Seminars in thrombosis and hemostasis最新文献

C1-inhibitor deficiency-associated hereditary angioedema (C1INH-HAE) is a rare congenital swelling disorder caused by mutations in the SERPING1 gene. Despite evidence of a systemic procoagulant state in C1INH-HAE, dogma held that this disorder was not associated with thrombotic pathologies. Recent population scale epidemiological evidence has directly challenged this, with C1INH-HAE being associated with a significantly increased risk of venous thromboembolism (VTE). This review considers the growing body of evidence supporting associations between HAE and both a systemic procoagulant state and an increased risk of VTE. In the setting of C1INH-HAE, the relationship between the observed procoagulant and thrombotic phenotypes is a prime example of "where there's smoke, there's fire." This review also discusses the impact of C1INH-HAE disease modifying therapies on coagulation and VTE. Further, the utility of preclinical mouse models of C1-inhibitor deficiency is considered.

Venous thromboembolism (VTE) after hospital discharge poses a serious health risk. Assessments of patient characteristics, prophylaxis, treatment, outcomes, and over time changes lack consistency. Data on 16,901 hospitalized patients in the Registro Informatizado Enfermedad TromboEmbolica registry (2003-2022) were analyzed to evaluate trends in baseline characteristics, prophylaxis, treatments, and 90-day outcomes among medical (6,218) and surgical (10,683) patient cohorts. Multivariable logistic regression was used to assess the risks of the composite of fatal pulmonary embolism (PE) or recurrent VTE and major bleeding. The proportion of patients who presented with PE increased among medical (from 54 to 72%) and surgical patients (from 55 to 58%). Prophylaxis use increased in medical patients (from 53 to 71%), while decreasing in surgical patients (from 67 to 58%). Notably, the 90-day composite of fatal PE or recurrent VTE decreased in medical (from 3.9 to 1.8%) and surgical patients (from 2.9 to 1.2%; p < 0.001 for both). Conversely, major bleeding increased (3.1 to 4.5%) in medical patients (p = 0.008), with no change in surgical patients (from 2.5 to 2.4%). Risk-adjusted analysis showed a yearly decrease in the risk for the composite outcome (subhazard ratio [sHR]: 0.95; 95% confidence interval [CI]: 0.93-0.98) in medical and surgical patients and an increase in the risk for major bleeding in medical patients only (sHR: 1.04; 95% CI: 1.01-1.07). Results were consistent after excluding coronavirus disease 2019 patients. Over 20 years, the composite of fatal PE or recurrent VTE within 90 days had significantly decreased in VTE patients after hospitalization for medical or surgical care. Medical patients, however, exhibited an increase in major bleeding.

Coronary artery disease (CAD) is a leading cause of morbidity and mortality worldwide, with platelet reactivity playing a central role in its pathogenesis. Recent research has identified microRNAs (miRNAs; miRs) as potential biomarkers for CAD, due to their ability to regulate platelet function and reactivity. This review focuses on four key miRNAs-miR-223, miR-126, miR-21, and miR-150-known to influence platelet reactivity and their implications in CAD. miR-223, which is highly expressed in platelets, has shown associations with CAD and myocardial infarction, while miR-126 has been linked to thrombus formation and vascular health. Additionally, miR-21 and miR-150 have also emerged as important players, with roles in platelet reactivity and cardiovascular outcomes. However, despite their potential, the use of miRNAs as clinical biomarkers faces several challenges, including variability in reported results across studies. These inconsistencies often arise from differences in sample material, preanalytical conditions, and normalization strategies. Furthermore, the influence of antiplatelet therapy on miRNA expression adds another layer of complexity, making it difficult to determine whether observed changes in miRNA levels are due to disease states or therapeutic interventions. This review therefore highlights the need for standardization in miRNA research to enhance the reliability of findings. By addressing these methodological challenges, miRNAs could become powerful tools in personalized medicine, aiding in the development of tailored therapeutic strategies for CAD patients and ultimately improving clinical outcomes.

Depressive disorders and suicidal behaviors represent major causes of health loss. Modifications of brain microvasculature, and specifically alterations of the blood-brain barrier have been supposed to participate in the vulnerability to those disorders along with cognitive impairment, especially in the older adults. In this article, we addressed evidence linking blood-brain barrier impairments with mood disorders and suicide. Secondly, we investigated their relationship with depression in old age, and with neurodegenerative processes. Particular attention was drawn toward the potential interactions between the coagulation processes and the blood-brain barrier dysfunctions, as innovative treatment strategies may emerge from research in those fields. Overall, the studies reviewed highlight the implication of multiple dysfunctions of the blood-brain barrier in mood disorders and suicide. Impairments of the blood-brain barrier show relationships with altered expression of endothelial cell junction proteins. These modifications also implicate receptors of the extracellular matrix, the vascular endothelial growth factor, changes in perivascular astrocytes, and has links with local and systemic inflammatory processes. Dysfunctions of the blood-brain barrier underly chronic stress and participate in psychiatric diathesis in old age. In addition, we outline that coagulation processes are likely to interact with the blood-brain barrier and further contribute to neurodegenerative disorders. In conclusion, new pathophysiological models offer perspectives toward detecting new biomarkers in mood disorders and suicide. In parallel, these models open avenues for developing innovative therapeutic agents, although further considering their potential risks and eventual benefits is needed.

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The prevalence of factor XI (FXI) deficiency is 1 per 10 to 20,000 in the general population, much higher than that reported in most texts. The prevalence is higher in Ashkenazi Jews where it is about 1:20. Clinically, FXI deficiency presents as a mild bleeding disorder mostly associated with posttraumatic or postsurgical hemorrhages or unexplained minor bleeding. It is often discovered due to incidental finding of a prolonged activated partial thromboplastin time (aPTT) on routine laboratory screening. FXI deficiency is an autosomal recessive bleeding disorder with many causative F11 gene defects. Diagnosis is based on FXI activity, antigen levels, and molecular diagnostics. As FXI levels do not correlate with bleeding symptoms, identification of pathogenic genetic variants may be a more accurate predictor of bleeding risk and therefore aid in the clinical management of the patient. Two variants in the F11 gene account for most cases found in the Jewish and Arab populations. Patients with FXI deficiency can develop inhibitors to FXI although spontaneously acquired inhibitors are extremely rare. We will discuss laboratory and molecular assays used to diagnose FXI deficiency as well as interferences that can complicate diagnosis including new anticoagulants and acquired FXI inhibitors.

Glanzmann thrombasthenia (GT) is the most common inherited platelet disorder (IPD) with mucocutaneous bleeding and a failure of platelets to aggregate when stimulated. The molecular cause is insufficient or defective αIIbβ3, an integrin encoded by the ITGA2B and ITGB3 genes. On activation αIIbβ3 undergoes conformational changes and binds fibrinogen (Fg) and other proteins to join platelets in the aggregate. The application of next-generation sequencing (NGS) to patients with IPDs has accelerated genotyping for GT; progress accompanied by improved mutation curation. The evaluation by NGS of variants in other hemostasis and vascular genes is a major step toward understanding why bleeding varies so much between patients. The recently discovered role for glycoprotein VI in thrombus formation, through its binding to fibrin and surface-bound Fg, may offer a mechanosensitive back-up for αIIbβ3, especially at sites of inflammation. The setting up of national networks for IPDs and GT is improving patient care. Hematopoietic stem cell therapy provides a long-term cure for severe cases; however, prophylaxis by monoclonal antibodies designed to accelerate fibrin formation at injured sites in the vasculature is a promising development. Gene therapy using lentil-virus vectors remains a future option with CRISPR/Cas9 technologies offering a promising alternative route.

Factor XIII-A (FXIII-A) deficiency is an ultra-rare bleeding disorder characterized by high rates of morbidity and mortality, primarily resulting from intracranial hemorrhage, umbilical cord bleeding, and miscarriage, whereas patients with severe FXIII-B deficiency present with a milder phenotype. Although the estimated incidence of severe FXIII-A deficiency is one per 2 million, a high prevalence ranging from 0.8 to 3.5% has been observed for heterozygous FXIII-A deficiency. Unlike most bleeding disorders, individuals with heterozygous FXIII-A deficiency, particularly women, are more likely to experience hemorrhagic complications during hemostatic challenges. About 200 Mutations have been observed in F13A and F13B genes, with most being missense mutations, while large deletions are the rarest. There is no correlation between genotype and phenotype and a moderate to strong correlation between factor activity and clinical severity in FXIII-A deficiency, making it difficult to predict bleeding patterns based on genotype and FXIII activity levels. Primary prophylaxis is mandatory for all patients with severe FXIII-A deficiency, while those with heterozygous deficiency are generally asymptomatic and may require on-demand therapy during hemostatic challenges, most commonly in women. On the other hand, patients with severe FXIII-B deficiency may only require on-demand therapy, while heterozygotes are generally asymptomatic. Although there are general recommended therapeutic regimens for prophylaxis or on-demand therapy in different situations, personalized pharmacokinetic-based replacement therapy represents the optimal approach that can optimize intervention efficacy. In such an approach, several factors may affect the effectiveness of treatment and determine the dose and type of intervention, including the classification of FXIII deficiency, residual plasma levels of FXIII, clinical situation requiring intervention, age, weight, and also gender.