Thrombosis and haemostasis最新文献

Aims:  Patients presenting with acute coronary syndrome (ACS) are frequently treated with the P2Y₁₂-inhibitor ticagrelor. Some patients prematurely discontinue ticagrelor, but the incidence of reasons for and clinical implications of treatment modification are relatively unknown.

Methods and results:  Data from 4,278 ACS patients (mean age: 63.6 years, 26.1% women) who were discharged on ticagrelor and enrolled in the FORCE-ACS registry between 2015 and 2020 were used. Treatment modifications were categorized as physician-recommended discontinuation, alteration, interruption, or disruption and occurred in 26.7, 20.1, 2.8, and 3.1% of patients within 12 months of follow-up (VISUAL SUMMARY: ). Underlying reasons for treatment modification differed per type of modification. Overall, the rate of ischemic events defined as all-cause death, myocardial infarction, or stroke was 6.6% at 12 months of follow-up. Cox regression analysis using time-updated modification variables as independent variables showed that treatment interruption (adjusted hazard ratio [HR]: 2.93, 95% confidence interval [CI]: 1.48-5.79, p < 0.01) and disruption (adjusted HR: 2.33, 95% CI: 1.07-5.07, p = 0.03) were associated with an increased risk of ischemic events even after adjustment for relevant confounders. Discontinuation and alteration were not associated with increased ischemic risk.

Conclusion:  In clinical practice, treatment modifications in ACS patients discharged on ticagrelor are common, although type and reasons for modification are heterogeneous. Treatment interruption and disruption are associated with excess cardiovascular risk.

Background:  About 7% of patients with cancer-associated venous thromboembolism (CAT) develop a recurrence during anticoagulant treatment. Identification of high-risk patients may help guide treatment decisions.

Aim:  To identify clinical predictors and develop a prediction model for on-treatment recurrent CAT.

Methods:  For this individual patient data meta-analysis, we used data from four randomized controlled trials evaluating low-molecular-weight heparin or direct oral anticoagulants (DOACs) for CAT (Hokusai VTE Cancer, SELECT-D, CLOT, and CATCH). The primary outcome was adjudicated on-treatment recurrent CAT during a 6-month follow-up. A clinical prediction model was developed using multivariable logistic regression analysis with backward selection. This model was validated using internal-external cross-validation. Performance was assessed by the c-statistic and a calibration plot.

Results:  After excluding patients using vitamin K antagonists, the combined dataset comprised 2,245 patients with cancer and acute CAT who were treated with edoxaban (23%), rivaroxaban (9%), dalteparin (47%), or tinzaparin (20%). Recurrent on-treatment CAT during the 6-month follow-up occurred in 150 (6.7%) patients. Predictors included in the final model were age (restricted cubic spline), breast cancer (odds ratio [OR]: 0.42; 95% confidence interval [CI]: 0.20-0.87), metastatic disease (OR: 1.44; 95% CI: 1.01-2.05), treatment with DOAC (OR: 0.66; 95% CI: 0.44-0.98), and deep vein thrombosis only as an index event (OR: 1.72; 95% CI: 1.31-2.27). The c-statistic of the model was 0.63 (95% CI: 0.54-0.72) after internal-external cross-validation. Calibration varied across studies.

Conclusion:  The prediction model for recurrent CAT included five clinical predictors and has only modest discrimination. Prediction of recurrent CAT at the initiation of anticoagulation remains challenging.

Background: Renal dysfunction is highly prevalent among patients with pulmonary embolism (PE). This study combined population-based study and Mendelian randomization to observe the relationship between renal function and PE.

Methods: A nested case-control study were performed using data of PE patients and controls were from two nationwide cohorts, the China pUlmonary thromboembolism REgistry Study (CURES) and China Health and Retirement Longitudinal Survey (CHARLS). Baseline characteristics were balanced using propensity score matching and inverse probability of treatment weighting. Restricted cubic spline models were applied for the relationship between estimated glomerular filtration rate (eGFR) decline and the risk of PE. Bidirectional two-sample Mendelian randomization (MR) analyses were performed using Genome-wide association study summary statistics for eGFR involving 1,201,909 individuals and for PE from the FinnGen consortium.

Results: The nested case-control study including 17,547 participants (6,322 PE patients) found that eGFR distribution was significantly different between PE patients and controls (P<0.001), PE patients had a higher proportion of eGFR<60 mL/min/1·73 m2. eGFR below 88 mL/min/1·73 m2 was associated with a steep elevation in PE risk. MR analyses indicated a potential causal effect of eGFR decline on PE (OR=4·26, 95%CI 2·07-8·79), with no evidence of horizontal pleiotropy and reverse causality.

Conclusions: Our findings support the hypothesis that renal function decline contributes to an elevated PE risk. Together with the high prevalence of chronic kidney diseases globally, there arises the necessity for monitoring and modulation of renal function in effective PE prevention.

Three mutually exclusive entities can underlie a postpulmonary embolism syndrome (PPES): not obstructed postpulmonary embolism syndrome (post-PE dyspnea), chronic thromboembolic pulmonary disease (CTEPD), and chronic thromboembolic pulmonary hypertension (CTEPH). Cardiorespiratory impairment in CTEPH and CTEPD underlies respiratory and hemodynamic mechanisms, either at rest or at exercise. Gas exchange is affected by the space effect, the increased blood velocity, and, possibly, intracardiac right to left shunts. As for hemodynamic effects, after a period of compensation, the right ventricle dilates and fails, which results in retrograde and anterograde right heart failure. Little is known on the pathophysiology of post-PE dyspnea, which has been reported in highly comorbid with lung and heart diseases, so that a "two-hit" hypothesis can be put forward: it might be caused by the acute myocardial damage caused by pulmonary embolism in the context of preexisting cardiac and/or respiratory diseases. More than one-third of PE survivors develops PPES, with only a small fraction (3-4%) represented by CTEPH. A value of ≈3% is a plausible estimate for the incidence of CTEPD. Growing evidence supports the role of CTEPD as a hemodynamic phenotype intermediate between post-PE dyspnea and CTEPH, but it still remains to be ascertained whether it constantly underlies exercise-induced pulmonary hypertension and if it is a precursor of CTEPH. Further research is needed to improve the understanding and the management of CTEPD and post-PE dyspnea.

Background:  Venous thromboembolism (VTE) etiology in children with acute lymphoblastic leukemia (ALL) is multifactorial. The use of global assays of hemostasis as a thrombin generation test (TGT) is useful to individualize VTE risk in adult patients. This prospective cohort study aimed to evaluate the usefulness of an automated TGT to evaluate VTE risk during ALL treatment in children.

Methods:  TGT (automated analyzer ST Genesia; ThromboScreen) and pro- and anticoagulant plasma proteins were analyzed during ALL treatment in pediatric patients following LAL-SEHOP-PETHEMA-2013 guidelines. Results were compared with a series of pediatric normal controls and evaluated according to pegylated asparaginase PEG-ASP administration and to VTE risk factors.

Results:  The study included 67 patients: males n = 35, B-ALL (n = 60). None had a VTE during the evaluated period. Compared to healthy controls, the normalized endogenous thrombin potential (N-ETP) ratio in patients was higher and ETP inhibition (ETP-inh) was lower, especially after PEG-ASP administration. Plasmatic protein C and protein S levels decreased after PEG-ASP administration, but antithrombin mean level did not. A bivariant analysis showed that ETP-inh was lower in patients >10 years old (p = 0.05) and in those with non-O blood type (p = 0.005). A linear mixed model also showed a higher TGT prothrombotic profile in patients with inherited thrombophilia.

Conclusion:  TGT could be a biomarker of a high VTE risk in ALL pediatric patients. Non-O blood group and inherited thrombophilia were associated with a significantly higher thrombotic profile, and an increased profile was also observed after administration of PEG-ASP.

Background:  Specifically positioned negatively charged residues within the cytoplasmic domain of the adaptor protein, linker for the activation of T cells (LAT), have been shown to be important for efficient phosphorylation of tyrosine residues that function to recruit cytosolic proteins downstream of immunoreceptor tyrosine-based activation motif (ITAM) receptor signaling. LAT tyrosine 132-the binding site for PLC-γ2-is a notable exception, preceded instead by a glycine, making it a relatively poor substrate for phosphorylation. Mutating Gly₁₃₁ to an acidic residue has been shown in T cells to enhance ITAM-linked receptor-mediated signaling. Whether this is generally true in other cell types is not known.

Methods:  To examine whether LAT Gly₁₃₁ restricts ITAM signaling in cells of the megakaryocyte lineage, we introduced an aspartic acid at this position in human induced pluripotent stem cells (iPSCs), differentiated them into megakaryocytes, and examined its functional consequences.

Results:  iPSCs expressing G131D LAT differentiated and matured into megakaryocytes normally, but exhibited markedly enhanced reactivity to glycoprotein VI (GPVI)-agonist stimulation. The rate and extent of LAT Tyr₁₃₂ and PLC-γ2 phosphorylation, and proplatelet formation on GPVI-reactive substrates, were also enhanced.

Conclusion:  These data demonstrate that a glycine residue at the -1 position of LAT Tyr₁₃₂ functions as a kinetic bottleneck to restrain Tyr₁₃₂ phosphorylation and signaling downstream of ITAM receptor engagement in the megakaryocyte lineage. These findings may have translational applications in the burgeoning field of in vitro platelet bioengineering.