Journal of thrombosis and haemostasis : JTH · 2025
Intravenous immunoglobulin prevents thrombosis in an endothelialized disease model of heparin-induced thrombocytopenia.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Witzemann Andreas, Uzun Günalp, Wolska Nina, Avci-Adali Meltem, Amiral Jean, Althaus Karina, Bakchoul Tamam, Zlamal Jan
Аннотация
BACKGROUND: Heparin-induced thrombocytopenia (HIT) is a serious adverse reaction to heparin, associated with increased risk of thromboembolic complications. Intravenous immunoglobulins (IVIGs) have been used as a therapeutic for HIT and are believed to alleviate thrombocytopenia and reduce thrombosis risk. Yet the antithrombotic effects of IVIG in HIT remain underexplored.
OBJECTIVE: To investigate the effect of IVIG on thrombus formation in an ex vivo model of HIT-IgG-induced thrombosis.
METHODS: Microfluidic channels were coated with a confluent monolayer of human umbilical vein endothelial cells that were primed with TNF-α to induce an activated, inflammatory state. Whole blood was exposed to unfractionated heparin, with or without IVIG before subjecting to treatment with a monoclonal HIT-like antibody (K070), or HIT-patient-IgG. Recalcified blood was perfused over human umbilical vein endothelial cells at venous shear stress. Thrombus structure and dynamics were investigated by immunofluorescence microscopy.
RESULTS: HIT-patient-IgGs and K070 induced thrombus formation in the presence of prophylactic heparin exposure, over TNF-α treated, inflamed endothelial cells. HIT thrombi were enriched in fibrin, phosphatidylserine-bearing platelets, and leukocyte aggregates. We observed thrombi being formed on adherent platelets, which gradually recruited leukocytes into a three-dimensional thrombus structure. Pretreatment of blood with IVIG significantly reduced cellular adhesions and prevented thrombus formation.
CONCLUSION: Our endothelialized ex vivo flow chamber system effectively recapitulates the immunothrombotic phenotype of HIT and offers a reliable tool to urgently validate the efficacy of IVIG intervention against HIT-IgG-induced thrombosis in patients.
OBJECTIVE: To investigate the effect of IVIG on thrombus formation in an ex vivo model of HIT-IgG-induced thrombosis.
METHODS: Microfluidic channels were coated with a confluent monolayer of human umbilical vein endothelial cells that were primed with TNF-α to induce an activated, inflammatory state. Whole blood was exposed to unfractionated heparin, with or without IVIG before subjecting to treatment with a monoclonal HIT-like antibody (K070), or HIT-patient-IgG. Recalcified blood was perfused over human umbilical vein endothelial cells at venous shear stress. Thrombus structure and dynamics were investigated by immunofluorescence microscopy.
RESULTS: HIT-patient-IgGs and K070 induced thrombus formation in the presence of prophylactic heparin exposure, over TNF-α treated, inflamed endothelial cells. HIT thrombi were enriched in fibrin, phosphatidylserine-bearing platelets, and leukocyte aggregates. We observed thrombi being formed on adherent platelets, which gradually recruited leukocytes into a three-dimensional thrombus structure. Pretreatment of blood with IVIG significantly reduced cellular adhesions and prevented thrombus formation.
CONCLUSION: Our endothelialized ex vivo flow chamber system effectively recapitulates the immunothrombotic phenotype of HIT and offers a reliable tool to urgently validate the efficacy of IVIG intervention against HIT-IgG-induced thrombosis in patients.