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\begin{document}

\title{Predictive value of d-dimer/albumin ratio and fibrinogen/albumin ratio~
for in-hospital mortality in patients with COVID-19~~~~~~~~~~~~}



\author[1]{Kadir Küçükceran}%
\author[1]{Mustafa Kürşat Ayrancı}%
\author[1]{Sadik Girisgin}%
\author[1]{Sedat Koçak}%
\affil[1]{Necmettin Erbakan University Meram Medical Faculty Hospital}%


\vspace{-1em}



  
  \date{May 25, 2024}


\begingroup
\let\center\flushleft
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\endgroup





\selectlanguage{english}
\begin{abstract}
\textbf{Introduction:} Due to the high mortality of coronavirus disease
2019 (COVID-19), there are difficulties in the managing emergency
department. We investigated whether the d-dimer/albumin ratio (DAR) and
fibrinogen/albumin ratio (FAR) predicts mortality in the COVID-19
patients.

\textbf{Methods:} A total of 717 COVID-19 patients who were brought to
the emergency department from March to October 2020 were included in the
study. Levels of d-dimer, fibrinogen, and albumin, as well as DAR, FAR,
age, gender, and in-hospital mortality status of the patients were
recorded. The patients were grouped by in-hospital mortality.
Statistical comparison was conducted between the groups.

\textbf{Results:} Of the patients included in the study, 371(51.7\%)
were male, and their median age was 64 years (50--74). There was
in-hospital mortality in 126 (17.6\%) patients. The area-under-the-curve
(AUC) and odds ratio values obtained by DAR to predict in-hospital
mortality were higher than the values obtained by the all other
parameters (AUC of DAR, albumin, d-dimer, FAR, and fibrinogen: 0.773,
0.766, 0.757, 0.703, and 0.637, respectively; odds ratio of
DAR\textgreater{}56.36, albumin\textless{}4.015,
d-dimer\textgreater{}292.5, FAR\textgreater{}112.33, and
fibrinogen\textgreater{}423: 7.898, 6.216, 6.058, 4.437, and 2.794,
respectively). In addition; patients with concurrent
DAR\textgreater{}56.36 and FAR\textgreater{}112.33 had an odds ratio of
21.879 with respect to patients with concurrent DAR\textless{}56.36 and
FAR\textless{}112.33.

\textbf{Conclusion:} DAR may be used as a new marker to predict
mortality in COVID-19 patients. In addition the concurrent high DARs and
FARs were found to be more valuable in predicting in-hospital mortality
than either separately.\textbf{}

\textbf{Keywords:} Covid-19, D-dimer, Fibrinogen, Serum Albumin,
in-Hospital Mortality{}%
\end{abstract}%



\sloppy


\textbf{Introduction:} Due to the high mortality of coronavirus disease
2019 (COVID-19), there are difficulties in the managing emergency
department. We investigated whether the d-dimer/albumin ratio (DAR) and
fibrinogen/albumin ratio (FAR) predicts mortality in the COVID-19
patients.

\textbf{Methods:} A total of 717 COVID-19 patients who were brought to
the emergency department from March to October 2020 were included in the
study. Levels of d-dimer, fibrinogen, and albumin, as well as DAR, FAR,
age, gender, and in-hospital mortality status of the patients were
recorded. The patients were grouped by in-hospital mortality.
Statistical comparison was conducted between the groups.

\textbf{Results:} Of the patients included in the study, 371(51.7\%)
were male, and their median age was 64 years (50--74). There was
in-hospital mortality in 126 (17.6\%) patients. The area-under-the-curve
(AUC) and odds ratio values obtained by DAR to predict in-hospital
mortality were higher than the values obtained by the all other
parameters (AUC of DAR, albumin, d-dimer, FAR, and fibrinogen: 0.773,
0.766, 0.757, 0.703, and 0.637, respectively; odds ratio of
DAR\textgreater{}56.36, albumin\textless{}4.015,
d-dimer\textgreater{}292.5, FAR\textgreater{}112.33, and
fibrinogen\textgreater{}423: 7.898, 6.216, 6.058, 4.437, and 2.794,
respectively). In addition; patients with concurrent
DAR\textgreater{}56.36 and FAR\textgreater{}112.33 had an odds ratio of
21.879 with respect to patients with concurrent DAR\textless{}56.36 and
FAR\textless{}112.33.

\textbf{Conclusion:} DAR may be used as a new marker to predict
mortality in COVID-19 patients. In addition the concurrent high DARs and
FARs were found to be more valuable in predicting in-hospital mortality
than either separately.\textbf{}

\textbf{Keywords:} Covid-19, D-dimer, Fibrinogen, Serum Albumin,
in-Hospital Mortality{}

\textbf{Predictive value of d-dimer/albumin ratio and fibrinogen/albumin
ratio for in-hospital mortality in patients with COVID-19{}}

Kadir
K\selectlanguage{ngerman}ÜÇÜKCERAN\textsuperscript{1}\emph{kadirkucukceran@hotmail.com}0000-0001-9758-0803

Mustafa Kür\selectlanguage{polish}ş\selectlanguage{english}at
AYRANCI\textsuperscript{1}\emph{drmka157@gmail.com}0000-0002-7196-0856

Abdullah Sad\selectlanguage{polish}ı\selectlanguage{english}k
G\selectlanguage{polish}İ\selectlanguage{english}R\selectlanguage{polish}İŞ\selectlanguage{english}G\selectlanguage{polish}İ\selectlanguage{english}N\textsuperscript{1}\emph{sgirisgin@yahoo.com}0000-0003-2669-0532

Sedat
KO\selectlanguage{ngerman}ÇAK\textsuperscript{1}\emph{drskocak06@hotmail.com}0000-0001-8265-9615

\textsuperscript{1} Emergency Department, Necmettin Erbakan University,
Meram School of Medicine, Konya

\textbf{Running Title:} Role of DAR in predicting mortality

\textbf{Keywords} : Covid-19, D-dimer, Fibrinogen, Serum Albumin,
in-Hospital Mortality

\textbf{Ethics Committee Approve:} Necmettin Erbakan University Meram
Medical Faculty Pharmaceutical and Non-Medical Device Studies Ethical
Committee by the decision number of 2021/3022

\textbf{Funding:} This study did not need financial funding

\textbf{Conflict of Interest:} The authors declare no conflict of
interest

\textbf{Human rights:} During the research, the World Medical
Association(WMA) Declaration of HELSINKI and/ or the World Psychiatric
Association HAWAII Declaration of Good Clinical Practice rules were
complied with

\textbf{Corresponding author:} Dr. Kadir Küçükceran

Necmettin Erbakan University, Meram School of Medicine, Konya, Turkey

Phone: +90 505 553 24 14 / +90 332 223 40 53

e-mail:\emph{kadirkucukceran@hotmail.com}



\textbf{ABSTRACT}

\textbf{Introduction:} Due to the high mortality of coronavirus disease
2019 (COVID-19), there are difficulties in the managing emergency
department. We investigated whether the d-dimer/albumin ratio (DAR) and
fibrinogen/albumin ratio (FAR) predicts mortality in the COVID-19
patients.

\textbf{Methods:} A total of 717 COVID-19 patients who were brought to
the emergency department from March to October 2020 were included in the
study. Levels of d-dimer, fibrinogen, and albumin, as well as DAR, FAR,
age, gender, and in-hospital mortality status of the patients were
recorded. The patients were grouped by in-hospital mortality.
Statistical comparison was conducted between the groups.

\textbf{Results:} Of the patients included in the study, 371(51.7\%)
were male, and their median age was 64 years (50--74). There was
in-hospital mortality in 126 (17.6\%) patients. The area-under-the-curve
(AUC) and odds ratio values obtained by DAR to predict in-hospital
mortality were higher than the values obtained by the all other
parameters (AUC of DAR, albumin, d-dimer, FAR, and fibrinogen: 0.773,
0.766, 0.757, 0.703, and 0.637, respectively; odds ratio of
DAR\textgreater{}56.36, albumin\textless{}4.015,
d-dimer\textgreater{}292.5, FAR\textgreater{}112.33, and
fibrinogen\textgreater{}423: 7.898, 6.216, 6.058, 4.437, and 2.794,
respectively). In addition; patients with concurrent
DAR\textgreater{}56.36 and FAR\textgreater{}112.33 had an odds ratio of
21.879 with respect to patients with concurrent DAR\textless{}56.36 and
FAR\textless{}112.33.

\textbf{Conclusion:} DAR may be used as a new marker to predict
mortality in COVID-19 patients. In addition the concurrent high DARs and
FARs were found to be more valuable in predicting in-hospital mortality
than either separately.\textbf{}

\textbf{Keywords:} Covid-19, D-dimer, Fibrinogen, Serum Albumin,
in-Hospital Mortality



\textbf{Introduction}

In December 2019, a disease of unknown etiology emerged in Wuhan, China,
with clinical symptoms of acute upper respiratory tract infection (1).
This disease, called coronovirus disease 2019 (COVID-19), was evaluated
in the pandemic category by the World Health Organization (WHO) in
January 2020 (2). According to WHO data, approximately 117 million
people have been infected, while approximately 2.6 million people died.
The mortality rate is 30\% in hospitalized cases (3), ranging between
30\% and 100\% in cases requiring a ventilator (4). Hospitalized
COVID-19 patients pose difficulties in emergency department management,
especially due to high mortality rates. In order to accelerate the
outcome of COVID 19 patients in the emergency department, parameters to
predict mortality that can be applied easily and quickly are needed.

Hypercoagulation, which is the cause of high d-dimer and fibrinogen, is
common in hospitalized COVID-19 patients, and is a predictor of severity
(5). Fibrinogen to albumin ratio (FAR) was found to be more sensitive
and specific predictor than fibrinogen in showing the progression of
hypercoagulation (6). Some studies of COVID 19 patients have used
d-dimer, albumin, fibrinogen and FAR for this purpose (7-9), but to the
best of our knowledge, no studies have used the d-dimer to albumin ratio
(DAR). Therefore, in this study we aimed to investigate and compare the
predictive value of DAR and FAR for mortality in patients with COVID-19.

\textbf{Method}

Ethics committee approval for this single-center, retrospective, and
observational study was obtained from the Necmettin Erbakan University
Meram Medical Faculty Pharmaceutical and Non-Medical Device Studies
Ethical Committee, decision number of 2021/3022.

This study was carried out in a tertiary university hospital. Patients
suspected of having COVID-19 who were admitted to the emergency
department and hospitalized and whose PCR test was positive were
included in the study from March to October 2020. Regardless of the
number of tests submitted, any PCR result that appeared positive at
least once was considered positive, while other results were considered
negative. Patients who were discharged against medical advice and
referred to other hospitals were excluded from the study. Patients, who
were discharged against medical advice; transferred to other hospitals
and had no results of at least one of the d-dimer, fibrinogen and
albumin parameters were excluded.

The following pieces of patient data were recorded from the patients'
e-files using the Hospital Information Management Systems program:
d-dimer level; fibrinogen level; albumin level; complaint (fever, cough,
shortness of breath); vital signs; comorbidities; information about
their ward/ICU admission; hospital outcome (discharge, exitus
in-hospital); and in-hospital mortality status. The DAR was obtained by
dividing the d-dimer level by the albumin level. The FAR was obtained by
dividing the fibrinogen level by the albumin level. The primary outcomes
of the study were prediction of in-hospital mortality using DAR and FAR
and determination of whether DAR or FAR was a more accurate predictor
than using d-dimer, fibrinogen, and albumin levels.

Statistical analysis of the data was performed using the SPSS 20.0 (SPSS
Inc., Chicago, IL) package program. Histograms and the
Kolmogorov-Smirnov test was used to test the normality of the data.
Following the normality analysis result, all quantitative data were
expressed as median (25\% -75\% quarters) since they did not show a
normal distribution, while categorical variables were expressed as
frequency (percentage). The differences between the groups were
investigated using the Mann--Whitney U test. Intragroup comparisons of
the categorical variables were made using the chi square test and the
Fisher's exact test. Receiver operating characteristic (ROC) analysis
was performed to determine predictive power of the d-dimer, fibrinogen,
and albumin levels and DAR and FAR for in-hospital mortality. The
optimum cut-off levels of the biochemical parameters were determined
using Youden's index (sensitivity + 1\selectlanguage{english}-specificity). The sensitivity,
specificity, and positive and negative predictive values of the
parameters were calculated for the optimum cut-off levels. The odds
ratios of the groups categorized by the optimum cut-off values of
d-dimer, fibrinogen, albumin, DAR, and FAR in predicting in-hospital
COVID-19 mortality were calculated using univariate logistic regression
analysis. The area under the curve (AUC) and odds ratio values were used
to compare the mortality predictive power of parameters. Statistical
significance was set at p\textless{}0.05.

\textbf{Results}

A total of 749 patients who were brought to the emergency department
with suspected COVID-19 within the period from March to September 2020
and who had a positive PCR test result were identified. Of these 749
patients, 11 were excluded from the study because they sought hospital
discharge against medical advice, 8 because they were referred to
another hospital, 13 because they had no result of at least one of the
d-dimer, fibrinogen and albumin parameters. The remaining 717 patients
were included in the study.

Of the 717 patients who were included in the study, 371(51.7\%) were
male, their median age was 64 years (50--74), and their median length of
hospital stay was 9 days (5--14). The median d-dimer, fibrinogen,
albumin, DAR, and FAR values were found to be 223(130--454) ng/mL,
419(324--534) mg/dL, 4.05(3.68--4.42) g/dL, 56(30.43--119.69) and
104.3(77.46--138.88), respectively. A total of 495 patients (69\%) had
at least one comorbidity in their medical history, the most frequent
which was hypertension (260 patients, 36.3\%). A total of 550 patients
(76.7\%) were hospitalized in the ward unit, and 167(23.3\%) were
admitted to the ICU. In-hospital mortality occurred in 126 patients
(17.6\%) and did not occur in 591(76.7\%). Table 1 shows the detailed
data of the cases.

The median d-dimer value in the non-survivor group was significantly
higher than that in the survivor group (non-survivor: 471ng/mL
{[}264--869{]}; survivor: 184 mg/dL {[}116.5--364{]};
p\textless{}0.001). The median fibrinogen value, that in the
non-survivor group was significantly higher than in the survivor group
(non-survivor: 474 mg/dL {[}388--577{]}; survivor: 403 mg/dL
{[}315--514.5{]}; p\textless{}0.001). The median albumin value, that in
the non-survivor group was significantly lower than that in the survivor
group (non-survivor: 3.6 g/dL {[}3.31--3.95{]}; survivor: 4.16 g/dL
{[}3.79--4.48{]}; p\textless{}0.001). The median DAR value in the
non-survivor group was significantly higher than that in the survivor
group (non-survivor: 127.79 {[}75.5--240.2{]}; survivor: 47.8
{[}27.29--94.47{]}; p\textless{}0.001). The median FAR value in the
non-survivor group was significantly higher than in the survivor group
(non-survivor: 133.49 {[}108.27--161.18{]}; survivor: 98.12
{[}73.56--131.84{]}; p\textless{}0.001). Table 2 shows the detailed
intragroup comparisons by in-hospital mortality.

We performed ROC analysis to determine the in-hospital COVID-19
mortality predictive power of the d-dimer, fibrinogen, and albumin
levels, and DAR and FAR. The AUC value of the DAR was found to be 0.773
(Figure 1), and 84.9\% sensitivity, 58.4\% specificity, 30.3\% PPD, and
94.8\% NPD were reached with a DAR cut-off value of 56.36. For FAR, its
AUC value was found to be 0.703 (Figure 1), and 71.4\% sensitivity, 64\%
specificity, 29.7\% PPD, and 91.3\% NPD were reached with a FAR cut-off
value of 112.33. The detailed results of the ROC analysis are given in
Table 3.

The odds ratios for predicting in-hospital COVID-19 mortality were as
follows: patients with d-dimer\textgreater{}292.5 ng/mL had an odds
ratio of 6.058, those with fibrinogen\textgreater{}423 mg/dL had 2.794,
those with albumin\textless{}4.015 g/dL had 6.216, those with
DAR\textgreater{}56.36 had 7.898, and those with FAR\textgreater{}112.33
had 4.437. In addition, patients with concurrent DAR\textgreater{}56.36
and FAR\textgreater{}112.33 had an odds ratio of 21.879 with respect to
patients with concurrent DAR\textless{}56.36 and FAR\textless{}112.33.
Detailed odds ratio results are given in Table 4.

\textbf{Discussion}

In this study, we investigated d-dimer, fibrinogen, albumin, DAR, and
FAR parameters as predictors for in-hospital mortality of COVID-19
patients. According to the results of this study, while DAR was found to
be most valuable predictive parameters, FAR was found to be more
valuable as a predictor than only fibrinogen. In addition concurrent
high DAR and FAR values as compared to concurrent low DAR and FAR values
were found to be more predictively valuable than high values of DAR and
FAR separately with respect to low DAR and FAR taken separately.

According to the results of the ROC analysis performed to predict
in-hospital mortality, the d-dimer levels reached a 0.757 AUC value and
d-dimer levels above 292.5 ng/mL had a predictive odds ratio of 6.058.
Other studies have also associated high d-dimer levels with high
mortality. Zhang et al. (10) carried out a study with 343 COVID-19
patients and found that a d-dimer level with a 0.89 AUC value was able
to predict in-hospital mortality. Zhou et al. (11) studied a total of
191 COVID-19 patients with 54 patients in the nonsurvivor group and
found that a d-dimer level above 1 \selectlanguage{greek}μ\selectlanguage{english}g/mL reached an odds ratio of 20.04
in predicting mortality with respect to a d-dimer level below 0.5 \selectlanguage{greek}μ\selectlanguage{english}g/mL.

There are many possible reasons for the relationship between a high
d-dimer level and COVID-19 mortality. The fact that COVID-19 causes
hypercoagulation (12), may explain this relationship, because it can
increase the risk of microthrombus formation and further aggravate the
risk of organ failure due to inflammation (13). High d-dimer levels are
expected as a result of hypercoagulation (14). Pulmonary embolism and
venous thromboembolism are more frequent in hospitalized COVID-19
patients compared to patients hospitalized for other reasons (5).
Pulmonary intravascular coagulation and vascular occlusion are frequent
findings reported in autopsies of patients who died of COVID-19 (5).
COVID-19 leads to an increased risk of arterial thrombosis such as
ischemic stroke, myocardial infarction and limb ischemia (5).
Hypercoagulation due to COVID-19 may occur for various reasons. Hypoxia
caused by COVID-19 triggering thrombosis may be one of these reasons
(15). In addition, patients with severe COVID-19 are more comorbid, more
immobile, and exposed to more invasive procedures, increasing the
likelihood of thrombotic events (10).

The results of the ROC analysis performed to predict in-hospital
mortality showed that fibrinogen levels reached a 0.637 AUC value.
Fibrinogen levels above 423 mg/dL had an odds ratio of 2.794 in
predicting the in-hospital mortality of COVID-19 patients. Bi et al. (9)
found that fibrinogen levels above 4 g/L reached a hazard ratio of 3.284
in predicting disease severity with respect to fibrinogen levels below 4
g/L. The reason for the relationship between high fibrinogen levels and
COVID-19 mortality is hypercoagulation (16), which is also caused by
high d-dimer levels. Hyperfibrinogenemia increases the risk of coronary
artery disease, deep vein thrombosis, and ischemic stroke (17-19).
Although both d-dimer and fibrinogen are indicators of coagulation and
inflammation, d-dimer was found to be more predictive of in-hospital
mortality than fibrinogen (AUC of d-dimer and fibrinogen: 0.757, 0.637;
odds ratio of d-dimer and fibrinogen: 6.058, 2.794). The reason of this
is that while fibrinogen levels increase in the early stage of
inflammation, they tend to peak and then decrease in the late stages
when the disease is severe (16).

In the ROC analysis performed to predict in-hospital mortality, albumin
levels reached a 0.766 AUC value. Albumin levels below 4.015 g/dL had an
odds ratio of 6.216. This is consistent with the results of prior
studies. For example, de la Rica et al. (20) found that in a total of 48
COVID-19 patients with 21 patients in the ICU group, albumin levels were
statistically significantly lower in ICU group than non-ICU group. Violi
et al. (8) found that in a total of 319 hospitalized COVID-19 patients
with 64 patients in the nonsurvivor group, albumin levels below 3.2 g/dL
had an odds ratio of 2.48 in predicting in-hospital mortality. As with
d-dimer and fibrinogen, hypercoagulation is one possible explanation for
the relationship between hypoalbuminemia and COVID-19 mortality. Some
studies have shown that arterial and venous thromboembolic events
increase with hypoalbuminemia (21,22).

Finally, according to the result of the ROC analysis performed to
predict in-hospital COVID-19 mortality, the DAR and FAR AUCs reached
0.773 and 0.703, respectively. While DAR\textgreater{}56.36 had an odds
ratio of 7.898 and FAR\textgreater{}112.33 had an odds ratio of 4.437.
Some studies have indicated that FARs increase in hypercoagulation
states such as cardiovascular disease, cerebrovascular disease, and
chronic venous insufficiency (6,23,24). As mentioned earlier, we did not
any prior studies of the predictive value of DAR. The study Bi et al.
(9) of a total of 113 COVID-19 patients with 22 patients in the serious
group found that hazard ratios obtained by FAR for predicting severity
of COVID-19 were higher than those obtained by fibrinogen levels (hazard
ratio of FAR\textgreater{}0.0883: 5.212, hazard ratio of
fibrinogen\textgreater{}4: 3.284). In addition, Karahan et al. (6) found
FAR to be a more sensitive and specific predictor than fibrinogen in
showing the progression of venous insufficiency. In this study, the AUC
and odds ratio values obtained using FARs for predict in-hospital
COVID-19 mortality were higher than the values obtained by only using
fibrinogen levels. However, the AUC and odds ratio values obtained using
DARs to predict in-hospital COVID-19 mortality were higher than the
values obtained using any other parameter. In addition; we found that
in-hospital mortality risk due to concurrent high DARs and FARs compared
to concurrent low DARs and FARs (odds ratio: 21.879) were found to be
higher than the in-hospital mortality risk when evaluated separately
(DAR odds ratio: 7.898, FAR odds ratio: 4.437). We have not found any
previous studies in the literature evaluating concurrent high levels of
DAR and FAR.

The limitations of our study were as follows: the limited number of
cases, being a retrospective and single-center study, exclusion of
discharged COVID-19 patients in the study, and failure to evaluate
treatment protocols. Another limitation is that patients using
anticoagulant drugs were not excluded from the study; patients using
anticoagulant drugs may be less affected by hypercoagulation due to
COVID-19.

\textbf{Conclusion}

In this study while FAR was found to be more valuable than using only
fibrinogen levels to predict in-hospital COVID-19 mortality, DAR was
found to be more valuable than any other parameter. In addition,
concurrent high DAR and FAR were found to be more predictive of
in-hospital COVID-19 mortality than either taken separately.

\textbf{References}

\textbf{1.~~~~~} Yang X, Yu Y, Xu J, Shu H, Liu H, Wu Y, et al. Clinical
course and outcomes of critically ill patients with SARS-CoV-2 pneumonia
in Wuhan, China: a single-centered, retrospective, observational study.
Lancet Respir Med. 2020;8(5):475-81.

\textbf{2.~~~~~} Demir ET, Kilic F. Determination of The Anx\selectlanguage{polish}ı\selectlanguage{english}ety Level
in Pregnant Women Who Administer to The Obstetrics Clinic Within The
Covid-19 Pandemia Period. Selcuk Med J 2020;36(4):352-356.

\textbf{3.~~~~~} Martins-Filho PR, de Souza Ara\selectlanguage{ngerman}újo AA, Pereira LX,
Quintans-Júnior LJ, de Souza Barboza W, Cavalcante TF, et al. Factors
Associated with Mortality among Hospitalized Patients with COVID-19: A
Retrospective Cohort Study. Am J Trop Med Hyg. 2020;104(1):103-5.

\textbf{4.~~~~~} Akbudak \selectlanguage{polish}İ. \selectlanguage{english}Retrospective evaluation of critical
patients followed in intensive care with the diagnosis of Covid-19
infection: single center experience. Pam~Med~J. 2021; 14(2): 18-18.

\textbf{5.~~~~~} Gerotziafas GT, Catalano M, Colgan M-P, Pecsvarady Z,
Wautrecht JC, Fazeli B, et al. Guidance for the management of patients
with vascular disease or cardiovascular risk factors and COVID-19:
position paper from VAS-European Independent Foundation in
Angiology/Vascular Medicine. Thromb Haemost. 2020;120(12):1597.

\textbf{6.~~~~~} Karahan O, Yavuz C, Kankilic N, Demirtas S, Tezcan O,
Caliskan A, et al. Simple blood tests as predictive markers of disease
severity and clinical condition in patients with venous insufficiency.
Blood Coagul Fibrinolysis. 2016;27(6):684-90.

\textbf{7.~~~~~} Bansal A, Singh AD, Jain V, Aggarwal M, Gupta S,
Padappayil RP, et al. A Systematic Review and Meta-analysis of D-Dimer
Levels in Patients Hospitalized with Coronavirus Disease 2019
(COVID-19). medRxiv. 2020

\textbf{8.~~~~~} Violi F, Cangemi R, Romiti GF, Ceccarelli G, Oliva A,
Alessandri F, et al. Is albumin predictor of mortality in COVID-19?
Antioxidants \& redox signaling. 2020.

\textbf{9.~~~~~} Bi X, Su Z, Yan H, Du J, Wang J, Chen L, et al.
Prediction of severe illness due to COVID-19 based on an analysis of
initial Fibrinogen to Albumin Ratio and Platelet count. Platelets.
2020;31(5):674-9.

\textbf{10.~} Zhang L, Yan X, Fan Q, Liu H, Liu X, Liu Z, et al. D-dimer
levels on admission to predict in-hospital mortality in patients with
Covid-19. ~J Thromb Haemost. 2020;18(6):1324-9.

\textbf{11.~} Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, et al. Clinical
course and risk factors for mortality of adult inpatients with COVID-19
in Wuhan, China: a retrospective cohort study. The lancet.
2020;395(10229):1054-1062.

\textbf{12.~} Connors JM, Levy JH. Thromboinflammation and the
hypercoagulability of COVID-19. Thromb Haemost. 2020;18(7):1559-61.

\textbf{13.~} So LK, Lau AC, Yam LY, Cheung TM, Poon E, Yung RW, et al.
Development of a standard treatment protocol for severe acute
respiratory syndrome. The Lancet. 2003;361(9369):1615-7.

\textbf{14.~} Danese E, Montagnana M, Cervellin G, Lippi G.
Hypercoagulability, D-dimer and atrial fibrillation: an overview of
biological and clinical evidence. Ann Med. 2014;46(6):364-71.

\textbf{15.~} Gupta N, Zhao Y-Y, Evans CE. The stimulation of thrombosis
by hypoxia. Thromb Res. 2019;181:77-83.

\textbf{16.~} Thachil J. The protective rather than prothrombotic
fibrinogen in COVID-19 and other inflammatory states. J Thromb Haemost.
2020;18(8):1849-52.

\textbf{17.~} Karahan O, Acet H, Erta\selectlanguage{polish}ş \selectlanguage{english}F, Tezcan O, \selectlanguage{ngerman}Çali\selectlanguage{polish}ş\selectlanguage{english}kan A, Demir M,
et al. The relationship between fibrinogen to albumin ratio and severity
of coronary artery disease in patients with STEMI. Am J Emerg Med.
2016;34(6):1037-42.

\textbf{18.~} Wuillemin W, Korte W, Waser G, L\selectlanguage{ngerman}ämmle B. Usefulness of the
D\selectlanguage{english}-dimer/fibrinogen ratio to predict deep venous thrombosis. J Thromb
Haemost. 2005;3(2):385-7.

\textbf{19.~} Shi J, Shi R, Qin W, Zhang X, Liu H, Xu J, et al. Dynamic
Changes in Fibrinogen and Prognosis of Acute Ischemic Stroke Patients
Treated with Intravenous Thrombolysis. Neurotox Res. 2020;38(3):775-84.

\textbf{20.~} de la Rica R, Borges M, Aranda M, Del Castillo A, Socias
A, Payeras A, et al. Low albumin levels are associated with poorer
outcomes in a case series of COVID-19 patients in Spain: a retrospective
cohort study. Microorganisms. 2020;8(8):1106.

\textbf{21.~} Chi G, Gibson CM, Liu Y, Hernandez AF, Hull RD, Cohen AT,
et al. Inverse relationship of serum albumin to the risk of venous
thromboembolism among acutely ill hospitalized patients: Analysis from
the APEX trial. Am J Hematol. 2019;94(1):21-8.

\textbf{22.~} Ronit A, Kirkegaard-Klitbo DM, Dohlmann TL, Lundgren J,
Sabin CA, Phillips AN, et al. Plasma albumin and incident cardiovascular
disease: results from the CGPS and an updated meta-analysis.
Arterioscler Thromb Vasc Biol. 2020;40(2):473-82.

\textbf{23.~} Sapmaz I, Saba T, Haberal C, Toktamis A, Cakmak M, Cicek
D. Fibrinogen-albumin ratio: an intriguing relationship for assessing
trombosis risk and suspicious effect on blood viscosity.
~\href{https://www.sid.ir/en/journal/JournalList.aspx?ID=11745}{International
Cardiovascular Research Journal}. 2011; 5(4):153-154.

Ozcan Cetin EH, Konte HC, Temizhan A. Blood viscosity should not be
overlooked when evaluating the fibrinogen to albumin ratio. Angiology.
2019;70(5):465-6.



\textbf{}

\begin{enumerate}
\item
\end{enumerate}

\textbf{Table 1:} Features of Participants\selectlanguage{english}
\begin{longtable}[]{@{}lll@{}}
\toprule
Number of Persons & & 717(100\%)\tabularnewline
\midrule
\endhead
Age & & 64(50-74)\tabularnewline
Gender & Male & 371(51.7\%)\tabularnewline
& Female & 346(48.3\%)\tabularnewline
Vital Signs & Fever (C\selectlanguage{ngerman}º) & 36.5(36.2-36.9)\tabularnewline
& Pulse (per minute) & 91(82-103)\tabularnewline
& Systolic Blood Pressure (mmHg) & 130(120-141)\tabularnewline
& Diastolic Blood Pressure (mmHg) & 74(70-80)\tabularnewline
& MAP (mmHg) & 93(86.66-101)\tabularnewline
& Saturation (\%) & 93(90-96)\tabularnewline
Complaints & Fever & 357(49.8\%)\tabularnewline
& Cough & 376(52.4\%)\tabularnewline
& Shortness of Breath & 343(47.8\%)\tabularnewline
Laboratory Results & D-Dimer (ng/mL) & 223(130-454)\tabularnewline
& Fibrinojen (mg/dL) & 419(324-534)\tabularnewline
& Albumin (g/dL) & 4.05(3.68-4.42)\tabularnewline
& DAR & 56(30.43-119.69)\tabularnewline
& FAR & 104.3(77.46-138.88)\tabularnewline
Medical History & Comorbidity\textsuperscript{*} &
495(69\%)\tabularnewline
& Hypertension & 260(36.3\%)\tabularnewline
& Diabetes Mellitus & 197(27.5\%)\tabularnewline
& Cardiovascular Disease & 137(19.1\%)\tabularnewline
& Asthma-COPD & 118(16.5\%)\tabularnewline
& Malignancy & 74(10.3\%)\tabularnewline
& CRF & 31(4.3\%)\tabularnewline
& Cerebrovascular Disease & 16(2.2\%)\tabularnewline
Length of Hospital Stay (Day) & & 9(5-14)\tabularnewline
Emergency Service Outcome & Ward Unit & 550(76.7\%)\tabularnewline
& ICU & 167(23.3\%)\tabularnewline
Hospital Outcome & Discharged & 591(76.7\%)\tabularnewline
& Ex & 126(17.6\%)\tabularnewline
In-Hospital Mortality & Survivor & 591(76.7\%)\tabularnewline
& Nonsurvivor & 126(17.6\%)\tabularnewline
\bottomrule
\end{longtable}

COPD: Chronic Obstructive Pulmonary Disease, MAP: Mean Arterial
Pressure, ICU: Intensive Care Unit, CRF: Chronic Renal Failure

* Having at least one additional disease in his / her medical history

\textbf{Table 2:} Evaluation of Participants by In-Hospital Mortality\selectlanguage{english}
\begin{longtable}[]{@{}lllll@{}}
\toprule
& & Non-survivor(126) & Survivor(591) & p value\tabularnewline
\midrule
\endhead
Age & Age & 76(68-83) & 61(46.5-71) & \textless{}0.001\tabularnewline
Temperature (\selectlanguage{ngerman}°C) & Temperature (\selectlanguage{ngerman}°C) & 36.7(36.3-36.7) & 36.5(36.1-36.9)
& 0.029\tabularnewline
Pulse (per minute) & Pulse (per minute) & 90(81-106) & 92(82-103) &
0.715\tabularnewline
SBP (mmHg) & SBP (mmHg) & 130(110-144) & 130(120-140) &
0.165\tabularnewline
DBP (mmHg) & DBP (mmHg) & 70(60-80 & 75(70-80) & 0.001\tabularnewline
MAP (mmHg) & MAP (mmHg) & 90(79-100) & 93(87-101.33) &
0.009\tabularnewline
Saturation (\%) & Saturation (\%) & 89(80-93) & 94(91-96) &
\textless{}0.001\tabularnewline
D-dimer (ng/mL) & D-dimer (ng/ml) & 471(264-869) & 184(116.5-364) &
\textless{}0.001\tabularnewline
Fibrinogen (mg/dL) & Fibrinogen (mg/dl) & 474(388-577) & 403(315-514.5)
& \textless{}0.001\tabularnewline
Albumin (g/dL) & Albumin (g/dl) & 3.6(3.31-3.95) & 4.16(3.79-4.48) &
\textless{}0.001\tabularnewline
DAR & DAR & 127.79(75.5-240.2) & 47.8(27.29-94.47) &
\textless{}0.001\tabularnewline
FAR & FAR & 133.49(108.27-161.18) & 98.12(73.56-131.84) &
\textless{}0.001\tabularnewline
Length of hospital stay (Days) & Length of hospital stay (Days) &
13(9-23) & 8(5-12) & \textless{}0.001\tabularnewline
Gender & \textbf{Male} & 78(61.9\%) & 293(49.6\%) & 0.012\tabularnewline
& \textbf{Female} & 48(38.1\%) & 298(50.4\%) &\tabularnewline
Fever & Fever & 52(41.3\%) & 305(51.6\%) & 0.035\tabularnewline
Cough & Cough & 66(52.4\%) & 310(52.5\%) & 0.988\tabularnewline
Shortness of Breath & Shortness of Breath & 83(65.9\%) & 260(44\%) &
\textless{}0.001\tabularnewline
Comorbidity\textsuperscript{*} & Comorbidity\textsuperscript{*} &
108(85.7\%) & 387(65.5\%) & \textless{}0.001\tabularnewline
Hypertension & Hypertension & 64(50.8\%) & 196(33.2\%) &
\textless{}0.001\tabularnewline
Diabetes Mellitus & Diabetes Mellitus & 42(33.3\%) & 155(26.2\%) &
0.105\tabularnewline
Asthma-COPD & Asthma-COPD & 20(15.9\%) & 98(16.6\%) &
0.845\tabularnewline
Cardiovascular Disease & Cardiovascular Disease & 35(27.8\%) &
102(17.3\%) & 0.006\tabularnewline
Malignancy & Malignancy & 21(16.7\%) & 53(9\%) & 0.010\tabularnewline
CRF & CRF & 11(8.7\%) & 20(3.4\%) & 0.007\tabularnewline
Cerebrovascular Disease & Cerebrovascular Disease & 6(4.8\%) & 10(1.7\%)
& 0.046\tabularnewline
\bottomrule
\end{longtable}

COPD: chronic obstructive pulmonary disease, CRF: chronic renal failure,
MAP: mean arterial pressure

* Having at least one additional disease in his / her medical history

\textbf{Table 3:} ROC Analysis Result by In-Hospital Mortality Status\selectlanguage{english}
\begin{longtable}[]{@{}lllllll@{}}
\toprule
& & D-Dimer & Fibrinogen & Albumin & DAR & FAR\tabularnewline
\midrule
\endhead
In-Hospital Mortality & \textbf{AUC (95\% CI)} & 0.757(0.716-0.797) &
0.637(0.586-0.689) & 0.766(0.724-0.809) & 0.773(0.734-0.812) &
0.703(0.656-0.749)\tabularnewline
& \textbf{Cut-off level} & \textgreater{}292.5 ng/mL & \textgreater{}423
mg/dL & \textless{}4.015 g/dL & \textgreater{}56.36 &
\textgreater{}112.33\tabularnewline
& \textbf{Sensitivity} & 74.6\% & 68.3\% & 81\% & 84.9\% &
71,4\%\tabularnewline
& \textbf{Specificity} & 67.3\% & 56.5\% & 59.4\% & 58.4\% &
64\%\tabularnewline
& \textbf{PPV} & 32.8\% & 25.1\% & 29.8\% & 30.3\% &
29.7\%\tabularnewline
& \textbf{NPV} & 92.6\% & 89.3\% & 93.6\% & 94.8\% &
91.3\%\tabularnewline
\bottomrule
\end{longtable}

CI: Confidence interval; AUC: Area under the curve; PPV: Positive
Predictive Value; NPV: Negative Predictive Value

\textbf{Table 4:} Odds ratio results obtained according to optimum cut
off values\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
& & Odds rate & 95\% CI\tabularnewline
\midrule
\endhead
in-Hospital Mortality & D-Dimer\textgreater{}292.5 ng/mL & 6.058 &
3.915-9.372\tabularnewline
& D-Dimer\textless{}292.5 ng/mL & 1 &\tabularnewline
& Fibrinogen\textgreater{}423 mg/dL & 2.794 & 1.856-4.205\tabularnewline
& Fibrinogen\textless{}423 mg/dL & 1 &\tabularnewline
& Albumin\textless{}4.015 g/dL & 6.216 & 3.869-9.985\tabularnewline
& Albumin\textgreater{}4.015 g/dL & 1 &\tabularnewline
& DAR\textgreater{}56.36 & 7.898 & 4.721-13.213\tabularnewline
& DAR\textless{}56.36 & 1 &\tabularnewline
& FAR\textgreater{}112.33 & 4.437 & 2.911-6.762\tabularnewline
& FAR\textgreater{}112.33 & 1 &\tabularnewline
& DAR\textgreater{}56.36 and FAR\textgreater{}112.33 & 21.879 &
9.879-48.703\tabularnewline
& DAR\textless{}56.36 and FAR\textless{}112.33 & 1 &\tabularnewline
\bottomrule
\end{longtable}

CI: Confidence interval

\textbf{Figure Legends}

\textbf{Figure 1:} ROC Curve by In-Hospital Mortality\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-1-ROC-Curve-by-In-Hospital-Mortality/Figure-1-ROC-Curve-by-In-Hospital-Mortality}

\end{center}
\end{figure}

\selectlanguage{english}
\FloatBarrier
\end{document}

