Fibrinogen and D-dimer variances and anticoagulation recommendations in Covid-19: current literature review

Hayıroğlu, Mert İlker; Çınar, Tufan; Tekkeşin, Ahmet İlker

doi:10.1590/1806-9282.66.6.842

Brasil

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REVIEW ARTICLE • Rev. Assoc. Med. Bras. 66 (6) • June 2020 • https://doi.org/10.1590/1806-9282.66.6.842 linkcopy

Fibrinogen and D-dimer variances and anticoagulation recommendations in Covid-19: current literature review

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SUMMARY

INTRODUCTION Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a newly described virus responsible for the outbreak of the coronavirus disease 2019 (Covid-19), named by the World Health Organization (WHO) in February/2020. Patients with Covid-19 have an incidence of acute respiratory distress syndrome (ARDS) of 15.9-29% and sepsis is observed in all deceased patients. Moreover, disseminated intravascular coagulation (DIC) is one of the major underlying causes of death among these patients. In patients with DIC, there is a decrease in fibrinogen and an increase in D-dimer levels. Some studies have shown that fibrinogen and one of its end products, D-dimer, might have a predictive value for mortality in patients with non-Covid sepsis secondary to complications of DIC. Therefore, anticoagulation, considering its mortality benefits in cases of non-Covid sepsis, may also have an important role in the treatment of Covid-19.

METHODS We reviewed the literature of all studies published by April 2020 on patients infected with Covid-19. Our review was limited to D-dimer and fibrinogen changes and anticoagulation recommendations.

RESULTS Anticoagulation therapy can be started following the DIC diagnosis in Covid-19 patients despite the bleeding risks. In addition, the current evidence suggests a routine use of anticoagulation, particularly in patients with higher D-dimer levels (> 3.0 μg/mL).

CONCLUSION Covid-19 is a systemic, hypercoagulable disease requiring more studies concerning treatment. Aanticoagulation is still an issue to be studied, but D-dimer rise and disease severity are the indicative factors to start treatment as soon as possible.

Coronavirus Infections; Anticoagulants; Disseminated intravascular coagulation; Fibrin fibrinogen degradation products; Blood Coagulation

	Study design	Study population	Coagulation parameters	Results	P value	Supplementary information
Zhou et al.²	Retrospective	Covid-19 patients survivor (n= 137) vs. Covid-19 patients non-survivor (n=54)	D-dimer, μg/mL	0.6 vs. 5.2	< 0.001	*Value of D-dimer above 1 was associated with 18-fold higher mortality [OR= 18.42, 95%CI: 2.64-128.55, p= 0.0033].
Han et al.¹³	Retrospective	Control (n=40) vs. Covid-19 patients (n=94)	D-dimer, mg/dl Fibrinogen, g/L	0.26 vs. 10.36 2.90 vs. 5.02	< 0.001 < 0.001	*Significantly higher D-dimer and fibrinogen levels were present in patients with Covid-19 diseases.
Tang et al.¹⁴	Retrospective	Covid-19 surviving patients (n= 162) vs. Covid-19 non-surviving patients (n= 21)	D-dimer, mg/dl Fibrinogen, g/L	0.61 vs. 2.12 4.51 vs. 5.16	<0.001 0.149	*D-dimer level above 3 and fibrinogen level below 1 were present in 85.7% and 28.6%, respectively, in Covid-19 patients who developed DIC.
Cui et al.¹⁵	Retrospective	Covid-19 non-VTE patients (n=61) vs. Covid-19 VTE patients (n= 20)	D-dimer, μg/mL	0.8 vs. 5.2	< 0.001	*> 1.5 μg/mL as the D-dimer cut-off value to predicting VTE
Liu et al.¹⁶	Retrospective	Mild Covid-19 patients (n= 26) vs. severe Covid-19 patients (n=4)	D-dimer, mg/dl	0.26 vs. 1.54	<0.001	*Severe Covid-19 patient had higher D-dimer values compared to mild cases.
Qui et al.¹⁷	Retrospective	Mild Covid-19 pediatric patients (n= 17) vs. moderate Covid-19 pediatric patients (n=19)	D-dimer, μg/mL	0.21 vs. 0.36	0.028	*Moderate Covid-19 pediatric patients had increased D-dimer levels compared to those with mild Covid-19 disease
Chen et al.¹⁸	Retrospective	Moderate Covid-19 patients (n= 10) vs. severe Covid-19 patients (n= 11)	D-dimer, μg/mL	0.3 vs. 2.6	0.029	*Severe Covid-19 patients had increased D-dimer levels compared to those with moderate Covid-19 disease
Zhang et al.¹⁹	Retrospective	Non-severe Covid-19 patients (n= 82) vs. severe Covid-19 patients (n=56)	D-dimer, mg/dl	0.2 vs. 0.4	<0.001	*More elevated D-dimer levels were found in severe Covid-19 patients compared to non-severe Covid-19 patients
Zhou et al.²⁰	Retrospective	Covid-19 patients without aggravation (n= 12) vs. Covid-19 patients with aggravation (n=5)	D-dimer, mg/dl	0.29 vs. 0.28	0.922	*D-dimer was not a factor associated with disease progression in patients infected with Covid-19
Wu et al.²¹	Retrospective	Covid-19 patients without ARDS (n= 117 ) vs. Covid-19 patients with ARDS (n= 84)	D-dimer, μg/mL	0.52 vs. 1.16	0.001	*D-dimer was associated with a higher risk of the development of ARDS [OR= 1.03, 95%CI: 1.01-1.04; p< 0.001].
Wu et al.²¹	Retrospective	Covid-19 patients with ARDS (alive) (n= 40) vs. Covid-19 patients with ARDS (died) (n=44)	D-dimer, μg/mL	0.49 vs. 3.95	0.001	*D-dimer was associated with a higher risk of death in Covid-19 patients with ARDS [OR= 1.02, 95%CI: 1.01-1.04; p= 0.002].
Yin et al.²²	Retrospective	Covid-19 patients with severe pneumonia (n= 449) vs. non-Covid-19 patients with severe pneumonia (n=104)	D-dimer, μg/mL	1.94 vs. 2.52	0.140	*When D-dimer exceeded 3.0 μg/mL (six-fold the upper limit of normal), significantly lower mortality in heparin users than nonusers was found in Covid-19 patients (32.8% vs. 52.4%, p=0.017).
Tang et al.²³	Retrospective	Covid-19 surviving patients (n= 315) vs. Covid-19 non-surviving patients (n= 134)	D-dimer, mg/dl	1.47 vs. 4.70	<0.001	D-dimer was positively correlated with 28-day mortality in multivariate analysis [OR= 1.058, 95%CI: 1.028-1.090; p< 0.001]. The 28-day mortality of heparin users was lower than that of nonusers in patients with D-dimer > 6 fold the upper limit of normal (32.8% vs. 52.4%, p=0.017).
Zhang et al.²⁴	Retrospective	Covid-19 surviving patients (n= 89) vs. Covid-19 non-surviving patients (n= 6)	D-dimer, mg/L	The D-dimer level was present as ≤ 1 and >1, respectively	0.001	For the >1 mg/L group, 81.2% of the patients were severe Covid-19 cases, and 71.9% of the patients reached the composite endpoints including intensive care unit admission or death. Higher D-dimer level was strongly related to severe Covid-19 pneumonia and composite endpoints, including intensive care unit admission or death (p< 0.001).

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[TFN1] Abbreviations: VTE - venous thromboembolism; ARDS - acute respiratory distress . syndrome; DIC - disseminated intravascular coagulation; OR - odds ratio; CI - confidence interval.