Thrombosis and haemostasis最新文献

Background:  Lipoprotein(a), or Lp(a), has been recognized as a strong risk factor for atherosclerotic cardiovascular disease. However, the relationship between Lp(a) and bleeding remains indistinct, especially in the secondary prevention population of coronary artery disease (CAD). This investigation aimed to evaluate the association of Lp(a) with long-term bleeding among patients with CAD.

Methods:  Based on a prospective multicenter cohort of patients with CAD consecutively enrolled from January 2015 to May 2019 in China, the current analysis included 16,150 participants. Thus, according to Lp(a) quintiles, all subjects were divided into five groups. The primary endpoint was bleeding at 2-year follow-up, and the secondary endpoint was major bleeding at 2-year follow-up.

Results:  A total of 2,747 (17.0%) bleeding and 525 (3.3%) major bleeding were recorded during a median follow-up of 2.0 years. Kaplan-Meier survival analysis showed the highest bleeding incidence in Lp(a) quintile 1, compared with patients in Lp(a) quintiles 2 to 5 (p < 0.001), while the incidence of major bleeding seemed similar between the two groups. Moreover, restricted cubic spline analysis suggested that there was an L-shaped association between Lp(a) and 2-year bleeding after adjustment for potential confounding factors, whereas there was no significant association between Lp(a) and 2-year major bleeding.

Conclusion:  There was an inverse and L-shaped association of Lp(a) with bleeding at 2-year follow-up in patients with CAD. More attention and effort should be made to increase the clinician awareness of Lp(a)'s role, as a novel marker for bleeding risk to better guide shared-decision making in clinical practice.

Background:  Increased adhesivity of red blood cells (RBCs) to endothelial cells (ECs) may contribute to organ dysfunction in malaria, sickle cell disease, and diabetes. RBCs normally export nitric oxide (NO)-derived vascular signals, facilitating blood flow. S-nitrosothiols (SNOs) are thiol adducts formed in RBCs from precursor NO upon the oxygenation-linked allosteric transition in hemoglobin. RBCs export these vasoregulatory SNOs on demand, thereby regulating regional blood flow and preventing RBC-EC adhesion, and the large (system L) neutral amino acid transporter 1 (LAT1; SLC7A5) appears to mediate SNO export by RBCs.

Methods:  To determine the role of LAT1-mediated SNO import by ECs generally and of LAT1-mediated SNO import by ECs in RBC SNO-dependent modulation of RBC sequestration and blood oxygenation in vivo, we engineered LAT1^fl/fl; Cdh5-Cre⁺ mice, in which the putative SNO transporter LAT1 can be inducibly depleted (knocked down, KD) specifically in ECs ("LAT1^ECKD").

Results:  We show that LAT1 in mouse lung ECs mediates cellular SNO uptake. ECs from LAT1^ECKD mice (tamoxifen-induced LAT1^fl/fl; Cdh5-Cre⁺) import SNOs poorly ex vivo compared with ECs from wild-type (tamoxifen-treated LAT1^fl/fl; Cdh5-Cre^-) mice. In vivo, endothelial depletion of LAT1 increased RBC sequestration in the lung and decreased blood oxygenation after RBC transfusion.

Conclusion:  This is the first study showing a role for SNO transport by LAT1 in ECs in a genetic mouse model. We provide the first direct evidence for the coordination of RBC SNO export with EC SNO import via LAT1. SNO flux via LAT1 modulates RBC-EC sequestration in lungs after transfusion, and its disruption impairs blood oxygenation by the lung.

Background:  In patients with acute venous thromboembolism (VTE), the rates of recurrence and major bleeding are highest during the first weeks of anticoagulation. The CARAVAGGIO trial demonstrated noninferiority of apixaban to dalteparin for treatment of cancer-associated VTE without an increased risk of major bleeding. We compared the early time course of VTE recurrence and major bleeding events of apixaban compared with dalteparin at 7, 30, and 90 days of treatment in patients with cancer-associated VTE.

Methods:  The study design of the CARAVAGGIO trial has been described. Eligible patients were randomly assigned to receive monotherapy with either apixaban or dalteparin for 6 months. The primary efficacy outcome was the incidence of objectively confirmed recurrent VTE. The primary safety outcome was major bleeding.

Results:  In 1,155 patients, recurrent VTE after 7, 30, and 90 days occurred in 6 (1%), 15 (2.6%), and 27 (4.7%) patients in the apixaban arm versus 5 (0.9%), 20 (3.5%), and 36 (6.2%) patients respectively in the dalteparin arm. By day 7, 30, and 90, major bleeding events had occurred in 3 (0.5%), 9 (1.6%), and 16 (2.8%) patients in the apixaban group versus 5 (0.9%), 11 (1.9%), and 17 (2.9%) patients in the dalteparin group.

Conclusion:  The frequencies of recurrent VTE and major bleeding events at 7, 30, and 90 days of apixaban compared with dalteparin were similar in patients with cancer-associated VTE. This supports the use of apixaban for the initiation and early phase of anticoagulant therapy in cancer-associated VTE.

Background:  Polycythemia vera (PV) patients are classified as high or low thrombotic risk based on age and prior history of thrombosis. Despite adherence to treatment recommendations, vascular events remain frequent, leading us to question whether thrombotic risk stratification could be improved. We previously reported an association between thrombotic events and mutations in DTA genes (DNMT3A, TET2, and ASXL1). The objective of this study was to confirm this observation in a larger series of PV patients.

Methods:  PV patients with a minimum follow-up of 3 years were recruited from 8 European centers. Medical history was searched for thrombotic event recorded at any time and next-generation sequencing carried out with a myeloid panel. Multivariable logistic regression evaluated the impact of variables on thrombotic risk. Kaplan-Meier thrombosis-free survival curves were compared by the log rank test. Associations in the total cohort were confirmed in a case-control study to exclude selection bias.

Results:  Of the 136 patients recruited, 74 (56.1%) had a thrombotic event, with an incidence density of 2.83/100 person-years. In multivariable analysis, DTA mutation was a risk factor for thrombotic event, being predictive for shorter thrombosis-free survival in the whole cohort (p = 0.007), as well as in low-risk patients (p = 0.039) and older patients (p = 0.009), but not for patients with a prediagnostic event. A gender- and age-matched case-control study confirmed the increased risk of thrombotic event for PV patients with a DTA mutation.

Conclusion:  Our results support the use of molecular testing at diagnosis to help predict which PV patients are at higher risk of developing thrombosis.

Endothelial dysfunction together with a dysregulated immune response and lipid accumulation are important confounding factors in the onset and chronic development of atherosclerosis. Much data has recently emerged on the sequential involvement of different immune cell types, including monocytes, in the pathology of this disease.1 In this condensed review, we aim to highlight some of the recent basic research and clinical findings on monocyte subsets published since our joint ESC consensus document2, and analyze their potential relevance as surrogate biomarkers in coronary artery disease (CAD).

Background Patients receiving endovascular treatment for unruptured intracranial aneurysms (UIA) face varying risks and benefits with antithrombotic management. This study aimed to evaluate the perioperative and long-term effects of antithrombotic strategies, identify the populations that would benefit, and explore the predictive factors affecting the long-term outcomes. Methods UIA patients undergoing endovascular treatment including stent-assisted coiling (SAC) or flow diversion (FD) between June 2019 and June 2022 were enrolled. We compared perioperative and long-term complications between tirofiban and dual antiplatelet therapy groups. Optimal candidates for each antithrombotic treatment were identified using multivariate logistic regression. Nomograms were developed to determine the significant predictors for thromboembolic complications during follow-up. Results Among 181 propensity-score (PS) matched pairs, tirofiban group showed a trend towards a lower rate of thromboembolic complications than DAPT group without elevating major bleeding risk in either period. Homocysteine (Hcy) level ≥ 10 μmol/L was a significant independent factor associated with thromboembolic complication in both periods. Subgroup analysis highlighted that in patients with high Hcy levels, tirofiban and sustained antiplatelet treatment for ≥ 12 months were protective factors, while a history of stroke was an independent risk factor for thromboembolic events in follow-up. Four variables were selected to construct a prognostic nomogram, history of hypertension, prior stroke, Hcy level, and the duration of antiplatelet therapy. Conclusion Perioperative low-dose tirofiban and extended antiplatelet therapy demonstrated a favorable trend in long-term outcomes for UIA patients with preoperative Hcy levels≥10μmol/L undergoing endovascular treatment. The prognostic model offers reliable risk prediction and guides antithrombotic strategy decisions.

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.

Background:  Cancer patients have an increased risk of venous thromboembolism (VTE). Currently, the availability of highly discriminatory prediction models for VTE in cancer patients is limited. The implementation of biomarkers in prediction models might lead to refined VTE risk prediction. In this systematic review and meta-analysis, we aimed to evaluate candidate biomarkers and their association with cancer-associated VTE.

Methods:  We searched Medline, EMBASE, and Cochrane Central for studies that evaluated biomarkers in adult cancer patients from inception to September 2022. We included studies reporting on VTE after a cancer diagnosis with biomarker measurements performed at a defined time point. Median/mean differences (for continuous measures) and odds ratios (for dichotomous measures) with 95% confidence intervals were estimated and pooled using random-effects models.

Results:  We included 113 studies in the systematic review. Of these, 50 studies were included in the meta-analysis. We identified two biomarkers at cancer diagnosis (factor VIII and time to peak thrombin), three biomarkers pre-chemotherapy (D-dimer, fibrinogen, and mean platelet volume), and one biomarker preoperatively (platelet count) that had significant median or mean differences. Additionally, we found that hemoglobin <100 g/L and white blood count >11 × 10⁹/L were significantly associated with future VTE risk only when measured at cancer diagnosis. Pre-chemotherapy neutrophil-to-lymphocyte ratio ≥3 and preoperative platelet count ≥400 × 10⁹/L were also found to be associated with future VTE risk.

Conclusion:  In conclusion, this study identified nine candidate blood biomarkers that may help in optimizing VTE prediction in cancer patients that should be further explored in future studies.

Introduction:  Prethrombin-1 is a Gla-domain lacking enzymatically inactive split product that results from the cleavage of fragment 1 from prothrombin by thrombin in a feedback reaction.

Methods:  A prethrombin-1 preparation derived from human plasma was tested for its hemostatic and thrombogenic properties. Animal models of nail clipping (for rabbits) and tail clipping (for mice) were developed to measure blood loss in FVIII-inhibitor or rivaroxaban anticoagulated rabbits and mice, respectively. A modified Wessler test was used in rabbits to assess the thrombogenic potential by Wessler score and clot weight. Studies were performed in groups of three to six for prethrombin-1 dose escalation and comparison with prothrombin, Beriplex®, FEIBA®, and saline as a control. Data were analyzed using t-statistics or the Mann Whitney U test as applicable.

Results:  Prethrombin-1 has excellent hemostatic properties in anticoagulated mouse and rabbit bleeding models. Wessler tests suggest that in contrast to activated and nonactivated prothrombin complexes, prethrombin-1 has negligible thrombogenic potential.

Conclusion:  The thrombin zymogen prethrombin-1 promotes hemostasis with reduced risk of thrombosis. Prethrombin-1 may have potential to become a life-saving treatment for patients who bleed or are at risk of bleeding.

This is an executive summary of the recent guidance produced by the Scottish Intercollegiate Guidelines Network (SIGN) dementia guideline group with regards to the investigation of suspected dementia. This is a sub-section of the broader SIGN 168 guideline released in November 2023. The guideline group included clinicians with expertise in Old Age Psychiatry, Neurology, Radiology, and Nuclear Medicine supported by colleagues from the SIGN and Healthcare Improvement Scotland teams. There was representation from carers and support organizations with experience of dementia, to ensure the recommendations were appropriate from the perspective of the people being assessed for possible dementia and their carers. As the 2018 National Institute for Health and Clinical Excellence (NICE) dementia review included a review of the evidenced investigation of dementia, the SIGN guideline development group decided to focus on a review on the up-to-date evidence regarding the role of imaging and fluid biomarkers in the diagnosis of dementia. To give context to the consideration of more advanced diagnostic biomarker investigations, the guideline and this summary include the NICE guidance on the use of standard investigations as well as more specialist investigations. The evidence review supports consideration of the use of structural imaging, nuclear medicine imaging, and established Alzheimer's cerebrospinal fluid biomarkers (amyloid and tau) in the diagnosis of dementia. Although routine use of amyloid positron emission tomography imaging was not recommended, its potential use, under specialist direction, in patients with atypical or young-onset presentations of suspected Alzheimer's dementia was included as a clinical good practice point.