4. Conclusions
COVID-19 is an acute infectious disease caused by a new type of coronavirus (SARS-CoV-2). The onset of COVID-19 presents as fever, mild or sever, in a few cases [4–6]. Some patients may gradually develop dyspnea. However, in severe cases, the disease progresses rapidly, and patients develop severe septic shock and die [7–10]. The severity and prognosis of COVID-19 are complicated by the diversity of symptoms, radiological manifestations, and disease progression. It is particularly noteworthy that some severe, critical, and deceased patients have significant coagulation dysfunction [1, 4]. The pathological changes of the disease have been added into the seventh edition of the COVID-19 Treatment Plan issued by the National Health Commission of China, in which both autopsy and histopathologic examinations demonstrate thrombus or microthrombus in the lung, heart, kidney, and/or liver.
Upon SARS-CoV-2 entering the body through the angiotensin-converting enzyme 2 (ACE2) receptor adsorbed on the surface of mucosal epithelial cells [7, 8], its pathogen-associated molecular pattern (PAMP) can be quickly recognized by the immune system, and immune response is activated to clear the virus. However, overactivated immune response could cause a cytokine storm. As a result, cytokine storm causes vascular endothelial damage, activates the coagulation system, and inhibits the fibrinolytic and anticoagulating systems. Excessive thromboses in the microvascular system lead to disseminated intravascular coagulation (DIC) and, ultimately, microcirculatory disorder and serious multiple organ dysfunction syndrome [11]. Therefore, early detection and correction of coagulation dysfunction could effectively reduce mortality.
Commonly used laboratory coagulation indicators include DD, PT, APTT, and Fg. DD is the product of fibrinolytic solubilization of fibrin, and the elevated level of DD indicates that there is a hypercoagulating state and secondary fibrinolysis in the body, which can be seen in increased fibrinolytic activity of the body system [12–15]. PT and APTT are exogenous and endogenous coagulating system factors, which can be used for early diagnosis of DIC. Fg is a protein with coagulation function synthesized by the liver, which is an important substance in the process of coagulation and thrombosis. High level of Fg is an important indicator for a variety of thrombotic diseases. DD, PT, APTT, and Fg can be used as sensitive indicators to reflect different degrees of coagulating dysfunction. Therefore, in this article, the study was focused on if these indicators are related to the severity of COVID-19.
The results of this study showed that DD and Fg could be used as new indicators for the clinical classification of COVID-19. In the first test of DD, 50 of 115 patients had abnormal levels of DD (>0.55 mg/L), accounting for 43.5% (50/115). Of the 28 critically ill patients, 17 were >0.55 mg/L, accounting for 60.7%. (17/25), and 14 cases had two times more than the normal reference value. 70.4% (81/115) of the COVID-19 patients had abnormal concentration of Fg. Additionally, it is noticed that the level of Fg was significantly increased in severe and critically ill patients, with 70.3% of severe and critical patients (52/74) >4.00 g/L. The results of the study indicate that the levels of DD and Fg significantly increased in severe and critically ill patients, and some patients deteriorated during treatment, suggesting that COVID-19 patients, especially severe patients, have a high risk of thrombosis, which is consistent with previous reports [1, 4].
In addition, the results of this study also show a significant correlation between coagulating factors and disease outcome, suggesting DD, PT, and APTT could serve as diagnostic indicators for disease progression. Among the 23 patients who deceased, 18 had abnormal DD in the first test, accounting for 78.3% (18/23), among which 12 had DD level two times more than the normal reference value. In the second and third tests, 8 exacerbating cases had DD level > 1.10 mg/L. Additionally, among 23 deceased patients, 21 cases had DD level two times more than the normal reference value. In the first test of PT, there were two abnormalities (15 sec) in 8 aggravating patients whereas 5 abnormalities (15 sec) in 23 deceased patients. While in the second and third PT tests, there were 10 and 18 abnormalities (> 15 sec), respectively, in 23 deceased patients. The gradually increasing DD and PT levels suggest the significant correlation with disease progression.
Using discharged and deceased cases as the basis of positive division, the ROC curve analyses showed the areas under the curve (AUCs) were 0.742, 0.818, and 0.851, respectively. The third time of PT and APTT test had AUCs at 0.937 and 0.856, respectively, indicating that PT and APTT had great value in disease prognosis.
Based on the study results, the levels of D-dimer, PT, and APTT were significantly higher, whereas Fg in deceased cases was significantly lower than those in survival cases, suggesting the dynamic coagulating process in patients with COVID-19 is likely the hypercoagulating state followed by the activation of fibrinolysis. In this study, PT and APTT prolonged in 23 deceased patients, and the prolongation was more significant in the second and third tests, indicating the patients were in the transition from the high coagulating state into fibrinolytic state due to the excessive consumption of coagulating factors. Additionally, the study results showed DD, one of the fibrinolytic degradation products, gradually increased throughout the disease, indicating that the patients were possibly in hyperfibrinolytic state, which is consistent with Chen et al.'s report [16].
CT imaging has been regarded as a valuable tool in diagnosis and prognosis of COVID-19. The study results showed that DD was correlated with CT imaging in predicting the progression of disease. Specifically, the increased level of DD suggests hypercoagulating state and the possible pulmonary embolism, which could be further confirmed by CT angiography (CTA).
One limitation of this study exists on that it was carried out in a single medical center with absence of the control group design due to the emergent situation of COVID-19 breakout. In the future, the researchers should integrate with a few medical centers in the area and draw the control group to boost the reliability of the study.
In conclusion, the results of this study showed that hypercoagulation was likely present in patients with COVID-19 at the early stage. And hypercoagulation is closely related to disease progression and clinical outcome. Therefore, the coagulation indicators such as DD and PT should be monitored as early as possible in order to detect thrombotic complications. It is imperative to take preventive treatment to reduce the risk of thromboembolism and DIC secondary to coagulation disorder, thereby decreasing the morbidity and mortality of COVID-19-infected patients.