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Complement mediates binding and procoagulant effects of ultralarge HIT immune complexes.

Publication ,  Journal Article
Khandelwal, S; Barnes, A; Rauova, L; Sarkar, A; Rux, AH; Yarovoi, SV; Zaitsev, SS; Lambris, JD; Myoung, SS; Johnson, A; Lee, GM; Duarte, M ...
Published in: Blood
November 25, 2021

Heparin-induced thrombocytopenia (HIT) is a prothrombotic disorder mediated by ultra-large immune complexes (ULICs) containing immunoglobulin G (IgG) antibodies to a multivalent antigen composed of platelet factor 4 and heparin. The limitations of current antithrombotic therapy in HIT supports the need to identify additional pathways that may be targets for therapy. Activation of FcγRIIA by HIT ULICs initiates diverse procoagulant cellular effector functions. HIT ULICs are also known to activate complement, but the contribution of this pathway to the pathogenesis of HIT has not been studied in detail. We observed that HIT ULICs physically interact with C1q in buffer and plasma, activate complement via the classical pathway, promote codeposition of IgG and C3 complement fragments (C3c) on neutrophil and monocyte cell surfaces. Complement activation by ULICs, in turn, facilitates FcγR-independent monocyte tissue factor expression, enhances IgG binding to the cell surface FcγRs, and promotes platelet adhesion to injured endothelium. Inhibition of the proximal, but not terminal, steps in the complement pathway abrogates monocyte tissue factor expression by HIT ULICs. Together, these studies suggest a major role for complement activation in regulating Fc-dependent effector functions of HIT ULICs, identify potential non-anticoagulant targets for therapy, and provide insights into the broader roles of complement in immune complex-mediated thrombotic disorders.

Duke Scholars

Published In

Blood

DOI

EISSN

1528-0020

Publication Date

November 25, 2021

Volume

138

Issue

21

Start / End Page

2106 / 2116

Location

United States

Related Subject Headings

  • Thrombosis
  • Thrombocytopenia
  • Receptors, IgG
  • Platelet Factor 4
  • Immunology
  • Immunoglobulin G
  • Humans
  • Heparin
  • Complement C3
  • Complement Activation
 

Citation

APA
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MLA
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Khandelwal, S., Barnes, A., Rauova, L., Sarkar, A., Rux, A. H., Yarovoi, S. V., … Cines, D. B. (2021). Complement mediates binding and procoagulant effects of ultralarge HIT immune complexes. Blood, 138(21), 2106–2116. https://doi.org/10.1182/blood.2020009487
Khandelwal, Sanjay, Ayiesha Barnes, Lubica Rauova, Amrita Sarkar, Ann H. Rux, Serge V. Yarovoi, S Sergei Zaitsev, et al. “Complement mediates binding and procoagulant effects of ultralarge HIT immune complexes.Blood 138, no. 21 (November 25, 2021): 2106–16. https://doi.org/10.1182/blood.2020009487.
Khandelwal S, Barnes A, Rauova L, Sarkar A, Rux AH, Yarovoi SV, et al. Complement mediates binding and procoagulant effects of ultralarge HIT immune complexes. Blood. 2021 Nov 25;138(21):2106–16.
Khandelwal, Sanjay, et al. “Complement mediates binding and procoagulant effects of ultralarge HIT immune complexes.Blood, vol. 138, no. 21, Nov. 2021, pp. 2106–16. Pubmed, doi:10.1182/blood.2020009487.
Khandelwal S, Barnes A, Rauova L, Sarkar A, Rux AH, Yarovoi SV, Zaitsev SS, Lambris JD, Myoung SS, Johnson A, Lee GM, Duarte M, Poncz M, Arepally GM, Cines DB. Complement mediates binding and procoagulant effects of ultralarge HIT immune complexes. Blood. 2021 Nov 25;138(21):2106–2116.

Published In

Blood

DOI

EISSN

1528-0020

Publication Date

November 25, 2021

Volume

138

Issue

21

Start / End Page

2106 / 2116

Location

United States

Related Subject Headings

  • Thrombosis
  • Thrombocytopenia
  • Receptors, IgG
  • Platelet Factor 4
  • Immunology
  • Immunoglobulin G
  • Humans
  • Heparin
  • Complement C3
  • Complement Activation