Abstract Number: OC 46.5
Meeting: ISTH 2022 Congress
Background: Carbamylation is a post-translational modification that results from the interaction between isocyanic acid with free functional groups of proteins. It preferentially occurs on the ε-NH2 of lysine residues, thus generating homocitrulline (HCit). Importantly, conversion of lysine residues of fibrin(ogen) to HCit was shown to impair t-PA-mediated fibrinolysis. Although non-enzymatic, carbamylation can be promoted by neutrophils through their myeloperoxidase (MPO) activity that favors isocyanic acid formation. We and others have shown that neutrophils are important components of thrombi responsible for large vessel occlusion (LVO)-related acute ischemic stroke (AIS). It remains unknown whether carbamylation occurs in such thrombi.
Aims: We aimed to determine whether carbamylation occurs in AIS thrombi and whether it affects recanalization therapies.
Methods: A total of 30 thrombi from AIS patients with LVO, all recovered by endovascular therapy, were analyzed for the presence of carbamylated products by anti-HCit immunostaining and by quantitative measurement of fibrin(ogen)- and von Willebrand factor (vWF)-associated HCit. Correlations between fibrin(ogen) carbamylation and thrombolysis resistance were investigated in ex vivo thrombolysis assays in which AIS thrombi were treated with a mixture of tPA/plasminogen, and lysis supernatants analyzed for quantification of carbamylated fibrin(ogen). The impact of carabamylation on mechanical thrombectomy was determined by comparing the response to thrombectomy of non-carbamylated and carbamylated blood clots produced in vitro and injected in-flow in a Biomodex Evias Plus simulation system.
Results: All AIS thrombi contained carbamylated fibrin(ogen) and vWF whose levels were positively correlated to thrombus MPO and DNA content. Resistance to ex vivo thrombolysis was significantly correlated with thrombus carbamylated fibrin(ogen), MPO, and DNA content. Carbamylation led to an increase in thrombus frailty and fragmentation during simulated thrombectomy procedure.
Conclusion(s): Carbamylation occurs in AIS thrombi and negatively interferes with both pharmacological thrombolysis and mechanical thrombectomy.
To cite this abstract in AMA style:Ollivier V, Freiherr Von Seckendorff A, Solo Nomenjanahary M, BOURRIENNE M, Desilles J, Mazighi M, Ho-Tin-Noé B. Carbamylation in acute ischemic stroke thrombi impairs t-PA-mediated thrombolysis and increases thrombus frailty [abstract]. https://abstracts.isth.org/abstract/carbamylation-in-acute-ischemic-stroke-thrombi-impairs-t-pa-mediated-thrombolysis-and-increases-thrombus-frailty/. Accessed September 26, 2022.
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