Seminars in thrombosis and hemostasis最新文献

Unfractionated heparin (UFH) remains a major anticoagulant therapy applied within the acute hospital system. Due to intra- and interpatient variability, UFH monitoring needs to be applied to ensure patients remain free of thrombotic and bleeding complications at too low and too high an UFH level, respectively. Monitoring of UFH therapy is usually achieved using either an activated partial thromboplastin time (aPTT) or an anti-factor Xa (anti-Xa) method. The former is a clotting assay that evaluates both the anti-factor IIa (anti-IIa or anti-thrombin) and anti-Xa anticoagulant activity of UFH and the latter is a chromogenic assay that evaluates just the anti-Xa anticoagulant activity of UFH. The aPTT method is perhaps more widely utilized since aPTT testing is performed by all hemostasis laboratories performing routine coagulation tests. However, the aPTT method requires establishment of an aPTT UFH therapeutic range. The anti-Xa method is favored in larger hospital sites and by most experts and uses a standard UFH therapeutic range. We report findings for aPTT and anti-Xa testing for UFH monitoring in our geographic region using recent data (testing for the past 5 years; 2020-2024 inclusive) from the Royal College of Pathologists of Australasia Quality Assurance Program, an international external quality assessment (EQA) program, with over 110 enrolments for this EQA module. Four samples are assessed each year, with these comprising various levels of UFH. Good reproducibility was observed for duplicate samples sent in different surveys. Coefficient of variation (%) data revealed moderate variation for samples containing UFH (10-40% for anti-Xa; 10-25% for aPTT). Anti-Xa reagents containing dextran sulphate tended to yield higher anti-Xa values than those without. Interpretations regarding UFH levels being below, within, or above therapeutic levels were generally reported as expected, according to the level of UFH present in the sample, especially for anti-Xa testing.

Hemophilia is a rare inherited bleeding disorder associated with recurrent musculoskeletal bleeding, chronic pain, and functional decline. Advances in prophylactic therapies, including extended half-life factors, non-factor therapies like emicizumab, and gene therapies, have fundamentally transformed care, enabling a paradigmatic shift from activity restriction to promotion. This review synthesizes recent evidence to examine the multifaceted role of physical activity (PA) in people with hemophilia (PwH), current challenges, and strategies to optimize health outcomes. PA confers substantial benefits for PwH, improving muscle strength, coordination, bone density, cardiovascular fitness, mental health, and quality of life. It modulates chronic pain through neuroplastic, anti-inflammatory, and neuroendocrine mechanisms, while exercise-derived molecules (exerkines) may directly influence cartilage health. With individualized prophylaxis and structured programming, both resistance and aerobic exercise can be prescribed safely using evidence-based risk stratification (categories I-III) and comprehensive monitoring approaches, including accelerometers, questionnaires, and subjective effort scales. Persistent barriers include chronic pain, fear of injury, insufficient professional guidance, and treatment inequities, while facilitators encompass enjoyment, social support, and adequate prophylactic coverage. Therapies providing continuous hemostatic protection have further expanded safe PA opportunities, supporting participation in previously restricted activities. In this new therapeutic era, PA should be recognized as a fundamental pillar alongside medical care. Not only for musculoskeletal preservation, but also as a strategy promoting metabolic and mental health. Ensuring access for all patients to both advanced therapies and tailored PA prescription, supported by education, enabling policies, and multidisciplinary care, is essential for democratizing active lifestyles within the global hemophilia community.

Sepsis is now considered a dysregulated host response in which inflammation, coagulation, and endothelial injury converge to create a self-amplifying network of thromboinflammation. This definition reflects maladaptive immunothrombosis-a defense mechanism that becomes pathogenic when excessive, rather than an isolated inflammatory process. This review integrates recent mechanistic advances linking damage-associated molecular patterns (DAMPs), endothelial dysfunction, and intravascular coagulation. Endogenous alarmins, such as high-mobility group box 1, histones, and mitochondrial DNA, engage in pattern recognition (Toll-like receptors, receptor for advanced glycation end products) to propagate leukocyte activation, platelet aggregation, and endothelial disruption. The resulting loss of critical endothelial anticoagulant molecules (thrombomodulin, endothelial cell protein C receptor, antithrombin) and glycocalyx degradation convert the vascular endothelium into a procoagulant interface. Complement activation and protease-activated receptor signaling reinforce this loop, producing microvascular thrombosis, capillary leakage, and organ ischemia. Platelet-leukocyte aggregates and neutrophil extracellular traps (NETs) serve as intravascular scaffolds for fibrin deposition, thereby propagating disseminated intravascular coagulation (DIC). Targeted interventions, including recombinant thrombomodulin, antithrombin supplementation, neutralization of NETs and DAMPs, complement blockade, and endothelial-protective strategies, seek to restore vascular homeostasis. A multidomain biomarker approach integrating DAMPs, endothelial markers, and coagulation indices, combined with machine learning-based phenotyping, may enable precision stratification of sepsis endotypes. The convergence of DAMP signaling, immune activation, and coagulation underlies the pathophysiologic continuum from sepsis-induced coagulopathy to DIC. Therapeutically interrupting this axis represents the most promising avenue toward personalized, mechanism-driven treatment in sepsis.

Lipoprotein(a) (Lp(a)) is a genetically determined, lifelong cardiovascular risk factor strongly associated with atherosclerotic cardiovascular disease (ASCVD) despite optimal low-density lipoprotein cholesterol (LDL-C) lowering. The current management is challenged by the absence of outcome-proven Lp(a)-specific therapies. Statins, ezetimibe, bempedoic acid, and lifestyle interventions have little or no effect on Lp(a). Statins may modestly raise levels; niacin is now contraindicated as it has not been shown to reduce cardiovascular or all-cause mortality, while PCSK9 (Proprotein Convertase Subtilisin/Kexin type 9) inhibitors and inclisiran reduce Lp(a) concentrations by approximately 20 to 30%, though this effect remains secondary to their LDL-C-lowering effect. The only U.S. Food and Drug Administration (FDA)-approved therapy specifically addressing Lp(a) is lipoprotein apheresis, which reduces Lp(a) levels by 60 to 75%, but is restricted to specific patient populations due to invasiveness, high cost, and limited availability. Future promise lies in RNA-based therapies, including antisense oligonucleotides (pelacarsen) and small-interfering RNAs (olpasiran, lepodisiran, SLN360), which achieve 80 to 95% sustained Lp(a) reductions. Large outcome trials will determine whether this biochemical efficacy translates into tangible clinical benefits. Current guidelines now recommend one-time lifetime Lp(a) measurement, treating ≥125 nmol/L (≥50 mg/dL) as a risk-enhancing factor. High or extreme elevations, especially with ASCVD, mandate aggressive LDL-C lowering, optimization of modifiable risk factors, family cascade screening, and apheresis or referral to RNA-therapy trials in select cases. Thus, while therapeutic options remain limited, systematic measurement and risk stratification are ethically justified to prepare for the imminent arrival of Lp(a)-targeted therapies.

Acquired von Willebrand syndrome (AVWS) is a rare condition characterized by an acquired functional and/or absolute deficiency of the von Willebrand factor (VWF) protein. The absence of widely accepted diagnostic criteria has hampered accurate estimates of incidence and prevalence, which are largely currently unknown. As bleeding symptoms are not included in the most widely used definitions, AVWS should be managed as a risk factor for bleeding, rather than a specific disease entity. The diagnostic workup is cumbersome, involving measurement of both VWF antigen, VWF glycoprotein Ib binding activity, VWF collagen binding activity, and, preferentially, also VWF multimer analyses. Moreover, since the presence of bleeding symptoms is not required for diagnosis, the condition is probably underdiagnosed. In contrast to acquired hemophilia, AVWS is seldom caused by the presence of specific antibodies, but rather secondary to another disorder, most commonly lymphoproliferative, myeloproliferative, cardiovascular, and autoimmune disorders. Pathogenesis of AVWS varies according to the underlying disorder and includes nonspecific adsorption of VWF to antibodies, adsorption onto surfaces of neoplastic cells, mechanical injury, or VWF proteolysis. Treatment includes treating the underlying cause as well as stopping acute bleeds. Here, we present a comprehensive review of what is currently known regarding demographics, diagnostics, and clinical presentation of the syndrome. Since no prospective treatment studies have been performed, treatment choices must be based on data from registries and case reports that are also summarized. Moreover, we present treatment experiences of previously unpublished Nordic cases.

Acute emotional stress can trigger acute coronary syndrome (ACS), potentially via hypercoagulable states. Circulating D-dimer is an established marker of fibrin turnover and stress-related coagulation activation, yet predictors of D-dimer stress reactivity remain unclear, especially in high-risk groups such as male physicians with burnout. We examined predictors of D-dimer changes during acute stress and recovery in 60 male physicians with and without burnout. Participants underwent the Trier Social Stress Test, with D-dimer and other biomarkers assessed across four time points over 1 hour. The area under the curve (AUC) for D-dimer was calculated to capture overall reactivity. We applied the least absolute shrinkage and selection operator (LASSO) regression to identify relevant predictors among demographic, behavioral, psychosocial, and physiological variables, followed by traditional linear regression to estimate effect sizes. LASSO regression identified five key predictors of D-dimer stress reactivity: Prestress D-dimer, habitual alcohol consumption, prestress cortisol, stress-induced epinephrine (EPI) surge, and adverse childhood experiences (ACEs). In linear regression, all but prestress cortisol remained significant independent predictors, collectively explaining 50.4% of the variance in D-dimer AUC. Specifically, higher alcohol consumption (ΔR ² = 0.117, p < 0.001), larger EPI surge (ΔR ² = 0.081, p = 0.003), and more ACEs (ΔR ² = 0.044, p = 0.026) were associated with heightened D-dimer responses, while higher prestress D-dimer was associated with attenuated reactivity (ΔR ² = 0.208, p < 0.001). Our findings highlight the role of early adversity, alcohol consumption, and sympathoadrenal activation in stress-induced coagulation activation, as reflected by D-dimer reactivity. If validated, these predictors may help identify individuals at elevated risk for stress-triggered ACS and inform targeted prevention strategies.

Bleeding complications are a frequent and clinically significant problem in patients with chronic kidney disease (CKD), with prevalence increasing as kidney function declines, and in those receiving dialysis. The bleeding tendency in CKD is multifactorial: arising from platelet dysfunction, uremic/inflammatory states, renal anemia, and the common concurrent use of anticoagulants in this population. Together, these mechanisms all contribute to impairment in hemostasis and increased risk of both spontaneous and procedural-hemorrhages. Current bleeding risk assessment tools perform poorly in the CKD population, limiting their utility for guiding clinical decision-making. Emerging evidence suggests that albuminuria, as an independent marker for both renal dysfunction and hemorrhage risk, may improve bleeding risk stratification in this cohort. This review summarizes the pathophysiological mechanisms underlying bleeding in CKD and the impact of dialysis and declining renal function. It also highlights the unmet need for more accurate, CKD-specific bleeding risk assessment tools.