Discussion
In this study, we wanted to predict the in-hospital mortality of COVID-19 patients using the d-dimer, fibrinogen, albumin, DAR, and FAR parameters. According to the results of this study, while DAR was found to be more valuable than all other parameters, FAR was found to be more valuable only fibrinogen in predicting the in-hospital mortality of COVID-19 patients. In Addition concurrent high value of DAR and FAR (DAR>56.36 and FAR>112.33) with reference to concurrent low value of DAR and FAR (DAR<56.36 and FAR<112.33); was found to be more valuable than separately high value of DAR and FAR, with reference to separately low of DAR and FAR in predicting the in-hospital mortality (DAR>56.36 and FAR>112.33‒DAR<56.36 and FAR<112.33, odds ratio: 21.879; DAR>56.36‒DAR<56.36, odds ratio: 7.898; FAR>112.33‒FAR<112.33, odds ratio: 4.437).
In this study, the d-dimer levels were significantly higher in the non-survivor group than in the survivor group. In addition, the d-dimer levels reached a 0.757 AUC value according to the result of the ROC analysis performed to predict in-hospital mortality. The d-dimer level above 292.5 ng/ml had an odds ratio of 6.058 in predicting the in-hospital mortality of COVID-19 patients. Zhang et al. (8) carried out a study with 343 COVID-19 patients; they found that the d-dimer level with a 0.89 AUC value was able to predict in-hospital mortality. In the study conducted by Cai et al. (9) in a total of 432 COVID-19 patients with 125 patients in the serious group; they found that in the ROC analysis performed to determine the severity of the disease, the d-dimer reached a value of 0.65 AUC. In the study conducted by Zhou et al. (10) in a total of 191 COVID-19 patients with 54 patients in the nonsurvivor group; they found that d-dimer level to be above 1 μg/mL reached an odds ratio of 20.04 in predicting mortality with reference to d-dimer level below 0.5 μg/mL. There may be many reasons for the relationship between a high d-dimer level and COVID-19 mortality. The fact that COVID-19 causes hypercoagulable (11), may explain this relationship. Because hypercoagulation can increase the risk of microthrombus formation and furthermore aggravate the risk of organ failure inflammation (12). High d-dimer levels is expected as a result of hypercoagulation (13). Hypercoagulation due to COVID-19 may have many reasons. Hypoxia caused by COVID-19 that triggering thrombosis; may be shown as one of these reasons (14). In addition, patients with severe COVID-19 are more comorbid, more immobile, and exposed to more invasive procedures, increasing the likelihood of thrombotic events (8).
In this study as well the fibrinogen levels were significantly higher in the non-survivor group than in the survivor group. In addition, the d-dimer levels reached a 0.637 AUC value according to the result of the ROC analysis performed to predict in-hospital mortality. The fibrinogen level above 423 mg/dl had an odds ratio of 2.794 in predicting the in-hospital mortality of COVID-19 patients. In the study conducted by Bi et al. (7) in a total of 113 COVID-19 patients with 22 patients in the serious group; they found that fibrinogen levels was statistically significantly higher in severity group than non severity group (4.23 g/L vs. 3.07 g/L p=0.002). In addition they found that fibrinogen level to be above 4 g/l reached a hazard ratio of 3.284 in predicting severity of disease with reference to fibrinogen level below 4 g/l (15). The reason for the relationship between high fibrinogen levels and COVID-19 mortality is due to hypercoagulation (15), just like d-dimer. Although both d-dimer and fibrinogen are indicators of coagulation and inflammation, d-dimer was found to be more valuable in predicting in-hospital mortality than fibrinogen in this study (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; while the levels of fibrinogen increase in the early stage of inflammation, its levels may decrease in the late stage when the disease is severe (15). D-dimer levels peak, especially in the late period, when the disease is most severe (15).
In this study as well, the albumin levels were significantly lower in the non-survivor group compared to the survivor group. In addition, according to the result of the ROC analysis performed to predict in-hospital mortality, they reached a 0.766 AUC value. The albumin level below 4.015 g/dl had an odds ratio of 6.216 in predicting in-hospital COVID-19 mortality. In the study conducted by de la Rica et al. (16) in a total of 48 COVID-19 patients with 21 patients in the ICU group; they found that albumin levels was statistically significantly lower in ICU group than non-ICU group (2.9 g/dl [1.84‒3.64], 3.92 g/dl [3.36‒4.74], p<0.001). In the study conducted by Violi et al. (6) in a total of 319 hospitalized COVID-19 patients with 64 patients in the nonsurvivor group; they found that the albumin level below 3.2 g/dl had an odds ratio of 2.48 in predicting in-hospital mortality. There may be many reasons for the relationship between hypoalbuminemia and COVID-19 mortality. As with D-dimer and fibrinogen, hypercoagulation may explain this relationship. There are publications in the literature showing that arterial and venous thromboembolic events increase with hypoalbuminemia (17,18). Another reason for this relationship is malnutrition. Malnutrition is a risk factor for in-hospital mortality (19), and there is a higher rate of malnutrition in elderly patients (21). Also, albumin is used to assess malnutrition (20). The fact that high age is a risk factor for COVID-19 mortality (3) and there is a high prevalence of malnutrition in elderly patients with COVID-19 (21) may explain the relationship of hypoalbuminemia with COVID-19 mortality.
Finally, the DAR and FAR levels in this study were significantly higher in the non-survivor group than in the survivor group. In addition, according to the result of the ROC analysis performed to predict in-hospital COVID-19 mortality, the DAR and FAR levels reached 0.773 and 0.703 AUC value. While the DAR level above 56.36 had an odds ratio of 7.898 in predicting in-hospital COVID-19 mortality, the FAR level above 112.33 had an odds ratio of 4.437. As mentioned earlier, while there is a study conducted by Bi et al. (7) related to FAR in COVID-19 patients in the literature, we did not come across any study related to DAR in any patient groups. In the study conducted by Bi et al. (7) in a total of 113 COVID-19 patients with 22 patients in the serious group; they found that hazard ratios obtained by FAR for predicting severity of COVID-19 were higher than those obtained by the fibrinogen (hazard ratio of FAR>0.0883: 5.212, hazard ratio of fibrinogen>4: 3.284). In this study, the AUC and odds ratio values obtained by FAR for predicting in-hospital COVID-19 mortality were higher than the values obtained by only the fibrinogen levels. However, the AUC and odds ratio values obtained by DAR for predicting in-hospital COVID-19 mortality were higher than the values obtained by the all other parameters. In addition; in this study in-hospital mortality risk arisen from due to concurrent high DAR and FAR levels compared to concurrent low DAR and FAR levels (odds ratio: 21.879), were found to be higher than the in-hospital mortality risk arisen from when evaluated them separately (odds ratio of DAR: 7.898, odds ratio of FAR: 4.437). In the literature we could access, we did not find a study conducted with a methodology evaluating concurrent high levels of DAR and FAR.
The limitations of our study were as follows: being a retrospective and single-center study; failure to include discharged COVID-19 patients in the study; and failure to evaluate treatment protocols.