Patients at extremes of body weight are underrepresented in randomized controlled trials of direct-acting oral anticoagulants (DOACs). Therefore, their optimal anticoagulant treatment remains a topic of debate. The aim of this narrative review is to summarize the evidence on the pharmacokinetic and pharmacodynamic profile of DOACs for treating patients at extremes of body weight in venous thromboembolism (VTE) and in the prevention of cardioembolic stroke in nonvalvular atrial fibrillation (NVAF). A literature search was conducted in the main bibliographic databases, and the most relevant reviews and original articles on the topic were selected. Although data in these patient groups are limited, apixaban and rivaroxaban show a favorable pharmacokinetic and pharmacodynamic profile in obese VTE treatment and NVAF patients and, in the case of apixaban, also in underweight patients. In particular, these drugs demonstrated comparable efficacy and safety to standard therapy. Very few data were available for dabigatran and edoxaban; the latter drug was safer at a lower dose, mainly in underweight patients. Our findings are in line with the last International Society of Haemostasis and Thrombosis position paper and European Heart Rhythm Association 2021 practical guide, suggesting the use of apixaban and rivaroxaban in morbidly obese patients (>120 kg or body mass index ≥40 kg/m²) and the reduced dosage of edoxaban in low-weight patients. Future studies should focus on large populations of patients at extremes of body weights to acquire more clinical and pharmacokinetic evidence on all available DOACs, especially those currently less investigated. Received: 28 July 2023 Accepted: 16 October 2023 Article published online: 08 January 2024 © 2024. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/) Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart, Germany

Hepatocellular carcinoma (HCC) is characterized by a complex disruption of hemostatic balance, increasing the risk of both thrombotic and hemorrhagic events. Thrombotic complications, most notably portal vein thrombosis (PVT) and venous thromboembolism (VTE), have a significant impact on clinical outcomes and therapeutic strategies. Cirrhosis contributes to the precarious equilibrium between pro- and anticoagulant forces through impaired synthesis of coagulation factors, endothelial dysfunction, and systemic inflammation. In the presence of HCC tumor-driven mechanisms, such as tissue factor expression, extracellular vesicle release, platelet activation, and suppression of fibrinolysis exacerbate this prothrombotic state. In this scenario, advanced diagnostic tools such as thrombin generation assay (TGA) and rotational thromboelastometry (ROTEM) offer a more accurate assessment of coagulation dynamics than conventional tests, enabling better risk stratification especially for therapeutic purposes. Anticoagulant therapy has demonstrated clinical benefit in selected cases of non-malignant PVT and VTE, particularly when liver function is preserved. While prophylactic strategies are still under investigation, data suggest they may be safely implemented in selected surgical patients. In the setting of immunotherapy, especially regimens involving anti-VEGF agents, anticoagulation may be considered with careful management of bleeding risk due to portal hypertension. An individualized approach to anticoagulation, supported by functional coagulation testing, is gaining acceptance as a means to safely reduce thrombotic burden and potentially improve outcomes in patients with HCC.

It is still uncertain whether direct oral anticoagulants (DOACs) perform better than vitamin K antagonists (VKAs) in subjects with non-valvular atrial fibrillation (NVAF) and advanced chronic kidney disease (CKD). The aim of the study was to compare safety and effectiveness of DOACs and VKAs in patients with NVAF and stage 4 CKD (creatinine clearance 15–29 mL/min). We searched the hospital databases of two academic centers to retrospectively identify patients with stage 4 CKD who were on treatment with DOACs or VKAs for NVAF. Safety was the primary outcome of the study and was assessed in terms of incidence of major bleeding (MB). Secondary outcomes were clinically relevant non-major bleeding (CRNMB) and death for any cause. A total of 176 patients (102 on DOACs and 74 on VKAs) were found and included in the analysis. The incidence rate of MB was not statistically different between groups (8.6 per 100 patients-year in the DOAC group and 5.6 per 100 patients-year in the VKA group). Rates of IS/SSE and CRNMB were statistically similar in the two treatment groups, as well. There were less deaths for any cause in the DOAC group than in the VKA group (8.6 and 15.8 per 100 patients-year, respectively), but the difference was not statistically significant. This study found no difference in terms of safety and effectiveness between patients with NVAF and stage 4 CKD treated with DOACs and VKAs. Larger prospective or randomized studies are needed to confirm these findings.

In cancer-associated venous thromboembolism (CAT), extended anticoagulation should be considered when the risk–benefit profile is favorable. However, optimal predictors of major bleeding (MB) remain unclear. This multicenter observational study included CAT patients treated with direct oral anticoagulants (DOACs). Study objectives were: (i) assess the performance of nine bleeding risk scores (ATRIA, CAT-BLEED, CHAP, DOAC, HAS-BLED, Kuijer, ORBIT, RIETE, VTE-BLEED), (ii) identify predictors of MB (ISTH definition), and (iii) propose an improved bleeding risk model (Perform score). Overall, 823 patients were followed (mean 1.6 years). MB occurred in 44 cases (3.4% per patient-year). The predictive performance of bleeding risk scores was modest (c-statistics range 0.513–0.606). Risk factors included increasing age (HR 1.04, 95% CI 1.00–1.07), use of steroids (HR 2.69, 95% CI 1.34–5.40), antimetabolites (HR 2.51, 95% CI 1.28–4.93), and unresected gastrointestinal cancer (HR 7.30, 95% CI 1.70–31.30). Conversely, prior cancer surgery (HR 0.41, 95% CI 0.20–0.82) and anticancer hormones (HR 0.22, 95% CI 0.05–0.92) showed a possible protective effect toward MB risk. The Perform score provided a slight enhancement in risk prediction (c-statistics 0.678), but remained suboptimal. In this real-world cohort of CAT patients treated with DOACs, unresected gastrointestinal cancer and use of steroids or antimetabolites were associated with increased MB risk, while prior cancer surgery and anticancer hormones were linked to a lower risk. These factors, not considered in current bleeding risk scores, may refine bleeding prediction. Further studies should clarify their role in guiding anticoagulation decisions and improving personalized risk assessment.