Our main findings were as follows: 1) the overall incidence of major bleeding was 2.0% (57/2894), which reached as high as 12.3% in patients with severe COVID-19; 2) the GI tract was the most common bleeding site; 3) the incidence of major bleeding was independently associated with history of major bleeding, COVID-19 severity at admission, and anticoagulant use; 4) the incidence of major bleeding was positively correlated with the accumulated risks; and 5) major bleeding was an independent risk factor for longer duration of hospitalization and higher mortality.
The reported incidence of major bleeding in hospitalized patients with COVID-19 ranges from 0.5 to 11.4% in prior studies (3, 8-14, 25, 26), which varies depending on the COVID-19 severity, anticoagulation drugs, and geographical differences in the availability of medical resources. In our study enrolling consecutive COVID-19 patients with any disease severities, the overall incidence of major bleeding was 2.0%, which was consistent with previous reports. However, the incidence rate increased to 12.3% among patients with severe COVID-19, which is higher than previously reported incidence rates in severe status of COVID-19 (3.0%–10.6%) (3, 8, 10, 14). This indicates a critical need for an attention against bleeding events when managing patients with severe COVID-19. Notably, the incidence of major bleeding is not significantly higher in COVID-19 than in other critical illnesses(3, 27). This is intriguing because thrombotic events, especially pulmonary thromboembolism, have a higher incidence rate among patients with COVID-19 than in those with other acute illnesses (28). This could be attributed to a COVID-19-specific coagulopathy characterized by in-situ formation of immune-thrombosis in the lungs(1). Further research on this is required.
In our study, the most common bleeding site was the GI tract, followed by surgery-related/iatrogenic and intracranial bleeding, which is consistent with previous reports on patients with COVID-19 (27, 29-32) and other patients on anticoagulants (33, 34). This suggests that COVID-19 lacks a disease-specific profile for bleeding sites. Gastric ulcers are the most common cause of GI tract bleeding in patients with COVID-19(35), which suggests that preventive medication, such as proton pump inhibitors, is especially important in COVID-19. This is because diagnostic workup, including endoscopy, is substantially limited given the high transmissibility of the virus. Contrastingly, in our study, intracranial bleeding developed only in a small number of patients (4 cases), which is consistent with previous reports (12, 36). Nevertheless, intracranial bleeding tends to develop in young individuals and can be fatal in patients with COVID-19(37). Therefore, the possibility of intracranial bleeding should be carefully considered when handling patients with COVID-19.
Previous studies reported that risk factors for major bleeding in COVID-19 included high levels of D-dimer and ferritin, COVID-19 severity, and anticoagulant use (8, 9, 15, 29, 31, 36, 38); among these, high-dose anticoagulant administration has been consistently associated with an increased risk of major bleeding. This is consistent with our findings, where patients receiving a therapeutic dose of anticoagulants showed a markedly higher risk for major bleeding compared with those without anticoagulation. These findings demonstrate the importance of an optimal use of anticoagulants in patients with COVID-19. Specifically, the administration of a therapeutic dose of anticoagulants should be carefully considered especially in patients with mild COVID-19 given their low risk of VTE (39). Alternatively, as recommended by Kessler et al., de-escalating the anticoagulant dose may be considered upon the improvement of the COVID-19 severity and reduction of the risk of pulmonary thromboembolism (38).
A recent Spanish study reported an increased bleeding risk among patients with multiple risk factors(8). Further, they proposed a grading system that included intensive care unit stay, D-dimer and ferritin levels, and therapeutic anticoagulation (9). Here, high-risk and very-low-risk patients had a incidence of major bleeding of 15.4% and 1%, respectively. Consistent with these previous reports, we observed that the incidence rate of major bleeding was positively correlated with the accumulated risks. This suggests the importance of evaluating multiple bleeding-related risk factors when handling patients with COVID-19. However, risk factors related to potential bleeding could vary according to disease severity, ethnicity, and geographical areas. Accordingly, further research is warranted to establish a method for an easy and precise estimation of the risk of bleeding in patients with COVID19.
Among patients with COVID-19, those with bleeding events have a higher mortality rate than those without (8, 40-42). Accordingly, we observed that major bleeding was independently associated with higher mortality. Further, patients with major bleeding had a longer duration of hospital stay than those without. Sex, hospital location, and pre-existing kidney or liver disease are factors that affect the hospitalization duration (23, 43); however, it remains unclear how bleeding events affect the duration of hospitalization in patients with COVID-19. Given the considerable impact of the hospitalization duration on the cost and burden to the medical staff and facilities, further research is warranted on the effect of in-hospital events, including bleeding, on the hospitalization duration.
This study has several limitations. First, there was a small number of bleeding events; therefore, we only included a limited number of variables in the multivariable analysis. Second, this was a retrospective observational study, which could result in various biases. For example, the therapeutic decision-making, including pharmacological thromboprophylaxis, was left to the discretion of the attending physicians, which could have affected clinical outcomes such as death and hospitalization duration. Finally, we did not examine blood parameters, including serum ferritin, which are associated with major bleeding(8, 9, 25, 41). However, the 3 risk factors identified in our study (history of major bleeding, COVID-19 severity, and use of anticoagulants) can be readily obtained at the time of hospitalization; therefore, they can be applied easily in clinical practice.
In conclusion, our findings demonstrated that among hospitalized patients with COVID-19, the overall incidence of major bleeding was 2.0 % during hospitalization, but increased up to 12.3% in patients with severe COVID-19. The independent risk factors for major bleeding were a history of major bleeding, COVID-19 severity, and use of anticoagulant. Bleeding events were associated with a longer duration of hospitalization and higher mortality. Accurate recognition of the risk of bleeding, along with that of thromboembolic events, is warranted to optimize the use of anticoagulants and improve outcomes in patients with COVID-19.