The main finding of this retrospective study is that D-dimer level at admission above 1128 ng/mL is an independent predictor of in-hospital mortality for COVID-19 patients. This multicenter French study of patients hospitalized for COVID-19 is the current largest non-monocentric study to date for hospitalized patients in medical ward to provide evidence that initial D-dimer levels could be a valuable tool to predict further in-hospital mortality. Moreover, to the best of our knowledge, we show for the first time that VTE occurrence during hospitalization did not interfere with the predictive value of D-dimers for in-hospital mortality.
High D-dimer level has been largely reported to be one of the most common laboratory findings reported in COVID‐19 patients at hospital admission. We previously demonstrated that D-dimer measurement at admission is a discriminant factor during COVID-19 suspicion. Indeed, adding a D-dimer cut-off beyond 500 ng/mL to female gender and absence of pneumonia at CT scan could exclude COVID-19 diagnosis with a high sensitivity and specificity (4). Moreover, we and others previously showed that D‐dimer level at admission was higher in patients needing ICU referral compared to those who did not require it (5, 20). Moreover, several reports have described that increased D-dimer levels were related to in-hospital mortality (14, 21–23). Only one study provided a well evaluated cutoff for D‐dimers (15) at 2000 ng/mL for relation with in hospital mortality in 343 patients. However, this study did not specify if patients were hospitalized in medical ward, in ICU or if patients were directly hospitalized in ICU, making proper and accurate use of this cut-off difficult for clinicians. Our study only includedCOVID-19 patients admitted in medical ward. Some of them were secondary referred to ICU but no one was directly hospitalized in ICU. Our results propose COVID-19-increased D-dimer level as a clear consequence of respiratory disease through the development of capillary microthrombosis, as observed in post-mortem studies (3, 11) and attributed to a vascular thickening or vascular congestion (24). Thus, in COVID-19, hypothesis of microthrombosis is proposed in lung but also in kidney since the elevation of serum creatinine was associated with higher levels of D-dimers (> 500 ng/mL) (25). The SARS-CoV-2 receptor (ACE2) is strongly expressed in endothelial cells (26). Infection of endothelial cells could therefore induce endothelial lesions triggering massive activation of coagulation and diffuse microthrombotic process impairing renal function and respiratory gas exchanges. We previously described increased numbers of circulating endothelial cells in COVID-19 patients (4) and an association between circulating biomarkers of endothelial activation in COVID-19 and ICU admission (5). Angiopoietin-2 was also inversely correlated to respiratory system compliance in this study, paving the way of relationship between endothelial dysfunction and pulmonary disease severity. Integrity of endothelial cells allows providing an antithrombotic environment that is reversed during COVID-19 upon the burst of inflammation related to IL-6. Therefore, SARS-CoV-2 infection induces a disruption of endothelial thrombo-protective barrier that lead to this coagulopathy and increased D-dimers. Since in the present cohort, patients were in the same step of disease according to same time to onset symptoms of disease, endothelial induced coagulopathy reflected by D-dimers could be a consequence of viral loading phase and severity of viral infection. Importance in viral loading hypothesis needs to be confirmed with association between D-dimers and viremia quantified with sensitive tests.
Major confounding factor for D-dimers increase could be macrothrombosis since high incidence of VTE (PE or DVT) (7, 9, 27) have been described in COVID-19. In clinical practice, D-dimer measurements have been used only to exclude VTE. Indeed, no such D-dimer-based strategy has been described during COVID-19-associated coagulopathy with patients with a high level of D-dimers. Even if increased D-dimer levels at admission have been associated with VTE during follow-up in COVID-19 patients (28), no threshold is currently available to diagnose VTE. Furthermore, the International Society of thrombosis and Haemostasis (ISTH) does not recommend routine screening for VTE based on elevated D-dimer levels in COVID-19 patients (29). We demonstrate here that 1128 ng/mL D-dimer cut-off at admission is independently correlated to in-hospital mortality regardless VTE occurrence during hospitalization. D-dimers might be used to monitor COVID-19 worsening. Indeed, previous studies have observed that progressive increase of D-dimers was observed in non-survivors of COVID-19 (1). Microthrombosis generating D-dimers allow to makes prognosis in COVID-19 outcome and also opens the way of D-dimer monitoring to guide whether anticoagulation therapy should be initiated in COVID-19. D-dimer monitoring has been described in a randomized clinical trial in patients with mechanical valve replacement as a good tool to guide anticoagulation intensity in patients receiving warfarin therapy (30) but also to determine the duration of oral anticoagulation in patients with VTE (31). Thus, our results suggest that therapeutic anticoagulation could be initiated in COVID-19 patients with high D-dimer level at admission in contrast to patients with D-dimers beyond this cut-off that should only benefit from prophylactic anticoagulation. Moreover, D-dimer-based strategy to guide anticoagulation regimen needs to be evaluated in prospective randomized clinical trials.
Our study has several limitations. First, in this multicentric study, we could not identify the manufacturer or type of D-dimer assay used for all tested D-dimers as suggested by ISTH (32) Second, we do not have the delay from COVID-19 admission to VTE onset during hospitalization. Third, serial D-dimer monitoring has been suggested by ISTH (32) as helpful in determining prognosis in COVID-19 patients. Indeed, a peak of D-dimers has been found associated with VTE in COVID-19 (33, 34) but in the present study, we only assessed D-dimers at admission. However, since VTE occurrence did not to modify in-hospital mortality in the present study, this lack of continuous monitoring of D-dimers is unlikely to modify results.