TH open : companion journal to thrombosis and haemostasis最新文献

Background: Recent data on inferior vena cava filter (IVCF) placement mainly originate from the United States, with limited evidence from Europe.

Methods: We used nationwide, patient-level data from 2004 to 2023, including hospitalizations with mention of IVCF placement or venous thromboembolism (VTE). Placement was classified as secondary prevention if VTE was documented during the hospitalization, otherwise as primary prevention. We assessed IVCF placement rates overall and in patients with pulmonary embolism (PE), and studied in-hospital case fatality rates, retrieval rates, and length of hospitalization. Analyses were stratified by prevention type and sex.

Results: IVCF placement was recorded in 5,123 (81.1% secondary prevention) patients. The age-standardized rate of IVCF placement increased from 3.4 (95% confidence interval [CI]: 2.0; 4.8) per 1,000 PE-related hospitalizations in 2004 to 19.2 (95% CI: 16.7; 21.6) per 1,000 PE-related hospitalizations in 2023. The IVCF-related in-hospital case fatality rate increased from 7.1% (95% CI: 1.1; 13.2) in 2004 to 10.2% (95% CI: 7.2; 13.3) in 2023 and was higher after IVCF placement for secondary prevention than for primary prevention. The estimated retrieval rate within an average of 6 months was 31.9% (95% CI: 29.9; 34.0), peaking at 34.6% (95% CI: 32.4; 36.8) after excluding deaths during index hospitalization. The retrieval rate decreased progressively over time. IVCFs were less likely to be retrieved among older patients and in patients with intracranial hemorrhage or cancer, whereas the removal rate was higher among patients with recent trauma.

Conclusion: We showed an increasing trend of IVCF placement procedures. The IVCF retrieval rate decreased over time, emphasizing the need for improved follow-up protocols.

Background: Protein C concentrate (Ceprotin®; Baxalta US Inc., a Takeda company, Cambridge, MA; Takeda Manufacturing Austria AG, Vienna, Austria) is approved for intravenous (IV) use in severe congenital protein C deficiency (SCPCD), with pharmacokinetic (PK)-guided dosing. Subcutaneous (SC) administration may reduce treatment burden, especially for pediatric and neonatal patients; however, the use of SC protein C concentrate has so far been empirical, and PK data are required to support dose optimization.

Objectives: This study aimed to characterize the population PK (PopPK) of SC protein C concentrate in patients with SCPCD.

Methods: A PopPK model was developed for SC protein C concentrate, based on a previously developed model for IV administration. Simulations were conducted across eight three-stage dosing scenarios that patterned the IV dosing regimens in the U.S. product label (initial dose [stage 1]: 60-120 IU/kg; subsequent three doses [stage 2]: 60-80 IU/kg every 6 hours; maintenance dose [stage 3]: 45-120 IU/kg every 12 hours). Additional simulations were performed across six one-stage dosing scenarios that were based on dosing reported in clinical practice (50-60 IU/kg every 12 hours, 200-350 IU/kg every 48 hours). Target maximum ( C _max ) and trough ( C _trough ) concentration levels used as references were 100 IU/dL and 25 IU/dL, respectively.

Results: The dataset included 86 observations from 13 patients with SCPCD receiving SC protein C concentrate. Model-based simulations predicted that, after the first dose, 6-9% and 5-45% of patients in the three- and one-stage dosing scenarios, respectively, would attain C _max >100 IU/dL. At steady state, ≥83% of patients were predicted to attain C _trough >25 IU/dL for all scenarios. In three-stage dosing scenarios, while initial (stage 1 [dose 1]) and subsequent doses (stage 2 [doses 2-4]) determined speed to steady state, exposure at steady state was driven by the maintenance dose (stage 3 [dose 5 onwards]).

Conclusions: The PopPK model was robust and described SC protein C concentrate PK data well. Evidence provided by model-based simulations supports the use of various SC dosing regimens across age groups in acute or prophylactic settings according to the intended protein C activity levels. A high loading dose may be required to rapidly attain target therapeutic concentrations.

Background: Although the European Society of Cardiology (ESC) predicts mortality in acute pulmonary embolism (PE), it may overtriage the level of clinical monitoring needed. The National Early Warning Score (NEWS) is used to triage level of care in many diseases, but it is rarely reported in PE literature.

Methods: In this retrospective, single-center, observational cohort study of consecutive adults with acute PE, between 2017 and 2020, we aim to assess the association between NEWS and the risk of hemodynamic (HD) deterioration or PE-related death in intermediate-high risk PE patients. The NEWS at admission and after 24 hours were determined. A baseline NEWS of ≥5 or the maximum score of a single parameter was considered an indication of high risk of our primary outcome (hemodynamic deterioration and/or PE-related mortality).

Results: ESC classified 99 of 318 patients with PE as intermediate-high risk; 8 patients (8%) met the primary outcome. A total of 52 (52%) patients had an elevated NEWS and 7 of these met the primary outcome (13%), while only 1 patient with a non-elevated NEWS (2.0%) met the primary outcome (negative predictive value of 98%; 95% CI 90-98%). Sensitivity of elevated NEWS in patients with intermediate-high risk was 88% (95% CI 74-90%) and the specificity was 51% (95% CI 41-61%).

Conclusion: Using NEWS in intermediate-high risk, acute PE patients may improve accuracy in identifying patients with a higher risk of adverse outcomes and may guide the decision to monitor a patient in a high-care department, especially in patients with intermediate-high risk PE.

Background: Acute kidney injury (AKI) is common among intensive care unit (ICU) patients and is associated with increased bleeding risk. The impact of fibrinolysis in AKI-related bleeding has not been explored previously.

Objectives: (1) Compare fibrinolytic capacity in ICU patients with and without AKI. (2) Investigate the association between fibrinolytic capacity, as well as other laboratory and clinical variables, and bleeding within the first 7 ICU days in AKI patients.

Methods: Adult ICU patients were prospectively enrolled and stratified by AKI presence and severity at ICU admission. On the morning after admission, fibrinolytic capacity was assessed using a modified rotational thromboelastometry (ROTEM-tPA) assay. The primary outcome was the difference in ROTEM-tPA lysis time on day 1 of ICU admission between AKI and non-AKI patients.

Results: AKI patients ( n  = 160) had more bleedings and higher 30-day mortality than non-AKI patients ( n  = 99). ROTEM-tPA analysis showed progressively impaired fibrinolysis with increasing AKI severity. AKI stage 3 patients ( n  = 53) demonstrated significant impairment across all fibrinolysis parameters compared with non-AKI patients. Among AKI stage 2 to 3 patients ( n  = 106), bleeding patients ( n  = 61) had more pronounced fibrinolytic impairment than non-bleeding patients ( n  = 45). Bleeding risk in AKI stage 2 to 3 was associated with increasing severity of illness (OR: 1.21 (95%CI 1.04-1.42) per 1 point increase in non-renal Sequential Organ Failure Assessment (SOFA) score, p  = 0.01).

Conclusions: AKI severity in ICU patients was associated with progressively impaired fibrinolysis. Despite this, AKI patients had more bleedings within the first 7 days of ICU admission.

Introduction: Hemophilia is a rare X-linked bleeding disorder leading to recurrent hemarthroses, hemophilic arthropathy, and impaired quality of life. A chronic lifelong disease, hemophilia might be associated with accelerated biological aging. Here, we investigated whether biological age derived from epigenetic age estimators differs in hemophilia.

Patients/methods: We collected blood samples from men with severe (<1 IU/dL; PWSH, n  = 20) or mild hemophilia (≥5 IU/dL; PWMH, n  = 20), and age-matched healthy male controls ( n  = 20). DNA methylation of cytosine-phosphate-guanine (CpG) dinucleotides at five genes ( ASPA , ITGA2B , PDE4C , FHL2 , CCDC10SB ) was measured by bisulfite pyrosequencing. Biological age was estimated using two epigenetic aging signatures, each including three CpGs. We investigated differences in biological age and the rate of biological aging between study groups using separate linear regressions on chronological age and study group without and with an interaction, respectively.

Results: Deviations of epigenetic from chronological age were high for both 3-CpG age estimators, with results suggesting systematic overprediction. In both linear regressions using the two 3-CpG estimates, respectively, evidence for a different rate of biological aging in severe hemophilia was weak. The rate of biological aging in PWSH was 0.24 (95% CI, 0.01-0.48) and 0.21 (0.04-0.37) higher compared with PWMH, and 0.05 (-0.19-0.29) and 0.17 (-0.00-0.34) higher compared with healthy controls, respectively. Hemophilic arthropathy was associated with an increased rate of biological aging.

Conclusion: Evidence for a difference in epigenetic aging as reflected by two 3-CpG estimators in severe compared with mild hemophilia or healthy controls was weak.

Coronavirus disease 2019 (COVID-19) and active cancer are each independently associated with excess risk of thrombotic and cardiovascular events. However, data are limited regarding the risk of these events in outpatients with active cancer and concomitant COVID-19.

Objectives: This study aimed to retrospectively examine the association between active cancer and thrombotic and cardiovascular outcomes among non-hospitalized patients with COVID-19.

Methods: Data from the outpatient cohort with confirmed COVID-19 from the 10,420-patient multicenter U.S. CORONA-VTE Network registry were used. Active cancer was defined as having a malignancy diagnosis (excluding non-melanoma skin cancer) or receiving cancer-related treatment within the past year. Outcomes were independently adjudicated and included a composite of venous and arterial thromboembolism, and a composite of major adverse cardiovascular events, including thromboembolism, heart failure, myocarditis, new atrial fibrillation, and cardiovascular death within 90 days of COVID-19 diagnosis.

Results: The registry included 6,576 outpatients, of whom 166 (2.5%) had active cancer (mean age 61 ± 16, 53% female). For outpatients with and without active cancer, the 90-day cumulative incidences of thromboembolism after developing COVID-19 were 4.2% and 1.2%, respectively (hazard ratio [HR]: 3.65; 95% confidence interval [CI]: 1.73-7.69, p  < 0.001). Corresponding 90-day cumulative incidences of cardiovascular events were 5.4% and 1.9% (HR: 2.97; 95% CI: 1.46-6.05, p  = 0.003). In adjusted analyses, non-hospitalized patients displayed an increased risk of thrombotic outcomes (HR: 2.48, 95% CI: 1.13-5.45, p  = 0.024) but not cardiovascular outcomes (HR: 1.76, 95% CI: 0.85-3.62, p  = 0.13).

Conclusion: Outpatients with COVID-19 and active cancer demonstrated an increased hazard of thrombotic events compared with outpatients without cancer.

Introduction: Direct oral anticoagulants (DOACs) have been widely used in patients with thromboembolism. We previously reported that among DOACs, edoxaban (EDX), a factor Xa (FXa)-specific DOAC, most effectively inhibited the growth of syngeneic non-metastatic murine colon cancer cells implanted in mice via the protease-activated receptor 2 (PAR2) pathway. This study aimed to analyze the effects and mechanism of action of DOACs targeting thrombin or FXa on the metastasis of murine melanoma B16 cells implanted in mice.

Materials and methods: B16 cells (10 ⁶ cells in 100 μL) were implanted into the tail vein of 8-week-old female C57BL/6j mice ( n  = 5 per group), followed by daily oral administration of DOACs targeting thrombin (dabigatran etexilate [DABE], 50 mg/kg body weight [bw]) or FXa (rivaroxaban [RVX], 5 mg/kg bw; EDX, 10 mg/kg bw) for 14 days. The effects on tumor metastasis on day 15 and the inhibitory mechanism of the DOAC with the strongest inhibitory effect were analyzed.

Results: Lung metastasis of B16 cells implanted in mice was significantly suppressed in the following order: EDX > RVX ≥ DABE, compared with the saline-treated group. DOPA (3,4-dihydroxyphenylalanine)-positive cell density was significantly reduced from approximately 1,250 cells/mm ² in the saline group to approximately 600 cells/mm ² (RVX and DABE) and approximately 400 cells/mm ² (EDX; p  < 0.05 or 0.01). Investigating the inhibitory mechanism of EDX revealed that inflammation-associated factors such as PAR2, interleukin 6 (IL-6), and transforming growth factor β1 (TGFβ1); angiogenic factors such as vascular endothelial growth factor A and angiopoietin-2; and epithelial-mesenchymal transition (EMT)-associated factors such as vimentin and snail, which were increased in the lungs of the saline-treated group, all significantly decreased in the EDX-treated group ( p  < 0.05 or 0.01). In contrast, intercellular tight junction factors exhibited an opposite trend. EDX also inhibited FXa-dependent production of melanin, IL-6, and TGFβ1 in in vitro cultured B16 cells.

Conclusion: Among the tested DOACs, EDX showed the strongest inhibition of B16 cell metastasis in mice, likely via the suppression of inflammation, angiogenesis, and EMT mediated by the FXa-dependent PAR2 and TGFβ pathways in tumor and surrounding tissue cells.

Plasminogen activator inhibitor type 1 (PAI-1) is the key regulator of the fibrinolytic system, thereby acting as a potent mediator in thrombosis. Plasminogen activators such as PAI-1 mediate the conversion of the inactive zymogen plasminogen to plasmin, an active serine protease. As a member of the serpin superfamily, the highly conserved structure of PAI-1 is critical for its regulatory function. This review elucidates PAI-1 structure, function, and genetic architecture, and then discusses intracellular and extracellular functions that have broad implications for proliferative signaling and cell death, angiogenesis, cellular transit, and emerging roles in cancer biology. By understanding the complex and elaborate mechanism of PAI-1 in the fibrinolytic system and as a biomarker, PAI-1 may have broad implications across many disease states not related to its historical roles in fibrinolysis and thrombosis.

Background: Venous thromboembolism (VTE) is a significant contributor to global morbidity and mortality. Although management strategies and the distribution of risk factors have evolved, contemporary epidemiologic data are limited and have not been previously reported for Belgium. We aimed to characterize the epidemiology of VTE in a contemporary Belgian population.

Methods: We conducted secondary analyses of 1,448 participants from the Flemish Study on Environment, Genes, and Health Outcomes (FLEMENGHO), an observational, community-based, prospective cohort study. VTE cases occurring between 2000 and 2024 were identified through standardized health questionnaires, medical records, and expert adjudication. The incidence and lifetime risk of VTE were determined, and risk factors for incident VTE were assessed using Cox regression.

Results: Between 2000 and 2024, 63 VTE events occurred during 34,906 person-years of follow-up, corresponding to an incidence rate of 1.80 per 1,000 person-years. At the age of 45, the estimated remaining lifetime risk of VTE was 8.2% (95% CI: 5.6-10.8). Isolated lower extremity deep vein thrombosis was the most common presentation (42.9%), followed by isolated pulmonary embolism (36.5%). Transient major risk factors were identified in 30.2% of cases. In multivariable analyses, higher BMI (adjusted hazard ratio [HR _adj ]: 1.48, 95% CI: 1.13-1.93) and a history of VTE (HR _adj : 10.4, 95% CI: 4.1-26.3) were independent predictors of incident VTE.

Conclusion: Despite advancements in management strategies, the burden of VTE remained substantial in this representative and well-characterized Belgian cohort. The incidence rate is consistent with findings in other Western countries.

[This corrects the article DOI: 10.1055/a-2621-9749.].