The coronavirus disease 2019 (COVID-19) pandemic is responsible for high intensive care unit (ICU) admission rates and high mortality.1–3 COVID-19 is also associated to a high risk of venous thromboembolism (VTE) and a significant coagulopathy that correlates with disease severity.1,3,4 In this sense, high D-dimer levels, fibrinogen and C-reactive protein (CRP), as well as prolonged prothrombin time (PT), have been associated with increased need of ICU admission and worse outcomes.1,4,5 Previous studies have described a rate of VTE in ICU patients on standard-dose VTE prophylaxis that varies between 7.6% and 69%.2,5,6 Recent studies have suggested a decreased mortality associated with anticoagulant treatment in severe COVID-19.4,7,8 Consequently, the Italian Medicines Agency and some thrombosis Medical Societies recommend the use of intermediate-dose VTE prophylaxis in selected patients with major risk of thrombosis (ICU patients, weight over 80kg or high D-dimer levels).9–11

Remarkably, Al-Samkari and colleagues found that elevated D-dimer levels at admission predicted not only thrombotic complications, critical illness and death, but also bleeding complications.5 Due to these findings, it has been postulated that the elevated D-dimer levels, thrombotic manifestations and bleeding events are related to a coagulation system activation in the setting of severe inflammation and that local thrombi both in the lungs and other organs, rather than emboli from peripheral veins, appear to be the hallmark of severe COVID-19.12 In fact, post-mortem studies have highlighted marked pathological changes involving the lung microvasculature, including disseminated micro-thrombi and significant haemorrhagic necrosis,13 which suggest that the diffuse bilateral pulmonary inflammation observed in COVID-19 is associated with a novel pulmonary-specific vasculopathy termed pulmonary intravascular coagulopathy.1

In consequence, considering that therapeutic doses of heparin are not indicated for treatment of other types of thrombotic microangiopathies, higher than prophylactic doses of heparin may not be more effective preventing VTE and can yield an increased risk of bleeding (especially in critically ill patients who have major thrombosis risk, but also high bleeding risk,14 thereby worsening their prognosis.

Until now, there is a lack of evidence for the risk-benefit of intermediate or therapeutic doses in ICU patients with COVID-19 infection. The aim of this study was to evaluate the rate of thrombosis, bleeding and mortality comparing prophylactic, intermediate and therapeutic doses of anticoagulation in critically ill COVID-19 patients.

The aim of our study was to assess the rates of VTE, bleeding and mortality in critically ill COVID-19 patients and explore if higher doses of anticoagulation (intermediate and therapeutic) can offer a clinical benefit to these patients without increasing the bleeding risk. Our results show that patients receiving intermediate or therapeutic doses of heparin appear to have a higher risk of bleeding without a decrease of VTE events and mortality.

Patients were divided in three groups depending on the maximum anticoagulant doses they received during the hospitalization prior to a VTE confirmed event. Regarding clinical characteristics, patients in the intermediate dose group were most frequently obese, which was previously expected, as in our local protocol patients with>80kg must receive higher anticoagulant doses. Patients of the intermediate and therapeutic anticoagulant group were older than the ones of the prophylactic group. These results may be explained by the fact that older people usually present higher D-dimer levels than young people16 and, in consequence, due to the indication of higher anticoagulant doses when D-dimer levels were>3000ng/ml, older people could have been more susceptible to receive higher doses.

We found an overall VTE rate of 20%, which is consistent with previous data in the literature.2,5,6 PE was the most frequent form of presentation (80%), but it is important to remark that 80% of them were peripheral, which might not have the same clinical relevance as a central PE. When we explored the prevalence of VTE in the different anticoagulant groups, we did not find significant differences. Taking into account a type I error rate of 0.05, an event rate of VTE of 0.20 and a minimum detectable effect of VTE between groups of 0.15, we estimate a probability of type II error of 0.22 in this analysis. These results are very similar to the ones obtained in a recent published meta-analysis that compares the rate of VTE and bleeding with different intensity of anticoagulation17 and are also in consonance with de recent published INSPIRATION Randomized Trial, which compares intermediate dose versus standard dose prophylactic anticoagulation in patients with COVID-19 admitted to the ICU.18

In contrast to numerous reports assessing the high prevalence of VTE, only few studies have reported bleeding rates. These rates vary between 3 and 7.6% using prophylactic doses,5,7 and between 1.9 and 21.4%17,19–21 with higher anticoagulant doses.

Our results show a high bleeding rate (13%), including a high rate of major bleedings (8%), especially in patients receiving therapeutic anticoagulant doses. These results differ from those obtained by Mattioli et al.,19 who described lower rates (1.9% of major bleeding) in a cohort of 105 hospitalized patients with intermediate dose. Nevertheless, it is important to note that while these were not strictly ICU patients, the authors report that 6.7% of the patients needed transfusion of red blood cells, which can signal that the rate of overall haemorrhage was higher. A higher incidence, and more similar to our results, has been reported by Kessler and colleagues,20 who reported 6% of major bleeding in patients with intermediate doses and a 4.6% of fatal bleeding with full anticoagulant doses, which is not insignificant. Pesavento et al.21 also described a higher rate of relevant bleeding events (Hazard ratio [HR] 3.89; 95% CI, 1.9–8) in patients treated with (sub) therapeutic doses of anticoagulants instead of prophylactic doses.

We did not found statistically significant differences in bleeding between the intermediate and the therapeutic anticoagulant group (p=0.06), despite it seems to be clinically relevant (15% vs 31% respectively).

To confirm our results, we performed a multivariable analyses that showed a significant association between the therapeutic anticoagulant doses and bleeding events (OR, 5.93; 95% CI, 1.55–22.7), but not with the intermediate doses, despite it seems to be a clinical impact (OR, 3.1; 95% CI 0.94–10.45). We also found an association between the need of IMV and bleeding, which is consistent with the results obtained with Paranjpe et al.7 who describe higher bleeding rates in intubated patients than in non-intubated patients. This association may be in relation to disease severity. In contrast, we did not find any association between the anticoagulant regimen and VTE events.

We found no differences in mortality rates between groups, contrary to the results obtained by Jonmarker S et al.,8 who described a 67% decreased risk of death the first 28 days among those who received high vs low dose prophylaxis, without a major rate of bleeding. These differences can be partially explained because in our study, we followed patients until hospital discharge (not only the first 28 days), so we registered later bleeding events and mortality related with complications due to large hospitalization period. In contrast, our results are consistent with dose obtained in the INSPIRATION Randomized Trial18 and with those described in a pre-print article based on a recent international multiplatform randomized clinical trial, which concludes that therapeutic anticoagulation did not improve hospital survival in sever Covid-19 patients compared with standard doses.21

According to our results, a significant increase in bleeding rates overall, and especially in patients with intermediate (15%) and therapeutic (31%) anticoagulant doses, should raise awareness of this complication in COVID-19 critically ill patients. This high bleeding rates suggest that the presence of organ failure, coagulopathy and need for invasive interventions may increase the risk of bleeding on their own, and be further aggravated by adding high anticoagulant doses.

Nevertheless, due to the fact that higher anticoagulant doses are probably given to patients that are at highest risk of VTE, the absence of differences of VTE between groups could mean that with higher doses we may be preventing these patients of a VTE event that, otherwise, could have happened. In this sense, when suspected, the confirmation of the VTE events radiologically is important to adequate as soon as possible the anticoagulant dose.

Overall, it seems that intermediate anticoagulant doses may present a better benefit-risk profile in critically ill COVID-19 patients than the prophylactic and therapeutic doses, being able to prevent VTE events with lowest bleeding rates than therapeutic doses.

In this sense, there appears to be a need for large prospective randomized clinical trials to establish the real risk-benefit of higher than prophylactic dose in critically ill COVID-19 patients.

The present study has some limitations and the results must be interpreted with caution. First, this is a retrospective study, so it lacks the rigour of a prospective randomized study. Second, as it was a non-interventional study, treatment strategies were conditioned by the clinical practice. Third, there were fewer patients in the therapeutic anticoagulant dose group than in the prophylactic and intermediate groups (29 versus 94 and 78 respectively), limiting statistical power. Finally, we did not have reliable data on the use of aspirin and were therefore unable to include this variable in the logistic regression analysis.

Our results show a significantly higher risk of bleeding and of major bleedings in patients receiving intermediate and therapeutic anticoagulant doses without a decrease in VTE events and mortality among critically ill COVID-19 patients.

C. Gabara was involved in data collection, data analysis and interpretation and drafting the article.

B. Solarat was involved in data collection and critical revision of the article.

P. Castro was involved in data collection and critical revision of the article.

S. Fernández was involved in data collection and critical revision of the article.

J. Badia was involved in data collection and critical revision of the article.

D. Toapanta was involved in data collection and critical revision of the article.

S. Schulman was involved in critical revision of the article.

J.C. Reverter was involved in data collection and critical revision of the article.

A. Soriano was involved in data collection and critical revision of the article.

J. Moisés was involved in the conception, design of the work, critical revision of the article.

J. Aibar was involved in the conception, design of the work, critical revision of the article.

All authors read, revised and approved the final manuscript.

This work has been funded by Contractes Clínic de Recerca “Emili Letang-Josep Font” 2020 (CG).

The authors do not report conflicts of interest related to this article.