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Modulation of ultralarge immune complexes in heparin-induced thrombocytopenia.

Publication ,  Journal Article
Cai, Z; Bdeir, K; Yarovoi, SV; Rauova, L; Arepally, GM; Khandelwal, S; Rollin, J; Gruel, Y; Zaitsev, S; Poncz, M; Greene, MI; Cines, DB
Published in: J Thromb Haemost
March 2023

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.

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Published In

J Thromb Haemost

DOI

EISSN

1538-7836

Publication Date

March 2023

Volume

21

Issue

3

Start / End Page

652 / 666

Location

England

Related Subject Headings

  • Thrombosis
  • Thrombocytopenia
  • Receptors, IgG
  • Platelet Factor 4
  • Humans
  • Heparin
  • Fondaparinux
  • Cardiovascular System & Hematology
  • Antigen-Antibody Complex
  • Anticoagulants
 

Citation

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ICMJE
MLA
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Cai, Z., Bdeir, K., Yarovoi, S. V., Rauova, L., Arepally, G. M., Khandelwal, S., … Cines, D. B. (2023). Modulation of ultralarge immune complexes in heparin-induced thrombocytopenia. J Thromb Haemost, 21(3), 652–666. https://doi.org/10.1016/j.jtha.2022.11.043
Cai, Zheng, Khalil Bdeir, Serge V. Yarovoi, Lubica Rauova, Gowthami M. Arepally, Sanjay Khandelwal, Jerome Rollin, et al. “Modulation of ultralarge immune complexes in heparin-induced thrombocytopenia.J Thromb Haemost 21, no. 3 (March 2023): 652–66. https://doi.org/10.1016/j.jtha.2022.11.043.
Cai Z, Bdeir K, Yarovoi SV, Rauova L, Arepally GM, Khandelwal S, et al. Modulation of ultralarge immune complexes in heparin-induced thrombocytopenia. J Thromb Haemost. 2023 Mar;21(3):652–66.
Cai, Zheng, et al. “Modulation of ultralarge immune complexes in heparin-induced thrombocytopenia.J Thromb Haemost, vol. 21, no. 3, Mar. 2023, pp. 652–66. Pubmed, doi:10.1016/j.jtha.2022.11.043.
Cai Z, Bdeir K, Yarovoi SV, Rauova L, Arepally GM, Khandelwal S, Rollin J, Gruel Y, Zaitsev S, Poncz M, Greene MI, Cines DB. Modulation of ultralarge immune complexes in heparin-induced thrombocytopenia. J Thromb Haemost. 2023 Mar;21(3):652–666.
Journal cover image

Published In

J Thromb Haemost

DOI

EISSN

1538-7836

Publication Date

March 2023

Volume

21

Issue

3

Start / End Page

652 / 666

Location

England

Related Subject Headings

  • Thrombosis
  • Thrombocytopenia
  • Receptors, IgG
  • Platelet Factor 4
  • Humans
  • Heparin
  • Fondaparinux
  • Cardiovascular System & Hematology
  • Antigen-Antibody Complex
  • Anticoagulants