The effectiveness of early anticoagulant treatment in Covid-19 patients

Abstract

Objectives

Coronavirus disease 2019 (Covid-19) is an emerging, fast-spreading and worldwide infectious disease that would be deteriorated with the precipitation of systemic or local thrombosis. The aim of current study was evaluating the effects of early anticoagulant treatment in hospitalized Covid-19 patients.

Method

The present retrospective and comparative cohort study investigated 413 hospitalized Covid-19 patients treated with or without Low Molecular Weight Heparin (LMWH) (n = 187 and 226, respectively) in the Covid Clinics of Gulhane Education and Research Hospital in Ankara, Turkey, between March 18 and May 03, 2020. The treatment groups were consisted of the patients evaluated before and after The Covid-19 Treatment Guide update on April 12, 2020 that included the anticoagulant treatment thereafter.

Results

The mean age of all 413 patients (204 male and 209 female) at disease onset was 50.6 ± 16.7 years. The LMWH-treated patients had significantly higher coagulation markers such as d-dimer and platelet count than LMWH-untreated patients (p values < 0.05). The inflammatory markers, ferritin, interleukin-6 and procalcitonin were significantly increased in LMWH-untreated patients (p values < 0.05). The presence of any comorbidity was significantly more common in LMWH-treated patients compared to LMWH-untreated group (39.6% vs 19.9%, respectively; p < 0.001). Hypertension and diabetes mellitus were the most frequent comorbidities in both groups. The number of intensive care unit (ICU) transfer and longer length of hospital stay were more commonly observed in LMWH-untreated patients (p values <0.05).

Conclusions

Early anticoagulant treatment with relatively higher doses of LMWH may improve the clinical outcome of Covid-19 patients and shorten the length of hospital stay.

Keywords

Covid-19 disease infectious disease anticoagulation heparin thrombosis

Introduction

The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) causes coronavirus disease 2019 (Covid-19) that was first reported in Wuhan, Hubei Province in January 2020. It has quickly become an emerging, serious, fast-spreading, and worldwide health disaster. Covid-19 has a high mortality rate that was reported as high as 8%. Until June 2020, 529.601 of people died among 11.219.696 infected cases in 213 different countries around the world.¹

Mostly the pulmonary system was defined as the main target of SARS-CoV2, but the mortality concept of this disease presented with a more severe and systemic disease including shock, multi organ failure, pyrexia resistant to treatment, and acute lung injury with acute respiratory distress syndrome (ARDS).² The coagulation abnormalities that reported in most of the severe Covid-19 patients showed significant differences from the systemic coagulopathies associated with severe infections, such as disseminated intravascular coagulation (DIC) or thrombotic microangiopathy.³ Substantial rate of mortality has been attributed to the abnormal coagulopathy in Covid-19 patients.⁴

Up to date Covid-19 studies indicated that the tendency of thrombosis, observed at the beginning of disease, could be originated from the impaired clotting and platelet activation of the patients with pneumonia.^5,6 The anticoagulant treatment was rarely used at the beginning of Covid-19 outbreak, because the absence of enough evidence on early anticoagulant treatment. But the recent studies with positive results encouraged the use of anticoagulant drugs at an early phase of Covid-19 treatment.⁷

In Turkey, Covid-19 patients have been treated according to the Covid-19 Treatment Guide edited and released by Turkish Republic Ministry of Health Science Board of Covid-19. The 5^th version of this guide was updated on April 12, 2020, and an early phase anticoagulant treatment was included in the treatment protocol of hospitalized Covid-19 patients. We hypothesized that treating the hospitalized Covid-19 patients with higher than usual doses of low molecular weight heparin (LMWH) at early stage could prevent the exacerbation of disease and contribute to early discharge. To test our hypothesis the present retrospective and comparative cohort study was designed. Here we investigated the clinical outcomes of Covid-19 patients that treated with or without LMWH^8,9 according to the valid treatment guide during the hospitalization period of the patients.

Material and methods

The hospitalized Covid-19 patients in the Covid Clinics of Gulhane Education and Research Hospital in Ankara, Turkey were enrolled in the present study. Total of 413 patients were treated with or without LMWH (n = 187 and 226, respectively) between March 18 and May 03, 2020.

The diagnosis, treatment and management of Covid-19 patients have been regulated with the valid Covid-19 Guides edited and updated by Turkish Republic Ministry of Health Science Board since January 21, 2020. The 3^rd version of Covid Treatment Guide edited at March 11, 2020 by Ministry of Health Science Board included uptodate treatments such as suitable antiviral therapies (e.g. oseltamivir, hidroxychloroquine, favipiravir, lopinavir and ritonavir), oxygen supply, supportive medical therapies and indicated antibiotics. According to this guide, the diagnosis of Covid-19 patients was verified whether with a positive result of SARS-CoV2 in reverse transcription polymerase chain reaction (RT-PCR) test or having relevant anamnesis, clinical symptoms or signs of typical pulmonary computerized tomography (CT) imaging with negative RT-PCR test results.⁸

The 5^th version of Covid Treatment Guide revised and edited at April 12 by Turkish Republic Ministry of Health Science Board included not only all the managments mentioned by the 3^rd version, but also included the early anticoagulant treatment in patients without any contraindication. The usage of anticoagulant treatment had been recommended in the patients with low or high-risk status. The patients having a serum d-dimer level lower than 1 µg/ml was defined as low risk group. In this group, the recommended LMWH (i.e. enoxaparin) dosage was 40 mg/day for the patients having lower than 40 kg/m² of body mass index (BMI) and 80 mg/day for the ones having higher than 40 kg/m² of BMI. The patients having a serum d-dimer level higher than 1 µg/ml or having the severe disease symptoms were defined as high risk group. The recommended anticoagulant treatment for high-risk patients was using 0.5 mg/kg/12-hour dosage of LMWH during hospitalization, and continuation of the anticoagulant treatment for a month after discharge from hospital.⁹ In the current study none of the patients has been developed acute renal injury during the treatment and follow-up period, and we did not have to change or cease the LMWH treatment.

Regarding the hypothesis of the current study, the primary outcome measure was length of hospital stay, and the secondary outcome measure was transfer rate to the intensive care unit (ICU).

The present study was approved by Ankara Provincial Health Directorate (approval number: 2020-05-04T11_25_21), and The Ministry of Health, Gulhane Education and Training Hospital, Non-Invasive Local Ethic Board (approval number: 178/2020) at May 5, 2020.

The R software was used for the statistical analyses of the data obtained in the study. Data were summarized as the mean and standard deviation (SD) for the continuous variables, and as the absolute values and percentages for the categorical variables. The normal distribution of the continuous variables was analyzed using Kolmogorov-Smirnov test and Shapiro Wilks test. Chi-square test was used to compare categorical variables. Student’s t-test (paired or independent samples) or Mann-Whitney U for unpaired and Wilcoxon Signed Rank test for paired samples were used to compare groups for the continuous variables in parametric or non-parametric nature. P values lower than 0.05 were considered as statistically significant with a 95% confidence interval.

Results

Totally 561 Covid-19 patients, hospitalized in the Covid Clinics of Gulhane Education and Research Hospital from March 18 to May 03, 2020 were evaluated. The 148 of 561 the patients were excluded from the study (Figure 1). Among the excluded patients, 47 of them were directly admitted to the ICU; 42 patients were hospitalized for shorter than 4 days; 26 patients were younger than 18 years old; files of 19 patients were not available; 9 patients had a chronical renal insufficiency, and 5 patients were treated with oral anticoagulants. The remaining 413 patients treated with or without LMWH were included into the present study and their data were analyzed and evaluated.

Figure 1.

Flowchart for patient inclusion.

Mean biochemical parameters and demographic properties of all patients on admission were presented in Table 1. The comparison of these parameters for LMWH-treated and LMWH-untreated groups were also presented in Table 1. The mean age of LMWH-treated patients was significantly higher than LMWH-untreated patients (p = 0.003). The gender distribution was similar in these two groups (p > 0.05). LMWH-treated patients had significantly shorter average length of stay in hospital (8.2 vs 10.2 days; p < 0.001, Table 1).

Table 1.

Comparison of demographic and biochemical parameters between LMWH-treated and -untreated patients.

Parameters	All patients (n = 413)	LMWH-treated mean ± SD (min-max)	LMWH-untreated mean ± SD (min-max)	P value
Age, years	50.6 ± 16.7	53.4 ± 17.9	48.4 ± 15.4	0.003
Gender, Male/Female	204/209	101/86	103/123	0.088
D-Dimer, µg/ml (admission)	1.00 ± 2.5 (0-29.95)	1.00 ± 1.17 (0-16)	1.16 ± 3.19 (0-29.95)	0.551
D-Dimer, µg/ml (discharge)	0.77 ± 1.2 (0-10.62)	0.75 ± 1.15 (0-7.19)	0.81 ± 1.33 (0-10.62)	0.719
D-Dimer (paired comparisons) (p)	0.001	<0.001	0.458
Platelets x10³/ μL (admission)	218.14 ± 74.44	226.06 ± 84.69	206.61 ± 62.0	0.046
Platelets x10³/ μL (discharge)	282.6 ± 101.9	288.96 ± 114.67	277.45 ± 90.0	0.635
Platelets (paired comparisons) (p)	<0.0001	<0.0001	<0.0001
Hemoglobin, g/L	13.8 ± 6.2	13.5 ± 1.9	14.1 ± 8.2	0.309
Lymphocyte, μL	1406.3 ± 602.5	1383.9 ± 594.7	1424.8 ± 609.6	0.494
Ferritin, ng/mL	221.1 ± 297.2	187.0 ± 226.9	327.5 ± 440.2	0.097
IL-6, pg/ml	31.5 ± 28.3	25.6 ± 18.2	40.6 ± 38.5	0.251
C-reactive protein (CRP) mg/dl	40.4 ± 59.7	51.9 ± 65.8	30.7 ± 52.3	<0.001
Procalcitonin, ng/ml	0.180 ± 1.116	0.097 ± 0.454	0.251 ± 1.458	0.167
Transfer to ICU	6 (0-6)	0/187	6/226	0.034
Length ofHospital Stay	9.3 ± 4.0(median:9, 4 to 26 days)	8.2 ± 3.6(median:7; 4 to 22 days)	10.2 ± 4.1(median: 10; 4 to 26 days)	<0.001

CRP: C-Reactive Protein, LMWH: Low-Molecular-Weight Heparin, ICU: Intensive Care Unit, SD: Standard Deviation.

D-dimer and platelet levels were evaluated as coagulation factors. The average d-dimer levels of the patients were siginificanly decreased during discharge compared to the levels at admission (p = 0.001, Table 1). When the patient groups were evaluated according to LMWH administration, only LMWH-treated patients showed a significant decrease in d-dimer levels during discharge (p < 0.001, Table 1 and Figure 2). D-dimer levels in LMWH-treated patients tended to be higher than the LMWH-untreated patients during first admission, however that difference did not reach statistically significant levels (p > 0.05, Table 1). On the other hand, platelet levels were significantly higher in LMWH-treated patients compared to the LMWH-untreated group (p < 0.05, Table 1 and Figure 3). The platelet levels of the patients were significantly increased both in LMWH-treated and -untreated groups during the discharge (p < 0.0001, Table 1 and Figure 3).

Figure 2.

The comparison of admission and dischage d-dimer levels of low molecular weight heparin (LMWH)-treated and -untreated patients, and intensive care unit (ICU) transferred patients (*p < 0.05, Wilcoxon Signed Ranks Test, compared with the admission level).

Figure 3.

The comparison of admission and dischage platelet levels of low molecular weight heparin (LMWH)-treated and -untreated patients, and intensive care unit (ICU) transferred patients (*p < 0.05, Student’s t test for paired samples, compared with the admission levels; #p < 0.05, Student’s t test for independent samples, compared with LMWH-untreated group).

Comparing the inflammatory markers indicated that the LMWH-treated patients had significantly higher CRP level than the LMWH-untreated patients (p < 0.001, Table 1). On the other hand, the inflammatory markers such as ferritin, IL-6, and procalcitonin levels were similar in these two gropus of the patients (p values> 0.05, Table 1).

The comorbidity status and comparison of comorbidities between two groups were analyzed and summarized in Table 2. Having at least one comorbidity was significantly more common in LMWH-treated patients compared to LMWH-untreated group (p < 0.001, Table 2). The hypertension and diabetes mellitus (DM) were the most frequent comorbidities in the patients. Coronary artery disease, chronic respiratory diseases (Chronic Obstructive Pulmonary Disease-COPD/Asthma), and cancer were among the common comorbidities in the patients. Hypertension, coronary arterial disease and cancer were significantly more common in LMWH-treated patients (p values< 0.05, Table 2). On the other hand, LMWH-treated and -untreated patients had similar rates for having DM or COPD/Asthma (p values > 0.05, Table 2).

Table 2.

Comparison of comorbidities between LMWH-treated and -untreated patients.

Comorbidity	LMWH-treated Patients n (%)	LMWH-untreated patients n (%)	P value
Havingat least one co-morbidity	74 (39.6%)	45 (19.9%)	<0.001
Hypertension	46 (60.5%)	30 (39.5%)	0.003
Diabetes Mellitus	24 (57.1%)	18 (42.9%)	0.103
Coronary ArteryDisease	19 (70.4%)	8 (29.6%)	0.007
COPD/Asthma	14 (53.8%)	12 (46.2%)	0.365
Cancer	9 (75%)	3 (25%)	0.036

LMWH: Low-Molecular-Weight Heparin, SD: Standard Deviation, COPD: Chronic Obstructive Pulmonary Disease.

Only 6 patients were transferred to ICU among all the patients, and all 6 of the patients were from LMWH-untreated group (p < 0.05, Table 1). The ICU transfer reason for the patients were macrophage activation syndrome (MAS) (n = 2), pulmonary embolism (PE) proven with doppler ultrasonography and pulmonary CT angiography (n = 2), cardiac arrhythmia (n = 1), and respiratory insufficiency (n = 1). The 5/6 of the ICU transferred patients were male (Table 3). The biochemical and demographical data of the ICU transferred patients were presented in Table 3. The two patients with PE were undergone mechanical ventilation in ICU. All the patients included in the current study were discharged with recovery. Because of the limited number of ICU transferred patients we did not perform any statistical comparison in these patients.

Table 3.

Mean clinical and biochemical parameters of ICU transferred patients.

Parameters		Mean ± SD (min.-max.)
Age, years		52 ± 12.8 (34-73)
Gender, male/female		5/1
Hemoglobin, g/L		13.5 ± 2.3 (9.8-15.8)
Lymphocyte, μL		733.3 ± 301.1 (300-1100)
Platelets x10³/ μL (admission)		141.4 ± 36.77 (86-183)
Platelets x10³/ μL (discharge)		301.4 ± 76.7 (176-378)
D-Dimer, µg/ml(admission)		4.24 (1.91-10,1)
D-Dimer, µg/ml(discharge)		0.9 (0.49-1.06)
Ferritin, ng/mL		611.5 ± 648.9 (19-1500)
IL-6, pg/ml		69.1 ± 53.2 (5.27-129.3)
CRP, mg/dl		107.2 ± 96.1 (8.87-268.4)
Procalcitonin, ng/ml		0.180 ± .224 (0.04-057)
Length of Hospital Stay		16 ± 7.5 (5-26)
Reason (n)
	MAS	2
	PE	2
	Cardiac Arrythmia	1
	Respiratory Insufficiency	1

CRP: C-Reactive Protein, SD: Standard Deviation, ICU: Intensive Care Unit, MAS: macrophage activation syndrome, PE: pulmonary embolism.

Discussion

The present study investigated the clinical outcomes of Covid-19 patients that treated with or without LMWH. Our results indicated that LMWH-treated patients had shorter hospital stay time although they were older, had more comorbid diseases, and had higher inflammatory activity than the LMWH-untreated patients. Moreover, LMWH-treatment significantly decreased the ICU transfer rate of the Covid-19 patients.

Routinely using of anticoagulants in hospitalized Covid-19 patients was proposed after the evidences that Covid-19 infection could be defined as a hypercoagulation inducing condition with superfluous thrombin production and fibrinolysis shutdown.^10,11 Similarly, the hypoxia notified at severe Covid-19 patients could induce thrombosis through not only enhancing blood viscosity but also inducing a signal path due to hypoxia-inducible transcription factor.¹² A recent study investigating the postmortem lung dissections of Covid-19 patients had an evidence of occlusion and microthrombosis formation in pulmonary small vessels.¹³ Thus, The Covid-19 Treatment Guide, updated on April 12, 2020 included the routine anticoagulant treatment in hospitalized patients without any contraindications.

Increase in d-dimer level expresses the collection of thrombus and fibrin lysis on pulmonary vasculature. In the present study average d-dimer level of the patients were more than two times higher than the normal range of 0.5 µg/mL. However, platelet count of the patients was between normal ranges. Thus, the Covid-19 patients were compatible with early-phase Covid-19 related pulmonary intravascular or immunovascular coagulopathy, defined as evident microvascular thrombosis and haemorrhage due to immense alveolar and interstitial inflammation that resembles with macrophage activation syndrome (MAS).¹⁴

Previously, Guan et al. (2020) showed that 46% of the 1099 Covid-19 patients had elevated levels of d-dimer level, and only 5% of these patients had a decreased platelet count (<100x10³/μL).¹⁵ Tang et al. (2020) reported that the average d-dimer concentration of non-survived Covid-19 patients was 2.12 µg/ml compared to 0.61 µg/ml in Covid-19 survivors.⁴ In another study by Tang et al. (2020) evaluation of 449 Covid-19 patients supported those findings by indicating elevated d-dimer levels in addition to decreased platelet counts in non-survivor group compared to survivor group.⁷ A meta analysis comparing the thrombotic tendency of severe and non-severe Covid-19 patients revealed that elevated d-dimer levels and decreased platelet counts were presented in severe Covid-19 patient group.^4,16–18 Increased d-dimer level was also associated with poor survival in those patients.¹⁸

In the present study, significant decrease in d-dimer levels only in the LMWH-treated patients indicated that inclusion of antithrombotic treatment in all hospitalized Covid-19 patients with the 5^th version of the Guide might have some substantial beneficial effects in their treatment. One of the indicators for the effectiveness of LMWH treatment was that none of the ICU transferred patients was from LMWH-treated group. The levels of coagulation and inflammatory markers, such as d-dimer, CRP, ferritin and IL-6 were higher, and the platelet counts were lower in ICU transferred patients than the rest of the patients. Klok et al. (2020) reported that 28 patients (15% of total; cumulative rate 27%) among the 184 Covid-19 patients were transferred to the ICU while treated for thromboprophylaxis, and 25 of those patients had pulmonary embolism (PE).¹⁹ A recent study by Helms et al. (2020) notified that thromboembolic complications in Covid-19 patients with ARDS were significantly higher than a historical control group of non-Covid-19 ARDS patients (11.7% vs 2.1%) although they had anticoagulant treatment.^20,21 In the present study, early start of LMWH treatment might increase the effectiveness of anticoagulant treatment and preventing patients from transfer to ICU.

The short length of hospital stay is another important indicator for showing the effectiveness of the treatment. The present study clearly indicated that LMWH treatment significantly shortened the hospital stay length of Covid-19 patients form 10.2 days to 8.2 days in average. A median 9 days of hospital stay length in our study highly resembles the reported 9.3 days hospital stay length in 1840 Covid-19 patients in CA, USA.²¹ Moreover, we showed that LMWH treatment significantly decrease hospital stay duration although LMWH-treatment group had more comorbidities and had higher inflammatory markers. Wolfel et al. (2020) claimed that the widespread immunothrombosis on a broad pulmonary vascular network best explains the adverse impact of male gender, hypertension, obesity, and diabetes on the prognosis of patients with Covid-19 without confirmation of Covid-19 viraemia in early disease period.²²

The rate of comorbid states in LMWH-treated patients in our study seemed not only higher than the LMWH-untreated group in our study but also higher than the previous reports in Covid-19 patients.¹⁸ For example, Tang et al. (2020) found 39.4% of Covid-19 patients had hypertension, and 20.7% of the patients had DM. In our study these rates were almost two times more common; ie. 60.5% hypertension and 57.1% DM.¹⁸

Luo et al. (2020) investigated the predictive values of several variables such as age, neutrophil count, platelet count, and CRP in Covid-19 patients.²³ They identified those variables as independent predictors of adverse outcome. Among the others increased CRP exhibited an important predictor for poor outcome with a cut-off value of 41.4 mg/dL. In the present study LMWH-treated patients had a higher CRP levels than that calculated cut-off value, but LMWH-untreated patients had significantly lower levels of CRP (51.9 vs 30.7 mg/dL, respectively). Thus, our results on the effectiveness of LMWH treatment might reflect even more value if the more severe clinical state of the patients were taken into consideration.

Previously, it was proclaimed that LMWH treatment, as an anticoagulant treatment, provided new, promising, better prognosis in relation to mortality in a sepsis induced coagulopathy (40.0% vs 64.2%).²⁴ LMWH was also found as protective at critically ill patients against PE. Besides, LMWH has been proposed to have an anti-inflammatory effect that might provide an additional benefit in Covid-19 infection where proinflammatory cytokines were significantly elevated.^15,16,25 In another study from China, early application of anticoagulant treatment in severe Covid-19 was suggested for improving outcome however, no specific inclusion or exclusion criteria has been pointed out so far.²⁶ Currently, the effectiveness of anticoagulant treatment for sepsis associated DIC seems still controversial. Even the Japanese guideline for management of sepsis is against the use of heparin or heparin analogs as a standard treatment in sepsis associated DIC. On the other hand, several studies claimed that septic patients might benefit from early recognition and specific treatment of disease.^27–30 Because the specific pathogen is identified and the lung is the essential organ damaged in severe Covid-19 patients, the coagulation features might not be identical with sepsis in general. Thrombopoietin might reactively increase following the pulmonary inflammation.³¹

Anticoagulant treatment would be risky in patients without significant coagulopathy, even though the activation of coagulation also contributes to compartmentalization of pathogens and reduces their invasion.³² The increased probability of thrombosis in patients with Covid-19 may lead to an increase in the clinical severity of patients defined as the patient’s deterioration and longer hospital stay. The begining of early and higher than usual dosages of anticoagulant at the hospitalized Covid-19 patients could prevent the probable deteroriation of patients with immunovascular coagulopathy which shares common features with MAS. Thus, inclusion of the anticoagulant treatment to the hospitalized Covid-19 patients may provide an early and a healthy discharge.

Regarding the gender distribution in the current study, no statistically significant difference was found in both groups, but generally male patients were reported to have higher risk in recent Covid-19 disease studies from different countries like China and Italy. Mean age of all patients in current study has been 50.6 year that was lower than mean patient ages in previous studies. The characteristic of Turkish population may responsible for the difference of gender and mean ages with the results of studies from China and Italy.^7,14

The present study has several limitations. The retrospective feature of current study is a limitation, and further prospective studies would empower and improve these results. Another limitation of the present study was unavailability of any critical care score assigned during admission. Thus, we could not evaluate the initial disease severity.

In conclusion, combining the current literature with our results in the current study encouraged us for using higher than usual doses of anticoagulant treatment at hospitalized Covid-19 patients at an early stage.¹⁹

Footnotes

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

Ethical approval

Guarantor

None.

Contributorship

Y.A; Design, evaluating and editing study. G.Y; Discussing. D.D; Ethical approval and statistical analysis. M.H; Collecting data. H.C; Collecting data. N.O:Discussing. U.S; Evaluating results. G.F; Evaluating results. C.T; Editing study.

Acknowledgments

We would like to thank all the healthcare professionals working devotedly in the Covid-19 clinics and intensive care units of Health Sciences University, Gulhane Training and Research Hospital. This study has emerged thanks to them. Also, we would like to thank to Dr. Hakan KAYIR for his generous help for editing the current study.

ORCID iD

Yakup Arslan

References

Worldmeter COVID-19 data, www.worldometers.info/ coronavirus/ (accessed 4 July 2020).

Bhatraju

Ghassemieh

Nichols

, et al. Covid-19 in critically ill patients in the Seattle region – case series. N Engl J Med 2020; 382: 2012–2022.

Levi

Scully

How I treat disseminated intravascular coagulation. Blood 2018; 131: 845–854.

Tang

Wang

, et al. Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia. J Thromb Haemost 2020; 18: 844–847.

Cangemi

Casciaro

Rossi

, et al.; SIXTUS Study Group. Platelet activation is associated with myocardial infarction in patients with pneumonia. J Am Coll Cardiol 2014; 64: 1917–1925.

Cangemi

Della Valle

Calvieri

, et al.; SIXTUS Study Group. Low-grade endotoxemia and clotting activation in the early phase of pneumonia. Respirology 2016; 21: 1465–1471.

Tang

Bai

Chen

, et al. Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy. J Thromb Haemost 2020; 18: 1094–1099.

Turkish Republic Ministry of Health Science Board. Covid-19 guide. 3rd Version. Turkey: Turkish Republic Ministry of Health Science Board, 2020.

Turkish Republic Ministry of Health Science Board. Covid-19 guide. 5th Version. Turkey. Turkish Republic Ministry of Health Science Board, 2020.

10.

Levi

van der Poll

Coagulation and sepsis. Thromb Res 2017; 149: 38–44.

11.

Schmitt

FCF

Manolov

Morgenstern

, et al. Acute fibrinolysis shutdown occurs early in septic shock and is associated with increased morbidity and mortality: results of an observational pilot study. Ann Intensive Care 2019; 9: 19.

12.

Gupta

Zhao

Evans

CE.

The stimulation of thrombosis by hypoxia. Thromb Res 2019; 181: 77–83.

13.

Luo

Gou

, et al. Histopathologic Findings in the Explant Lungs of a Patient With COVID-19 Treated With Bilateral Orthotopic Lung Transplant. Transplantation 2020; 104: e329–e331.

14.

Lodigiani

Iapichino

Carenzo

, et al.; on behalf of the Humanitas COVID-19 Task Force. Venous and arterial thromboembolic complications in COVID-19 patients admitted to an academic hospital in Milan, Italy. Thromb Res 2020; 191: 9–14.

15.

Guan

, et al. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med 2020; 382: 1708–1720.

16.

Huang

Wang

, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020; 395: 497–506.

17.

Zhou

, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet 2020; 395: 1054–1062.

18.

Chen

Cai

, et al. Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan, China. JAMA Intern Med 2020; 180: 934.

19.

Klok

Kruip

MJHA

van der Meer

NJM

, et al. Incidence of thrombotic complications in critically ill ICU patients with COVID-19. Thromb Res 2020; 191: 145–147.

20.

Helms

Tacquard

Severac

, et al. High risk of thrombosis in patients in severe SARS-CoV-2 infection: a multicenter prospective cohort study. Intensive Care Med 2020; 46: 1089–1098.

21.

Lewnard JA,

Liu VX,

Jackson

, , et al. Incidence, Clinical Outcomes, Andtransmission Dynamics of Severe Coronavirus Disease 2019 in California Andwashington: prospective Cohort Study. BMJ (Published Correction Appears in BMJ 2020 June 4; 369: m2205) 2020; 369.

22.

Wölfel R,

Corman V M,

Guggemos

, , et al. Virological Assessment of Hospitalized Patients with COVID-2019. Nature 2020; 581: 465–469. DOI: 10.1038/s41586-020-2196-x.

23.

Luo X,

Zhou W,

Yan

, , et al. Prognostic Value of C-Reactive Protein in Patients with Coronavirus 2019. Clinical Infectious Diseases 2020. DOI: 10.1093/cid/ciaa641.

24.

Iba

Nisio

Levy

, et al. New criteria for sepsis-induced coagulopathy (SIC) following the revised sepsis definition: a retrospective analysis of a nationwide survey. BMJ Open 2017; 7: e017046.

25.

Poterucha

Libby

Goldhaber

SZ.

More than an anticoagulant: do heparins have direct anti-inflammatory effects?

Thromb Haemost 2017; 117: 437–444.

26.

Shanghai Clinical Treatment Expert Group for Covid-19. Comprehensive treatment and management of coronavirus disease 2019: expert consensus statement from shanghai (in Chinese). China J Infect Dis 2020; 38: E016-E016.

27.

Aikawa

Shimazaki

Yamamoto

, et al. Thrombomodulin alfa in the treatment of infectious patients complicated by disseminated intravascular coagulation: subanalysis from the phase 3 trial. Shock 2011; 35: 349–354.

28.

Liu

Wang

Liu

, et al. Low-dose heparin as treatment for early disseminated intravascular coagulation during sepsis: a prospective clinical study. Exp Ther Med 2014; 7: 604–608.

29.

Nishida

Ogura

Egi

, et al. The Japanese clinical practice guidelines for management of sepsis and septic shock 2016 (J-SSCG 2016). Acute Med Surg 2018; 5: 3–89.

30.

Umemura

Yamakawa

Ogura

, et al. Efficacy and safety of anticoagulant therapy in three specific populations with sepsis: a meta-analysis of randomized controlled trials. J Thromb Haemost 2016; 14: 518–530.

31.

Menter

Kopetz

Hawk

, et al. Platelet “first responders” in wound response, cancer, and metastasis. Cancer Metastasis Rev 2017; 36: 199–213.

32.

Sun

Wang

Degen

, et al. Reduced thrombin generation increases host susceptibility to group a streptococcal infection. Blood 2009; 113: 1358–1364.