A small-molecule hemostatic agent for the reversal of direct oral anticoagulant-induced bleeding.

Background: The bleeding risk associated with direct oral anticoagulants (DOACs) remains a major concern, and rapid reversal of anticoagulant activity may be required. Although specific and nonspecific hemostatic biotherapies are available, there is a need for small-molecule DOAC reversal agents that are simple and cost-effective to produce, store, and administer. Objectives: To identify and characterize a small molecule with procoagulant activity as a DOAC reversal agent. Methods: We sought to identify a small procoagulant molecule by screening a chemical library with a plasma clotting assay. The selected molecule was assessed for its procoagulant properties and its ability to reverse the effects of the DOACs in a thrombin generation assay. Its activity as a DOAC reversal agent was also evaluated in a tail-clip bleeding assay in mice. Results: The hemostatic molecule (HeMo) dose-dependently promoted thrombin generation in plasma, with dose values effective in producing half-maximum response ranging between 3 and 5 µM, depending on the thrombin generation assay parameter considered. HeMo also restored impaired thrombin generation in DOAC-spiked plasma and reversed DOAC activity in the mouse bleeding model. HeMo significantly reduced apixaban-induced bleeding from 709 to 65 µL (vs 43 µL in controls; P < .01) and dabigatran-induced bleeding from 989 to 155 µL (vs 126 µL in controls; P < .01). Conclusion: HeMo is a small-molecule procoagulant that can counterbalance hemostatic disruption by a thrombin inhibitor (dabigatran) or factor Xa inhibitors (apixaban and rivaroxaban). The compound's effective clot formation and versatility make it a possible option for managing the inherent hemorrhagic risk during DOAC therapy.

Treatment of cancer-associated venous thromboembolism: A focus on special populations.

Current evidence-based clinical practice guidelines recommend the use of both low-molecular-weight heparin (LMWH) and direct factor Xa inhibitors (apixapan, edoxaban and rivaroxaban) as first-line options for the treatment of venous thromboembolism (VTE) in patients with cancer. However, most of these guidelines refer to the general cancer patient population and provide limited guidance for specific subgroups of patients at particularly high risk of bleeding, such as those with gastrointestinal cancers, primary or metastatic brain tumors, thrombocytopenia, or renal impairment. In these complex populations, the management of cancer-associated thrombosis (CAT) poses unique challenges and requires a nuanced approach based on the primum non nocere principle. This comprehensive review critically examines the relevant literature and discusses the therapeutic options currently available for the management of CAT in these special situations.

Using an age and fibrinogen levels adjusted D-dimer cutoff significantly improves the specificity of two equivalent D-dimer assays for excluding pulmonary embolism.

OBJECTIVES: Our single-center prospective study compared two methods of D-dimer determination used in the exclusion of pulmonary embolism: bioMérieux method, VIDAS® D-Dimer Exclusion™ II, and Diagnostica Stago method, STA®-Liatest® D-Di Plus. For each of these two methods, we calculated optimized variable cutoffs based on fibrinogen and/or age to improve the specificity of the methods. PATIENTS - METHODS: 2530 patients admitted to the Emergency Department of the Brest University Hospital for suspected pulmonary embolism were included in this study. The comparison of the two methods was performed by calculating their different characteristics: sensitivity, specificity and negative predictive value for different cutoffs systems: fixed or age-adjusted according to Douma et al. An optimization of the variable cutoff according to age and fibrinogen was then performed. RESULTS: The two methods VIDAS and STAGO are approximately equivalent in terms of performance even if the STAGO method presents a better specificity (57.1 %) at the fixed cutoff of 0.5 µg/mL. The adoption of age-adjusted, fibrinogen-adjusted or doubly-adjusted (age and fibrinogen) cutoffs, significantly improves the specificity of the tests without affecting their excellent sensitivity. These specificities peak respectively at 75.8 % and 76 % for the VIDAS and STAGO tests when using a doubly-adjusted, age and fibrinogen, cutoff, i.e. a gain in specificity of approximately 10 % compared with the age-adjusted cutoff of Douma et al. and of approximately 20 % compared with the fixed cutoff of 0.5 µg/mL. CONCLUSION: Adopting an optimized variable cutoff based on fibrinogen and/or age significantly improves specificity of D-dimer methods for pulmonary embolism exclusion.

Apport du dosage des monomères de fibrine en situations obstétricales aiguës.

Depuis 2013, nous utilisons le dosage des monomères de fibrine au laboratoire d'hématologie du CHU de Brest. Ce marqueur précoce de l'activation de la coagulation nous permet de détecter très tôt une coagulation intravasculaire disséminée (CIVD) et de suivre son évolution grâce à l'utilisation du rapport monomères de fibrine/D-dimères. Le dosage des monomères de fibrine est utile dans plusieurs contextes cliniques et il est complémentaire de celui des D-dimères. Au travers de deux cas clinico-biologiques, nous allons montrer l'intérêt de ces paramètres dans deux situations obstétricales aigues. Le premier cas clinique traite d'une hémorragie du post-partum compliquée d'une coagulation intravasculaire disséminée. Dans ce cas, les monomères de fibrine ont permis de détecter rapidement l'activation de la coagulation. Le deuxième cas clinique traite d'une prise en charge d'un placenta percreta compliqué d'une coagulation intravasculaire disséminée, pour lequel les monomères ont aidé à la prise en charge chirurgicale.