compared to critically ill non-COVID-19 infected patients is markedly high. While the venous thromboses appear in proliferation of publications, the data about the incidence of arterial and capillary thromboses are still scant. While the authors have addressed most of the points accurately in their manuscript, I have a few concerns

Minor Points:

Comment 1

This is a thoughtful and intriguing study, however, many studies published during this pandemic talk about thromboses in COVID infected patients. How is this study different from the rest of them?? or what is it, in this study that separates and distinguishes it from the already published literature has not been made clear by the authors.

Response: We recognized that there are many studies published during this pandemic about thromboses. We think that one of our strengths is the size of the study. This issue allow us to consider that our sample is representative of a larger population.

Comment 2

'Results' section of this manuscripts gives statistics of the study in very fine details. However, it becomes difficult to maintain the flow while reading - if simplified further, maybe by adding a couple of paragraphs, will be a good addition to this paper.

Response: According to reviewer 2’ comment we have re-written the results section.

Comment 3

Please mention the inclusion and exclusion criteria clearly in the material and methods section.

Response: According to reviewer 2’ comment we have described the inclusion and exclusion criteria

Comment 4

A flowchart depicting the study population, excluded and included patients will be a good addition to this paper

Response: According to reviewer 2’ comment we have added a flowchart depicting the study population.

Comment 5

Line no. 49 - 'Emerging' will be a better word than 'on going' in this place

Response: We have considered reviewer 2 comment in the new version of the manuscript

Responses to Reviewer #3

Comment

Venous thromboembolism (VTE), clinically manifested as deep vein thrombosis or pulmonary embolism, is the third most common acute cardiovascular syndrome after myocardial infarction and stroke worldwide [2]. Endothelial injury, hypercoagulability, and blood stasis (Virchow factors) are the three risk factors for thrombosis. Infection is a common trigger for VTE. Acute infection was assigned 1 point under the Padua Prediction Score [3]. In our meta-analysis, we concluded that the prognosis of patients with VTE was significantly worse than that of patients without thrombus; moreover, the disease was more severe in patients with VTE than in those without thrombus [4], which was consistent with the results of the author's study.

A meta-analysis by Tan BK et al. mentioned that patients with severe COVID-19 had a higher risk of VTE on admission. A certain risk of arterial embolization was present, but relevant data remained inadequate [5].

However, our study mainly focused on VTE and did not include the outcome of arterial thrombotic events in patients with COVID-19. McBane RD 2nd argued that most reports focused on VTE, and few studies provided the incidence of arterial thrombotic events, which varied from 2% to 5% [6]. Fournier M et al. also analyzed arterial thrombosis, but the prevalence remained relatively low [7]. The prevalence of arterial thrombotic events (acute ischemic stroke, systemic arterial embolism, and myocardial infarction) considered by the authors was low. CTE was mentioned in 64 cases, but 76.6% of them were VTE [1].

Arterial thrombus formation generally occurs because of certain underlying diseases or certain inducements or risk factors. For instance, acute thrombotic events may occur with coronary stents after percutaneous transluminal coronary intervention for acute myocardial infarction. However, acute arterial embolism occurs because as a “foreign body,” the stent induces platelet aggregation. The origin of arterial thrombosis is thus difficult to determine.

Therefore, whether the authors ignore arterial thrombotic events and only consider studying venous thrombosis has to be determined. On the basis of the present study, the correlation between arterial thrombosis and venous thrombosis in patients with COVID-19 may be separately studied. Regardless of the aforementioned point, we agree with the author's view that patients with COVID-19 experiencing thrombotic events have poor prognoses and increased mortality. Therefore, during clinical treatment, antithrombotic therapy should be administered in patients with COVID-19.

Response: We have considered reviewer’s comments in the new version of the manuscript.

We have defined better the primary outcome of the study in the abstract and in the text.

TEE was defined by the occurrence of venous thromboembolism (VTE), acute ischemic stroke (AIS), systemic arterial embolism or myocardial infarction (MI).

We agree that it would be interesting to have information about treatments. We add this aspect in the limitation section.

Our study has some important limitations as well. First, the retrospective nature of the study might constraint the dataset. Second, we analyzed data supplied by HM Hospitales and it would have been beneficial to perform a revision of the electronic medical records of the included patients, concretely the TEE group to refine some of the variables and get a deeper description. Third, information of previous treatments like anticoagulants or antiplatelet agents was not available. Fourth, we were not able to evaluate a relevant cofounder such as the motivation of hospitalization (clinical or surgical). These limitations avoid us making a recommendation of thrombosis prophylaxis although, due to the large number of patients included we considered that our sample is representative of a larger population. A recent meta-analysis concluded that there is currently insufficient evidence to determine the risks and benefits of prophylactic anticoagulants for people hospitalized with COVID-19

Submitted filename: ResponsetoReviewers_R1.docx

Click here for additional data file.

14 May 2021

Influence of thromboembolic events in the prognosis of COVID-19 hospitalized patients. Results from a cross sectional study

PONE-D-21-03654R1

Dear Dr. Purroy,

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Academic Editor

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25 May 2021

PONE-D-21-03654R1

Influence of thromboembolic events in the prognosis of COVID-19 hospitalized patients. Results from a cross sectional study.

Dear Dr. Purroy:

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