Seminars in thrombosis and hemostasis最新文献

Congenital fibrinogen disorders (CFDs) result from deficiencies in the fibrinogen-encoding genes FGA, FGB, and FGG, causing either quantitative or qualitative fibrinogen abnormalities. In this study, we conducted an extensive evaluation on clinical, laboratory, and genetic characteristics of 102 CFD patients. Fibrinogen levels were determined by Clauss method and/or prothrombin time (PT)-derived method. Routine coagulation parameters including PT, activated partial thromboplastin time (APTT), and thrombin time (TT) were also assessed. Genetic mutations were detected through either next-generation sequencing or comprehensive whole-exome sequencing. The case series comprised 38 males and 64 females, with a median diagnosis age of 33 years. In patients where laboratory results were available, the function fibrinogen levels tested by Clauss method were decreased, whereas only 51.7% exhibited reduced fibrinogen concentrations by PT-derived method. A total of 55 germline mutations were identified, including 26 novel mutations not previously documented in the literature. Forty-two percent of unrelated patients were carriers of hotspot mutations. The laboratory results and clinical symptoms were highly variable among patients, even within patients harboring the same mutation. However, TT was significantly prolonged in qualitative CFDs compared with quantitative CFDs. All the patients harboring the hotspot mutations showed qualitative deficiency of fibrinogen. We also demonstrated that qualitative CFDs were particularly prone to harboring missense variants, whereas nearly all the null mutations were classified into the quantitative group. This study presents a genetic landscape of CFD patients, and their gene-phenotype relationships. The novel identified genetic variants expand the known genetic spectrum of CFDs.

Thrombosis is a comorbidity associated with autoimmune, allergic, and infectious conditions; however, the mechanistic basis for this elevated risk is poorly understood. The simultaneous activation of the immune and coagulation systems to assist in response to injury and efficient pathogen clearance, termed immunothrombosis, is typically described as a bidirectional interaction between the innate immune and coagulation systems. More recently, however, data have emerged highlighting the involvement of adaptive immune cells in this process. In this review, we discuss the role of adaptive immune cells in clot formation and resolution, and explore how the adaptive immune system modulates procoagulant activity in autoimmune diseases such as inflammatory bowel disease, systemic lupus erythematosus, and graft versus host disease; allergic disorders, such as dermatitis and asthma; infectious diseases, such as coronavirus disease 2019 (COVID-19) and human immunodeficiency virus (HIV); and ischemic conditions such as myocardial infarction and stroke.

Direct oral anticoagulants (DOACs), including direct thrombin inhibitors (dabigatran) and direct factor Xa inhibitors (apixaban, rivaroxaban, edoxaban), have transformed anticoagulant management in recent years due to their predictable pharmacodynamics, rapid onset of action, and fixed dosing without the need for routine laboratory monitoring. Unfractionated heparin (UFH) remains the anticoagulant of choice for patients who are acutely unwell and treated in intensive care units due to its short half-life, reversibility, ease of dose titration, and nonrenal dependent excretion. It is therefore not uncommon for an individual's anticoagulation management to require rapid changing from DOAC to UFH. Due to UFH's complex pharmacokinetics, including nonspecific binding to acute phase proteins and dose-dependent clearance, careful laboratory monitoring, generally with activated partial thromboplastin time (APTT) or anti-factor Xa (anti-Xa) activity, is necessary. When transitioning from a DOAC to UFH, overlapping pharmacologic effects can significantly interfere with coagulation assays, particularly if residual DOAC levels persist at the time UFH is initiated. DOACs can prolong the APTT and elevate anti-Xa activity, leading to overestimation of UFH activity, inappropriate dose adjustments, and increased risk of bleeding or thromboembolic events. Here, we examine the laboratory implications of transitioning from DOAC therapy to UFH, with a focus on the performance and interpretation of APTT and anti-Xa assays in the presence of residual DOAC levels and how to overcome the interference of DOAC in UFH monitoring. We suggest an algorithm to follow during this transition.

Clinical laboratory results are inherently uncertain. Variability arises when repeating measurements of the same sample under different conditions. Measurement uncertainty (MU) is a metrological framework that quantifies this variability, enabling clinical interpretation and comparison of results within and between patients. In hemostasis assays, MU describes uncertainty propagation across the entire traceability chain-from international standards to final patient results.The Guide to the Expression of Uncertainty of Measurement (GUM) offered a statistically rigorous but complex method for estimating MU, limiting its widespread adoption. A relatively recent technical specification (TS) from the International Standardization Organization (ISO; ISO/TS 20914:2019) introduced a top-down approach that balances rigor with operational feasibility, supporting ISO 15189 compliance. However, its applicability to specialist areas such as hemostasis has been questioned. Furthermore, despite improved understanding of calculation methods, international guidance recommends against reporting results, together with MU, directly to service users; instead, the laboratory is required to provide it upon request. This review explores the implementation of different approaches for MU in hemostasis laboratories.

Lupus anticoagulant (LA) positive only (negative anticardiolipin antibodies [aCL] and anti-β2 glycoprotein I antibodies [aβ2GPI]) thrombosis represents a clinical challenge. It is often unclear whether the cause of thrombosis is LA or whether other clinical conditions have led to an episode of venous thromboembolism (VTE) or arterial thromboembolism (ATE). Recent antiphospholipid syndrome (APS) classification criteria assign different scores to thrombotic events based on the presence of confounding risk factors. In the presence of strong associated risk factors, patients are not classified as having APS as a score less than 3 points is assigned to the clinical domain. This study evaluated patients LA positive only included in the group of APS in the START2 Antiphospholipid Registry. The aim of the study was to determine how many of them did not meet the new APS classification criteria due to the presence of associated risk factors. Of the 488 patients enrolled in the START Antiphospholipid Registry, 86 (18%) had LA positive only and 43 had a previous thromboembolic event (33 VTE and 10 ATE). Of the 33 patients with VTE (9%), 3 had a high-risk VTE profile and 2 had a high-risk ATE profile and did not meet the new classification criteria. The updated criteria appropriately limit the inclusion of patients with high-risk thrombotic profiles in APS research studies. Although risk factors and not LA may be the cause of thrombosis, the presence of LA can complicate treatment decisions in clinical practice.

Congenital factor V (FV) deficiency, affecting approximately 1 in 1 million individuals worldwide, remains among the rare bleeding disorders (RBDs) without a licensed factor-specific replacement therapy. While other RBDs have successfully transitioned from plasma-based treatment to approved factor concentrates-exemplified by factor X deficiency's progression to US Food & Drug Administration (FDA)-approved Coagadex and two FDA-approved concentrates for factor XIII deficiency-FV deficiency treatment has remained unchanged for decades, relying solely on plasma and platelet transfusions. Two promising therapeutic candidates have emerged: a human plasma-derived FV concentrate demonstrating in vitro correction of severe deficiency, and an engineered activated FV (superFVa) showing potent hemostatic activity in preclinical models. This commentary outlines a pragmatic pathway to clinical trials, leveraging proven development strategies from other RBDs, existing registry infrastructure, and regulatory incentives for rare diseases. We propose phased trials combining pharmacodynamic endpoints with clinical outcomes, enabling feasible enrollment while generating decision-grade evidence. The time has come to extend modern therapeutic development to FV deficiency.

Traditionally, platelet function has been defined in the context of their role in hemostasis and thrombus formation. In recent years, however, the concept of platelet function has expanded, as emerging evidence supports that platelets-despite their small size-serve as versatile and potent modulators in a wide range of biological processes, including immune responses. In the neonatal period, the immune response is immature and particularly susceptible to dysregulation. The distinct properties of neonatal platelets, compared with those of adults, may influence both the sensitivity and the magnitude of the inflammatory response. The aim of this review is to summarize current knowledge regarding the involvement of platelets in neonatal sepsis, to highlight the immunological and molecular characteristics implicated in this process, and to identify research gaps that limit the use of platelets as diagnostic and therapeutic targets in this particularly vulnerable population.

Disseminated intravascular coagulation (DIC) is a severe complication often associated with critical illness. DIC is characterized by an uncontrolled systemic activation of the hemostatic system, leading to substantial consumption of platelets and coagulation factors. The diagnosis of DIC relies on a combination of clinical findings and laboratory results, yet DIC remains challenging to confirm, especially in early stages. This systematic review investigates the reported associations between platelet function and DIC and evaluates the potential of using platelet function markers as a supplement for DIC diagnosis. PubMed and Embase were searched for relevant literature. Human studies, which included patients with DIC and assessed platelet function using dynamic platelet function assays or soluble markers, were included. In total, 24 studies met the inclusion criteria. We found that DIC patients generally exhibit increased platelet activation in vivo, indicated by elevated plasma levels of soluble markers, while ex vivo platelet aggregation was consistently reduced compared to non-DIC patients and healthy controls; however, not all studies adjusted their results for platelet count. Soluble P-selectin was the most frequently studied plasma marker and was consistently increased in DIC patients; this was most pronounced when adjusted for platelet count. However, there was considerable heterogeneity between studies regarding both study design, patient populations, platelet function assessment, and DIC diagnosis, which complicates the comparison of findings across studies. Future studies accounting for low platelet counts in dynamic function tests are necessary to assess the role of platelet aggregation in relation to DIC.

Venous thromboembolism (VTE) represents a significant global health challenge, ranking as the third leading cause of cardiovascular-related mortality. VTE pervades diverse clinical specialties, posing substantial risks to patient well-being and imposing considerable economic strains on health care systems. While platelets have long been recognized as pivotal players in hemostasis, emerging evidence underscores their multifaceted immune functions and their capacity to engage in crosstalk with other immune cells, such as neutrophils, thereby fostering immune-related thrombosis. Notably, investigations have elucidated the pivotal role of platelets in the pathogenesis of VTE. This review provides a comprehensive overview of platelet physiology, encompassing their activation, secretion dynamics, and implications in VTE. Moreover, it delineates the impact of platelet interactions with various immune cells on the initiation and progression of VTE, explores the correlation between platelet-related laboratory markers and VTE, and elucidates the role of platelets in thrombosis regression.