Although emerging data suggest that acutely ill patients with COVID-19 have an increased risk for APE, the actual prevalence of APE in this clinical setting is not well known. Most information on the thrombotic complications of COVID-19 derives from studies including critical ill patients admitted to ICUs [8,10-15], and data on severe – not critical – acutely ill subjects are lacking.
In the present study we found that among acutely ill patients admitted to internal medicine department wards with a diagnosis of severe – not critical – COVID-19, in whom a CTPA was performed because of respiratory deterioration after admission, near 20% presented a confirmed APE. The best discriminating cut-off value of D-dimer for predicting APE was approximately 10 fold the standard threshold (2454 ng/mL), showing a trend to be associated with confirmed APE, albeit not statistically significant (RR: 3.21; CI95%: 0.92-13.97; p = 0.073). The values of D-dimer, when the standard and the age adjusted cut-offs were applied, the simplified Wells score, and other laboratory test did not appear to be clinically useful to identify patients with confirmed APE.
Our study aimed to investigate the prevalence of APE specifically performed in acutely ill patients with severe COVID-19 admitted to internal medicine department wards, and some points are worth discussing.
Firstly, the prevalence of APE we found in this clinical setting was markedly high, and similar to the figures found in critical ICU patients. This finding is even more noticeable when considering that most patients were receiving heparin at anticoagulant doses. As mentioned, most data on prevalence of APE and thrombotic events in general, are from COVID-19 ICU critical patients [8,10-15]. COVID- 19 patients admitted to the ICUs of 3 Dutch hospitals, Klok and colleagues found a cumulative incidence of the composite thromboembolic outcome of 31% (CI95%: 20-41%) with APE representing 81% of all these thrombotic complication (n = 25) . The rate of thromboembolic complications, mainly APE, was higher (11.7%) in COVID-19 patients referred to ICU from a French hospital, than that observed in a historical control group of non-COVID-19 ARDS patients (2.1%) . Among patients with severe COVID-19 infection examined with CTPA in another study , 23% [CI95%, 15-33%] presented APE and were more likely to require mechanical ventilation than those without APE. These figures are much higher than the rates of APE observed in non COVID-19 ICU patients with sepsis or shock receiving guideline-recommended thromboprophylaxis [18,19]. In one of the very few studies which describing thromboembolic events in non ICU COVID-19 patients, Mestre-Gomez et al found that 29 out of 91 subjects (31.9%) who underwent CTPA presented APE, after admission to the internal medicine department . Our results confirm the finding of a high incidence of APE in internal medicine department non-critical COVID-19 patients.
Second, the tools currently used in non COVID-19 patients to estimate the pre-test probability of APE as part of the diagnostic workup (Wells score and standard or age adjusted D-dimer values) seem not to be useful for predicting APE in COVID-19 patients. This was also true for other laboratory test, such as arterial blood gas analysis, interleukin- 6, antithrombin III, AST, ALT, LDH, and serum creatinine. Our results suggest that a very high D-dimer cut-off (approximately 10 fold the standard threshold) may be associated to confirmed APE. A recent study reported that a D- dimer threshold of 2660 μg/L detected all subject with APE among hospitalized COVID-19 patients , and in the formerly mentioned study by Mestre-Gomez et al., the best cut-off point was 5000 ug/dL . These cut-off values are much higher than those used to exclude pulmonary embolus in non-ICU patients [22-23]. Even though a diagnostic strategy for APE suspicion based on a single variable (D-dimer) showed evident limitations and guidelines recommend multivariable predicting algorithms , the diagnostic value of a sharp increase of D-dimer as marker of increased risk of APE in COVID-19 patients remains to be establish. Some authors have proposed using age-adjusted D-dimer cut-off levels to rule out venous thromboembolism in COVID-19 patients . Yet, in our study the so adjusted threshold did not show to be clinically useful.
Third, in our study most acutely ill patients admitted to the internal medicine department wards with a diagnosis of COVID-19 and presenting respiratory deterioration after admission, were under treatment with full anticoagulant doses of heparin before performing CTAP. The fact that these patients have certainly been considered at a very high risk of having APE  probably lead physicians to prescribe full anticoagulation instead of prophylaxis with heparin. Interestingly, also in the study by Klok et al  it was described as heparin regimes differed between hospitals and the doses increased over time, presumably reflecting an increasing concern on the risk of developing APE in COVID-19 patients. However, empirical use of anticoagulant doses of heparin may not only be ineffective but deleterious since it has been well established that high-dose LMWH administration may be associated with increased incidence of major and fatal bleeding . In fact, pending the results of randomized clinical trials, in patients without a confirmed diagnosis of APE, most authors recommend thromboprophylaxis with LMWH for non-ICU COVID-19 patients [5,27].
Finally, in COVID-19 patients, given the high prevalence of APE, the unavailability of satisfactory tools for estimating pretest probability and the potential high risk of complications associated with the use of empirical anticoagulation, a low threshold for obtaining CTPA should be strongly recommended. Main contraindications for CTPA are an impaired renal function and hemodynamic instability to undergo the test. Our results show that these conditions are relatively rare among non-ICU COVID-19 patients.
The main limitations of our study are retrospective and monocentric design and small sample size, with large CI95% limiting the precision of estimates and the generalizability of results. Yet, we included all consecutive subjects fulfilling the inclusion criteria, to reduce selection bias. Thus, our study population would represent a real world sample severe COVID-19 patients admitted to internal medicine department wards in whom a CTPA was performed due to respiratory deterioration. Nevertheless, to confirm our findings, larger and multicenter studies are needed.