Dutch national guidelines for therapeutic treatment with low-molecular-weight heparins (LWMHs) in patients with renal insufficiency recommend dose adjustment based on observed anti-Xa levels. The literature on the relati...Dutch national guidelines for therapeutic treatment with low-molecular-weight heparins (LWMHs) in patients with renal insufficiency recommend dose adjustment based on observed anti-Xa levels. The literature on the relationship between anti-Xa levels and clinical outcome in terms of bleeding events is inconsistent. The primary aim of this study was to investigate the incidence and correlation of bleeding events in relation to anti-Xa levels in patients with impaired renal function, using therapeutic nadroparin according to the national guidelines. The secondary objective was to investigate the correlation between the LMWH dose and bleeding events. This was a retrospective study of patients with impaired renal function treated with therapeutic nadroparin for which anti-Xa levels were monitored. Bleeding and thrombotic events were assessed for each patient. This study included 243 patients, of whom 61 (25%) had a bleeding event. There was no correlation between anti-Xa levels and the occurrence of bleeding. Although there was no difference in renal function, weight, or body mass index (BMI) between patients with or without a bleeding event, the median dose of nadroparin was significantly higher ( < 0.005) in patients with a bleeding event. In conclusion, for this study population, there was a high incidence of bleeding. No correlation was found between anti-Xa levels and the occurrence of a bleeding event, with the majority of anti-Xa levels being subtherapeutic. However, a correlation was found between the dose and the occurrence of a bleeding event. Therefore, it is questionable whether the focus on monitoring anti-Xa levels is a justified method to reduce the risk of a bleeding event.
Hemostasis in humans has traditionally been considered to be a function of platelets, coagulation, and the subendothelial matrix, but the role of red blood cells (RBCs) has been increasingly recognized. RBCs regulate hem...Hemostasis in humans has traditionally been considered to be a function of platelets, coagulation, and the subendothelial matrix, but the role of red blood cells (RBCs) has been increasingly recognized. RBCs regulate hemostasis through biophysical and biochemical means. For the former, faster-moving RBCs in the center of vessels marginalize platelets and plasma to the vessel walls, where the platelets constantly probe the endothelial surface for injury. RBC counts also determine blood viscosity, which regulates the shear stress of laminar blood flow. For the latter, RBCs are the largest pool of adenosine triphosphate (ATP), which, upon release, is rapidly hydrolyzed to adenosine diphosphate (ADP). Both ATP and ADP activate platelets. Quantitative and qualitative abnormalities in RBCs have also been consistently identified as significant risk factors for arterial and venous thrombosis. Thrombosis is a major complication associated with diseases such as polycythemia vera, secondary erythrocytosis, and sickle cell anemia, all of which present with changes in numbers and physical properties of RBCs. Thrombosis is also common in conditions with significant hemolysis, such as paroxysmal nocturnal hemoglobinuria, severe infections, and when patients are on mechanical support. In this review, we discuss findings from clinical observations and mechanistic studies of how RBCs regulate hemostasis and contribute to thrombosis.
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 c...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 , indicated by elevated plasma levels of soluble markers, while 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.
Coagulation factor XIII (FXIII) is an essential protein that stabilizes the hemostatic plug formed in the final stage of the coagulation reaction and controls its dissolution. In the blood, it exists as a heterotetramer...Coagulation factor XIII (FXIII) is an essential protein that stabilizes the hemostatic plug formed in the final stage of the coagulation reaction and controls its dissolution. In the blood, it exists as a heterotetramer consisting of A subunit dimers and B subunit dimers. Genetic defects in each subunit result in a congenital deficiency, which causes fatal or mild bleeding symptoms. Acquired FXIII deficiency can develop owing to reduced production or increased consumption of FXIII, and its severe form can cause various bleeding symptoms. In particular, autoimmune FXIII deficiency (AiF13D) causes fatal bleeding symptoms due to the suppression of FXIII activity by anti-FXIII autoantibodies and/or accelerated clearance of FXIII. AiF13D is characterized by extremely severe FXIII deficiency and severe bleeding symptoms. It is associated with the highest hemorrhagic mortality rate among autoimmune coagulation factor deficiencies, making it essential to differentiate it from other non-immune FXIII deficiencies (NiF13D), such as those arising from liver cirrhosis or leukemia. The probable and definitive diagnosis of AiF13D require the presence of FXIII inhibitors and anti-FXIII autoantibodies, respectively. FXIII inhibitors can be detected by a general FXIII activity assay in the mixed plasma of patients and healthy controls, and can be measured in a regular laboratory. In contrast, immunological assays are conducted in limited research facilities because they are not commercially available. NiF13D is usually treated by hemostatic therapy with FXIII concentrates, but AiF13D requires hemostatic therapy plus autoantibody eradication therapy with immunosuppressants. Since the disease often becomes resistant to treatment, long-term follow-up is strongly recommended.
Wohner N, Balog Virag K, Raska A
… +1 more, Kolev K
Semin Thromb Hemost
· 2026 Jul · PMID 40461019
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ABSTRACT: Tranexamic acid (TXA) is a widely used and cost-effective antifibrinolytic agent that has been utilized for decades in various clinical situations involving bleeding complications. Over time, a growing amount o...ABSTRACT: Tranexamic acid (TXA) is a widely used and cost-effective antifibrinolytic agent that has been utilized for decades in various clinical situations involving bleeding complications. Over time, a growing amount of clinical evidence has emerged, offering a robust basis for its applications. ABSTRACT: However, in certain clinical scenarios, TXA appears to be less effective, highlighting the need for further research into its mechanisms of action beyond its well-known antifibrinolytic effects. One area of particular interest is the interaction between TXA and blood cells, especially red blood cells (RBCs). This interaction has garnered significant attention due to intriguing findings from large clinical trials, such as the WOMAN-1 and -2 studies, which evaluated the efficacy of TXA in preventing bleeding in postpartum hemorrhage, a major childbirth complication. These trials revealed that TXA was less effective in anemic patients, raising important questions about its broader mechanisms of action. ABSTRACT: Emerging evidence suggests that the relationship between TXA and blood cells plays a crucial role at various stages of hemostasis, expanding its established role in fibrinolysis inhibition. Recent investigations into the interactions between TXA and RBCs have been particularly compelling and may provide valuable insights for improving clinical outcomes. ABSTRACT: This review provides a fresh look at the interplay between RBCs, TXA, and the hemostatic system, focusing on basic molecular mechanisms and their potential implications for clinical practice.
Huang G, Wu H, Lin B
… +5 more, Deng D, Liu Y, Qu J, Xu J, Wang B
Semin Thromb Hemost
· 2026 Feb · PMID 40461018
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Acute ischemic stroke (AIS) is a life-threatening thrombotic disorder, with intravenous thrombolysis (IVT) serving as the first-line treatment during its acute phase. However, thrombolysis resistance diminishes the succe...Acute ischemic stroke (AIS) is a life-threatening thrombotic disorder, with intravenous thrombolysis (IVT) serving as the first-line treatment during its acute phase. However, thrombolysis resistance diminishes the success rate of early reperfusion. Recent studies have highlighted neutrophil extracellular traps (NETs) as a critical factor contributing to thrombolysis resistance. Targeting NETs with deoxyribonuclease I (DNase I) has been shown to significantly improve the thrombolytic efficacy of recombinant tissue plasminogen activator (rt-PA) and reduce the risk of hemorrhagic transformation. In this review, we summarize current knowledge on the mechanisms by which NETs contribute to thrombosis and thrombolysis resistance, explore the prospective and feasibility of targeting NETs to improve thrombolysis, providing information about the creation of innovative thrombolytic treatment approaches for AIS.
Neutrophils are astonishing cells involved in nonspecific immunity, especially against bacterial and fungal infections. Their half-life is short, but despite their important role in nonspecific immunity, they defend the...Neutrophils are astonishing cells involved in nonspecific immunity, especially against bacterial and fungal infections. Their half-life is short, but despite their important role in nonspecific immunity, they defend the host even after their death by providing secondary structures such as neutrophil extracellular traps (NETs). NETs are a network comprising DNA, histones, and proteins, including elastase, cathepsin G, and myeloperoxidase. In this context, in addition to their primary role in hemostasis, they also play a role in thrombosis, an area that has received less attention. Nonetheless, NETs can promote both venous and arterial thrombus formation (immuno-thrombosis), by their effects on primary and secondary hemostasis; their participation in thrombus formation includes the release of microparticles and components of the inflammasome. Neutrophils in interaction with other cells including platelets can further contribute to thrombosis. Activated platelets can capture neutrophil-derived microparticles containing tissue factor (TF), leading to TF accumulation and increased fibrin deposition. Furthermore, neutrophil inflammasomes as a regulator of the generation of IL-1 family proteins have been shown to augment thrombosis formation in response to hypoxia. Overall, understanding the complex and reciprocal effects of neutrophils with other hemostasis-related cells and components provides important insights into hemostatic mechanisms, and this may open avenues in medical research and potential therapeutic interventions.
Thrombosis and hemostasis are critical processes that maintain vascular integrity, yet imbalances can lead to life-threatening cardiovascular events. Traditionally, erythrocytes were considered passive bystanders in coag...Thrombosis and hemostasis are critical processes that maintain vascular integrity, yet imbalances can lead to life-threatening cardiovascular events. Traditionally, erythrocytes were considered passive bystanders in coagulation, but emerging evidence highlights their active role in thrombogenesis, particularly through redox biology. Erythrocytes generate reactive oxygen and nitrogen species (RONS) via Hb autoxidation, NADPH oxidase activation, and external uptake from other blood components. This oxidative environment induces structural and functional modifications, including increased rigidity, phosphatidylserine exposure, microvesicle release, and enhanced adhesion to endothelial cells and platelets, all contributing to a prothrombotic phenotype. Hemorheological alterations such as increased aggregation and decreased deformability further exacerbate blood stasis and thrombus formation. Oxidative stress also accelerates hemolysis, releasing free Hb and heme, which trigger inflammatory responses and endothelial dysfunction, further amplifying thrombogenic potential. Additionally, erythrocyte-derived microvesicles act as carriers of procoagulant factors, enhancing thrombin generation and fibrin network formation. These mechanisms underscore the erythrocyte-ROS axis as a crucial determinant of thrombosis. Despite these insights, the full scope of erythrocyte-mediated redox signaling in thrombotic processes remains incompletely understood. This review discusses the multifaceted impact of erythrocyte oxidative stress on thrombosis and hemostasis, exploring its implications in cardiovascular diseases, metabolic disorders, and hematological conditions. Understanding these pathways may lead to novel therapeutic approaches targeting erythrocyte redox homeostasis to mitigate thrombotic risk and improve patient outcomes.
Platelet function testing is essential for diagnosing and managing platelet function disorders, but faces significant challenges due to complex protocols and variability in results. While light transmission aggregometry...Platelet function testing is essential for diagnosing and managing platelet function disorders, but faces significant challenges due to complex protocols and variability in results. While light transmission aggregometry remains the gold standard for assessing platelet aggregation, it suffers from several limitations, including labor-intensive protocols, variability in reagents, and poor standardization. Over the decades, improvements such as lumi-aggregometry, which integrates granule secretion testing, and impedance whole-blood aggregometry, which simplifies sample handling, have addressed some of these challenges. Advanced granule secretion assays, including high-performance liquid chromatography and flow cytometry, have further enhanced diagnostic capabilities, although these techniques still depend on specialized expertise and expensive equipment. Recently, significant advancements have been made with automated aggregometers, such as the Sysmex CS series, and high-throughput 96-well plate assays, which improve consistency, throughput, and reproducibility. Nonetheless, further refinement in standardized reagents and consensus-driven protocols is required. Microfluidic technologies, exemplified by systems like the Total Thrombus Analysis System (T-TAS), incorporate physiological shear conditions and real-time thrombus formation assessment, providing enhanced diagnostic insights into platelet behavior. Despite their automation and clinical feasibility, these flow-based systems still require broader validation for routine clinical implementation. Further developments should prioritize integrating complementary assays, enhancing automation, and advancing miniaturization to improve standardization and diagnostic accuracy. Future technologies combined with artificial intelligence-based data interpretation hold the promise to transform platelet diagnostics, enabling personalized patient care. However, achieving widespread clinical adoption requires ongoing collaboration between clinicians, laboratories, industry, and regulatory bodies.
Acute pulmonary embolism (PE) is potentially life-threatening, with up to 15% risk of death. We compared four risk stratification models to identify outpatients at risk of mortality up to 90 days post acute PE. A retrosp...Acute pulmonary embolism (PE) is potentially life-threatening, with up to 15% risk of death. We compared four risk stratification models to identify outpatients at risk of mortality up to 90 days post acute PE. A retrospective cohort study included outpatients aged ≥18 years with confirmed PE from June 1, 2014 to May 31, 2019, identified via diagnostic imaging reports. Simplified Pulmonary Embolism Severity Index (sPESI) and Hestia scores were calculated as per original derivation methods. Patients were stratified by four models: sPESI alone, Hestia alone, sPESI plus right ventricular dysfunction (RVD), and Hestia plus RVD. Model accuracy and discriminatory power for 30- and 90-day mortality were assessed by area under the receiver operating curve (AUC). The study comprised 785 outpatients (mean age 65.0 years; 42.2% male). Overall mortality rates were 4.1% at 30 days and 7.8% at 90 days. sPESI identified 31.5% as low risk versus 19.1% by Hestia. All models demonstrated 100% sensitivity and negative predictive value for 30-day mortality, but modest discriminatory power (AUC range: 59.2-67.1). sPESI consistently outperformed other models in both timeframes. Including RVD with sPESI or Hestia did not enhance accuracy and slightly reduced performance. The net reclassification index indicated minor improvement in non-event classification with RVD, but no benefit for identifying deaths. sPESI remains a modest yet effective predictor of mortality risk within 90 days following acute PE, consistently outperforming sPESI + RVD, Hestia alone, and Hestia + RVD at both 30 and 90 days. Adding RVD minimally improved predictive accuracy.
Sepsis is a complex syndrome characterized by physiological, pathological, and biochemical abnormalities induced by infection, with up to 70% of patients experiencing coagulation alterations, ranging from subclinical coa...Sepsis is a complex syndrome characterized by physiological, pathological, and biochemical abnormalities induced by infection, with up to 70% of patients experiencing coagulation alterations, ranging from subclinical coagulopathy to disseminated intravascular coagulation (DIC). The multifactorial nature of sepsis-related coagulopathy and the limitations of standard diagnostic parameters, such as platelet count and traditional coagulation tests, complicate its definition and management. Assessing coagulopathy related to sepsis presents significant challenges due to current definitions primarily focusing on diagnosing advanced stages of coagulation dysfunction, thereby overlooking the dynamic and evolving nature of the condition. Viscoelastic hemostatic assays (VHAs) have emerged as valuable tools in this context, offering real-time insights into clot formation, stabilization, and lysis by integrating both plasma and cellular contributions to coagulation. Data from clinical studies suggest that early stages of sepsis coagulopathy are characterized by hypercoagulability, while advanced stages may lead to hypocoagulability and DIC. Moreover, specific point-of-care assays can evaluate platelet performance in the clotting mechanism and potentially help the diagnosis of platelet dysfunction in sepsis. Additionally, the phenomenon of fibrinolysis inhibition contributes to the persistence of fibrin clots, promoting tissue ischemia and multiorgan dysfunction. Modified VHAs appear promising for detecting fibrinolysis impairment, which is associated with poorer outcomes, but the standardization of results is still a work in progress. Incorporating VHAs data into treatment strategies could lead to more targeted therapies, potentially improving outcomes in septic patients by addressing both hypercoagulable and hypocoagulable states, as well as fibrinolysis abnormalities.
Coronavirus disease 2019 (COVID-19), a viral respiratory illness caused by severe acute respiratory disease coronavirus 2 (SARS-COV-2), has caused in the last 5 years a global pandemic of unprecedented scale in the moder...Coronavirus disease 2019 (COVID-19), a viral respiratory illness caused by severe acute respiratory disease coronavirus 2 (SARS-COV-2), has caused in the last 5 years a global pandemic of unprecedented scale in the modern era. Other than the typical respiratory symptoms, patients suffering from moderate to severe COVID-19 are at risk of developing a peculiar systemic coagulopathy, known as COVID-19-associated coagulopathy. In addition to a predominantly hypercoagulable state, COVID-19 patients may experience hemorrhagic complications triggered by the viral infection. The current knowledge on the underlying molecular mechanisms, the laboratory and clinical characteristics of coagulation abnormalities associated with COVID-19, along with their management, will be summarized in this narrative review.
Chronic kidney disease (CKD) affects over 10% of the global population and significantly increases the risk of cardiovascular disease as well as arising bleeding. There are alterations in hemostasis, which are multifacto...Chronic kidney disease (CKD) affects over 10% of the global population and significantly increases the risk of cardiovascular disease as well as arising bleeding. There are alterations in hemostasis, which are multifactorial, involving complex interactions between coagulation, platelets, and the vessel wall. Hemostasis evaluation in CKD is critical for the optimal management of patients. However, conventional coagulation testing and renal function do not fully reflect the hemostatic alterations and do not adequately represent the risk of bleeding and/or thrombosis in patients with CKD. Global hemostatic assays, including thrombin and fibrin generation assays, provide a more wholesome assessment of the process, including the interaction between procoagulants, anticoagulants, platelets, and fibrinolysis. This review critically appraises published studies reporting the use of global coagulation assays to evaluate hemostasis in patients with CKD, as well as associated clinical outcomes.