Browsing by Subject "Hemostatics"

Now showing 1 - 3 of 3
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    Factor VIII trafficking to CD4+ T cells shapes its immunogenicity and requires several types of antigen-presenting cells
    (American Society of Hematology, 2023) Kaczmarek, Radoslaw; Piñeros, Annie R.; Patterson, Paige E.; Bertolini, Thais B.; Perrin, George Q.; Sherman, Alexandra; Born, Jameson; Arisa, Sreevani; Arvin, Matthew C.; Kamocka, Malgorzata M.; Martinez, Michelle M.; Dunn, Kenneth W.; Quinn, Sean M.; Morris, Johnathan J.; Wilhelm, Amelia R.; Kaisho, Tsuneyasu; Munoz-Melero, Maite; Biswas, Moanaro; Kaplan, Mark H.; Linnemann, Amelia K.; George, Lindsey A.; Camire, Rodney M.; Herzog, Roland W.; Pediatrics, School of Medicine
    Despite >80 years of clinical experience with coagulation factor VIII (FVIII) inhibitors, surprisingly little is known about the in vivo mechanism of this most serious complication of replacement therapy for hemophilia A. These neutralizing antidrug alloantibodies arise in ∼30% of patients. Inhibitor formation is T-cell dependent, but events leading up to helper T-cell activation have been elusive because of, in part, the complex anatomy and cellular makeup of the spleen. Here, we show that FVIII antigen presentation to CD4+ T cells critically depends on a select set of several anatomically distinct antigen-presenting cells, whereby marginal zone B cells and marginal zone and marginal metallophilic macrophages but not red pulp macrophages (RPMFs) participate in shuttling FVIII to the white pulp in which conventional dendritic cells (DCs) prime helper T cells, which then differentiate into follicular helper T (Tfh) cells. Toll-like receptor 9 stimulation accelerated Tfh cell responses and germinal center and inhibitor formation, whereas systemic administration of FVIII alone in hemophilia A mice increased frequencies of monocyte-derived and plasmacytoid DCs. Moreover, FVIII enhanced T-cell proliferation to another protein antigen (ovalbumin), and inflammatory signaling-deficient mice were less likely to develop inhibitors, indicating that FVIII may have intrinsic immunostimulatory properties. Ovalbumin, which, unlike FVIII, is absorbed into the RPMF compartment, fails to elicit T-cell proliferative and antibody responses when administered at the same dose as FVIII. Altogether, we propose that an antigen trafficking pattern that results in efficient in vivo delivery to DCs and inflammatory signaling, shape the immunogenicity of FVIII.
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    Immune complications and their management in inherited and acquired bleeding disorders
    (American Society of Hematolog, 2022) Arruda, Valder R.; Lillicrap, David; Herzog, Roland W.; Pediatrics, School of Medicine
    Disorders of coagulation, resulting in serious risks for bleeding, may be caused by autoantibody formation or by mutations in genes encoding coagulation factors. In the latter case, antidrug antibodies (ADAs) may form against the clotting factor protein drugs used in replacement therapy, as is well documented in the treatment of the X-linked disease hemophilia. Such neutralizing antibodies against factors VIII or IX substantially complicate treatment. Autoantibody formation against factor VIII leads to acquired hemophilia. Although rare, antibody formation may occur in the treatment of other clotting factor deficiencies (eg, against von Willebrand factor [VWF]). The main strategies that have emerged to address these immune responses include (1) clinical immune tolerance induction (ITI) protocols; (2) immune suppression therapies (ISTs); and (3) the development of drugs that can improve hemostasis while bypassing the antibodies against coagulation factors altogether (some of these nonfactor therapies/NFTs are antibody-based, but they are distinct from traditional immunotherapy as they do not target the immune system). Choice of immune or alternative therapy and criteria for selection of a specific regimen for inherited and autoimmune bleeding disorders are explained. ITI serves as an important proof of principle that antigen-specific immune tolerance can be achieved in humans through repeated antigen administration, even in the absence of immune suppression. Finally, novel immunotherapy approaches that are still in the preclinical phase, such as cellular (for instance, regulatory T cell [Treg]) immunotherapies, gene therapy, and oral antigen administration, are discussed.
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    Whole Blood, Fixed Ratio, or Goal-Directed Blood Component Therapy for the Initial Resuscitation of Severely Hemorrhaging Trauma Patients: A Narrative Review
    (MDPI, 2021-01-17) Walsh, Mark; Moore, Ernest E.; Moore, Hunter B.; Thomas, Scott; Kwaan, Hau C.; Speybroeck, Jacob; Marsee, Mathew; Bunch, Connor M.; Stillson, John; Thomas, Anthony V.; Grisoli, Annie; Aversa, John; Fulkerson, Daniel; Vande Lune, Stefani; Sjeklocha, Lucas; Tran, Quincy K.; Medicine, School of Medicine
    This narrative review explores the pathophysiology, geographic variation, and historical developments underlying the selection of fixed ratio versus whole blood resuscitation for hemorrhaging trauma patients. We also detail a physiologically driven and goal-directed alternative to fixed ratio and whole blood, whereby viscoelastic testing guides the administration of blood components and factor concentrates to the severely bleeding trauma patient. The major studies of each resuscitation method are highlighted, and upcoming comparative trials are detailed.