Discussion
D-dimer is a biomarker of fibrin degradation that can be measured in plasma. D-Dimer content of normal human plasma is very low, but is increased relating to thrombosis. Plasma D-Dimer level has high sensitivity in the diagnosis of VTE, but with modest specificity. It can be confused by numerous pathophysiological events, such as inflammation, malignancy, pregnancy, myocardial infarction, DIC, aortic dissection, and liver and kidney dysfunction10.
In our study, we report the levels of D-Dimer spread around 1.37-2.89mg/L in the stage of low-flow oxygen in COVID-19, may be caused by inflammation, and (or) thrombosis, or other factors. An obvious increasing trend can be found at the D-Dimer levels while the condition of the patient deteriorated further. Moreover, risk of aggravation of COVID-19 with D-Dimer>3mg/L is more than 15 times than those D-Dimer≤3mg/L. Though lack multi-factor regression analysis, other researchers have reported similar associations. Guan and Tang reported the significant increase with D-Dimer in COVID-19 death11. Wu found D-Dimer was a risk factors associated with the development of acute respiratory distress syndrome (ARDS) and progression from ARDS to death12. Despite the reason is various and complicated for D-Dimer abnormalities in COVID-19, disease aggravation accompanied by increased plasma D-Dimer levels. It is conceivable that D-Dimer may be an effective parameter to assess the degree of illness.
Whether the D-Dimer abnormalities were directly responsible for VTE cannot be determined, as its modest specificity. The high infectivity and pathogenicity of SARS-CoV-2 limit the routine screening of VTE by Doppler studies of lower limb veins and pulmonary artery CTA. Diagnosis should be decided according to the peculiar circumstances and available related tests of the patients, and how to consider D-Dimer abnormalities in perspective may provide new ideas for identifying VTE. Inflammatory reactions can activate the coagulation system, but some differences were found in Zhou’s research that elevated D-dimer levels occurred earlier than that of inflammatory factor, suggesting that the very high D-dimer levels observed in COVID-19 patients are not only secondary to systemic inflammation, but also reflect true thrombotic disease, possibly induced by cellular activation that is triggered by the virus13-14. In addition, a study reported that the incidence of VTE in severe COVID-19 patients in the Intensive Care Unit (ICU) was 25%4. Besides, 30% patients had acute pulmonary embolus when pulmonary CT angiograms performed for COVID-19 patients showed in a study of France with 106 patients15. In a cohort study of Wang forecasted that 40% of COVID-19 patients had a high risk of VTE16. Unlike SARS-CoV, small vessel thrombosis was found not only in pulmonary but also in multiple organs after SARS-CoV-2 infection in humans13. Based on a comprehensive analysis of these consequences, it was hypothesized that D-Dimer abnormalities and VTE in COVID-19 had a close relationship. It should be noted that, in one interesting study, plasmin may cleave a newly inserted furin site in the S protein of SARS-CoV-2, extracellularly, which increases its infectivity and virulence17. Elevated plasmin is a shared feature in people with underlying medical conditions, including hypertension, diabetes, cardiovascular disease, cerebrovascular disease, and chronic renal illness. Those people are susceptible to SARS-CoV-2 infection, their elevated plasmin was responsible for D-Dimer abnormalities.
In addition to its assessment of risk and diagnostic use, D-Dimer has been proposed to guide anticoagulant therapy gradually. Tang et al18 showed that the prophylactic anticoagulation regimen can reduce the COVID-19 patient mortality when D-Dimer levels greater than six times of the normal upper limit value. What is more, Lin et al19suggested beginning prophylactic anticoagulation regimen once D-Dimer up to four times of the normal. Larger prospective studies are to be required to support the D-Dimer value can become guidelines on anticoagulant therapy in the future, but now its severity of the abnormal value and rate of the significant change can provide a basis and direction for clinical treatment. In our present study, in patients on anticoagulant therapy, the recovery was quick of those plasma D-Dimer≤3mg/L when anticoagulant therapy was initiated than that of plasma D-Dimer>3mg/L. Nevertheless, their hospital stays had no significant difference, it may be related to our discharge criteria that the condition was significantly alleviated and nucleic acid tests were negative. Viral infection is a self-limiting disease, the anticoagulant role of LMWH may alleviate the illness but does not have a prominent antiviral function.
However, due to the limited number of cases included in our study, especially hard to collect the matched no anticoagulant therapy patients, we could not perform further and more conceivable analysis. Through the analysis of D-Dimer changes at different stages of illness and its function to suggest much more benefits could be made at early-stage anticoagulation therapy in severe COVID-19, the guidance of D-Dimer should not be ignored and should be studied further.