In the present study, many cases of severe COVID-19 were complicated with FDP fluctuations during the treatment period. Our results revealed that episodes of marked intravascular coagulofibrinolytic activation coincided in time with episodes of FDP elevation. Furthermore, these FDP elevations were associated with the development of thrombotic or bleeding complications, occasionally leading to meet SIC or DIC diagnostic criteria. This suggests that increasing FDP values may serve as a sign of the systemic progression of coagulofibrinolytic disorders with loss of localization in severe COVID-19. However, there were some differences in coagulofibrinolytic responses between CAC and SIC or DIC. Our results demonstrated that coagulation activation which can cause the development of systemic coagulopathy such as DIC, and suggested the limitation of the application of existing DIC and SIC diagnosis criteria to COVID-19.
In this study we evaluated coagulofibrinolytic responses by assessing changes in plasma biomarkers in ARDS-COVID-19 patients. We measured TAT and SF values as markers for coagulation activation and PIC levels as a marker for fibrinolytic activation. Because TAT is a covalent stable stoichiometric 1:1 complex of thrombin and antithrombin, TAT values reflect intravascular thrombin formation. SF, a marker of hypercoagulation, is generated during thrombin-fibrinogen reactions. PIC is a product of the inactivation of activated plasmin by α2 plasmin inhibitor, which represents fibrinolytic activity. The half-lives of TAT, SF and PIC are short, so these markers represent real time profiles of coagulofibrinolytic activity. Measuring these markers is essential for accurately evaluating systemic intravascular coagulofibrinolytic pathophysiology in COVID-19 patients . Activated plasmin lyses fibrinogen and fibrin to make FDP, which reflects primary and secondary fibrinolysis. This means that, especially in enhanced fibrinolytic conditions, FDP is a more sensitive indication of fibrinolysis than D-dimer, which reflects secondary fibrinolysis [4, 6, 21]. FDP values increase when coagulofibrinolytic activation occurs, we measured marker levels during episodes of FDP elevation and compared them to the levels observed on admission, i.e., not during FDP elevation.
COVID-19-associated coagulopathy, CAC has been associated with coagulation disorders; such cases are characterized by elevated D-dimer and fibrin degradation products (FDP) levels [3–7]. In the early stages of COVID-19, CAC is thought to occur and be localized overwhelmingly in the lungs [10, 11, 21–23]. On the other hand, CAC is associated with the development of systemic thromboembolic complications, suggesting a risk of progression from local to systemic coagulopathy [3–7, 14]. It is known that sepsis following an acute infection can be complicated by systemic coagulopathy, DIC . CAC overlaps with this sepsis-associated coagulopathy, although there are some differences between these two pathophysiologies [14, 16, 22].
One of the manifestations of DIC is dysregulated intravascular coagulation , excessive thrombin generation has not been definitively established in COVID-19 patients . High fibrinogen levels and thromboelastographic findings have revealed that hypercoagulation sometimes occurs in connection with COVID-19 [24, 25]. While some studies have reported mild intravascular coagulation activation on admission [23, 26, 27], it remains unclear whether this mild response causes the development of DIC. As in previous reports, no crucial coagulofibrinolytic activation was observed on admission in this study. However, our results revealed that many patients with severe COVID-19 exhibited FDP fluctuations during the treatment period. Furthermore, our results clearly demonstrated that significant intravascular coagulofibrinolytic activations, as evidenced by TAT, SF and PIC levels, coincide with episodes of FDP elevation, a finding that supports similarity between the pathogenesis of COVID-19-associated coagulopathy and that of DIC. Many studies have assessed coagulofibrinolytic status in COVID-19 patients on admission, but FDP elevations occur not only at the time of admission, but also in the middle of treatment. Furthermore, many of the FDP elevations observed in this study were fast and transient responses. Thus, there is a possibility that we may miss or underestimate these rapid responses if the markers are not measured regularly.
Our results demonstrated that severe COVID-19 patients could suffer coagulofibrinolytic activation with FDP elevation and also the thrombotic or bleeding complications, which is consistent with the definition of DIC. On the other hand, regarding consumption coagulopathy, it is known that decreased platelet count and a prolonged prothrombin time are uncommon or mild in COVID-19, in contrast to both SIC and DIC [12, 13]. In fact, we found that patients with severe COVID-19 have preserved PLT and PT-INR values. Moreover, in this study, the application of existing diagnosis criteria for DIC and SIC to CAC did not show certain tendency for coagulofibrinolytic responses; further these responses did not match a suppressed-fibrinolytic phenotype of DIC often seen in sepsis. Systemic coagulofibrinolytic activation due to disease exacerbation or secondary bacterial infection thought to cause a progression from local coagulopathy to DIC in COVID-19 . However, the existing diagnosis criteria for DIC and SIC could not evaluate the state of CAC adequately. The rate of COVID-19 complicated by DIC remains rare, but its mortality rate is very high [4, 12]. Furthermore, COVID-19 patients show a markedly high incidence of thrombotic and bleeding complications in connection with minimal coagulofibrinolytic abnormalities. We need to develop a specific diagnostic method for COVID-19-associated coagulopathy. Even though thrombus formation or bleeding can directly cause coagulofibrinolytic activation and FDP elevation, we cannot assume that local thrombosis events such as DVT lead to the development of DIC. It is likely that marked FDP elevation might be a sign reflecting the progression from local coagulopathy to DIC. We should assess the usefulness of FDP fluctuations as signs for early detection of the development of DIC and thrombotic or bleeding complications during the treatment period.
Several limitations of the present study should be addressed. First, the sample size of this observational study was small, so even though we obtained the present results using appropriate statistical methods, larger-scale studies are still needed to clarify our hypotheses. Second, imaging for the detection of thrombotic events was at the discretion of the treating clinician, which may have introduced additional bias and skewed the reporting of thrombotic events. Lastly, possible causes of FDP elevation other than SARS-CoV-2 infection, such as bacterial infection and anticoagulant prophylaxis, were not assessed in this study. Accordingly, a future study considering other factors affecting COVID-19-associated coagulopathy is needed.