Endothelial antigen assembly leads to thrombotic complications in heparin-induced thrombocytopenia
| العنوان: | Endothelial antigen assembly leads to thrombotic complications in heparin-induced thrombocytopenia |
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| المؤلفون: | Douglas B. Cines, Lubica Rauova, Ian Johnston, Vincent Hayes, Mortimer Poncz, Gowthami M. Arepally, Steven E. McKenzie |
| المصدر: | Journal of Clinical Investigation. 127:1090-1098 |
| بيانات النشر: | American Society for Clinical Investigation, 2017. |
| سنة النشر: | 2017 |
| مصطلحات موضوعية: | Blood Platelets, Male, 0301 basic medicine, Endothelium, 030204 cardiovascular system & hematology, Glycocalyx, Platelet Factor 4, Fibrin, 03 medical and health sciences, 0302 clinical medicine, Antigen, Heparin-induced thrombocytopenia, medicine, Animals, Humans, Platelet, Thrombus, Mice, Knockout, biology, Heparin, Chemistry, Receptors, IgG, Thrombosis, General Medicine, medicine.disease, Thrombocytopenia, Disease Models, Animal, 030104 developmental biology, medicine.anatomical_structure, biology.protein, Cancer research, Female, Platelet factor 4, Research Article, medicine.drug |
| الوصف: | 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. |
| تدمد: | 1558-8238 0021-9738 |
| DOI: | 10.1172/jci90958 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::6a819169e03204872c353aeaf19ee386 https://doi.org/10.1172/jci90958 |
| Rights: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....6a819169e03204872c353aeaf19ee386 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15588238 00219738 |
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| DOI: | 10.1172/jci90958 |