Talerico R, Cavallaro C, Iorio M
… +11 more, Capparella MA, Bossi F, Porfidia A, Abe K, Biglietto M, Chistolini A, Holt A, Lahousse L, Pola R, Becattini C, Vedovati MC
BACKGROUND: Direct oral anticoagulants (DOACs) and corticosteroids are frequently co-prescribed in clinical practice. While both drug classes independently increase bleeding risk, the impact of their concurrent use remai...BACKGROUND: Direct oral anticoagulants (DOACs) and corticosteroids are frequently co-prescribed in clinical practice. While both drug classes independently increase bleeding risk, the impact of their concurrent use remains unclear. AIM: To systematically review the literature on bleeding outcomes associated with combined DOAC and corticosteroid use. METHODS: We conducted a systematic review following PRISMA guidelines. PubMed, Web of Science, and Scopus were searched for studies reporting bleeding in patients receiving both DOACs and corticosteroids. Cumulative incidences of any bleeding and major bleeding (MB) were estimated using a random-effects model, and study quality assessed using the Newcastle-Ottawa Scale and the Cochrane RoB2. Subgroup analyses were performed for patients treated for atrial fibrillation (AF) and venous thromboembolism (VTE). RESULTS: Nine studies including 87,209 patients were included. The weighted cumulative incidence of any bleeding was 7.0% (95% CI 3.96-12.01%), and of MB 6.6% (95% CI 6.21-6.97%). Heterogeneity was high for any bleeding in the overall and in the AF populations, likely reflecting differences in patient characteristics, corticosteroid exposure, follow-up duration, and study design, whereas heterogeneity was minimal in the VTE subgroup. Variability in bleeding definitions, limited reporting of corticosteroid dose and duration, and absence of stratification by DOAC type/dose or bleeding site further contributed to differences in observed incidences. CONCLUSIONS: Available evidence suggests a clinically relevant incidence of bleeding among patients receiving concomitant DOAC and corticosteroid therapy. Clinicians should carefully evaluate the risk-benefit profile, monitor patients closely, and consider preventive strategies. Future studies are needed to improve risk characterization in this common clinical scenario. PROSPERO REGISTRATION: CRD420251045710.
BACKGROUND: Cancer-associated thrombosis (CAT) requires balancing recurrent venous thromboembolism (VTE) risk against bleeding from anticoagulation. Most risk scores are not specific for CAT, limiting their accuracy, whi...BACKGROUND: Cancer-associated thrombosis (CAT) requires balancing recurrent venous thromboembolism (VTE) risk against bleeding from anticoagulation. Most risk scores are not specific for CAT, limiting their accuracy, while cancer-specific tools lack robust external validation. OBJECTIVES: This study aimed to externally validate risk scores for predicting bleeding and recurrent VTE within 6 months in patients with CAT receiving anticoagulants. PATIENTS/METHODS: We conducted a retrospective cohort study of 1203 patients with CAT from a hospital registry between 2007 and 2022. Primary outcomes were clinically relevant bleeding (CRB) and recurrent VTE within 6 months. Ten bleeding (B-CAT, CAT-BLEED, ACCP-VTE, HAS-BLED, HEMORR2HAGES, VTE-BLEED, Kuijer, Martinez, Nieto and RIETE) and four recurrence scores (Ottawa, RIETE, HERDOO2, DASH) were assessed. Predictive performance was evaluated using the area under the receiver operating characteristic curve (AUC) for discrimination. For risk stratification analyses, odds ratios (OR) were calculated to assess the association between risk categories and primary outcomes. RESULTS: Among 1203 patients (mean age 63.9 ± 12.7 years; 52.6% male), 65 experienced CRB (5.4%) and 60 developed recurrent VTE (5.0%) within 6 months. Of the bleeding models, only the original three-category B-CAT score showed acceptable discriminative performance (c-statistic 0.70; 95% CI: 0.64-0.75), stratifying patients into low-, intermediate-, and high-risk groups with CRB incidences of 1.6%, 5.8%, and 20.4% (p < 0.001). For recurrent VTE, only the modified DASH score showed modest predictive ability (c-statistic 0.58; 95% CI: 0.52-0.64; p = 0.01), with recurrent VTE rates of 3.3% in the low-risk group and 6.3% in the high-risk group. CONCLUSIONS: In this real-world CAT cohort, the B-CAT score was externally validated as the best predictor of 6-month bleeding risk, while the modified DASH score showed only modest predictive ability for VTE recurrence.
Tao Y, Meng X, Tian H
… +28 more, Li X, Liang R, Chen Y, Chen H, Dong C, Shi Y, Xu X, Wang M, Zhu L, Ji Y, Shi J, Chen H, Cheng Z, Li Y, Deng C, Luo Q, Lu P, Zhang Y, Xi L, Wan J, Miao R, Yang P, Xiong C, Peng L, Wang S, Zhai Z, Wang C, CURES investigators
BACKGROUND: Older patients with pulmonary embolism (PE) are at increased risk of bleeding, which is associated with adverse outcomes, making early risk assessment particularly important. This study evaluated the short-te...BACKGROUND: Older patients with pulmonary embolism (PE) are at increased risk of bleeding, which is associated with adverse outcomes, making early risk assessment particularly important. This study evaluated the short-term performance of commonly used bleeding risk scores in patients aged ≥65 years. METHODS: An analysis was conducted in a multicenter, prospective study of patients aged ≥65 years with PE receiving anticoagulation (NCT02943343, 2016). The performance of the PE-SARD, Kuijer, RIETE, BACS, and ATRIA scores was evaluated using the time-dependent area under the curve (AUC) analysis. Calibration was assessed with calibration plots. Sensitivity, specificity, and positive predictive values were calculated. The primary outcomes were major bleeding (MB) at 7 and 14 days. RESULTS: Among 3661 anticoagulated patients aged ≥65 years with acute PE, MB occurred in 18 (0.5%) and 36 (1.0%) patients at 7 and 14 days, respectively, and clinically relevant non-major bleeding (CRNMB) in 69 (1.9%) and 105 (2.9%) patients. Patients with bleeding events had higher mortality than those without bleeding. Discrimination for short-term MB was low to moderate across scores, with RIETE (AUC 0.76, 95% CI 0.65-0.87) and PE-SARD (AUC 0.74, 95% CI 0.63-0.85) showing the most consistent performance at 7 days. Overall discrimination declined at 14 days. All scores demonstrated limited ability to predict CRNMB, and no model showed a consistent net clinical benefit. CONCLUSIONS: In older patients with PE, bleeding risk scores showed low-to-moderate discrimination for short-term bleeding, with moderate early performance observed only in selected scores. None of the scores reliably identified CRNMB, highlighting the limitations of baseline risk assessment in acute care settings.
Patients with end-stage renal disease face an increased thromboembolic risk but also have heightened susceptibility to bleeding. This dual risk poses a distinct challenge in managing conditions requiring anticoagulation....Patients with end-stage renal disease face an increased thromboembolic risk but also have heightened susceptibility to bleeding. This dual risk poses a distinct challenge in managing conditions requiring anticoagulation. In this article, we summarize the most recent evidence on anticoagulation for patients with end-stage renal disease, focusing on stroke prevention in atrial fibrillation and the management of venous thromboembolic disease, and we highlight practical considerations for clinical decision-making. It remains unclear whether atrial fibrillation confers the same attributable risk of stroke in the end-stage renal disease population compared to the general population. The bleeding risk is also disproportionately high in kidney failure and the relative incidence of hemorrhagic stroke increases as renal function declines. All direct oral anticoagulants are eliminated by the kidneys in varying degrees and appropriate dose adjustment is required. Vitamin K antagonists should not be considered entirely safe and are probably not superior to direct oral anticoagulants for stroke prevention. There is increasing evidence that the risk of bleeding may be higher with vitamin K antagonists, compared with apixaban or rivaroxaban. However, given the relatively low risk of ischemic stroke and the high risk of bleeding, it is reasonable to avoid anticoagulation for stroke prevention for many of these patients. For the treatment of venous thromboembolic disease, parenteral anticoagulation followed by vitamin K antagonists remains the standard of care. Limited data exists with apixaban in this setting. For both indications though, the need remains for larger, randomized trials to guide management of anticoagulation in end-stage renal disease.
BACKGROUND: Sepsis is a leading intensive care units (ICUs) mortality cause; simple biomarkers for early risk stratification are needed, and the prognostic value of platelet to WBC ratio (PWR) in sepsis lacks large multi...BACKGROUND: Sepsis is a leading intensive care units (ICUs) mortality cause; simple biomarkers for early risk stratification are needed, and the prognostic value of platelet to WBC ratio (PWR) in sepsis lacks large multicentre validation. OBJECTIVE: We validated PWR's association with 28-day mortality in ICU sepsis patients via eICU data and explored its incremental value with severity scores. METHODS: This retrospective cohort study utilised the eICU Collaborative Research Database (2014-2015), which contains data from 335 ICUs across 208 US hospitals. Adult patients meeting the Third International Consensus Definitions for Sepsis and Septic Shock criteria were included. The PWR was calculated from laboratory values within 24 h of ICU admission. The primary outcome was 28-day mortality. Multivariable logistic regression and Cox proportional hazards models were employed, adjusting for demographics, comorbidities and severity scores. Platelet to WBC ratio was analysed both as a continuous variable and as a categorical variable based on the optimal cutoff value derived from the Youden index to address non-linearity. RESULTS: Among 18,745 patients with sepsis, 3934 (21.0%) died within 28 days. Non-survivors had significantly lower PWR (median 15.2 vs 22.8, p < 0.001). Using the optimal cutoff of 18.5, patients with low PWR (≤18.5) had significantly higher 28-day mortality than those with high PWR (>18.5) (adjusted odds ratio: 2.18, 95%CI: 1.98-2.40, p < 0.001). The combination of PWR and Acute Physiology and Chronic Health Evaluation (APACHE) IV score significantly improved mortality prediction (area under the curve: 0.812 vs 0.768 for APACHE IV alone, DeLong test: p < 0.001). Subgroup analyses revealed consistent associations across different sepsis aetiologies and comorbidities. CONCLUSION: Lower PWR is associated with increased 28-day mortality in ICU patients with sepsis after adjusting for confounders. This simple, readily available biomarker may aid in early risk stratification and clinical decision-making.
Acute promyelocytic leukaemia is a distinct subset of acute myeloid leukaemia characterised by severe coagulopathy. Overall, patient prognosis is excellent, with outcomes revolutionized by the advent of all-trans retinoi...Acute promyelocytic leukaemia is a distinct subset of acute myeloid leukaemia characterised by severe coagulopathy. Overall, patient prognosis is excellent, with outcomes revolutionized by the advent of all-trans retinoic acid and arsenic trioxide-based regimens. However, despite these advances, early mortality from coagulopathy and severe haemorrhage poses a major challenge, with no clear improvement seen over the past few decades. In this review, we discuss the degree of the problem, the underlying pathogenesis, and attempt to assess bleeding and mortality risk. We consider the role of leukaemia-directed therapy in the management of coagulopathy and discuss current consensus recommendations for transfusion approaches and the evidence underpinning them. We also discuss the potential future role of viscoelastic testing in this field and ongoing key research questions.
Khan S, Jimenez Munarriz B, Hueniken K
… +13 more, Tianzhichao H, Patel D, Stockley T, Tsao M, Zer A, Moskovitz M, Rosenberg Y, Bradbury P, Eng L, Leighl NB, Sacher A, Liu G, Shepherd FA
BACKGROUND: The incidence of pediatric venous thromboembolism (VTE) has been increasing in recent years. Due to the unique hemostatic characteristics of children, thrombi are often difficult to resolve once formed and ma...BACKGROUND: The incidence of pediatric venous thromboembolism (VTE) has been increasing in recent years. Due to the unique hemostatic characteristics of children, thrombi are often difficult to resolve once formed and may result in long-term sequelae. Rivaroxaban has been approved for the treatment of pediatric VTE; however, real-world data on its use in Chinese pediatric populations remain limited. OBJECTIVES: This study aimed to evaluate the effectiveness and long-term safety of rivaroxaban in children with VTE and to provide real-world evidence to support its clinical use. METHODS: This single-center retrospective observational study included children aged >28 days and <18 years who were diagnosed with VTE and received rivaroxaban treatment for at least one month at Beijing Children's Hospital between January 2022 and April 2025. Demographic characteristics, clinical data, and treatment information were collected. Effectiveness outcomes included thrombus resolution and changes in thrombus burden assessed by imaging. Safety outcomes included bleeding events and adverse drug reactions. All patients were followed up for 3 months during treatment, with an additional 3 months of subsequent follow-up. RESULTS: A total of 189 pediatric patients with VTE treated with rivaroxaban were included between January 1, 2022 and April 1, 2025. The median age was 8.6 years, and 53.97% were male. The most common VTE risk factor was pulmonary disease (pneumonia) (58.20%), followed by catheter-related thrombosis (33.33%). At 3-month follow-up, complete thrombus resolution was achieved in 24.34% of patients, partial improvement in 57.67%, and no improvement in 14.29%. Thrombus recurrence occurred in 2.12% of patients, with no fatal VTE or death observed. Univariable logistic regression showed no significant predictors of thrombus recanalization (all P > 0.05). No significant difference in efficacy was found between patients with and without cancer (P = 0.148). For safety, bleeding events were rare and mostly mild (4.79% clinically relevant non-major bleeding), with one discontinuation due to melena and no fatal or intracranial hemorrhage. No significant risk factors for bleeding were identified in univariable analysis. CONCLUSIONS: In this real-world pediatric cohort, rivaroxaban demonstrated favorable effectiveness and an acceptable safety profile, consistent with findings from previous clinical trials. Larger multicenter real-world studies are warranted to further define the clinical value of rivaroxaban in pediatric VTE.
BACKGROUND: Coagulation dysfunction is a major contributor to the increased mortality associated with sepsis (Levi et al., 2013; Gando et al., 2019 [1,2]), in which platelet activation, neutrophil activation, and neutrop...BACKGROUND: Coagulation dysfunction is a major contributor to the increased mortality associated with sepsis (Levi et al., 2013; Gando et al., 2019 [1,2]), in which platelet activation, neutrophil activation, and neutrophil extracellular trap (NET) formation play important roles. Recent studies have suggested that HSP47 is involved in venous thromboembolism and platelet/neutrophil activation (Thienel et al., 2023a [3]); however, whether HSP47 contributes to platelet-mediated NET formation and coagulation dysfunction during sepsis remains unclear. OBJECTIVES: This study aimed to investigate the involvement of heat shock protein 47 (HSP47) in platelet activation, NET formation, and coagulation dysfunction during sepsis, and to evaluate the potential effect of pharmacological modulation of HSP47-associated responses. METHODS: A murine model of sepsis was established using cecal ligation and puncture (CLP), and mice were treated with Col003, a functional inhibitor of HSP47-associated responses. Platelet HSP47 signal, histopathological injury, coagulation parameters, platelet activation, granule release, platelet-leukocyte aggregate formation, and NET formation were assessed. Seven-day survival was monitored in the main CLP intervention experiment, and 48 h short-term survival was assessed in the Col003 timing experiment. Additional in vitro experiments using bone marrow-derived neutrophils were performed to explore the involvement of the TLR2-MyD88 pathway in HSP47-associated NET formation. RESULTS: CLP induced an increase in platelet HSP47 signal, coagulation abnormalities, inflammatory cytokine production, platelet activation, platelet granule release, platelet-leukocyte aggregate formation, and NET formation. Col003 treatment attenuated these CLP-associated changes and improved 7-day survival. In the timing experiment, early administration 3 h before CLP showed the most pronounced effects on platelet HSP47 signal, CitH3 expression, and 48 h survival. In platelet-neutrophil co-culture experiments, platelets from CLP mice promoted NET formation, whereas platelets from Col003-treated CLP mice showed a reduced NET-inducing capacity. In vitro pathway-validation experiments further showed that recombinant mouse HSP47 increased TLR2, MyD88, and CitH3 expression in bone marrow-derived neutrophils, while inhibition of TLR2 or MyD88 reduced HSP47-induced CitH3 expression. CONCLUSIONS: These findings suggest that HSP47-associated responses are involved in sepsis-associated coagulation dysfunction and are linked to platelet activation and NET formation. Early Col003 intervention attenuated CLP-induced pathological changes, supporting HSP47-associated pathways as potential targets for further investigation in sepsis-associated coagulopathy. Further studies are needed to determine whether delayed Col003 administration remains effective after sepsis has been established.
BACKGROUND: Deep vein thrombosis (DVT) is a common venous thrombotic disease associated with substantial morbidity and mortality. Its onset and progression are closely related to coagulation abnormalities and are also pr...BACKGROUND: Deep vein thrombosis (DVT) is a common venous thrombotic disease associated with substantial morbidity and mortality. Its onset and progression are closely related to coagulation abnormalities and are also profoundly influenced by inflammatory responses and immune regulatory networks. However, the molecular mechanisms underlying DVT in the context of systemic inflammation, particularly the key processes driven by coordinated immune-metabolic interactions, remain to be elucidated. METHODS: Twenty clinical parameters were integrated to systematically characterize patients with DVT. Whole-transcriptome sequencing of peripheral blood samples was performed to profile differentially expressed mRNAs, lncRNAs, miRNAs, and circRNAs. Core diagnostic markers were identified using an integrated machine learning strategy combining random forest, LASSO, and SVM-RFE. Single-sample gene set enrichment analysis (ssGSEA) was used to deconvolute immune microenvironment features, and quantitative metabolic pathway analysis was performed to explore the metabolic basis of neutrophil functional polarization. Finally, an independent external validation cohort (GSE48000) was used to evaluate the robustness of the key mechanisms and their potential value in recurrence risk stratification. RESULTS: Clinical analysis showed that D-dimer levels were significantly elevated in patients with DVT, and that the systemic inflammatory indices AISI and NLR were also increased, indicating an inflammatory phenotype characterized by enhanced myeloid stress and relative lymphocyte suppression. Whole-transcriptome sequencing identified a candidate biomarker panel centered on F7, MTRNR2L10, and SYT16, and the resulting diagnostic model showed excellent discriminatory ability. Immune deconvolution further identified Neu_NETotic_Hub as a key pathogenic subgroup in DVT, which was significantly enriched in the DVT group and closely associated with high expression of the core driver gene PADI4. Metabolic analysis showed that neutrophils in the DVT state exhibited marked lipid metabolic reprogramming and enhanced reactive oxygen species (ROS) generation, both of which were strongly positively correlated with the NETotic score (r > 0.8), suggesting that they may constitute an important metabolic basis for immunothrombosis. External validation showed that both the lipid metabolic score and the NETs-related score increased stepwise with recurrence risk grade, and that a combined model based on these two metrics showed good discriminatory ability for identifying high-risk recurrence states AUC =0.825. CONCLUSION: This study revealed an immune-metabolic coupling axis in which lipid metabolic reprogramming drives neutrophils toward a pathogenic NETotic phenotype, suggesting that this axis may represent an important mechanism promoting the onset, progression, and recurrence risk of DVT. These findings not only deepen our understanding of the biological basis of immunothrombosis in DVT, but also provide a theoretical foundation for early diagnosis, recurrence risk stratification, and targeted interventions aimed at neutrophil immunometabolism.
INTRODUCTION: Perioperative heparin bridging in surgical mechanical heart valve (MHV) patients aims to prevent thromboembolism but risks bleeding. Addressing a lack of comparative data, this study synthesizes current lit...INTRODUCTION: Perioperative heparin bridging in surgical mechanical heart valve (MHV) patients aims to prevent thromboembolism but risks bleeding. Addressing a lack of comparative data, this study synthesizes current literature to evaluate the net clinical outcomes of bridging versus no bridging. PURPOSE: To perform a meta-analysis providing clinically actionable estimates of the benefits and risks of perioperative bridging in surgical MHV patients. METHODS: We systematically searched PubMed, Embase, and the Cochrane Library for studies comparing heparin bridging versus no bridging in surgical MHV patients. We used a Bayesian random-effects meta-analysis to estimate risk ratios (RRs) and 95% credible intervals (95% CrIs). Posterior probabilities were then calculated to assess the treatment benefit or harm. RESULTS: Four studies comprising 1847 patients (64.48% bridged) met the inclusion criteria. The estimated RR for thromboembolism was 1.36 (95% CrI, 0.27 to 6.97), with only a 35.1% posterior probability of risk reduction (RR ≤ 1), suggesting no clear benefit. All-cause mortality estimates were uncertain (RR, 0.68; 95% CrI, 0.12 to 3.90). Conversely, safety endpoints yielded high probabilities of hemorrhagic complications. The RR for major bleeding was 2.04 (95% CrI, 0.81 to 5.14), carrying an 82.5% probability of clinically meaningful harm (RR > 1.33). Minor bleeding showed a similar pattern (RR, 1.53; 95% CrI, 0.61 to 3.93). CONCLUSIONS: Routine perioperative heparin bridging in surgical MHV patients increases bleeding risk without meaningful thromboembolic benefit, supporting a shift toward selective, risk-adapted management. REGISTRATION: PROSPERO identifier no. CRD420261359162.
Velasco-Rodríguez D, Revilla N, Mahíllo-Fernández I
… +8 more, Vega-Romero E, Ortega-Carriedo J, Laso RV, Martínez-Alfonzo I, Salvatierra G, Yuste M, Beltrán P, Llamas-Sillero P
BACKGROUND: Prolonged activated partial thromboplastin time (APTT) is a common laboratory finding that frequently triggers extensive diagnostic testing and may delay clinical decision-making, particularly in the preopera...BACKGROUND: Prolonged activated partial thromboplastin time (APTT) is a common laboratory finding that frequently triggers extensive diagnostic testing and may delay clinical decision-making, particularly in the preoperative setting. However, many patients have no clinically relevant bleeding disorder. Clot waveform analysis (CWA), generated during routine APTT testing, provides dynamic information on coagulation but remains underused in prolonged APTT. OBJECTIVES: To develop and temporally validate a CWA-based algorithm to assist in the evaluation of prolonged APTT. METHODS: In a multicenter cohort with prolonged APTT and normal prothrombin time, qualitative and quantitative CWA features were extracted. Two logistic regression models were developed: APTTO1 to identify patients unlikely to have etiological findings, and APTTO2 to differentiate lupus anticoagulant (LA) from intrinsic pathway factor deficiency or von Willebrand disease (VWD) among higher-risk cases. Discrimination, calibration, and decision-curve analysis (DCA) were evaluated using a temporally independent cohort. RESULTS: APTTO1 demonstrated good discrimination (AUC 0.88) and calibration, providing 99.5% sensitivity and 95.2% negative predictive value (NPV) at a prespecified threshold. APTTO2 showed good discrimination for differentiating LA from factor deficiency or VWD (AUC 0.86 after recalibration). DCA demonstrated net clinical benefit of both models over investigate-all and investigate-none strategies. The two-step APTTO algorithm reduced the proportion of patients requiring etiologic testing while maintaining a high NPV, supporting its potential to streamline diagnostic pathways. CONCLUSIONS: APTTO is a pragmatic, CWA-based, two-step algorithm that demonstrated robust performance for the evaluation of prolonged APTT and may support more efficient diagnostic triage. Prospective external validation is required before clinical implementation.
BACKGROUND: Older adults treated with anticoagulants for atrial fibrillation (AF) or venous thromboembolism (VTE) face heightened bleeding risk, which can affect physical, emotional and social wellbeing and function. Exi...BACKGROUND: Older adults treated with anticoagulants for atrial fibrillation (AF) or venous thromboembolism (VTE) face heightened bleeding risk, which can affect physical, emotional and social wellbeing and function. Existing instruments assess treatment satisfaction or generic quality of life but do not capture the specific impact of bleeding in this population. The goal of this study was to psychometrically validate HELIX (HEmorrhage Life Impact indeX), a novel patient-reported outcome (PRO) measure of bleeding-related quality of life in older adults on anticoagulation. METHODS: We enrolled adults aged ≥65 years with AF or VTE on oral anticoagulants. Psychometric testing of the previously derived, 19-item HELIX PRO included exploratory factor analysis, internal consistency (Cronbach's α), floor and ceiling effects, construct validity (correlations with PROMIS short forms), test-retest reliability (intraclass correlation coefficients), and responsiveness. RESULTS: Ninety-five participants (mean age 75, 45% women, 87% White; 66% AF, 33% VTE) participated. Factor analysis identified two subscales: bleeding symptoms (6 items) and quality of life (13 items). Internal consistency was high overall (α = 0.91), excellent for quality of life (α = 0.95), and acceptable for bleeding symptoms (α = 0.61). HELIX scores showed no floor or ceiling effects and demonstrated expected convergent and divergent validity with PROMIS measures. Test-retest reliability was good-to-excellent for most items. Responsiveness analysis suggested HELIX was more sensitive to within-person change than PROMIS. CONCLUSION: HELIX demonstrated strong initial psychometric performance as a bleeding-related quality of life instrument for older adults taking anticoagulants. It complements existing measures and warrants further validation in larger and more diverse populations to evaluate clinical utility and prognostic value.
BACKGROUND: Massive blood loss during surgery or trauma leads to dilutional coagulopathy. While fibrinogen is typically the first factor to reach critical levels, factor XIII (FXIII) also decreases proportionally, furthe...BACKGROUND: Massive blood loss during surgery or trauma leads to dilutional coagulopathy. While fibrinogen is typically the first factor to reach critical levels, factor XIII (FXIII) also decreases proportionally, further impairing clot stability. Routine coagulation tests are insensitive to FXIII, leading to unrecognised deficiency during acute bleeding. This study aimed to define an optimal fibrinogen-to-FXIII replacement ratio to empirically restore adequate haemostasis. METHODS: In an in-vitro haemodilution model using blood from 20 healthy volunteers, we simulated a 70% loss of circulating blood volume. Five incremental combinations of fibrinogen (0-200 mg/kg) and FXIII (0-50 IU/kg) were tested. Coagulation status was analyzed via standard laboratory parameters, viscoelastic testing and confocal microscopy. RESULTS: Haemodilution reduced fibrinogen from a median of 294 to 73 mg/dL and FXIII activity from a median of 130 to 31%. Fibrinogen monotherapy at 50 mg/kg restored fibrinogen target levels (≥ 150 mg/dL) but failed to reach FXIII targets (>60%). The lowest combination of fibrinogen and FXIII to achieve both therapeutic goals was 50 mg/kg and 25 IU/kg, respectively. FXIII demonstrated a strong synergistic effect on clot firmness (FIBtest MCF); when combined with 25 IU/kg FXIII, half the fibrinogen dose was needed to reach functional thresholds. Confocal imaging showed best interconnected fibrin networks with combined therapy. CONCLUSION: Our data indicate that a fibrinogen-to-FXIII replacement ratio of approximately 2:1 (mg/kg to IU/kg) effectively restores clot stability in dilutional coagulopathy. This ratio may provide a practical framework for empirical therapy when rapid FXIII assessment is unavailable.
Schellens J, Nagy M, Hulshof AM
… +14 more, van Rosmalen F, van Oerle R, van Herpt TTW, Alnima T, Mulder MMG, Hellenbrand D, Ten Cate H, Driessen RGH, Sels JEM, van der Horst ICC, Henskens YMC, van Bussel BCT, Spronk HMH, Dutch Covid and Thrombosis Coalition
BACKGROUND: Critically ill COVID-19 patients exhibit a hypercoagulable and hypofibrinolytic phenotype, further characterized by a prolonged clotting time in rotational thromboelastometry (ROTEM) measurements. We investig...BACKGROUND: Critically ill COVID-19 patients exhibit a hypercoagulable and hypofibrinolytic phenotype, further characterized by a prolonged clotting time in rotational thromboelastometry (ROTEM) measurements. We investigated the effects of immunosuppressants on measures of coagulability and fibrinolysis in these patients. PATIENTS/METHODS: In a nested case-control study within the Maastricht Intensive Care COVID cohort (MaastrICCht), three patient groups were age and sex matched: dexamethasone, dexamethasone and tocilizumab, and no anti-inflammatory treatment. Clotting time (CT) was assessed using the ROTEM EXTEM assay. Lysis onset time (LOT) and duration (lysis time (LT)) were assessed using tissue plasminogen activated (tPA)-ROTEM. Biomarkers of inflammation, coagulation, and fibrinolysis were also measured. Linear mixed-effect models compared trajectories of these markers between groups. RESULTS: Out of the full cohort of 324 patients, 36 patients (12 per group) were matched. CT-EXTEM was 23 s 95% CI [-52;5] shorter in dexamethasone and 36 s [-65;-7] shorter in tocilizumab versus no anti-inflammatory treatment group. LT appeared lowest in the week after administering tocilizumab, which effect became less clear over the next two weeks. Compared to no anti-inflammatory treatment, CRP was 235 mg/L 95% CI [-334;-137] lower in the dexamethasone and 318 mg/L [-416;-220] lower in the tocilizumab group, with diminishing effects over time. Plasminogen activator inhibitor 1 (PAI-1) was 3.2 ng/mL [-9.9;3.6] lower in the dexamethasone group and 9.3 ng/mL [-16.2;-2.4] lower in the tocilizumab group, which appeared lowest the week after administering tocilizumab and increased over the next two weeks. CONCLUSIONS: In critically ill COVID-19 patients, anti-inflammatory treatment, particularly tocilizumab, is associated with reduced PAI-1 levels and accelerated clot lysis, indicating alleviated fibrinolysis.
BACKGROUND: Abdominal vein thrombosis (AVT) is an uncommon manifestation of venous thromboembolism (VTE). Data pertaining to management and the clinical course of AVT are limited. OBJECTIVES: To investigate anticoagulant...BACKGROUND: Abdominal vein thrombosis (AVT) is an uncommon manifestation of venous thromboembolism (VTE). Data pertaining to management and the clinical course of AVT are limited. OBJECTIVES: To investigate anticoagulant treatment strategies, bleeding complications, recurrence, and all-cause mortality among patients with AVT. METHODS: From January 2005 to December 2024, 241 patients with objectively confirmed isolated AVT were identified from The Venous Thrombosis Registry in ØstfOLd HospitaL (TROLL), Norway. Bleeding events were categorized as major bleeding (MB) or clinically relevant non-major bleeding (CRNMB) during anticoagulant treatment, and recurrent events were assessed after anticoagulant treatment discontinuation. Cumulative incidences of bleeding and recurrent events were estimated using the Fine-Gray subdistribution hazard model, accounting for the competing risk of death. RESULTS: Among 241 patients, 117 (48.6%) were women, median age was 61 (IQR: 49-71), and 86 (35.7%) had solid cancer. The portal vein was most frequently affected (n = 93, 38.6%), and 14 (5.8%) had liver cirrhosis. Overall, 237 (98.3%) received anticoagulant treatment; 150 (63.3%) with direct oral anticoagulants (DOACs) and 75 (31.7%) with low-molecular weight heparins (LMWHs). The 6-month cumulative incidence of MB was 3.4% (95% CI: 1.6-6.3) and of CRNMB 6.7% (95% CI: 3.8-10.3). Seven of 8 MB and eight of 15 CRNMB events occurred with LMWH treatment. The 5-year cumulative incidence of VTE recurrence after anticoagulant discontinuation was 9.6% (95% CI, 4.6-16.8). CONCLUSION: Most patients were treated with DOACs. The incidence of MB and CRNMB was low. While the overall recurrence rate was also low, the upper-bound of CI indicates a non-negligible risk.