Fibrinogen, produced by the liver, is an important protein involved in the final step of blood clotting. After conversion to fibrin via a reaction with thrombin, fibrinogen forms an insoluble clot to prevent bleeding. Fibrinogen is also an acute-phase protein. Its elevated levels are found in patients with infections, injuries, cancer, stress-related disorders and increased cardiovascular disease (CVD) mortality ^[1][2][1,2]. During Coronavirus Disease 2019 (COVID-19) infection, a mean fibrinogen concentration around the upper limit of normal was observed, while patients who died showed a sudden reduction in fibrinogen before death ^[3][4][3,4]. Li et al. [5] studied hematological covariates in 1449 hospitalized patients with COVID-19. At baseline, patients who died had higher fibrinogen levels than survivors (median, 4.3 g/L (interquartile range [IQR], 3.2–5.2 g/L) vs. 3.6 g/L (IQR, 2.9–4.5 g/L)), but they had lower minimum fibrinogen levels (2.6 g/L (IQR, 1.7–3.9 g/L)) vs. 3.2 g/L (IQR, 2.6–3.9 g/L) [5]. The authors concluded that the dynamic changes in fibrinogen levels are correlated with the risk of death in patients with COVID-19. While fibrinogen testing is not routinely performed in all COVID-19 patients on admission to the hospital [6], this parameter might be useful in the early assessment of coagulation in this population.

Fibrinolysis is a normal body process that is an integral part of the hemostatic system. The activation of the fibrinolytic cascade results in fibrin degradation. Fibrinolysis is regulated by numerous enzymes, with plasmin being the key enzyme involved in the fibrinolytic system. Plasmin is responsible for the lysis of the fibrin clot, thus producing fibrin degradation products. Thrombin is also an important enzyme in the regulation of the coagulation system. Endogenous fibrinolysis is also strongly linked to thrombin, an enzyme responsible for significant resistance to fibrinolysis. High thrombin levels act as a potent platelet activator and facilitate the formation of stable clots by converting fibrinogen into fibrin, which binds platelets together. Moreover, thrombin inhibits endogenous fibrinolysis by activating thrombin-activatable fibrinolysis inhibitor, which prevents the binding and activation of plasminogen into plasmin [7]. Finally, it indirectly inhibits endogenous fibrinolysis by releasing plasminogen activator inhibitor-1 (PAI-1) from platelets, a principal inhibitor of tissue plasminogen activator (tPA) [7].

An impaired fibrinolytic process has been demonstrated in patients infected with SARS-CoV-2 with interstitial lung disease, including critically ill patients ^[8][9][10][8,9,10]. Hypercoagulation in these patients is a complex and multifactorial process. SARS-CoV-2 enters the cells via the angiotensin-converting enzyme 2 (ACE2) receptor. It is considered that with SARS-CoV-2 virus attachment, excess angiotensin increases the expression of PAI-1, which inhibits fibrinolysis on endothelial cells ^[3][11][3,11]. Patients with interstitial lung disease were also reported to have elevated levels of thrombin-activatable fibrinolysis inhibitor and protein C inhibitor (plasminogen activator inhibitor-3) [9]. SARS-CoV-2 infection leads to acute inflammation, which leads to an increase in bradykinin and tPA. However, increased tPA levels are not sufficient to counterbalance the high levels of PAI-1, which likely explains the impaired fibrinolysis and fibrin accumulation in the lung alveoli [12]. Fibrin deposits enhance inflammation and fibrosis, and lead to lung surfactant damage [9].

Plasmin is the major fibrinolytic protease. In their review article, Hong-Long et al. [13] summarized the current evidence for the presence of elevated plasmin levels in COVID-19 patients with hypertension, diabetes, coronary artery disease, cerebrovascular disorders, chronic obstructive pulmonary disease and kidney dysfunction. Plasmin, along with other proteases, may contribute to increased SARS-CoV-2 infectivity, and antiproteases targeting the plasmin(ogen) system may be a promising therapeutic option in patients with COVID-19 [13]. There is also an increasing body of evidence that systemic fibrinolysis may be an effective therapeutic approach in critically ill patients with COVID-19 ^[12][13][14][12,13,14]. Medcalf et al. [15] described the so-called plasmin paradox in patients with COVID-19, wherein plasmin formation can be either harmful or beneficial, although not at the same time. The authors suggested that an appropriate therapeutic approach aimed either at promoting or inhibiting fibrinolytic activity depends on the severity of infection. In patients with mild or moderate infection, suppression of fibrinolysis may reduce the amount of the virus and improve the immune response. On the other hand, activation of the fibrinolytic system may be protective in severe cases [15]. These conclusions may have important implications for management decisions in patients with COVID-19.

Considering that coagulopathy in patients with COVID-19 has different features that have not been fully understood so far, clinicians have made attempts to use different treatment options, including fibrinolysis. Della Bona et al. [14] reported a case series of four patients who developed PE despite heparin use, including during treatment with sodium heparin. In most cases, systemic fibrinolysis with alteplase proved effective. Other authors also reported clinical improvement in critically ill patients with COVID-19 after fibrinolytic therapy ^{[14][16][17][18]}[14,44,45,46]. It is suspected that pulmonary microemboli may contribute to respiratory failure in patients with COVID-19. Therefore, tPA therapy may offer clinical benefits in these patients ^[17][19][45,47], including those with comorbidities ^[20][48]. In a retrospective study in critically ill patients with COVID-19, So et al. ^[21][26] administered tPA to patients with a suspicion of PE. tPA infusion was associated with an improvement in 49.1% of patients. All-cause mortality in this population was 89.5% ^[21][26].

Plasminogen may be another interesting therapeutic agent in the fight against COVID-19. In a study by Della-Morte et al. ^[22][49], patients with COVID-19 with low plasminogen levels showed a 12-fold higher risk of mortality than COVID-19 patients with normal or high plasminogen levels (odds ratio, 12.57; 95% CI, 2.46–64.0; β = 2.53; p = 0.002). Wu et al. ^[23][50] studied the effect of atomization inhalation with freeze-dried plasminogen in patients with moderate to severe COVID-19. They showed that additional plasminogen may be effective in treating lung lesions and hypoxemia in these patients. The authors concluded that while further studies are needed, this fibrinolytic agent may be an adequate therapeutic option in this population of patients ^[23][50].

Consideration of systemic fibrinolysis should always involve a careful risk-to-benefit assessment in terms of possible adverse events. The risk of bleeding in COVID-19 patients was reported at 4.8%, with a slightly higher risk of 7.6% in those with critical disease ^[24][33]. Moreover, the initial enthusiasm as to the continuation of fibrinolytic therapy in critically ill patients with COVID-19 was dampened by the results of a randomized clinical trial in patients receiving thrombolytic therapy. Based on preliminary findings, thrombolytic therapy does not improve oxygenation in these patients. Moreover, major bleeding was reported in 10.2% of patients within 7 days of the infusion of recombinant tPA, while concomitant anticoagulation and tPA resulted in a higher risk of bleeding (in 5 of 6 patients with major bleeding) ^[25][51]. On the other hand, coagulopathy in critically ill patients with COVID-19 has prothrombotic potential. A large, multicenter, randomized controlled trial showed that the combination of tPA bolus and heparin is safe in COVID-19 patients with severe respiratory failure. None of the patients experienced major bleeding, including intracranial bleeding, although the authors noted that this might have been due to the careful patient selection ^[26][52].

Thus, based on current knowledge, it is difficult to conclusively answer the question of whether the routine use of fibrinolysis in COVID-19 patients with a severe course and/or with coexisting pulmonary embolism in hemodynamically stable patients is warranted.

Nevertheless, the distinct features of coagulopathy in this patient population have been well described. It is possible that the point-of-care testing with thromboelastography and rotational thromboelastometry could be helpful in selecting candidates for fibrinolytic therapy. Although the general vaccination program and virus evolution have changed the dynamics of the pandemic, the large discrepancies in the current literature necessitate further research to clarify treatment recommendations for patients with severe COVID-19.