The major finding of the present meta-analysis, the largest and most comprehensive to date, is that high levels of D-Dimer are associated with a more severe prognosis and increased mortality in patients with COVID–19. Finally, the mean platelet count is lower and mean prothrombin time more prolonged in Severe and Non-Survivor Covid–19 patients, supporting the concept that patients infected by COVID–19 may be at risk of developing disseminated intravascular coagulation (DIC). In fact, high d-dimer levels, low platelet count and prolonged PT are critical parameters of ISTH Criteria for DIC[3] as showed in a recent study by Tang and colleagues[17]. First, they showed that most of non-survivor patients with COVID–19 disease met the criteria for DIC. Moreover, elevated D-dimer values were associated with a worse clinical outcome, reflecting coagulation activation from infection, marked inflammation and multiorgan failure [45].
Recently, Lippi et al.[46] showed in a brief letter reporting a pooled analysis of 4 studies that D- dimer is associated with the severity of COVID–19 disease. The mean difference of the four studies which reported D-dimer values showed that they are significantly higher in COVID–19 patients with severe disease than in those with mild disease.
The obvious consideration is related to therapy with heparin to limit coagulopathy. Nonetheless, it is paramount to stimulate local fibrinolysis to degrade pre‐existing fibrin in the lung. Hence, a nebulizer form of tissue‐type plasminogen activator to treat COVID‐19 has been proposed recently [47].
Interestingly, a recent finding investigated the predictors of 28-day mortality in Severe COVID–19 patients and the association between death and low molecular weight heparin (LMWH) therapy. They showed that patients with elevated D-dimer values, prolonged PT and increased age presented a greater mortality at 28 days, while those with a higher platelet count had a lower 28-day mortality. Specifically, the use of anticoagulant therapy resulted in lower mortality in patients with severe coagulopathy with a SIC score ≥4 (LMWH: 40.0% vs No-LMWH: 64.2%, p = 0.03) or D-dimer >6-fold of the normal upper limit (32.8% vs 52.4%, p = 0.02. Still, there was no overall benefit between those who use heparin and those who do not. (30.3% vs 29.7%, p = 0.91) [17].
Although coagulopathy acknowledges various aetiological causes, our findings suggest that the worsening of coagulation parameters may indicate progressive severity of COVID–19 infection and may predict the need for more aggressive critical care and treatment. Thus, patients in the Intensive Care Unit (ICU) should have pharmacologic prophylaxis with heparin if there is not a caution. Consideration of clotting problems and antithrombotic therapy in the daily COVID–19 management process is essential, rather than focusing solely on the infection. Further, potential complications related to intravascular clotting should always be taken into consideration in the presence of worsening clinical conditions. The risk of bleeding should always be considered in individual patients when anticoagulant drugs are administered [48].
In conclusion, further studies to define whether adjunctive antithrombotic drugs may be helpful to treat patients properly with severe COVID–19 disease are still needed.
Limitations. Our study has some limitations. First, in the absence of randomized clinical trials, our analysis reported only data from retrospective and observational studies. Second, since there is significant heterogeneity, we used a random-effects model for all analyses. Third, the definition of the endpoints is variable in the different studies. Thus, we performed a subgroup analysis (Severe/Non Severe, Non Survivors/Survivors) to overcome this issue.