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Endothelial antigen assembly leads to thrombotic complications in heparin-induced thrombocytopenia
Vincent Hayes, … , Lubica Rauova, Mortimer Poncz
Vincent Hayes, … , Lubica Rauova, Mortimer Poncz
Published February 20, 2017
Citation Information: J Clin Invest. 2017;127(3):1090-1098. https://doi.org/10.1172/JCI90958.
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Research Article Hematology

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

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Abstract

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.

Authors

Vincent Hayes, Ian Johnston, Gowthami M. Arepally, Steven E. McKenzie, Douglas B. Cines, Lubica Rauova, Mortimer Poncz

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Figure 1

Widefield cremaster laser injury in a non-HIT hPF4+ murine model: In situ studies of hPF4 and HIT antigen distribution in thrombi.

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Widefield cremaster laser injury in a non-HIT hPF4+ murine model: In sit...
(A) Representative widefield study of more than 10 cremaster laser injuries in hPF4+ mice, with time 0 indicating the onset of injury. Images from a video of a laser injury; platelets are indicated in red, hPF4 is indicated in green, and the direction of blood flow in the vessel is denoted by blue arrows. Graph shows the accumulation of platelets and hPF4 over the study in relative value units (RVU) compared with time 0. (B) Same as in A, but with green showing binding of KKO to indicate the appearance of the HIT antigen. (C) Representative images from Supplemental Video 1 beginning 5 minutes after injury, the point at which 103 U/kg heparin was infused i.v. Platelets are indicated in red and KKO binding in green. The graph indicates that various doses of heparin were infused beginning 5 minutes after the cremaster injury. Percent mean ± 1 SEM for binding of KKO after heparin relative to the 5-minute time point is shown. The dashed line represents no change in KKO binding after heparin infusion compared with the 5-minute heparin time point. Original magnification, ×60.

Copyright © 2022 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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