In this single-centre, prospective, observational study we report that: hsTnT five-fold elevation is the greatest difference observed among a large plethora of clinical and biochemical parameters characterizing baseline phenotype of 266 patients hospitalized for COVID-19 and stratified for mortality; baseline hsTnT and D-dimer, but not CRP, are associated with in-hospital COVID-19 mortality; D-dimer accounts for a substantial proportion of the hsTnT variability; anticoagulant treatment during hospitalization substantially reduced the mortality risk, a benefit particularly evident in subjects with elevated hsTnT.
Our study aimed at exploiting, from a clinical in-hospital point of view, the complex interplay between inflammation, coagulation and cardiac injury. We showed that the activation of inflammatory/coagulation pathways might explain a large proportion of the increase in hsTnT levels commonly observed in the COVID-19, probably higher than the severity of hypoxia. Although changes in hsTnT levels during hospitalization were significantly related to the fluctuations of the CRP and D-dimer concentrations, only D-dimer presented an association with mortality similar to hsTnT. These findings suggest that cardiac injury and coagulation pathways might be relevant in defining the risk of mortality related to elevated hsTnT levels in patients with SARS-CoV-2-related pneumonia.
In our observation we found hsTnT, among a large numbers of serum biomarkers, the parameter with the major difference at baseline between survived vs deceased patients hospitalized for COVID-19. Cardiac injury, marked by troponin elevation, is frequent in patients with COVID-19 and related with adverse outcomes. In fact, while the most common clinical presentation of the SARS-CoV-2 infection is bilateral interstitial pneumonia often associated to respiratory failure, several reports have supported the capacity of cardiac injury, indirectly assessed by cardiac troponin due to the in-hospital real-life setting, to inform on the mortality risk in COVID-19 [1, 2, 3, 11]. Troponin elevation has been related with a large set of inflammatory serum markers, such as CRP, ferritin, IL-6, tumour necrosis factor-α and also thrombotic markers such as D-dimer. No previous studies, however, have accurately explored the potential and complex interaction between these three biologic systems and thus defined the putative determinants of hsTnT elevation levels in COVID-19.
In accordance with current literature, we document that hsTnT is associated to an increased risk of in-hospital mortality in subjects with and without previous history of CVD, suggesting that the exclusive presence of coronary atherosclerosis is unlikely to completely explain the high mortality risk of these patients. One plausible hypothesis is that cytokine storm induced by the SARS-CoV-2-related pneumonia can promote the activation of the coagulation system which, in turn, can result in a systemic microangiopathy, multi-organ failure and increased mortality. However, the relevance of the inflammation in defining the mortality outcome has recently been debated, as observed by Sinha et al. Indeed, similar to hsTnT, an increased D-dimer concentrations have been related to the mortality risk of infected patients [3, 7].
In our observation, also, we found that CRP, beyond its association with hsTnT, was related to the risk of ICU admission and requirement of mechanical ventilation, both outcomes defining the severity of the pneumonia. However, CRP was not predictive of mortality. Instead, D-dimer and hsTnT presented a strong relationship with mortality, but they were not informative on the risk of respiratory complications eventually leading to ICU admission. It’s plausible that while CRP might reflect more closely the pulmonary stage of the disease and the severity of cytokine storm related to pneumonia, the elevation of D-dimer and hsTnT might sign the evolution towards a systemic involvement of the infection. This is in line with the fact that, in our study, we observe a larger variability of hsTnT explained through D-dimer levels instead that through the severity of the hypoxia related to pneumonia. The development of disseminated intravascular coagulation (DIC) in patients with more severe interstitial pneumonia could partially explain the stronger relationship of D-dimer and hsTnT with the mortality risk compared to CRP. However, in ours and other studies, the pattern of coagulopathy observed during SARS-CoV-2 infection was substantially different to the DIC commonly seen in sepsis . Indeed, our population did not show severe thrombocytopenia which usually accompanies the sepsis-related DIC, and the D-dimer concentrations often reached higher levels than those expected in DIC. It has been repeatedly emphasized that most patients with COVID-19 related coagulopathy would not be classified as having DIC according to the recommendations of the International Society on Thrombosis and Haemostasis [7, 15]. However, a large involvement of the coagulation system in COVID-19 is undebatable: in post-mortem studies, a microangiopathy characterized by typical microvascular platelet-rich thrombotic depositions has been described not only in small vessels of the lung parenchyma but also in other tissues, such as the myocardium . Such microangiopathy could account more directly for the multi-organ failure and death in COVID-19 patients. Following this interpretation, the elevation of hsTnT might represent also an early marker of a systemic macroangiopathic involvement during COVID-19 infection, and its high prognostic capacity might depend on its higher sensitivity and specificity compared to other markers of tissue injury .
In our study only the treatment with low molecular weight heparin showed convincing evidence for an attenuation of the mortality risk. This is in line with the current literature: observations about anticoagulation therapy show promising results and expert opinions have recommended the use of prophylactic low molecular weight heparin in patients with COVID-19 in absence of clinical contraindications [6, 16]. Ayerbe et al reported an association between heparin and lower mortality in 2075 patients admitted with COVID-19 in 17 hospitals in Spain. In a retrospective study including 449 patients with severe COVID-19 in China, 99 of which received heparin, 28-day mortality of heparin users was lower than that of non-users in patients with D-dimer levels more than six-fold the upper limit of normal . An observational study including 2,773 patients hospitalized with laboratory-confirmed COVID-19 within the Mount Sinai Health System in New York City showed that systemic anticoagulation was associated with improved outcomes . As for other systemic diseases with high prevalence in older population, the prescription of an anticoagulation treatment should be weighed against the risk of bleeding. Otherwise, this may lead to controversial results. Indeed, Pesavento et al showed that, in a cohort of 324 patients showed that (sub)therapeutic doses of anticoagulants, when compared to standard prophylactic ones, are related to a major risk of bleeding (HR 3.89; 95%CI, 1.90 to 7.97) despite no beneficial effect on overall mortality.
In our study, we report, for the first time, that the benefit from anticoagulation therapy was more evident in subjects with higher hsTnT elevation. The positive effects obtained from the prescription of low molecular weight heparin and particularly in patients with higher hsTnT levels confirm the contribution of systemic coagulopathy to the myocardial injury detected in COVID-19. Moreover, due to the bleeding risk implied with the LMWH treatment, the identification of parameters that enable selection of patients who could receive the greatest benefits from anticoagulation therapies might be crucial to optimize the risk-benefit balance related to this treatment. Our data suggest that a prophylactic dose of low molecular weight heparin during admission might be particularly indicated in patients presenting with mild to moderate elevation of hsTnT levels. If these patients might benefit from the use of higher dose thromboprophylaxis than is generally given remains unknown. However, ongoing multicentre, randomized, controlled trials will be able to address this question (NCT04372589, NCT04367831, NCT04345848, and NCT04366960).
Our study has some strengths and limitations. The availability of makers informing on the severity of hypoxia, inflammatory response and coagulation abnormalities provided us with the opportunity to explore their relative importance in causing an increase in the hsTnT level and its association with mortality. In a subset of patients, serial measures of hsTnT, CRP and D-dimer were also available, making it possible, for the first time, to relate changes in hsTnT levels with the fluctuation of the inflammatory and coagulation responses to the disease. The presence of several outcome measurements enabled the assessment of the relative importance of the different pathways explored in the study with multiple complications of patients with COVID-19 infection. However, our study is monocentric, thus the results might be affected by local practice in the management of the COVID-19 infection and not be generalizable to other health care settings. Also, we used only D-dimer and CRP as markers of coagulation abnormalities and inflammation. The health care emergency imposed by the elevated number of SARS-CoV-2 positive patients admitted to the hospital in a short period of time did not provide us the opportunity to obtain a more accurate assessment of the COVID-19-related coagulopathy and inflammatory response. However, previous report have shown that the elevation in the circulating levels of D-dimer is amongst the most typical characteristics of the coagulopathy characterizing the SARS-CoV-2 infection and its assessment is commonly used in clinical practice as a screening tool for the presence of trombo-embolic events in other diseases. Similarly, CRP is commonly used in clinical practice to monitor the severity of the inflammatory response resulting from acute infections and is also considered a good marker to assess the inflammatory-related risk of cardiovascular events . The analysis on the beneficial effects of treatments should be interpreted cautiously, as it was not conducted on randomized groups and might be therefore affected by several measured and unmeasured confounding factors. Furthermore, we were not able to recover clear information on the indication for anticoagulation treatment.
In summary, our data support the hypothesis that the increase of hsTnT levels detected in COVID-19 infection is multifactorial, with inflammation and coagulation responses representing important factors contributing to this clinical manifestation. CRP can be used to monitor inflammation but might not represent the most accurate marker to discriminate between the severity of the respiratory and systemic inflammatory involvement during SARS-CoV-2-related pneumonia. Instead, an elevation of the D-dimer might sign the evolution towards a systemic involvement of the infection, with the development of a coagulopathy that could lead to multiorgan failure. Low molecular weight heparin is, indeed, a promising treatment to counteract the risk of mortality related to systemic COVID-19. Further studies are needed to clearly define the pathogenesis of COVID-19 and provide useful insight for tailored therapies. Troponin, in a context where risk stratification is of primary importance, due to its ability to predict mortality and the relevance of if prognostic capacity even in terms of identification of patients who would benefit more from specific treatments (such as anticoagulation), might play a fundamental role.