Available products for the treatment of von Willebrand disease (VWD) now include a new recombinant von Willebrand factor (rVWF) in addition to plasma-derived concentrates (pdVWF). However, these two therapies have never...Available products for the treatment of von Willebrand disease (VWD) now include a new recombinant von Willebrand factor (rVWF) in addition to plasma-derived concentrates (pdVWF). However, these two therapies have never been compared directly in either preclinical studies or real-world inpatient settings.The Hopscotch Will II study examined the treatment of VWD in hospitals and compared the use of pdVWF and rVWF.Five Rare Bleeding Diseases Centers in Western France retrospectively included patients with VWD over a 48-month period. The data was collected from the BERHLINGO Research Database as well as the French Hospital database, which contains medical information from patient records.Of the 866 patients evaluated in the study, 285 underwent 648 hospitalizations; 126 adult patients (VWD type 3 excluded) were given VWF concentrates during 249 of those hospital stays. rVWF was used in 61% of the cases. The majority of the hospitalizations were motivated by cutaneous-mucosal symptoms in gastroenterology, stomatology, gynecology, and obstetrics. Consumption of rVWF was lower, though the difference in total VWF consumption per stay or per patient per year was not significant: 51 (57)/34 (30) IU/kg/patient/year for pdVWF versus 40 (47)/27 (26) for rVWF (mean [SD]/median [IQR], Wilcoxon rank sum test, = 0.2025).rVWF was used in similar patient profiles and for identical procedures, but the cost of treatment with rVWF was significantly lower, regardless of whether or not FVIII was added.
Worldwide, one in four adults and three in four children fail to meet the physical activity targets recommended by the World Health Organization (WHO). Patients with chronic diseases and disabilities represent some of th...Worldwide, one in four adults and three in four children fail to meet the physical activity targets recommended by the World Health Organization (WHO). Patients with chronic diseases and disabilities represent some of the least active populations. WHO guidelines encourage regular physical activity for individuals with disabilities, considering functional capacity and clinical status. Recommended interventions include moderate-to-vigorous activity, muscle-strengthening exercises at least twice weekly, and functional balance training at least three times per week, with specialist consultation as needed. Data on physical activity and sports participation in patients with chronic conditions such as inherited bleeding disorders are very limited. This narrative review updates the literature, focusing on von Willebrand disease and rare coagulation defects and highlighting the need for individualized, multidisciplinary recommendations to promote safe physical activity and optimize health outcomes.
Congenital factor VII (FVII) deficiency is the most common rare hemorrhagic disorder. Acquired FVII deficiency can be isolated or associated with other low coagulation factor levels. FVII levels do not accurately predict...Congenital factor VII (FVII) deficiency is the most common rare hemorrhagic disorder. Acquired FVII deficiency can be isolated or associated with other low coagulation factor levels. FVII levels do not accurately predict a patient's bleeding risk. In the case of surgery, the perioperative management needs to be evaluated on a case-by-case basis, considering the patient's bleeding history and the type of surgery. We present 12 patients with congenital or acquired FVII deficiency and describe the perioperative management with plasma-derived nonactivated FVII (pd-FVII) concentrate. Patients with factor VII deficiency treated with pd-FVII for perioperative hemostasis, between April 2022 and May 2025. We report thirteen procedures in 12 patients (11 males and 1 female; age range: 15-78 years). Two patients were affected by acquired deficiency, and 10 patients presented congenital deficiency. Perioperative prophylaxis with pd-FVII was performed at doses ranging from 20 to 40 IU/kg/dose. Total pd-FVII consumption ranged between 20 and 320 IU/kg. During and after surgery, there were no major bleeding or thrombotic events. In the postoperative period, only one patient presented with hematuria.
Tan JY, De Guzman MRT, Wong WH
… +4 more, Yeo CK, Goh GH, Ng HJ, Tan CW
Semin Thromb Hemost
· 2026 Jun · PMID 41506647
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ABSTRACT: Clot waveform analysis (CWA) extends routine coagulation assays (activated partial thromboplastin time [aPTT] and prothrombin time [PT]) by incorporating continuous optical monitoring to generate kinetic profil...ABSTRACT: Clot waveform analysis (CWA) extends routine coagulation assays (activated partial thromboplastin time [aPTT] and prothrombin time [PT]) by incorporating continuous optical monitoring to generate kinetic profiles of clot formation. This method provides both qualitative and quantitative information on hemostasis, with increasing evidence for its clinical utility in detecting factor deficiencies and characterizing thrombotic and bleeding disorders. Despite the growing body of evidence, translation of CWA into routine clinical practice remains limited. ABSTRACT: This review identifies three principal barriers: (1) variability arising from differences in optical detection methods (absorbance vs. transmittance), (2) interreagent variation even within the same analyzer platform, and (3) lack of a clear distinction between standard CWA, performed with commercially available reagents, and modified CWA, incorporating in-house adjustments. To address these challenges, we encourage adopting distinct nomenclature for detection modalities (CWA-A; A for absorbance and CWA-T; T for transmittance), establishing standardized reporting requirements including reagent and platform details, and establishing quality assurance frameworks for CWA. ABSTRACT: Standardization of terminology and reporting will enhance reproducibility, enable cross-study comparisons, and accelerate the clinical translation of CWA from the laboratory bench to the bedside.
Although several studies have investigated the roles of neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), and monocyte-to-high-density lipoprotein (HDL) cholest...Although several studies have investigated the roles of neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), and monocyte-to-high-density lipoprotein (HDL) cholesterol ratio (MHR), the findings remain inconclusive and warrant further investigation, particularly regarding their utility in predicting in situ inferior vena cava thrombosis (iIVCT). This study aimed to explore the relationship between composite inflammatory ratios (CIRs) measured within 24 hours after inferior vena cava filter (IVCF) placement and the development of iIVCT, as well as to evaluate their predictive value. A retrospective case-control study was conducted on 154 patients with proximal deep vein thrombosis (DVT) who underwent IVCF implantation between April 2016 and June 2023. Among them, 50 developed iIVCT, while 104 did not. Compared with the non-iIVCT group, patients who developed iIVCT had significantly higher PLR, NLR, LMR, and MHR levels. Multivariate regression analysis showed that NLR, PLR, LMR, and MHR were independently associated with iIVCT, with adjusted hazard ratios of 1.25, 1.16, and 3.32, respectively. Receiver operating characteristic analysis demonstrated that NLR had the highest area under the curve (area under the curve = 0.79), significantly outperforming PLR, LMR, and MHR in predictive accuracy (all < 0.05, DeLong's test). These findings suggest that CIRs are useful and easily accessible biomarkers for identifying patients at risk of iIVCT following IVCF placement. Notably, NLR emerged as the most effective marker, showing superior discriminatory power compared with the other indicators.
Dysfunctional or quantitatively deficient von Willebrand factor (VWF) underlies von Willebrand disease (VWD), the most common inherited bleeding disorder. Type 2A VWD is a qualitative defect marked by impaired VWF-depend...Dysfunctional or quantitatively deficient von Willebrand factor (VWF) underlies von Willebrand disease (VWD), the most common inherited bleeding disorder. Type 2A VWD is a qualitative defect marked by impaired VWF-dependent platelet adhesion, typically reflected in disproportionately reduced ratios of platelet-dependent VWF activity to antigen (VWF activity/VWF:Ag) and collagen binding to antigen (VWF:CB/VWF:Ag). This phenotype results from a selective reduction or lack of high- and intermediate-molecular-weight multimers, which are essential for effective hemostasis under high shear stress. The lack of multimer arises from impaired multimer assembly and/or increased proteolytic cleavage of VWF by ADAMTS13. Clinically, type 2A tends to present with greater severity than other type 2 variants, manifesting as mucocutaneous bleeding, often including heavy menstrual bleeding, epistaxis, post-surgical bleeding and gastrointestinal hemorrhage from angiodysplasia. Diagnosis relies on functional assays and VWF multimer analysis, supported by genetic testing that identifies subtype-specific mutations affecting VWF multimeric structure and therefore its function. Type 2A is typically inherited in an autosomal dominant manner, with rare exceptions of autosomal recessive inheritance. Structural and molecular studies are continuing to elucidate how domain-specific variants disrupt multimeric structure and thus interactions with its ligands. Management is guided by bleeding severity and includes desmopressin (following responsiveness testing) and VWF replacement therapy. This review provides an in-depth update on type 2A VWD, covering its epidemiology, pathophysiology across distinct subtypes, clinical manifestations, diagnostic approach, molecular and structural insights, and current therapeutic strategies.
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-fac...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.
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 o...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.
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 criteri...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.
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 i...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)...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.
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 pre...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 (Δ = 0.117, < 0.001), larger EPI surge (Δ = 0.081, = 0.003), and more ACEs (Δ = 0.044, = 0.026) were associated with heightened D-dimer responses, while higher prestress D-dimer was associated with attenuated reactivity (Δ = 0.208, < 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.
Congenital fibrinogen disorders (CFDs) result from deficiencies in the fibrinogen-encoding genes , , and , causing either quantitative or qualitative fibrinogen abnormalities. In this study, we conducted an extensive eva...Congenital fibrinogen disorders (CFDs) result from deficiencies in the fibrinogen-encoding genes , , and , 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 coagu...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 th...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.