Patients in the ICU exhibit a higher risk of DVT compared to general hospital populations. Studies on DVT in critically ill patients have been conducted since the 1980s, but explorations specifically for sepsis are still inadequate^12,13. Current risk stratification tools demonstrate limited clinical utility in sepsis due to non-specific risk categorization and inadequate weighting of critical sepsis-related factors^14,15. Both the Caprini and the Wells scores are initially developed for the evaluation of DVT in the general population, which may not be reliable in septic patients. For instance, the latest update of the Caprini scale assigns only one point to serious infection¹⁶. Septic patients often present with altered mental status or are sedated, posing challenges in accurately evaluating certain clinical signs and symptoms included in the Wells score. Consequently, the risk of DVT in patients with sepsis may be underestimated by existing scales. Besides, international guidelines lack recommendations on DVT risk assessment models for critically ill patients¹⁷. Therefore, no applicable scale exists for evaluating DVT in critically ill patients with sepsis. To address these limitations, the development of a specific assessment tool that incorporates the unique risk factors and pathophysiological markers associated with sepsis is needed.

To our knowledge, this is one of few studies evaluating DVT risk factors specifically in classical sepsis patients after rigorous exclusion of major confounders including trauma, cancer, and pregnancy. In this study, we analyzed data from 1057 patients with sepsis and developed a nomogram for the prediction of DVT. The result showed that the use of intermittent pneumatic compression was a protective factor for DVT. Consistent with our findings, a prospective cohort study conducted in the adult medical-surgical ICU showed that pneumatic compression was associated with a lower risk of VTE, irrespective of concurrent administration of pharmacologic thromboprophylaxis¹⁸. However, mechanical thromboprophylaxis in critically ill patients is still debated¹⁹. A multicenter randomized controlled trial demonstrated that adding pneumatic compression to pharmacologic thromboprophylaxis did not result in a significantly lower incidence of DVT²⁰. Another study by Charlisa D. Gibson also found that there was no added benefit of dual chemical and mechanical prophylaxis compared to chemoprophylaxis alone²¹. A meta-analysis demonstrated that in critically ill adults, low-molecular-weight heparin significantly reduces DVT incidence compared to controls, including a composite of no prophylaxis, placebo, or compression stockings only, while unfractionated heparin and mechanical compression demonstrated potential benefit²². However, despite the appropriate use of pharmacologic thromboprophylaxis, critically ill patients still demonstrated high rates of DVT, which vary from 7.8–37.5%^{5,20,21,23,24,25}. In our study, the proportion of patients receiving pharmacologic thromboprophylaxis in the DVT group was greater than that in the group without DVT, while the subgroup analysis showed no statistical difference in anticoagulant duration or dose between the two groups. Critical knowledge gaps persist regarding the optimal dosing frequency of thromboprophylaxis and therapeutic drug monitoring timing in ICU patients²⁶. We speculated that currently recommended DVT prophylaxis strategies may not be as effective in critically ill populations compared with patients in the general ward, and the current level of anticoagulation for sepsis may be insufficient. However, clinical characteristics vary, and the balance of thrombotic and bleeding risk can change daily among critically ill patients, making it difficult to initiate and determine the dosage of anticoagulation for individual patients.

It should be highlighted that the high incidence of DVT was more than a failure to provide thromboprophylaxis. Rather, this means patients with sepsis frequently develop DVT and clinicians should maintain a high clinical suspicion for DVT in these patients even when appropriate prophylaxis has been used⁵. Flow stasis, endothelial damage, and hypercoagulability often occur contemporarily in critically ill patients with sepsis, so they are more likely to meet Virchow’s triad⁴. Moreover, the dysregulated hemostasis and coagulation in severe sepsis differ from that of non-infectious critical illnesses. Although exact mechanisms remain incompletely understood, sepsis-induced endotheliopathy and associated molecular dysfunction have been well documented. Coagulopathy has been proposed to play a key role through the crosstalk between inflammation and coagulation pathways as a result of the destructive endothelial response of the host²⁷. Inflammation, immunity, and coagulation participate in the systemic endothelial injury altogether, leading to hypercoagulability and impaired fibrinolysis^28,29. This imbalance between procoagulant and anticoagulant pathways not only exacerbates the inflammatory response but also potentiates thrombosis, thereby establishing a self-perpetuating cycle of thrombo-inflammation^30,31.

Our findings revealed that the prolonged use of vasoactive drugs was a significantly independent risk factor for DVT in patients with sepsis. Cook et al. also identified vasopressor use as a risk factor for acquired DVT in the ICU³². Prolonged use of vasoactive drugs often indicates microcirculatory disturbance and endothelial dysfunction, which again suggests the positive associations between endothelium and thrombosis. Besides, we found that the decreased oxygenation index and respiratory infection were associated with DVT. Previous studies have found that hypoxia is associated with the incidence of thrombosis^33,34. A real-world study revealed that patients with respiratory infections were more likely to have pulmonary embolism as initial VTE presentation than other types of infection³⁵. A letter published in Thrombosis Journal refers to hypoxia as a possible cause as well as a consequence of thrombosis in sepsis patients³⁶. Thus, a better understanding of the pathways between endothelial dysfunction and hypoxia in thrombus formation could aid in the development of novel prophylactic therapies against thrombosis. Further, the key to preventing DVT may lie in controlling the pathophysiologic disorders of sepsis.

In addition, age, D-dimer levels, and fibrinogen levels were independently associated with DVT in patients with sepsis. There were no significant differences in the insertion of CVC or PICC, SOFA score, duration of mechanical ventilation, ICU stay, and hospitalization between the two groups, which is similar to previous studies^15,21,37.

The risk assessment tool for DVT and optimal anticoagulation management has not been established in critically ill patients with sepsis. Large, well-designed, randomized control trials specifically studying thromboprophylaxis in patients with severe sepsis and septic shock are necessary to improve the prevention of DVT and advance our understanding and care of these vulnerable patients.

Our study has several strengths. We specifically focused on critically ill patients with sepsis. The potential interference of common risk factors of DVT such as trauma, cancer, and pregnancy were excluded in the selection of the study population. Nevertheless, our study has some limitations. First, the single-center/facility nature and small sample size of our study hinder the generalizability of our findings. Although our study of 1,057 patients surpasses the sample sizes of most sepsis-associated DVT studies conducted in Chinese populations^38,39, this sample size may still be insufficient for robust subgroup analyses, particularly in smaller strata such as antiplatelet therapy recipients. Second, our study did not differentiate between proximal and distal thromboses, which exhibit distinct clinical implications regarding both progression risk and therapeutic management. Furthermore, our nomogram requires external validation in independent cohorts and comparative evaluation against established risk assessment tools. Since the present study was retrospective, patients in ICU were not regularly screened for DVT. The exclusion of patients without venous ultrasound records may have disproportionately removed lower-risk DVT candidates from our study, potentially introducing selection bias. We cannot completely exclude the possibility of DVT that occurred before ICU admission, although we attempted to mitigate this possibility by excluding patients with the presence of DVT or without ultrasound data at baseline. Nevertheless, our study is still important for further understanding of the risk factors for DVT in critically ill patients with sepsis, as well as clinical practice.

Prospective clinical studies across diverse healthcare settings with protocolized ultrasound screening intervals and medication adherence timelines are necessary to clarify baseline thrombosis prevalence and to differentiate proximal or distal DVT outcomes. Multicenter validation of the nomogram against established scores in diverse populations is also needed. While heparin remains the primary treatment of DVT, its efficacy is limited, and superior alternatives are still lacking. Recent research reveals the interplay between immunity and coagulation. Understanding these mechanisms could improve thrombotic risk assessment and anti-inflammatory anticoagulant therapies⁴⁰.