Venous thromboembolism (VTE), comprising deep vein thrombosis (DVT) and pulmonary embolism (PE), is a common complication in hospitalized patients. Critically ill patients have a particularly high risk of VTE, and reported incidences vary between 1.4 and 15% (1–4). According to current European guidelines, pharmacological VTE prophylaxis in patients admitted to an intensive care unit (ICU) should preferentially be conducted using low molecular weight heparins (LMWH) at a fixed dose (2). LMWH can be monitored using the anti-factor Xa activity (antiXa) assay, but target ranges have thus far only been established for therapeutic anticoagulation (5). In patients receiving LMWH for thromboprophylaxis, antiXa should only be monitored to exclude LMWH accumulation when severe renal insufficiency is present (2). The utility of antiXa in judging the efficacy of LMWH thromboprophylaxis remains controversial, and it is uncertain whether (compared to patients on normal wards) decreased antiXa levels regularly encountered in critically ill patients are associated with an increased risk of VTE (6, 7). Nevertheless, recent studies have suggested lower VTE rates using dose-adjusted thromboprophylactic LMWH regimes targeting arbitrarily defined antiXa thresholds (8, 9). The results of these studies are limited by their small sample sizes, heterogeneous target antiXa thresholds and the uncertainty of whether peak or trough antiXa should be obtained. We thus performed a large retrospective observational study describing antiXa of critically ill patients who received prophylactically dosed enoxaparin. In addition, we assessed the relationship between antiXa and the development of VTE.

We assessed electronic health records of 2,510 eligible patients and included 1,352 patients with a total of 8,231 antiXa in the final analysis (Figure 1). Table 1 presents the baseline patient data.

Nineteen patients (1.4%) developed a total of 22 VTE (seven lower extremity DVT, five upper extremity DVT and ten PE). A detailed description of patients developing VTE is given as Supplementary Material. The median time to diagnosis of VTE after ICU admission was 36 days (4–48). All patients received pharmacological thromboprophylaxis with subcutaneous enoxaparin, which was started at a median of 8 h (6–16) after ICU admission, with a median daily cumulative dose of 4000 IU (4000–4900) on a median of 100% (94–100) of ICU days. We found no differences between patients without thrombosis and patients who developed VTE regarding the duration until the start of pharmacological thromboprophylaxis [8 (6–16) vs. 8 h (6–24), p = 0.61], cumulative daily enoxaparin dose [4000 IU (4000–4400) vs. 4200 IU (4000–5600), p = 0.23] and the proportion of days with pharmacological thromboprophylaxis [100 (94–100) vs. 96% (90–100), p = 0.06].

Overall, the included patients had a median of 2 (1–5) peak, 2 (1–6) 12-h trough and 2 (1–5) 24-h trough antiXa values. The median number of peak antiXa measurements in the respective subgroups (patients without thrombosis and patients with VTE) were 2 (1–5) vs. 1 (1–2; p = 0.31). The median number of 12-h trough values was 2 (1–6) vs. 5 (3–10; p = 0.07) and the median number of 24-h trough values was 2 (1–5) vs. 1 (1–4; p = 0.31). Table 2 shows median, minimum and maximum antiXa at the patient level in comparison between patients without thrombosis and patients with VTE.

In patients developing VTE, the most recent antiXa was obtained at a median of 2.5 days (1–25) prior to diagnosis of VTE. Median peak, 12 h and 24 trough antiXa prior to diagnosis of VTE were 0.27 IU/mL (0.1–0.3), 0.14 IU/mL (0–0.21) and 0 IU/mL (0–0).

Given that patients with VTE had a significantly higher severe acute physiology III (SAPS) score at admission, we performed a subgroup analysis and analyzed the relationship of antiXa with VTE in each of the four SAPS quarters. Median SAPS at admission in the first, second, third and fourth quarters was 35 (29–38), 46 (43–49), 58 (56–62), and 74 (69–81). The number of patients developing VTE in the respective groups was 3 of 317 (0.95%), 2 of 317 (0.63%), 6 of 317 (1.89%), and 8 of 316 (2.53%). For 85 patients, SAPS III at admission was missing and no patients developed VTE in this group. Median antiXa was not different between patients without VTE vs. patients who developed VTE in each of the four SAPS quarters. A detailed table is provided as Supplementary Material.

For this study, we analyzed a large cohort of critically ill patients and described antiXa obtained after prophylactic administration of enoxaparin. We also investigated the possible association between antiXa and the occurrence of VTE. Although 12 and 24-h trough antiXa were below thresholds that have been suggested to indicate effective thromboprophylaxis in previous studies, the incidence of VTE in our patient cohort was remarkably low. We did not identify a difference in peak, 12-h trough or 24-h trough antiXa between patients who did not develop venous thromboembolism and patients with VTE.

Throughout previous studies investigating weight-based or antiXa-guided LMWH dosing, considerable incongruity exists in which antiXa thresholds are regarded as indicating effective thromboprophylaxis. For instance, the combination of peak antiXa > 0.2 IU/mL and trough > 0.1 IU/mL was used in one study (10), whereas only trough levels between 0.1–0.2 IU/mL (9), peak levels > 0.2 IU/mL (8) or peak levels between 0.1–0.3 IU/mL (11), 0.2–0.5 IU/mL (12) or 0.3–0.5 IU/mL (13) were considered as targets by others. According to these studies, the patients included in the present study would have largely been classified as receiving inadequate pharmacological thromboprophylaxis. However, we observed a low VTE rate of 1.4%.

Compared to patients without thromboembolic complications, we found no differences in median, minimum or maximum antiXa in patients who developed VTE. This contrasts recent studies suggesting the measurement of antiXa to guide LMWH dosing for pharmacological thromboprophylaxis (14). The origins of antiXa-guided thromboprophylaxis are largely rooted in a study that found 12-h trough antiXa of at least 0.1 IU/mL to be associated with a significantly reduced VTE rate in non-critically ill patients (15). However, those findings lacked reproducibility in a similar study conducted 10 years later (16). Regarding critically ill patients, a recent systematic review found no association between antiXa and the occurrence of VTE (17). It reported high heterogeneity in-between studies, which may reflect poor study quality. Of the 18 included studies, only Malinoski et al. found an association between antiXa and the occurrence of VTE. The authors investigated 54 critically ill trauma patients and showed that 11 of 27 patients with a 12-h trough antiXa ≤ 0.1 IU/mL developed VTE compared to 3 of 27 patients with a trough antiXa > 0.1 IU/mL (7). The generalizability of these results may, however, be questionable because of the small sample size and routine screening for VTE, which may have inflated the reported VTE incidence. Similarly, Ko et al. who reported a lower VTE rate in critically ill injured patients receiving antiXa-guided thromboprophylaxis, employed routine ultrasound screening for the detection of VTE (9). In addition, the statistical significance of their findings was largely based on the differences in isolated distal DVT. However, our data support the results of various previous studies demonstrating that low antiXa is highly prevalent in critically ill patients but cannot be linked to VTE (18–21).

The low VTE rate of 1.4% found in this study supports recent studies reporting similar incidences (1, 22) but contradicts earlier studies that reported substantially higher rates of VTE in critically ill patients (4, 23). This can be explained by the early initiation of pharmacological thromboprophylaxis after a median duration of 8 h following ICU admission in our patient cohort, which has been shown to reduce VTE incidence (24–26). However, previous studies investigating antiXa-guided dosing of LMWH for thromboprophylaxis have reported delays of up to 7 days after ICU admission until thromboprophylaxis was started (3, 9, 11). In addition, enoxaparin was administered on nearly all days that patients were admitted to an ICU. Avoidance of missing LMWH doses is also known to reduce VTE incidence in critically ill patients (25). Another possible explanation for low VTE rates is that duplex ultrasound screening for DVT is not routinely performed at our institution. This follows current guidelines (2), given that the clinical impact of asymptomatic DVT is unclear (27). We also found that patients who developed VTE were significantly sicker at the time of ICU admission, as reflected by higher severe acute physiology scores and had a longer ICU stay alongside increased mortality. Thus, VTE might not necessarily represent failure of thromboprophylaxis but could rather be a manifestation of prolonged critical illness, as recently suggested (28).

Several limitations hinder the generalizability of our results and highlight the need for well conducted prospective trials. Most importantly, the retrospective nature of our study introduces a relevant risk of bias. Our assessment of the presence or absence of VTE relied on correct documentation by ICU physicians. It is thus possible that documented VTE were not captured by our search strategy or that VTE were not sufficiently documented by healthcare providers, both of which might cause an underestimation of true VTE incidence. Also, we did not assess VTE diagnosed after ICU discharge, which could possibly be dependent on thromboprophylaxis implemented during the ICU stay. As a result, our study is possibly underpowered due to the low VTE rate despite including a large cohort. We also did not conduct a power analysis for this study, but rather included all available patients confirming to inclusion, respectively exclusion criteria. Furthermore, we could not assess potential confounders, such as prior thromboembolic events or malignant disease in the patients’ past medical histories. However, we demonstrated that a low rate of clinical significant VTE can be achieved in the setting of highly effective prophylactic anticoagulation despite antiXa, that was lower than previously suggested “protective” levels.

In summary, we analyzed a cohort of 1,352 critically ill patients who received enoxaparin for pharmacological thromboprophylaxis according to current guidelines and found antiXa trough levels below thresholds often cited as being protective of VTE. Yet, we found a low VTE incidence of 1.4%. Patients who acquired VTE had similar peak and trough antiXa levels compared to those who did not suffer from thromboembolic complications. AntiXa thresholds protective of VTE still need to be determined for critically ill patients receiving prophylactically dosed LMWH.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving human participants were reviewed and approved by Ethics Committee of the Medical University of Vienna. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.

CD and ES conceived and planned the study. CD collected the data, performed the initial data analysis, and drafted the first version of the article. CD and AB performed the final statistical analysis. CD, JG, MW, ES, and AB critically discussed and interpreted the data. JG, MW, AB, and ES critically revised the manuscript. All authors read and approved the final manuscript.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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