Thrombosis research最新文献

Background

Clinical evidence surrounding edoxaban use in patients weighing <50 kg and >120 kg is lacking. The International Society of Thrombosis and Haemostasis Scientific and Standardisation Committee suggests avoiding edoxaban in patients >120 kg. Additionally, concerns exist regarding decreased efficacy in patients prescribed edoxaban for atrial fibrillation with a creatinine clearance (CrCl) >95 ml/min, a finding of the ENGAGE AF-TIMI 48 trial when edoxaban was compared to warfarin.

Objective

To derive a population pharmacokinetic (PopPK) model using clinical practice data, to understand the impact of bodyweight and renal function on edoxaban pharmacokinetics.

Method

Edoxaban plasma concentrations and patient characteristics were collated from King's College Hospital anticoagulation clinics between 11/2016 and 08/2022. A PopPK model was developed using non-linear mixed effects modelling and used to simulate edoxaban concentrations at the extremes of bodyweight and with varying renal function.

Results

Data from 409 patients (46 < 50 kg, 34 > 120 kg and 123 with a CrCl > 95 ml/min) provided 455 edoxaban plasma concentrations. A one-compartment model with between-subject variability on clearance with a proportional error model best described the data. The most significant covariates impacting on edoxaban exposure were CrCl and bodyweight. Our work suggests that edoxaban exposure in patients weighing up to 140 kg is comparable to those weighing 75 kg. Edoxaban exposure is reduced in patients weighing <50 kg due to the recommended dose reductions. There is also a reduction in AUCss when CrCl > 95 ml/min compared to CrCl 80 ml/min.

Conclusions

Our population PK model for edoxaban suggests that renal function is a key driver for overall edoxaban exposure. Further clinical outcome data is required to understand clinical effectiveness and adverse outcomes.

Background

Pediatric antiphospholipid syndrome (APS) is one of the most common acquired hypercoagulable states in children, yet it remains poorly characterized.

Objectives

To perform a systematic review and meta-analysis of the pooled incidence of thrombotic recurrence in this population (primary outcome), exploring the effect of age, APS type (primary vs. secondary to autoimmune diseases), and type of index thrombotic event. Secondary outcomes included the incidence of bleeding events and mortality.

Materials and methods

The MEDLINE, EMBASE, and COCHRANE databases were searched for studies reporting outcomes of cohorts of children aged ≤18 years with thrombotic APS as defined by the revised Sydney classification criteria.

Results

A total of 1011 studies were identified; of those, 9 were included in the final analysis (352 patients). The pooled incidence proportion of thrombosis recurrence was 0.27 [0.18–0.37], with an overall follow-up duration of a median of 2.7 to 5.8 years or a mean of 2.6 to 6.1 years. The estimate did not change meaningfully according to APS type (0.30 [0.18–0.46] for primary APS vs. 0.29 [0.19–0.42] for autoimmune APS), nor when the index thrombotic event was venous vs. arterial (0.30 [0.20–0.41] vs. 0.27 [0.27–0.51], respectively). The incidence of bleeding events was not reported in these studies. The incidence proportion of mortality was estimated at 0.07 [0.04–0.11] over the follow-up period, with 8/10 of the reported deaths directly associated with recurrent thrombotic events.

Conclusions

The incidence of thrombotic recurrence in children with APS is high and requires attention to evaluate anticoagulation management in this population.

Introduction

Hemophilia A is an inherited bleeding disorder caused by pathogenic variants in the factor VIII gene (F8), which leads to factor VIII (FVIII) deficiency. Immune tolerance induction (ITI) is a therapeutic approach to eradicate alloantibodies (inhibitors) against exogenous FVIII in people with inherited hemophilia A. Few studies have evaluated the role of F8 variants on ITI outcome.

Material and methods

We included people with severe hemophilia A (FVIII ˂ 1 international units/dL) and high-responding inhibitors (≥ 5 Bethesda units/mL lifelong) who underwent a first course of ITI. Socio-demographic, clinical and laboratory data were collected. ITI outcomes were defined as total, partial successes, and failure. Detection of intron 1 and 22 inversions was performed by polymerase-chain reaction, followed by F8 sequencing.

Results

We included 168 people with inherited hemophilia A and high-responding inhibitors, median age 6 years at ITI start. Intron 22 inversion was the most prevalent variant (53.6 %), followed by nonsense (16.1 %), small insertion/deletion (11.3 %), and large deletion (10.7 %). In comparison with intron 22 inversion, the odds of ITI failure were 15.5 times higher (odds ratio [OR] 15.50; 95 % confidence interval [95 % CI] 4.59–71.30) and 4.25 times higher (95 % CI, 1.53–12.3) among carriers of F8 large deletions and small insertions and deletions, respectively.

Conclusion

F8 large deletions and small insertions/deletions predicted ITI failure after a first course of ITI in patients with severe hemophilia A and high-responding inhibitors. This is the first study to show F8 large deletions and small insertions/deletions as predictors of ITI failure.

Background

Computed tomography pulmonary angiography (CTPA) simplifies the diagnosis of pulmonary embolism (PE) but is not suitable for all patients. Transthoracic lung ultrasound (LUS) is a potential alternative; this meta-analysis evaluates its accuracy for diagnosing PE.

Methods

We systematically searched PubMed, Embase and Cochrane Library from the inception of each database up to April 2024 according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses of Diagnostic Test Accuracy Studies guidelines. Study quality was assessed using the Quality Assessment of Diagnostic Accuracy Studies-2 tool, and a bivariate random effects model was used to pool sensitivity and specificity.

Results

A total of 18 studies with 2158 patients were analyzed. Lung ultrasound showed a sensitivity of 0.80 (95 %, confidence interval (CI): 0.71–0.86; I² = 85.2 %) and specificity of 0.87 (95 %, CI: 0.81–0.92; I² = 87.3 %). The diagnostic score was 3.27 (95 %, CI: 2.75–3.78; I² = 61.9 %), and the diagnostic odds ratio was 26 (95 %, CI: 16–44; I² = 100.0 %). The pooled positive likelihood ratio was 6.2 (95 %, CI: 4.2–9.1; I² = 79.2 %), and the negative likelihood ratio was 0.24 (95 %, CI: 0.16–0.34; I² = 83.7 %). The summary area under the curve was 0.91 (95 %, CI: 0.88–0.93). Significant heterogeneity was observed, which may impact the generalisability of the results, and no publication bias was detected.

Conclusion

Transthoracic LUS shows potential as an alternative to CTPA for PE diagnosis, but further research is needed to improve its accuracy and establish standardised diagnostic criteria. The observed heterogeneity highlights the need for a cautious interpretation of the results.

Background

The Chinese Haemophilia Individualized Prophylaxis Study (CHIPS), which was launched in 2016, reported a significant reduction in haemarthrosis over a one-year study. However, its long-term efficacy requires verification. This paper summarizes the clinical outcomes of 18 severe haemophilia A (SHA) patients who completed one year on the CHIPS and 3 more years of follow-up.

Methods

Clinical follow-up was based on the CHIPS protocol (from July 2018 to July 2021). Escalation was based on index joint bleeding, and serial ultrasound (greyscale and colour Doppler) examinations of the index joints (both sides of the ankles, knees and elbows) were conducted every 6 months via a scoring system.

Results

A total of 18 SHA patients completed the 3-year study. Fifteen patients dropped out due to the financial crisis during the COVID-19 pandemic in China. The median age was 5.4 (range 4.3–6.9) years. A significant reduction in haemarthrosis was achieved, with mean annual bleeding rates reduced from 18.9 ± 2.8 to 1.7 ± 0.4 (p < 0.001), annual joint bleeding rates from 3.1 ± 0.7 to1.2 ± 0.3 (p < 0.028). 5 out of 8 target joint resolved. Sixteen doses were escalated. At study exit, the heterogeneous treatment outcomes of the SHA boys were 5 at step 4 (20–25 lU/kg, every other day), 10 at step 3 (15–20 IU/kg, 3×/week), 2 at step 2 (10–15 lU/kg, 3×/week) and 1 at step 1 (10–15 lU/kg, 2×/week). The mean FVIII consumption was 2964 IU/kg/year, with savings. The quality of life improved, with Canadian Haemophilia Outcomes-Kids Life Assessment Tool (CHO-KLAT, Chinese Version 2.0) scores ranging from 68.8 to 78.8. There was no change in the ultrasound score.

Conclusion

Our follow-up data on the 18 SHA boys after completing one year on the CHIPS verify the long-term efficacy of the CHIPS for haemarthrosis reduction, joint health preservation, improvement in the quality of life of the boys and cost savings.

Background

The risk of venous thromboembolism (VTE) is 15 to 35-fold higher in the postpartum period compared to non-pregnant individuals. Clinical practice guidelines recommend the use of postpartum thromboprophylaxis with low molecular weight heparin (LMWH) for 6 weeks in individuals at high risk of developing VTE. However, a marked reduction in the risk of VTE risk occurs beyond the third week of the postpartum period.

Objective

We sought to characterize practice patterns of clinicians who manage postpartum individuals at high risk of VTE.

Methods

We conducted a cross-sectional study using a self-administered electronic questionnaire. The survey explored the use of postpartum thromboprophylaxis in high-risk individuals. Descriptive statistics were used to summarize survey responses.

Results

Of the 113 participants that responded to the initial invitation, 78 completed the survey (Europe (53.9 %); North America (23.2 %); Australia and New Zealand (19.0 %)). For individuals with a prior unprovoked or provoked deep venous thrombosis or pulmonary embolism, cerebral vein thrombosis and splanchnic vein thrombosis, 97.4 %, 93.5 %, 91.0 % and 88.5 % of the respondents recommended six weeks of postpartum thromboprophylaxis using LMWH, respectively. The recommendation for 6 weeks of thromboprophylaxis in patients with sickle cell disease and obstetric APS was comparatively lower (70.5 and 78.2 % respectively). Respondents with higher practice volumes and more years of experience in clinical practice were more likely to recommend a shorter duration of thromboprophylaxis.

Conclusion

Our study highlights the variability in clinician recommendations and the acceptability of treatment durations for postpartum thromboprophylaxis in high-risk conditions. Prospective studies are needed to determine optimal duration and establish evidence-based management.

Thrombosis is the primary cause of death in patients with cancer. Resveratrol inhibits platelet activation, a crucial pathophysiological basis of thrombosis, in healthy individuals. However, its effects and mechanisms of action in patients with colon cancer remain unknown. Here, we investigated the effect of resveratrol on platelet adhesion and aggregation in patients with colon cancer. Through numerous in vitro and in vivo analyses, including flow cytometry, western blotting, ELISA, and immunofluorescence and colon cancer rat models, we demonstrated that resveratrol reduced thrombosis in patients with colon cancer by inhibiting the phosphorylation of the MAPK and activating the cyclic-GMP/vasodilator-stimulated phosphoprotein pathway. These findings demonstrate the potential of resveratrol in reducing thrombosis in patients with colon cancer and could be used to develop novel therapeutic strategies for this condition.