Coronavirus disease-19 (COVID-19) caused by 2019-nCoV/SARS-CoV-2 has led to a global pandemic (Zhou et al., 2020b). While respiratory illness is the major cause of morbidity and mortality in the COVID-19 patients, coagulopathy (Wang et al., 2020; Zhou et al., 2020a), systemic inflammation (Inciardi et al., 2020) and myocardial injury (Aghagoli et al., 2020) are also involved in the pathogenesis of the disease. Elevated prothrombin (PT), activated partial thromboplastin time (aPTT) and D-dimer have been reported in COVID-19 patients (Chen et al., 2020b; Wang et al., 2020; Zhou et al., 2020a). During the disease progression, activation of the host defense system results in an imbalance between the procoagulant and anticoagulant systems (Liu et al., 2021). This leads to thrombi formation that is termed as immunothrombosis (Key et al., 1990; Engelmann and Massberg, 2013). D-dimer, as a fibrin degradation product, has been widely reported to be elevated in COVID-19 patients (Rostami and Mansouritorghabeh, 2020), though without standard reporting (Favaloro and Thachil, 2020; Thachil et al., 2020). However, fibrinogen as a clotting factor in coagulation and thrombosis, has not been well studied. In addition, fibrinogen acts as a positive acute phase reactants, which is increased during inflammatory response (Engelmann and Massberg, 2013). Furthermore, fibrinogen has been considered as an independent risk factor for cardiovascular disease (Ernst, 1990; Heinrich and Assmann, 1995; Sweetnam et al., 1996; Ahmed et al., 2012). It has been reported that fibrinogen levels are increased in COVID-19 patients (Arachchillage and Laffan, 2020). Additionally, autopsy studies of COVID-19 patients demonstrated the fibrin rich thrombi in small vessels and pulmonary capillaries (Fox et al., 2020). However, the overall profile of fibrinogen in COVID-19 patients has remained unclear. By analyzing the correlation of fibrinogen with disease severity, and laboratory markers, the goal of this study was to investigate the role of fibrinogen in the pathogenesis of COVID-19 and evaluate the role of fibrinogen as a biomarker for disease severity.

In this retrospective study, we assessed the distribution of fibrinogen in a cohort of COVID-19 patients. It is worth noting that fibrinogen levels are elevated in COVID-19 patients upon admission, especially in those with severe disease. Fibrinogen levels on admission were associated with elevated inflammatory markers, and elevated fibrinogen levels may be used as an early biomarker to predict disease severity and ICU admission.

COVID-19 is a systemic infection with significant impact on the coagulation system that often manifests in thrombotic complications and coagulopathy (Levi et al., 2020). Previous data have showed that fibrinogen levels are elevated among patients with COVID-19 (Toh and Hoots, 2007; Han et al., 2020) and decreased at later stage of the disease when disseminated intravascular coagulation happens (Tang et al., 2020). However, there is no consensus on the role of fibrinogen in predicting outcomes in COVID-19 patients regarding disease severity, ICU admission and mortality (Gao et al., 2020; Liu et al., 2020; Tang et al., 2020). Tang et al. have reported that fibrinogen levels are elevated in both survived and non-survived group, but the difference between two groups was not statistically significant (Tang et al., 2020). However, studies by other groups reported an association between elevated fibrinogen levels upon admission and poor outcome (Gao et al., 2020; Liu et al., 2020). In this study, we report that elevations in fibrinogen upon admission were significantly associated with disease severity and ICU admission in COVID-19 patients. Consistently, we found that LDH, a biomarker for severe disease or multiple organ failure was significantly associated with the fibrinogen level in our study.

Infection with bacterial, viral, or fungal pathogens initiates the systemic inflammation response. Significant inflammation is present in patients with 2019-nCoV/SARS-CoV-2 infection, based on increased IL-6, CRP and ESR levels upon admission (Chen et al., 2020a). In our study, the decreased negative acute phase reactant albumin and increased positive acute phase reactant CRP, ferritin, ESR and PCT indicated a systemic inflammation response in the patients. In COVID-19 patients with acute respiratory distress syndrome (ARDS), fibrinogen levels were reported to be associated with elevated interleukin-6 values (Ranucci et al., 2020). In the present study, we found that acute inflammatory markers, including CRP, ferritin, ESR and PCT were all significantly associated with elevated fibrinogen. RK Mahat et al. performed a meta-analysis of inflammatory markers in COVID-19, and they found that the inflammatory markers CRP, ferritin, ESR and PCT were associated with disease severity. However, fibrinogen was not analyzed in their study (Mahat et al., 2021).

Myocardial injury has been recognized as a common complication in COVID-19 patients (Boukhris et al., 2020). Myocardial injury is defined as the presence of at least one cardiac troponin value above the 99th percentile upper reference limit (URL) according to the Fourth Universal Definition of Myocardial Infarction (Thygesen et al., 2018). Consistent with many other reports (Lombardi et al., 2020; Garcia De Guadiana-Romualdo et al., 2021; Majure et al., 2021), elevated hsTnI was detected in the COVID-19 patients in our study. The mechanisms for myocardial injury in COVID-19 has not been elucidated. Several possible mechanisms have been proposed such as direct virus attack, inflammation-related injury, coronary plaque rupture, and microvascular thrombosis (Babapoor-Farrokhran et al., 2020; Imazio et al., 2020; Tajbakhsh et al., 2021). Fibrinogen may increase cardiovascular risk due to adverse effects of fibrinogen on plasma viscosity, coagulation, platelet activity, inflammation and atherogenesis (Kakafika et al., 2007). However, the direct myocardial injury biomarker, hsTnI, did not show significant association with fibrinogen level in our study (P=0.087).

The study has several limitations. First, this study was a single-center, retrospective study which needs to be further validated in a prospective study. Second, a proportion of asymptomatic, mild or moderate patients who did not have fibrinogen levels evaluated on admission were excluded from final analysis, which may underestimate the differences between groups. Third, dynamic changes of fibrinogen during the clinical course might also provide more information in the outcome of the patients.

In conclusion, our findings indicated that fibrinogen level on admission were associated with elevated inflammatory markers in COVID-19 patients, and elevated fibrinogen levels may predict severe disease and ICU admission. Monitoring fibrinogen level could be helpful in management of COVID-19 patients.

The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.

The studies involving human participants were reviewed and approved by University of Alabama at Birmingham Institutional Review Board. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.

JS and LC designed the study, collected the data and drafted the manuscript. DN and SG revised the manuscript. All authors contributed to the article and approved the submitted version.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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