von Willebrand disease (VWD) is the most commonly inherited bleeding disorder, with a prevalence surpassing hemophilia A. Unfortunately, VWD may be variously underdiagnosed, overdiagnosed, or misdiagnosed, depending on t...von Willebrand disease (VWD) is the most commonly inherited bleeding disorder, with a prevalence surpassing hemophilia A. Unfortunately, VWD may be variously underdiagnosed, overdiagnosed, or misdiagnosed, depending on the expertise of the managing clinician and testing laboratories. Diagnostic challenges are due to the heterogeneity of VWD and the complexities surrounding laboratory assessment, including reactive influences on VWF levels. At least six types of VWD can be identified, with these classified according to the functional defect and/or level of deficiency in the plasma protein von Willebrand factor (VWF). The VWF protein has several functions, most of which can be assessed by laboratory testing; however, this increases the diagnostic complexity, and clinicians/laboratory staff may not understand the differences in these tests and what they assess. Thus, a battery of laboratory tests is required to enable an effective diagnosis or exclusion of VWD, as well as its type classification. VWD was first identified in a young female patient by Erik von Willebrand in 1924, with a seminal publication on his findings appearing in the literature in 1926. This year, 2026, represents 100 years of VWD. We review some of the history of VWD, as well as outlining the contemporary diagnostic pathway for VWD, assisted by several illustrative case examples.
Coronavirus disease 2019 (COVID-19)-associated coagulopathy (CAC) is a thromboinflammatory syndrome marked by endothelial injury, micro- and macrovascular thrombosis, and, in a minority, late consumptive bleeding. D-dime...Coronavirus disease 2019 (COVID-19)-associated coagulopathy (CAC) is a thromboinflammatory syndrome marked by endothelial injury, micro- and macrovascular thrombosis, and, in a minority, late consumptive bleeding. D-dimer elevation was found to be one of the most consistent laboratory abnormalities and an established marker of severity. In this review, we explore how artificial intelligence methods were applied during the pandemic to predict thrombotic and mortality outcomes and to clarify mechanisms. Across studies, a consistent lesson was that D-dimer is most informative even when embedded within multivariable and time-aware models. Mechanistic machine learning (ML) analyses converged on an IL-6-centered immunothrombotic network, which associated cytokine signaling with complement activation. They highlighted how integrated proteomic and coagulation phenotyping can identify potentially actionable pathways. ML also quantified residual thrombotic risk despite standard thromboprophylaxis, suggesting that a high-risk minority may be detectable for closer monitoring or trial enrolment. Most CAC models, however, remain retrospective with limited external validation. They are also vulnerable to D-dimer assay heterogeneity and may drift across variants and vaccination eras. Future progress will depend on prospectively validated models that can stratify treatable subgroups and guide risk-adapted anticoagulation and immunomodulatory strategies beyond acute COVID-19.
Myeloproliferative neoplasms (MPNs) are clonal hematopoietic disorders characterized by elevated thrombotic and bleeding risk, and optimal risk stratification and management remain challenging. This review summarizes cur...Myeloproliferative neoplasms (MPNs) are clonal hematopoietic disorders characterized by elevated thrombotic and bleeding risk, and optimal risk stratification and management remain challenging. This review summarizes current evidence on the thrombotic complications in MPNs, including venous events (i.e., deep vein thrombosis, pulmonary embolism, and unusual site thrombosis), and arterial events (ischemic stroke, myocardial infarction, and peripheral arterial thrombosis), and the increased bleeding risk in these diseases. Mechanistically, JAK2-driven clonal hematopoiesis, elevated hematocrit, leukocytosis, platelet activation, endothelial dysfunction, and chronic inflammation interact to promote a pro-thrombotic state; conversely, extreme thrombocytosis, acquired von Willebrand syndrome, and anticoagulant/antiplatelet therapy contribute to bleeding risk. Clinically, thrombosis may precede MPN diagnosis, especially in unusual sites, and treatment should balance the risk of recurrent thrombosis against the risk of hemorrhagic complications. Antithrombotic strategies include low-dose aspirin, vitamin K antagonists, and direct oral anticoagulants, while cytoreductive therapy (hydroxyurea, anagrelide, interferon, and JAK inhibitors) is central for disease control as well as vascular risk reduction. Despite therapy, recurrence of thrombotic events and major bleeding persists, highlighting the need for optimized risk models and alternative therapeutic targets. Future research may focus on integrating molecular biomarkers, inflammation metrics, and vascular-specific endpoints to direct personalized preventive strategies.
Direct oral anticoagulants (DOACs) have largely replaced vitamin K antagonists owing to their predictable pharmacokinetics and improved safety. In emergency situations such as urgent surgery, major bleeding, or thromboly...Direct oral anticoagulants (DOACs) have largely replaced vitamin K antagonists owing to their predictable pharmacokinetics and improved safety. In emergency situations such as urgent surgery, major bleeding, or thrombolysis for acute ischemic stroke, rapid assessment of clinically relevant DOAC activity is essential. Conventional viscoelastic testing (VET) using devices such as ROTEM, TEG 5000, TEG6s, or ClotPro is insufficiently sensitive to detect DOACs, prompting the development of modified assays with specific activators. This systematic review summarizes recent advances in VET-based DOAC detection and evaluates the diagnostic performance of novel assay strategies and their correlation with plasma drug concentrations. A systematic search of PubMed and Google Scholar (January 2019-June 2025) was conducted in accordance with PRISMA 2020 recommendations. Twelve of 113 identified studies met the inclusion criteria. Ecarin-based assays demonstrated 100% sensitivity and specificity for detecting the direct thrombin inhibitor dabigatran. For direct factor Xa inhibitors-rivaroxaban, apixaban, and edoxaban-modified assays using Russell's Viper Venom, factor Xa-based reagents, and low-tissue-factor activation showed variable but generally good correlations with drug levels ( = 0.571-0.969). Sensitivity was lower for apixaban (83-97%) than for rivaroxaban (90-100%) and edoxaban (100%). Factor Xa-based and low-tissue-factor assays achieved sensitivities of 85 to 100% and specificities of 62 to 100%. In summary, modified VET assays show promise as rapid point-of-care tools for DOAC detection in emergency settings. Ecarin-based tests appear reliable for dabigatran, while Russell's Viper Venom and low-tissue-factor approaches may enable detection of direct factor Xa inhibitors. However, further clinical validation and standardization are required before routine implementation.
Efmoroctocog alfa (ELOCTATE) and rurioctocog alfa pegol (ADYNOVATE) are extended half-life (EHL) recombinant human coagulation factor VIII (rFVIII) products indicated for the prophylaxis of bleeding and in the perioperat...Efmoroctocog alfa (ELOCTATE) and rurioctocog alfa pegol (ADYNOVATE) are extended half-life (EHL) recombinant human coagulation factor VIII (rFVIII) products indicated for the prophylaxis of bleeding and in the perioperative setting in patients with hemophilia A. Continuous infusion (CI) using a standard half-life (SHL) rFVIII is an established alternative to bolus infusion (BI) for surgical procedures or major bleeds and has several advantages over BI, including the ability to maintain stable FVIII levels and cost savings due to reduced product usage. There is no published stability data for efmoroctocog alfa and rurioctocog alfa pegol, and the manufacturers currently recommend the use of rurioctocog alfa pegol via BI within 3 hours of reconstitution and efmoroctocog alfa via BI within 6 hours of reconstitution. The aim of this study was to determine the in vitro stability of efmoroctocog alfa and rurioctocog alfa pegol over a 5-day period. Triplicate samples of efmoroctocog alfa and rurioctocog alfa pegol were tested. After reconstitution, the product was diluted in FVIII-deficient plasma to achieve a baseline FVIII activity of 0.8 to 1.2 U/mL. Assessment of sample integrity and one-stage FVIII assays were performed on each sample at 0, 3, 6, 12, 24, 48, 72, and 96 hours. The in vitro FVIII did not decrease over the 96 hours following reconstitution. The average FVIII activity for efmoroctocog alfa was 1.03 ± 0.17 U/mL, and the average FVIII activity for rurioctocog alfa pegol was 1.06 ± 0.12 U/mL. Efmoroctocog alfa and rurioctocog alfa pegol demonstrated stability for 96 hours. This suggests that CI would be feasible for these EHL products.
Semin Thromb Hemost
· 2026 Mar · PMID 41802775
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Full text
Thrombosis is a central driver of both early and late arteriovenous fistula (AVF) failure. While symptomatic thrombosis contributes to early AVF occlusion and is treated promptly, the role of asymptomatic mural thrombi i...Thrombosis is a central driver of both early and late arteriovenous fistula (AVF) failure. While symptomatic thrombosis contributes to early AVF occlusion and is treated promptly, the role of asymptomatic mural thrombi in human AVF remains poorly understood. Indirect evidence suggests that these thrombi contribute to late juxta-anastomotic neointimal hyperplasia, luminal stenosis, and AVF failure. Using complementary mouse and rat AVF models, we recently demonstrated the interplay between disturbed arteriovenous (AV) flow, acute AV thrombus, and eccentric and heterogeneous neointimal lesions. These studies indicate that thrombus formation and organization are not merely acute events, but active modulators of juxta-anastomotic remodeling, highlighting the critical role of early thrombosis in AVF maturation and failure. This review summarizes recent advances in understanding the mechanistic role of thrombosis in AVF remodeling, stenosis, and access failure, providing insight into potential strategies to improve vascular access outcomes.
Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host immune response to an infection. Sepsis is often associated with significant hemostatic disorders that may lead to extensive intravasc...Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host immune response to an infection. Sepsis is often associated with significant hemostatic disorders that may lead to extensive intravascular thrombosis, disseminated intravascular coagulation (DIC), multi-organ dysfunction syndrome (MODS), and increased mortality. Sepsis-induced coagulopathy (SIC) is currently recognized as an early distinct phase of hemostatic derangement caused by sepsis, and a prodrome of overt DIC. SIC is characterized by endovascular clotting activation, hypercoagulability, and consumption of clotting factors and platelets. DIC, traditionally considered the final stage of this process, is now recognized as a part of a continuum of pathophysiological dysregulation with a distinct clinical significance. Despite being extensively studied in the adult population, SIC remains poorly defined in neonates. The distinct characteristics of neonatal hemostasis, coupled with immunological immaturity, pose significant challenges to the direct application of adult diagnostic approaches of SIC in this population. This review focuses on the pathophysiological mechanisms of SIC and the unique characteristics of neonatal hemostasis, summarizes current knowledge regarding the underlying mechanisms of neonatal SIC, and explores the developmental interplay between inflammation and hemostasis. By integrating current evidence, the review aims to establish a conceptual framework that will guide future experimental and clinical studies directed toward improving the management and outcomes of neonates who develop coagulopathy during sepsis.
Thrombin plays a central role in hemostasis, serving as both the primary enzyme driving fibrin formation and the central regulator of anticoagulant pathways. Routine coagulation assays, such as prothrombin time and activ...Thrombin plays a central role in hemostasis, serving as both the primary enzyme driving fibrin formation and the central regulator of anticoagulant pathways. Routine coagulation assays, such as prothrombin time and activated partial thromboplastin time, capture only a limited fraction of thrombin's role, overlooking inhibitory pathways and downstream regulation. Thrombin generation assays (TGAs) provide a global view of coagulation, measuring both formation and inhibition of thrombin over time. TGAs generate thrombin activity curves, from which parameters such as lag time, peak thrombin, time to peak, velocity index, and endogenous thrombin potential are derived. These parameters reflect hyper- or hypocoagulability and have been linked to clinical outcomes. Applications include monitoring anticoagulant therapy and reversal strategies, predicting venous thromboembolism recurrence, assessing thrombotic risk in cardiovascular disease and antiphospholipid syndrome, and stratifying bleeding risk in bleeding disorders. TGAs can also evaluate the efficacy of bypassing agents and novel hemostatic drugs in ex vivo settings. Barriers include technical complexity, preanalytical variability, and lack of standardization across laboratories. TGAs provide a global assessment of coagulation, demonstrating added value in both hyper- and hypocoagulable states. While most data remain research-based, growing evidence supports their utility in thrombotic risk prediction and bleeding risk assessment. Wider adoption in clinical practice will depend on assay standardization, validation in multicenter studies, and integration into clinical decision-making pathways.
Coagulopathies are common in hematological malignancies and can cause life-threatening bleeding or thrombosis. Extracellular vesicles (EVs), including exosomes, microvesicles, and apoptotic bodies, carry cargo that refle...Coagulopathies are common in hematological malignancies and can cause life-threatening bleeding or thrombosis. Extracellular vesicles (EVs), including exosomes, microvesicles, and apoptotic bodies, carry cargo that reflects their cellular origin. They frequently express tissue factor (TF) and expose phosphatidylserine (PS), which initiate and amplify coagulation and can also transport fibrinolytic mediators that modulate plasmin generation. Procoagulant EVs are commonly assessed using TF- and PS-dependent functional assays, global hemostasis tests such as overall hemostatic potential, and flow cytometric phenotyping. Clinical and experimental data show elevated EV numbers and activity at diagnosis in several hematological malignancies. In acute leukemias, EV-associated procoagulant activity often declines with treatment yet may remain above control levels, consistent with residual risk. In plasma cell disorders and myeloproliferative neoplasms, platelet-derived and TF/PS-positive EVs are frequently increased and have been linked to enhanced thrombin generation. EVs appear to play key roles across leukemias, multiple myeloma, lymphoid, and myeloproliferative neoplasms. However, considerable methodological heterogeneity, including differences in preanalytical handling, EV isolation, characterization, and activity measurement, limits comparability and clinical translation. Disease-specific mechanistic studies are needed to clarify how EVs modulate hemostasis in different hematologic malignancies. In parallel, standardized protocols and adequately powered clinical studies are required to validate EVs as biomarkers.
Salazar E, Smock KJ, Cazzolli T
… +12 more, Dlott JS, Lickteig N, Long TA, Mulvey JJ, Gil MR, Rollins-Raval M, Teruya J, Volod O, Walker CA, Wool GD, Zantek ND, Goodwin Iv AJ
Measurement of D-dimer, a fibrin degradation product, is crucial for diagnosing thrombotic and fibrinolytic conditions. Despite its expanding utility, D-dimer testing faces challenges due to varying assay methodologies a...Measurement of D-dimer, a fibrin degradation product, is crucial for diagnosing thrombotic and fibrinolytic conditions. Despite its expanding utility, D-dimer testing faces challenges due to varying assay methodologies and nonstandardized reporting. To understand D-dimer reporting practices, the College of American Pathologists Hemostasis and Thrombosis Committee analyzed proficiency testing data from D-dimer surveys conducted between 2020 and 2023 across multiple laboratories. The data demonstrate that laboratories commonly report units that differ from the assay package insert when reporting their proficiency testing results. We sought to assess variability in reporting practices and opportunities for improvement in D-dimer reporting amongst participants. To accomplish this, we harmonized all D-dimer results to ng/mL fibrinogen equivalent units from one distributed sample and assessed distinct populations of entries per instrument/reagent combination. Notable trends emerged from this analysis. Data from laboratories using the same instrument/reagent combinations clustered around different means, suggesting issues with unit reporting and/or conversion. Entries reported in mg/L or ug/mL D-dimer units commonly exhibited significant deviations from the dominant population. For one instrument/reagent combination, most reported values differed by approximately twice the certificate of analysis value. This analysis highlights potential issues with D-dimer reporting in proficiency testing. Whether these issues translate into issues with clinical D-dimer reporting requires further study.
Guidelines recommend placement of inferior vena cava filters (IVCFs) in patients with acute proximal lower extremity deep vein thrombosis (DVT) and a contraindication to anticoagulation. IVCF placement during pregnancy o...Guidelines recommend placement of inferior vena cava filters (IVCFs) in patients with acute proximal lower extremity deep vein thrombosis (DVT) and a contraindication to anticoagulation. IVCF placement during pregnancy or immediately postpartum presents technical challenges and is not extensively described in the existing literature.This study aimed to describe the use of IVCFs in the obstetric population along with outcomes related to filter placement.Retrospective chart review of all patients at Mayo Clinic from 2001 to 2020 with an IVCF at the time of conception or who underwent placement during pregnancy/postpartum.About 24 pregnancies in 23 women (mean age 26.3 years, range 18-41) were included: 5 (21%) with IVCF placement prior to pregnancy, 7 (29%) during pregnancy, and 12 (50%) during postpartum. IVCFs placed during pregnancy were frequently in the suprarenal position, in 5 (71%) cases. Meanwhile, 16 (94%) were deployed in an infrarenal position prior to pregnancy and postpartum. Complications included multiple attempts to remove the IVCF ( = 2), severe angulation ( = 4), embedded struts ( = 3), fracture ( = 1), and one case of cardiac tamponade ( = 1). Complications were more common when placement was performed prior to pregnancy or during pregnancy (2, 40% and 4, 57% respectively) versus postpartum (2, 17%).IVCF placement prior or during pregnancy/postpartum is uncommon and is associated with a high incidence of complications, although most did not fundamentally impact clinical outcomes. While IVCFs remain an option for clinicians treating pregnant and postpartum patients, these should be considered a last resource.
The antiphospholipid syndrome (APS) is a complex autoimmune disease that causes a state of hypercoagulability that can result in recurrent venous and arterial thromboses. APS may lead to cardiac manifestations requiring...The antiphospholipid syndrome (APS) is a complex autoimmune disease that causes a state of hypercoagulability that can result in recurrent venous and arterial thromboses. APS may lead to cardiac manifestations requiring cardiac surgery with cardiopulmonary bypass (CPB). Perioperative anticoagulation management in APS patients is complex. This complexity arises from both the prothrombotic nature of APS and the interference of antiphospholipid antibodies (aPLs) with phospholipid-dependent coagulation assays like activated clotting time. Given that current literature on CPB management in APS patients is largely limited to isolated case reports and lacks a comprehensive synthesis, this review summarizes the cardiac manifestations of APS, challenges posed by CPB, and current strategies for intraoperative anticoagulation management, including heparin dosing, anticoagulation monitoring methods, and protamine reversal practices. We further highlight gaps in evidence and propose a practical three-category framework for managing aPL-positive patients undergoing CPB.
Catastrophic antiphospholipid syndrome (CAPS) is a rare, potentially lethal, multiple-faceted, systemic disease, often triggered by a precipitating factor. Its tissue lesions are mainly the consequence of an antiphosphol...Catastrophic antiphospholipid syndrome (CAPS) is a rare, potentially lethal, multiple-faceted, systemic disease, often triggered by a precipitating factor. Its tissue lesions are mainly the consequence of an antiphospholipid antibody (aPL Abs)-mediated thrombotic microangiopathy associated with a so-called cytokine storm. Bleeding may coexist, making it difficult to manage. In an emergency situation, the differential diagnosis is not always straightforward in patients not known to be aPL Abs carriers, or with no history of thrombotic or obstetric complications. What we have gradually learned about its clinical presentation and therapeutic management mainly comes from the CAPS registry. So far, there have been no randomized controlled trials to guide treatment. The current therapeutic recommendations insist on prescribing first-line triple therapy, combining early anticoagulation, immunosuppression, and the removal/neutralization of aPL Abs, as early as possible. The prognosis has improved but remains bleak. Future research to develop pathophysiological treatments blocking the activation of target cells by aPL Abs is warranted.
People with hemophilia (PwH) face persistent joint damage risk despite prophylactic factor replacement therapies. Although muscles are recognized as biomechanical stabilizers, their broader protective mechanisms remain p...People with hemophilia (PwH) face persistent joint damage risk despite prophylactic factor replacement therapies. Although muscles are recognized as biomechanical stabilizers, their broader protective mechanisms remain poorly understood. This review provides an integrative theoretical framework that examines how muscles protect joints in PwH through three interconnected dimensions: (1) mechanical-via joint stabilization and force absorption; (2) neuromuscular control; and (3) biochemical regulation through exercise-induced myokines (exerkines). Muscle contractions provide joint stabilization and attenuate mechanical impacts via eccentric actions and muscle-tendon buffering, thereby reducing joint loading during daily activities. Neuromuscular control maintains joint stability through coordinated muscle activation, though excessive co-contraction in arthropathy can paradoxically increase joint stress. Critically, the endocrine function of skeletal muscle, producing anti-inflammatory and cartilage-protective exerkines including interleukin-6, irisin, and lubricin (among others), represents an underexplored yet crucial protective mechanism. Physical inactivity and intramuscular fat accumulation impair these protective functions, accelerating joint degeneration. This integrative theoretical perspective offers a comprehensive framework for understanding how muscles protect joints in hemophilia. Understanding these integrated mechanisms is essential for developing targeted rehabilitation strategies and guiding future research to optimize joint health in PwH.
Acquired Hemophilia A (AHA) is a rare bleeding disorder caused by factor VIII inhibitors. Standard therapies are limited by thrombotic risk and prolonged hospitalization. Emicizumab, approved for congenital Hemophilia A,...Acquired Hemophilia A (AHA) is a rare bleeding disorder caused by factor VIII inhibitors. Standard therapies are limited by thrombotic risk and prolonged hospitalization. Emicizumab, approved for congenital Hemophilia A, has emerged as a potential alternative in AHA based on case reports and early clinical trial data. To evaluate the efficacy and safety of Emicizumab in AHA through a retrospective real-world case series and a systematic literature review with patient-level data analysis. We retrospectively analyzed five AHA cases treated with Emicizumab at two Italian centers and performed a PRISMA-compliant systematic review of published reports, extracting and analyzing patient-level data using Joanna Briggs Institute tools. In the real-world cohort, early Emicizumab use in five patients with high-titer inhibitors and severe bleeding led to rapid hemorrhagic control, early withdrawal of bypassing agents, and no thrombotic or adverse events. All five patients received immunosuppression, and inhibitor eradication was achieved in 60% of patients, but for 40% follow up is still ongoing. The literature review identified 24 patients from 18 publications. Early Emicizumab administration (at admission) was associated with reduced bleeding recurrence (0% vs. 56.3%), shorter in-hospital stay (median 23.5 days vs. 39 days), and lower bleeding-related mortality (0% vs. 12.5%) compared with delayed administration. Early Emicizumab initiation appears to be a safe and effective strategy for AHA management, particularly in fragile or high-risk populations. Its subcutaneous route, favorable safety profile, and ability to reduce hospitalization support its integration into first-line therapeutic algorithms. Further prospective studies are warranted to define.