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Venous thromboembolism (VTE) is a potentially lethal clinical condition that is suspected in patients with common clinical complaints, in many and varied, clinical care settings. Once VTE is diagnosed, optimal therapeutic management (thrombolysis, IVC filters, type and duration of anticoagulants) and ideal therapeutic management settings (outpatient, critical care) are also controversial. Clinical prediction tools, including clinical decision rules and D-Dimer, have been developed, and some validated, to assist clinical decision making along the diagnostic and therapeutic management paths for VTE. Despite these developments, practice variation is high and there remain many controversies in the use of the clinical prediction tools. In this narrative review, we highlight challenges and controversies in VTE diagnostic and therapeutic management with a focus on clinical decision rules and D-Dimer. [ABSTRACT FROM AUTHOR]

The article discusses a guideline from the British Committee for Standards in Haematology, focusing on the non-coumarin anticoagulants and its effect on haemostasis. It states that the guideline was designed to provide a clear guidance for healthcare professionals on issues relative to laboratory assessment of non-coumarin anticoagulants. Other topics include effect of dabigatran on haemostasis tests, monitoring of unfractionated heparin, and the use of bivalirudin as an alternative heparin.

Objective: We compared the performance of aggregate data (AD)ebased and individual patient data (IPD)ebased meta-analyses to synthesize evidence on the ability of D-dimer to distinguish recurrence risk in patients with unprovoked venous thromboembolism (VTE) who stopped anticoagulation. Study Design and Setting: We compared the results of the published AD-based rate ratio of VTE recurrence for positive vs. negative D-dimer, estimated by a mixed-effect Poisson model, with those of the IPD-based hazard ratio obtained by a Cox regression stratified by trial. We performed three additional analyses to investigate the methodological reasons for differences between the two approaches, comparing the IPD Cox regression with AD generated from IPD Poisson regression (to control for differences in population on study), AD timeto- event meta-analysis, and AD generated from IPD meta-regression. Results: Published analyses agreed in direction and statistical significance when estimating the prognostic value of D-dimer even if IPD estimates suggested a stronger effect. The additional analyses suggested that differences in study populations might explain this slight difference. Poor reporting in published studies precluded a true comparison of AD- and IPD-based assessments of heterogeneity sources. Conclusion: AD and IPD meta-analyses yielded similar estimates of D-dimer effect to distinguish risk for recurrent VTE. The IPD approach was justified by the need to investigate sources of heterogeneity. [ABSTRACT FROM AUTHOR]

Abstract: The thrombin generation test (TGT) has demonstrated utility in evaluating overall hemostatic capacity both in bleeding and thrombotic disorders. Although the test is currently well accepted as a research tool, its role in clinical practice has not yet been defined through large prospective multicenter clinical studies. Such prospective studies have been limited by the lack of official standardization of the assay and its large inter-laboratory variability. This international study assessed the intra- and inter-assay imprecision of TGT as well as the inter-centre variability of results in one US and four European centres. Contact-inhibited plasmas from six healthy volunteers, one mild haemophilia A patient, and five patients with heterozygous prothrombin G20210 mutation were assayed. We demonstrated that, using identical equipement, standardized reagents, a carefully selected reference plasma for normalization of results and the same test procedure as described in our DVD, the assay variability was highly reduced compared to previously published data. Our results emphasize the importance of preheating on TGT results and the variability of the assay. In conclusion, our data demonstrated that the standardized TGT methodology evaluated in this study effectively reduces the variability of the assay to acceptable limits and may be used in clinical trials. [Copyright &y& Elsevier]

Summary: Antithrombin (AT) is the most important inhibitor of coagulation proteases. Its activity is stimulated by glycosaminoglycans, such as heparin, through allosteric and template mechanisms. AT utilises an induced-fit mechanism to bind with high affinity to a pentasaccharide sequence found in about one-third of heparin chains. The conformational changes behind this mechanism have been characterised by several crystal structures of AT in the absence and in the presence of pentasaccharide. Pentasaccharide binding ultimately results in a conformational change that improves affinity by about 1000-fold. Crystal structures show several differences, including the expulsion of the hinge region of the reactive centre loop from β-sheet A, which is known to be critical for the allosteric activation of AT. Here, we present data that reveal an energetically distinct intermediate on the path to full activation where the majority of conformational changes have already occurred. A crystal structure of this intermediate shows that the hinge region is in a native-like state in spite of having the pentasaccharide bound in the normal fashion. We engineered a disulfide bond to lock the hinge in its native position to determine the energetic contributions of the initial and final conformational events. Approximately 60% of the free-energy contribution of conformational change is provided by the final step of hinge-region expulsion and subsequent closure of the main β-sheet A. A new analysis of the individual structural changes provides a plausible mechanism for propagation of conformational change from the heparin binding site to the remote hinge region in β-sheet A. [Copyright &y& Elsevier]

The poor inhibitory activity of circulating antithrombin (AT) is critical to the formation of blood clots at sites of vascular damage. AT becomes an efficient inhibitor of the coagulation proteases only after binding to a specific heparin pentasaccharide, which alters the conformation of the reactive center loop (RCL). The molecular basis of this activation event lies at the heart of the regulation of hemostasis and accounts for the anti-coagulant properties of the low molecular weight heparins. Although several structures of AT have been solved, the conformation of the RCL in native AT remains unknown because of the obligate crystal contact between the RCL of native AT and its latent counterpart. Here we report the crystallographic structure of a variant of AT in its monomeric native state. The RCL shifted ∼20 Å, and a salt bridge was observed between the P1 residue (Arg-393) and Glu-237. This contact explains the effect of mutations at the P1 position on the affinity of AT for heparin and also the properties of AT-Truro (E237K). The relevance of the observed conformation was verified through mutagenesis studies and by solving structures of the same variant in different crystal forms. We conclude that the poor inhibitory activity of the circulating form of AT is partially conferred by intramolecular contacts that restrain the RCL, orient the P1 residue away from attacking proteases, and additionally block the exosite utilized in protease recognition. [ABSTRACT FROM AUTHOR]

The University of North Carolina Symposia on Hemostasis began in 2002, with The First Symposium on Hemostasis with a Special Focus on FVIIa and Tissue Factor. They have occurred biannually since and have maintained the primary goal of establishing a forum for the sharing of outstanding advances made in the basic sciences of hemostasis. The 2024 11th Symposium on Hemostasis will bring together leading scientists from around the globe to present and discuss the latest research related to coagulation factors and platelet biology. In keeping with the tradition of the conference, we expect novel cross-disciplinary collaborations to result from bringing together fundamental scientists and physician-scientists from different backgrounds and perspectives. The aim of these collaborations is to springboard the next generation of important advances in the field . This year's program was designed to discuss Coagulation and Platelet Biology at the Intersection of Health and Disease. The goal is to develop a better understanding of the pathophysiologic mechanisms leading to hemostatic and thrombotic disorders as this understanding is critical for the continued development of safe and efficacious therapeutics. Included in this review article are illustrated capsules provided by our speakers that highlight the main conclusions of the invited talks., (© 2024 The Author(s).)

Background: Venous thromboembolism (VTE) is a complex disease with an incidence rate of about 1 in 1000 per year. Despite the availability of validated biomarkers for VTE, unprovoked events account for 50% of first events. Therefore, emerging high-throughput proteomics are promising methods for the expansion of VTE biomarkers. One such promising high-throughput platform is SomaScan, which uses a large library of synthetic oligonucleotide ligands known as aptamers to measure thousands of proteins., Objective: The aim of this study was to evaluate the viability of the aptamer-based SomaScan platform for VTE studies by examining its agreement with standard laboratory methods., Methods: We examined the agreement between eight established VTE biomarkers measured by SomaScan and standard laboratory immunoassay and viscosity-based instruments in 54 individuals (27 cases and 27 controls) from the Thrombophilia, Hypercoagulability and Environmental Risks in Venous Thromboembolism study. We performed the agreement analysis by using a regression model and predicting the estimates and the 95% prediction interval (PI) of the laboratory instrument values using SomaScan values., Results: SomaScan measurements exhibited overall poor agreement, particularly for D-dimer (average fit, 492.7 ng/mL; 95% PI, 110.0-1998.2) and fibrinogen (average fit, 3.3 g/L; 95% PI, 2.0-4.7)., Conclusion: Our results indicate that SomaScan measurement had poor agreement with the standard laboratory measurements. These results may explain why some genome-wide association studies with VTE proteins measured by SomaScan did not confirm previously identified loci. Therefore, SomaScan should be considered with caution in VTE studies., (© 2021 The Authors. Research and Practice in Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis (ISTH).)

Purpose of Review: Arterial and venous thromboembolic diseases are associated with significant morbidity and mortality and present a major medical burden. Currently used anticoagulants for the prevention or treatment of thromboembolic events including heparins, vitamin K-antagonists and inhibitors of thrombin or factor Xa target enzymes of the coagulation cascade that are critical for fibrin formation. However, fibrin is also necessary for hemostatic mechanisms to terminate blood loss at injury sites. As a result currently used anticoagulants substantially raise the risk of bleeding and are associated with an increase in potentially life-threatening hemorrhage, partially offsetting the benefits of reduced thrombosis., Recent Findings: Within the last decade, experimental and preclinical data have revealed the existence of coagulation mechanisms that principally differ in thrombosis and haemostasis. Some coagulation proteins including, XI and XII have a differential role in haemostasis and thrombosis. Targeting these proteins may provide an opportunity to prevent thromboembolic disease without causing bleeding., Summary: This review summarizes recent studies on selective targeting of coagulation proteins that may allow prevention and treatment of thrombosis without causing bleeding. These novel approaches present a possibility for selective interference with fibrin formation in pathologic thrombosis that may lead to a new generation of safe anticoagulant drugs.

Purpose of Review: Hemophilia is a debilitating disease, marked by frequent, painful bleeding events, joint deterioration and early death. All current treatments consist of i.v. infusions of replacement factor or other procoagulant factors, and are incompletely effective, due in part to the short half-lives of the proteins. An alternative approach is to rebalance hemostasis by inhibiting natural anticoagulant mechanisms. In this article, we explain why activated protein C (APC) is an appropriate and safe target for the treatment of hemophilia., Recent Findings: A serpin (serine protease inhibitor) was engineered to specifically inhibit APC and was found to rescue hemostasis in a hemophilia mouse model, even after a severe tail clip injury. However, APC is also anti-inflammatory and has cytoprotective activities, raising safety concerns over the use of an APC inhibitor to treat hemophilia. We summarize the molecular basis of the anticoagulant and signaling activities of APC to assess the potential impact of targeting APC., Summary: We conclude that the signaling and anticoagulant functions of APC are in spatially and kinetically distinct compartments, and that it is possible to specifically inhibit the anticoagulant activity of APC. Targeting APC with a serpin is remarkably effective and may be safe for long-term prophylactic use in the treatment of hemophilia.

The role of the fibrinolytic system in the development of venous thrombosis (VT) is unclear. We studied the risk of first and recurrent VT associated with reduced fibrinolysis, as measured by clot lysis time (CLT). We also studied the relationship between CLT and thrombin generation to determine if any relationship between CLT and VT was affected by thrombin generation. Analyses were performed in the Thrombophilia Hypercoagulability Environmental risk for Venous Thromboembolism Study, a two-centre population-based case-control study, including 579 patients and 338 controls, with patients followed from the event to determine incidence of recurrent VT. Hypofibrinolysis was associated with a 1·8-fold increased risk of a first VT [95% confidence interval (CI) 1·2-2·7]. Adjustment for sex, age, study location and Endogenous Thrombin Potential (ETP) did not change the result. The risk of VT was 2·9-fold increased when the 90th percentiles of prolonged CLT and high ETP were combined, with the highest risk for unprovoked first events (Odds Ratio = 4·2, 95% CI 1·3-13·5). In the follow-up study the Hazard Ratio for a recurrent VT associated with hypofibrinolysis was 1·5 (95% CI 0·9-2·6). A weak dose response effect was observed in relation to prolongation of CLT and recurrent VT. Although hypofibrinolysis constitutes a risk factor for a first VT, an association with recurrence is, at best, weak., (© 2016 John Wiley & Sons Ltd.)