Modulation of ultralarge immune complexes in heparin-induced thrombocytopenia.
Autor: | Cai Z; Department of Pathology and Laboratory Medicine, Perelman-University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA., Bdeir K; Department of Pathology and Laboratory Medicine, Perelman-University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA., Yarovoi SV; Department of Pathology and Laboratory Medicine, Perelman-University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA., Rauova L; Children's Hospital of Philadelphia, Perelman-University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA., Arepally GM; Division of Hematology, Duke University Medical Center, Durham, North Carolina, USA., Khandelwal S; Division of Hematology, Duke University Medical Center, Durham, North Carolina, USA., Rollin J; Department of Hemostasis, University of Tours, Tours, France; Centre Hospitalier Régional Universitaire de Tours, Service d'Hémostase, Tours, France., Gruel Y; Department of Hemostasis, University of Tours, Tours, France; Centre Hospitalier Régional Universitaire de Tours, Service d'Hémostase, Tours, France., Zaitsev S; Department of Pathology and Laboratory Medicine, Perelman-University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA., Poncz M; Children's Hospital of Philadelphia, Perelman-University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA., Greene MI; Department of Pathology and Laboratory Medicine, Perelman-University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA., Cines DB; Department of Pathology and Laboratory Medicine, Perelman-University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA; Department of Medicine, Perelman-University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA. Electronic address: dcines@pennmedicine.upenn.edu. |
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Jazyk: | angličtina |
Zdroj: | Journal of thrombosis and haemostasis : JTH [J Thromb Haemost] 2023 Mar; Vol. 21 (3), pp. 652-666. Date of Electronic Publication: 2022 Dec 22. |
DOI: | 10.1016/j.jtha.2022.11.043 |
Abstrakt: | Background: Heparin-induced thrombocytopenia (HIT) is a serious thrombotic disorder caused by ultralarge immune complexes (ULICs) containing platelet factor 4 (PF4) and heparin that form the HIT antigen, together with a subset of anti-PF4 antibodies. ULICs initiate prothrombotic responses by engaging Fcγ receptors on platelets, neutrophils, and monocytes. Contemporary anti-thrombotic therapy for HIT is neither entirely safe nor entirely successful and acts downstream of ULIC formation and Fcγ receptor-initiated generation of thrombin. Objectives: To determine whether HIT antigen and ULIC formation and stability could be modified favorably by inhibiting PF4-heparin interactions with fondaparinux, together with blocking formation of PF4 tetramers using a humanized monoclonal anti-PF4 antibody (hRTO). Methods: Results: The combination of fondaparinux and hRTO inhibited HIT antigen formation, promoted antigen dissociation, inhibited ULIC formation, and promoted ULIC disassembly at concentrations below the effective concentration of either alone and blocked Fcγ receptor-dependent induction of factor Xa activity by monocytic THP1 cells and activation of human platelets in whole blood. Combined with hRTO, fondaparinux inhibited HIT antigen and immune complex formation and activation through Fcγ receptors at concentrations at or below those used clinically to inhibit FXa coagulant activity. Conclusions: HIT antigen and immune complexes are dynamic and amenable to modulation. Fondaparinux can be converted from an anticoagulant that acts at a downstream amplification step into a rationale, disease-specific intervention that blocks ULIC formation. Interventions that prevent ULIC formation and stability might increase the efficacy, permit use of lower doses, shorten the duration of antithrombotic therapy, and help prevent this serious thrombotic disorder. Competing Interests: Declaration of competing interest G.M.A. has an awarded patent for KKO (US Application No 60/143,536); M.I.G., C.Z., and D.C. have pending intellectual property applications involving hRTO. S.Y., S.Z., S.J., and K.B. declare no COIs. J.R. and Y.G. have received a research grant from Stago and that the University of Tours has licensed Stago to use 5B9 for diagnostic applications. (Copyright © 2022 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.) |
Databáze: | MEDLINE |
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