Cancer patients have an eleven-fold increased risk of venous thromboembolism (VTE) compared to the general population. In this hypothesis-generating study we investigated plasma protein levels in colorectal cancer patien...Cancer patients have an eleven-fold increased risk of venous thromboembolism (VTE) compared to the general population. In this hypothesis-generating study we investigated plasma protein levels in colorectal cancer patients with and without thrombosis using targeted absolute quantification of 269 plasma proteins. We included samples from 142 patients with stage III/IV colorectal cancer from MICA - a multinational prospective cohort study, and from 98 patients from CATS - a prospective cohort study with stage III/IV colorectal cancer. The primary outcome was objectively confirmed symptomatic or incidental deep vein thrombosis or pulmonary embolism during a 6-month follow-up period. In MICA, 11 (7.7%) developed VTE; in CATS 6 patients (6.1%) developed VTE within 6 months, and 10 (10.2%) within 2 years. Six differentially abundant proteins (DAPs) were identified in MICA: APOB100, CD5L, IGHG1, IGHM, PRG4, and TF. A model using these six proteins achieved a c-statistic of 0.687 (95% CI: 0.658-0.717) by internal cross-validation with 100 repeats and random 80% training sets. The optimism-corrected c-statistics was 0.675 (95% CI: 0.648-0.701). Using any subset of the DAPs yielded a c-statistics >0.67, with the best model reaching 0.768 (95% CI: 0.746-0.790). This outperformed the Khorana, modified-Vienna, PROTECHT, and CONKO models. The six DAPs had also predictive value in CATS with c-statistics at 0.70 (95% CI:0.671-0.728) for the 6-month, and 0.73 (95% CI:0.702-0.728) for 2-year follow-up. Two proteins showed inverted patterns between cohorts, likely due to chemotherapy. Our findings call for further investigation into the proteins identified, warranting further validation in larger, standardized studies.
BACKGROUND: Despite available observational data and post hoc analyses, the underprescription of DOACs in frail older adults and their underrepresentation in randomized trials have resulted in a still limited evidence ba...BACKGROUND: Despite available observational data and post hoc analyses, the underprescription of DOACs in frail older adults and their underrepresentation in randomized trials have resulted in a still limited evidence base. OBJECTIVE: To evaluate the safety of edoxaban in frail older patients in routine clinical practice in Spain. MATERIALS AND METHODS: EDO-FRAG-001 was a multicenter, prospective, observational, real-world, single-cohort study with 12 months of follow-up. Patients aged ≥75 years with non-valvular atrial fibrillation (NVAF), a FRAIL scale score between 3 and 5, and those who initiated edoxaban within the previous 6 months were enrolled. RESULTS: A total of 411 patients (63% women) were included, with a median age of 87 years. Fifty-five percent had previously received vitamin K antagonists. Edoxaban was prescribed according to the drug label in 89.1% of patients. During follow-up, 31 patients experienced major bleeding events [annualized rate: 8.7% (95% CI: 5.8-11.6)], and 5 individuals developed an ischemic stroke or systemic embolism [1.1% (95% CI: 0.1-2.2)]. One-year all-cause mortality was 18.8% (95% CI: 15.1-22.5), and cardiovascular mortality accounted for 8.7% (95% CI: 6.2-11.2). The incidence of bleeding-related death was 2.0% (95% CI: 0.5-3.5). CONCLUSION: This real-world study supports that the use of edoxaban in frail older adults with NVAF is associated with an acceptable rate of bleeding and stroke. Age and frailty alone should not preclude anticoagulation when treatment is carefully individualized.
BACKGROUND: Data on patients' adherence and satisfaction with prophylactic low molecular weight heparin (LMWH) after orthopaedic trauma surgery are lacking. OBJECTIVES: This observational prospective cohort study aimed t...BACKGROUND: Data on patients' adherence and satisfaction with prophylactic low molecular weight heparin (LMWH) after orthopaedic trauma surgery are lacking. OBJECTIVES: This observational prospective cohort study aimed to investigate adherence and satisfaction with subcutaneous self-administration of LMWH as postoperative thromboprophylaxis in orthopaedic trauma patients. PATIENTS/METHODS: One hundred adult patients who were prescribed ≥4 weeks of prophylactic LMWH after unplanned fracture surgery were included. After completing four weeks of LMWH, all patients received a questionnaire on administration adherence (Morisky Medication Adherence Scale 4-item; MMAS-4) and satisfaction (Anti-Clot Treatment Scale; ACTS) with LMWH, pain medication use and adverse effects of subcutaneous self-administration of LMWH at the injection site. RESULTS: Fifty-four patients reported high adherence with the administration of the prescribed LMWH (MMAS-4 score of 4), 29 patients reported moderate adherence (MMAS-4 score of 2-3) and 17 reported low adherence (MMAS-4 score of 0-1). The 46 patients with moderate/low adherence had a higher risk of adverse events at the injection site than the 54 patients with high adherence (bruising: OR2.81, 95% CI: 0.99-7.93); pain: OR8.27, 95% CI: 3.36-20.39); swelling: OR 3.58, 95% CI:1.32-9.73); minor bleeding: OR 4.27, 95% CI:1.50-12.11) and were less satisfied with their treatment (mean difference ACTS Benefits scale score: 2.0, 95% CI: 0.9-3.2; p < 0.001; mean difference ACTS Burdens scale score: 7.9, 95% CI: 5.3-10.5; p < 0.001). CONCLUSION: Nearly half of the patients reported moderate or low adherence with prophylactic LMWH after orthopaedic trauma surgery. As adherence may influence prophylactic effectiveness and increase postoperative venous thromboembolism risk, further investigations into more user-friendly alternatives are an unmet need.
INTRODUCTION: Inflammation and coagulation are closely interrelated process in the pathogenesis of sepsis. In this study, we investigated whether intravenous IgM-enriched immunoglobulin (IgM-IVIG) preparation could impro...INTRODUCTION: Inflammation and coagulation are closely interrelated process in the pathogenesis of sepsis. In this study, we investigated whether intravenous IgM-enriched immunoglobulin (IgM-IVIG) preparation could improve hemostatic abnormalities in a fulminant sepsis model. MATERIALS AND METHODS: Live Escherichia coli (E.coli) bacteria were administered to pigs with simultaneously (E. coli + Ig) or delayed (E. coli post Ig) of IgM-IVIG while control pigs received only physiological saline. Prothrombin time, activated partial thromboplastin time (APTT) and fibrinogen were measured by coagulometry. Hematologic parameters and soluble P-selectin were also measured. Furthermore, thrombin generation assay was carried out by fluorimetry and results were evaluated by the Thrombinoscope software. RESULTS: In septic pigs continous increase of fibrinogen levels and significant prolongation of APTT were observed. However, IgM-IVIG treatment significantly decreased fibrinogen levels and shortened the APTT after E. coli administration. In addition, in thrombin generation assay (TGA), that was performed without any exogenous coagulation trigger a significant increase of endogenous thrombin potential (ETP) and peak thrombin were observed in the E. coli-administered group which were abolished by IgM-IVIG treatment. Furthermore, in another TGA using phospholipid and tissue factor triggers, a significant decrease of ETP and thrombin peak were detected in septic-group, however IgM-IVIG treatment prevented the effect of E. coli. Increased level of soluble P-selectin was measured in E. coli-administered group, but it was attenuted by simultaneously administered IgM-IVIG treatment. CONCLUSIONS: We conclude that IgM-IVIG attenuates sepsis-induced hemostatic abnormalities, and the effect of simultaneously administered IgM-IVIG was more pronounced.
BACKGROUND: Despite evidence-based guidelines, venous thromboembolism (VTE) prevention in ambulatory cancer remains low. The "Vermont Model" is a multidisciplinary program wherein oncology nurses conduct VTE risk assessm...BACKGROUND: Despite evidence-based guidelines, venous thromboembolism (VTE) prevention in ambulatory cancer remains low. The "Vermont Model" is a multidisciplinary program wherein oncology nurses conduct VTE risk assessment, VTE patient-education to all patients starting anti-cancer therapy and refer high risk patients to thrombosis specialist to discuss thromboprophylaxis. The Vermont Model successfully improved targeted anticoagulation prophylaxis for high-risk patients, but efforts to reproduce the model in community oncology practices were less successful. The objective of this study was to evaluate stakeholder (clinician and patient) perceptions of the Vermont Model to inform adaptation to a fully oncology-delivered approach. METHODS: We conducted a concurrent multi-method study from September 2024-January 2025, including a clinician survey assessing normalizing of the Vermont Model into clinical practice and semi-structured interviews of participating clinicians and patients. RESULTS: Ten clinicians and four patients completed interviews. Based on 9 clinician surveys, the Vermont Model is normalized into practice. Factors important to its success reflected in both the survey and interviews data included a strong culture valuing VTE prevention and a local champion. Participants supported a fully oncology-delivered model, yet challenges to success include lapses in intervention education/training, communication among health care team, and relative priority with existing workload. CONCLUSION: We found high normalization of the Vermont Model among participating clinicians and highlight opportunities to enhance training, education, and interprofessional communication to scale out to a fully oncology-delivered model.
BACKGROUND: Post thrombotic syndrome is a fibrotic disease related to inflammation resolution. There are no direct therapies that can ameliorate this disease. Monocyte/macrophages (Mo/MØ) are the primary leukocyte involv...BACKGROUND: Post thrombotic syndrome is a fibrotic disease related to inflammation resolution. There are no direct therapies that can ameliorate this disease. Monocyte/macrophages (Mo/MØ) are the primary leukocyte involved with later venous resolution, and likely direct vein wall responses and healing. Herein, we explored the vein wall response with Mo/MØ depletion by two methods. METHODS: Using two mouse models of venous thrombosis (VT), complete stasis and a flow restricted model, Mo/MØ depletion was accomplished using CD11b-DTR mice administered diphtheria toxin, and clodronate micelle administration in wild type mice. Tissue assays for structural histology, immunohistochemistry and western blotting were performed. RESULTS: Mo/MØ depletion resulted in significantly less vein wall fibrotic thickness, in the stasis model at day 14 in both the CD11b-DTR mice and those receiving clodronate micelles. No significant effect of Mo/MØ depletion was observed in the flow restricted VT model. The decrease in vein wall fibrosis was associated with fewer DDR2+ vein wall cells in the CD11b-DTR mice, but no difference in endothelial luminal coverage. Decreased cytokine and growth factor expression of IL-6, FSP-1, and VEGFa were associated with Mo/MØ depletion. Lastly, PMN depletion was associated with increased proinflammatory Mo/MØ, and a trend towards increased vein wall fibrosis as compared with controls. CONCLUSION: Mo/MØ direct the post VT late fibrotic response, possibly by affecting fibroblasts and inflammatory cytokine expression. This effect was only found with the complete stasis model and is consistent with worsened PTS in humans with complete venous obstruction.
BACKGROUND: Pediatric pulmonary embolism (PE) incidence has shown a steady rise in recent years, underscoring a distinct and evolving etiological landscape. Infection-related PE, notably Mycoplasma pneumoniae (MPP), now...BACKGROUND: Pediatric pulmonary embolism (PE) incidence has shown a steady rise in recent years, underscoring a distinct and evolving etiological landscape. Infection-related PE, notably Mycoplasma pneumoniae (MPP), now accounts for an increasing proportion of pediatric PE cases, raising questions about a distinct in-situ thrombosis (ISPAT) pathophysiology. We aimed to systematically characterize the etiological spectrum of childhood PE and identify independent predictors of severe disease. METHODS: We conducted a 6-year retrospective cohort study of 113 pediatric PE pediatric patients diagnosed with PE at Department No.2 of Respiratory Medicine, Beijing Children's Hospital, from June 2018 to June 2024. Data included clinical and imaging findings, underlying conditions, and outcomes. Predictors of severe PE were assessed using multivariable logistic regression. RESULTS: The median age was 8.37 years. Infection was the leading etiology (89.4%), most commonly MPP (88.1%). Computed tomography pulmonary angiography (CTPA) revealed emboli were predominantly subsegmental/peripheral (80.5%), supporting the ISPAT phenotype. Post-infectious pulmonary vasculitis was identified in 8 patients, with NOD2, MPEG1, or CYBB variants detected in 3 cases. On multivariable analysis, infection-associated PE was independently linked to lower odds of severe PE (adjusted OR 0.12, 95% CI 0.03-0.54; p = 0.0055). CONCLUSION: Pediatric PE is predominantly an ISPAT phenomenon driven by MPP-associated immunothrombosis. The distinct thrombotic pattern and better prognosis in the infection group support etiology based risk stratification. Furthermore, the observed links with post-infectious vasculitis and variants in NOD2, MPEG1, or CYBB suggest that occult immune dysregulation may modulate thrombotic risk in susceptible children.
BACKGROUND: In severely injured patients, altered coagulation impairs stable clot formation and increases mortality. Traumatic brain injury (TBI) precipitates alterations in clot formation and breakdown. In this study, w...BACKGROUND: In severely injured patients, altered coagulation impairs stable clot formation and increases mortality. Traumatic brain injury (TBI) precipitates alterations in clot formation and breakdown. In this study, we aimed to characterize clotting kinetics, mechanics, fibrin networks, and circulating proteomic markers in TBI patients, and correlate these biomarkers to outcomes. METHODS: Plasma samples were collected from 63 injured patients upon presentation. Clotting kinetics, structure, fibrinolytic markers, thrombin generation, and proteomic profiles were analyzed. Clinical chart review was performed using our institution's trauma registry and medical records. RESULTS: We analyzed coagulation and clinical factors of 34 No-TBI, 29 TBI patients and 7 healthy donors. Demographics were comparable between patient groups. TBI patients had increased mortality and larger perturbations in coagulation mainly in intrinsic coagulation and fibrinolytic function. Upon admission, TBI patients had higher D-dimer, lower factor VIII, and lower von Willebrand factor than No-TBI patients. TBI patients had reduced coagulation factor XIII alpha chain than healthy donors. Subgroup analyses included isolated TBI, polytrauma with TBI, and varying TBI severities. We identified distinct contributions of intracranial and extracranial injury on coagulopathy, thrombin generation and coagulation factor concentrations. Along with this, Severe TBI was associated with increased prehospital fibrinolysis, without an increase in tissue plasminogen activator concentration or fibrinolysis at blood draw. CONCLUSION: TBI patients demonstrated patterns consistent with prehospital fibrinogen consumption and fibrinolysis. Unique differences were observed between the phenotypes of TBI, with severe isolated TBI patients exhibiting lower levels of vWF, Coagulation Factor VIII, Coagulation Factor XIII alpha chain, and PAI-1. These findings highlight the temporal and injury-phenotype contributions to TBI-induced coagulopathy.
PURPOSE: Acquired Factor XIII (FXIII) deficiency is prevalent in hospitalized or surgical patients, with FXIII activity <70% in over 20% of cases. A decrease in FXIII has been linked with postoperative bleeding, anastomo...PURPOSE: Acquired Factor XIII (FXIII) deficiency is prevalent in hospitalized or surgical patients, with FXIII activity <70% in over 20% of cases. A decrease in FXIII has been linked with postoperative bleeding, anastomotic insufficiency, and a greater likelihood of requiring reoperation. This study aims to identify patients at increased risk for postoperative complications by comparing open versus minimally invasive pancreatic and esophageal surgery. METHODS: This prospective, monocentric observational study was conducted at Heidelberg University Hospital (Germany). Inclusion criteria consisted of age ≥ 18 years, the ability to provide informed consent, and scheduled esophageal or pancreatic surgery. A coagulation panel was performed preoperatively, directly after surgery and on postoperative day (POD) 1, 2, 3, 4, 7, 10, and 13, along with repeated thromboelastography (ClotPro®) Tests. RESULTS: Finally, 112 patients were enrolled (n = 77 open and n = 35 minimally invasive). FXIII activity showed a more pronounced decrease in the open surgery group until day 7; in both groups, the lowest FXIII activity occurred between days 4 and 7. There were no significant group differences in readmissions, reoperations, or severe perioperative complications according to the Clavien-Dindo classification. CONCLUSION: Open surgery was associated with a significant decline in FXIII activity, with a nadir estimated to occur between POD 4 and 7. FXIII activity also remained significantly reduced until day 7 after surgery. Viscoelastic testing was not able to detect mild acquired FXIII deficiencies. The extent to which routine testing of FXIII activity should be performed prior to reoperation must be evaluated in further studies. German Clinical Trials Register (DRKS00028547, registration date: April 14, 2022).
BACKGROUND: Cardiac surgery with cardiopulmonary bypass (CPB) requires precise hemostasis management to limit postoperative bleeding. Fibrinogen, platelet count, and pro-coagulant factors guide transfusion decisions, yet...BACKGROUND: Cardiac surgery with cardiopulmonary bypass (CPB) requires precise hemostasis management to limit postoperative bleeding. Fibrinogen, platelet count, and pro-coagulant factors guide transfusion decisions, yet Clauss fibrinogen measurement during CPB is debated, and prothrombin time (PT) cannot be measured accurately due to interference from high-dose heparin. This study investigated whether intraoperative measurements of fibrinogen, prothrombin (FII), factor V (FV), and platelet obtained during CPB could reliably predict post-CPB values. METHODS: We conducted a single-center, prospective observational study involving 73 adult patients undergoing cardiac surgery with CPB. Blood samples were collected before aortic unclamping and five minutes after completion of protamine administration. Fibrinogen (Clauss method), FII, and FV activities were measured using HemosIL reagents on an ACL TOP analyzer. RESULTS: Using appropriate reagents, fibrinogen, FII, and FV were reliably measured during CPB, despite high-dose heparin. Strong correlations were observed between intra-CPB and post-CPB values for fibrinogen (r = 0.81), FII (r = 0.78), and FV (r = 0.73), supporting their reliability in anticipating post-bypass coagulation status. ROC curve analyses demonstrated good predictive performance for transfusion-relevant thresholds, with AUCs of 0.93 for platelet count <100 G/L, 0.86 for fibrinogen <1.5 g/L, and 0.84 for FII < 50% activity. CONCLUSIONS: This study showed that fibrinogen and factor II (a surrogate for PT) levels remain consistent between the CPB period and after protamine administration in adult cardiac surgery patients, confirming the reliability of their intraoperative assessment.
INTRODUCTION: Pregnancy is a hypercoagulable state that raises the risk of venous thromboembolism VTE), particularly in women with thrombophilia. D-Dimer levels increase during the activation of the coagulation cascade a...INTRODUCTION: Pregnancy is a hypercoagulable state that raises the risk of venous thromboembolism VTE), particularly in women with thrombophilia. D-Dimer levels increase during the activation of the coagulation cascade and are used to exclude VTE in non-pregnant women. This study aimed to analyze the influence of thrombophilia and the use of low molecular weight heparin (LMWH) on D-dimer levels in pregnant women. METHODS: We retrospectively analyzed data from pregnant women presenting at the hemostaseology outpatient clinic of the University Hospital of Leipzig between July 2016 and June 2023. The women were seen at intervals of four to six weeks and D-dimer concentrations were measured at every visit. RESULTS: A total of 301 women were included in the study, of whom 121 were diagnosed with thrombophilia. The concentration of D-dimer increased continuously throughout pregnancy both in women with and without LMWH. Patients diagnosed with thrombophilia had similar D-Dimer levels compared to women without thrombophilia, irrespective of LMWH administration. Women with heterozygous Factor-V-Leiden mutation who did not receive thromboprophylaxis had higher D-Dimer levels during most of their pregnancy than those without thrombophilia. The initiation of LMWH led to a significant reduction of D-dimers in early pregnancy, and patients started on LMWH prophylaxis early in pregnancy had lower D-dimers later in pregnancy. CONCLUSION: This is one of the largest studies evaluating D-dimer concentrations in women with high-risk pregnancies. Further studies with clinical endpoints are required to evaluate the role of D-dimers in deciding whether to initiate LMWH prophylaxis.
INTRODUCTION: To develop a European shared decision-support tool (SDST), a two-round Delphi process was used to achieve consensus on aspects relating to the antithrombotic therapy (ATT) deprescribing discussions and proc...INTRODUCTION: To develop a European shared decision-support tool (SDST), a two-round Delphi process was used to achieve consensus on aspects relating to the antithrombotic therapy (ATT) deprescribing discussions and process in end-of-life cancer patients. METHODS: Conducted between September 2024 and March 2025, the Delphi survey was developed by a multidisciplinary 24-member steering committee (SC), including medical specialists in oncology, hematology, palliative care, primary care, geriatrics, and vascular medicine. The survey involved 188 experts from these specialties across eight European countries. Consensus was defined with pooled items as ≥70 % agreement with a final decision by the SC. Themes covered deprescribing timing, stakeholders, reassessment and clinical drivers of patients with ATT, SDST, and choice of outcomes for a randomized controlled trial (RCT) to evaluate the SDST. RESULTS: Round 1 reached consensus for seven pooled questions (37 %), especially the reassessment of ATT deprescribing. Considering these results, the SC reformulated round 2 to reduce ambiguity and move toward consensus. The SC made the final decision. Three medical specialties should be involved in ATT deprescribing: palliative care specialists, oncologists, and general practitioners after a triggering circumstance such as clinical triggers or at 3-month prognosis. For the SDST design, the findings confirmed that this tool would be meaningful to clinicians. Eleven predefined outcomes were selected for a future RCT. CONCLUSION: These results succeeded in shaping the content of the future SDST and mapping its useability in palliative care clinical pathways across Europe, with the perspective to support informed decision-making, reduce complications, and improve quality of life in this population.
Most data supporting current knowledge about thrombotic thrombocytopenic purpura (TTP) come from high-income regions, while little is known about treatment access and prognosis in low- and middle-income countries. To add...Most data supporting current knowledge about thrombotic thrombocytopenic purpura (TTP) come from high-income regions, while little is known about treatment access and prognosis in low- and middle-income countries. To address this gap, we conducted a multicenter prospective study that included 85 TTP patients in Brazil between 2018 and 2024, with a 12-month follow-up. The median age was 37 years (IQR 27-45) and 76% were female. The median PLASMIC score was six (IQR 6.0-7.0), and ADAMTS13 activity was tested in 62.4% of patients (all <10%). The median time from symptom onset to hospital admission was 8 days. Neurological manifestations were the most frequent (75.3%), followed by bleeding symptoms (58.8%) and abdominal pain (32.9%). Seventy-four patients (87.1%) underwent therapeutic plasma exchange (TPE), which was initiated within one day of admission (IQR 1-2). Corticosteroids were administered in 95.3% and rituximab in 56.5% of patients. Twenty-three patients (27.1%) required advanced life support and 13 (15.3%) died during hospitalization. In-hospital mortality was associated with older age and hemodynamic instability upon admission. Among survivors, 26% experienced exacerbation or relapse, and 22.4% developed chronic sequelae, mostly neurological and psychiatric symptoms. Rituximab use was protective against TTP relapses. In conclusion, TTP mortality in Brazil is higher than that observed in recent cohorts. TTP diagnosis and treatment in the country are delayed and outdated, negatively affecting disease prognosis. Ensuring rapid diagnosis and the availability of TPE and rituximab, a cost-effective treatment strategy, is essential for improving outcomes and reducing morbidity, including in low- and middle-income countries.