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Endothelial antigen assembly leads to thrombotic complications in heparin-induced thrombocytopenia.

Publication ,  Journal Article
Hayes, V; Johnston, I; Arepally, GM; McKenzie, SE; Cines, DB; Rauova, L; Poncz, M
Published in: J Clin Invest
March 1, 2017

Heparin-induced thrombocytopenia (HIT) is a prothrombotic disorder initiated by antibodies against complexes between human platelet factor 4 (hPF4) and heparin. A better understanding of the events that initiate the prothrombotic state may improve approaches to antithrombotic management. Here, we visualized thrombus formation in an in vivo murine model and an endothelialized microfluidic system that simulate the pathogenesis of HIT. hPF4 released from platelets predominantly bound to peri-injury endothelium and formed HIT antigenic complexes that were dissociated by heparin. In mice expressing both hPF4+ and human platelet IgG Fc receptor IIA (FcγRIIA), infusion of the HIT-like monoclonal antibody KKO increased fibrin and platelet deposition at sites of injury, followed immediately by antigen formation on proximate endothelial cells. After a few minutes, HIT antigen was detected within the thrombus itself at the interface between the platelet core and the surrounding shell. We observed similar results in the humanized, endothelialized microfluidic system. hPF4 and KKO selectively bound to photochemically injured endothelium at sites where surface glycocalyx was reduced. These studies support the concept that the perithrombus endothelium is the predominant site of HIT antigen assembly. This suggests that disrupting antigen formation along the endothelium or protecting the endothelium may provide a therapeutic opportunity to prevent thrombotic complications of HIT, while sparing systemic hemostatic pathways.

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Published In

J Clin Invest

DOI

EISSN

1558-8238

Publication Date

March 1, 2017

Volume

127

Issue

3

Start / End Page

1090 / 1098

Location

United States

Related Subject Headings

  • Thrombosis
  • Thrombocytopenia
  • Receptors, IgG
  • Platelet Factor 4
  • Mice, Knockout
  • Male
  • Immunology
  • Humans
  • Heparin
  • Glycocalyx
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Hayes, V., Johnston, I., Arepally, G. M., McKenzie, S. E., Cines, D. B., Rauova, L., & Poncz, M. (2017). Endothelial antigen assembly leads to thrombotic complications in heparin-induced thrombocytopenia. J Clin Invest, 127(3), 1090–1098. https://doi.org/10.1172/JCI90958
Hayes, Vincent, Ian Johnston, Gowthami M. Arepally, Steven E. McKenzie, Douglas B. Cines, Lubica Rauova, and Mortimer Poncz. “Endothelial antigen assembly leads to thrombotic complications in heparin-induced thrombocytopenia.J Clin Invest 127, no. 3 (March 1, 2017): 1090–98. https://doi.org/10.1172/JCI90958.
Hayes V, Johnston I, Arepally GM, McKenzie SE, Cines DB, Rauova L, et al. Endothelial antigen assembly leads to thrombotic complications in heparin-induced thrombocytopenia. J Clin Invest. 2017 Mar 1;127(3):1090–8.
Hayes, Vincent, et al. “Endothelial antigen assembly leads to thrombotic complications in heparin-induced thrombocytopenia.J Clin Invest, vol. 127, no. 3, Mar. 2017, pp. 1090–98. Pubmed, doi:10.1172/JCI90958.
Hayes V, Johnston I, Arepally GM, McKenzie SE, Cines DB, Rauova L, Poncz M. Endothelial antigen assembly leads to thrombotic complications in heparin-induced thrombocytopenia. J Clin Invest. 2017 Mar 1;127(3):1090–1098.

Published In

J Clin Invest

DOI

EISSN

1558-8238

Publication Date

March 1, 2017

Volume

127

Issue

3

Start / End Page

1090 / 1098

Location

United States

Related Subject Headings

  • Thrombosis
  • Thrombocytopenia
  • Receptors, IgG
  • Platelet Factor 4
  • Mice, Knockout
  • Male
  • Immunology
  • Humans
  • Heparin
  • Glycocalyx