Abstract Number: OC 05.4
Meeting: ISTH 2020 Congress
Background: Intracerebral hemorrhage (ICH) is the most severe stroke subtype. Early hematoma growth occurs in one third of patients within 3 hours of stroke onset and is predictor of poor outcome. Clinical trials have shown that untargeted hemostatic therapy with rFVIIa reduced hematoma growth but conveyed an unacceptable rate of side effects. Targeted treatments able to selectively promote hemostasis at the site of bleeding are therefore necessary. Previous studies reported that monocyte-derived microparticles (mMPs) bearing tissue factor (TF) accumulate during thrombus formation and promote thrombin generation.
Aims: To generate large amount of pro-coagulant MPs to be used as hemostatic patches in preclinical models of ICH.
Methods: Monocytic cell-line THP-1 were grown in bioreactors and treated with TNF to generate TF+ mMPs. Isolated mMPs were characterized by laser-scanning confocal microscopy and flow cytometry. Functional studies were performed using human plasma clotting assays and TF-activity. In vivo, mice received an intrastriatal injection of collagenase VII to promote intraparenchymal hemorrhage. 30 minutes thereafter, exogenous mMPs were injected intravenously. Hematoma volume was quantified by MRI at 24h and neurological deficits were measured at 4h and 24h post-stroke.
Results: Large amounts of mMPs were generated in supernatants from TNF-stimulated monocytes in bioreactors. Those MPs presented monocyte-specific characteristics: a mean size of 430 nm and a high pro-coagulant activity reducing the clotting time in a dose- and TF-dependent manner. In preclinical studies of ICH, intravenous injection of mMPs improved stroke outcome in a dose-dependent manner. mMPs at 1 mg/kg prevented hematoma growth by 43% and improved neurological score at 4h and 24h compared to control mice (p< 0.01, n=15/group). This beneficial effect was also present in a more severe model of ICH in enoxaparin-treated mice. Immunohistological studies revealed accumulation of fluorescently-labeled mMPs at the bleeding site.
Conclusions: Exogenous microparticles bearing TF improve outcome after collagenase-induced ICH by acting as intravascular patches.
To cite this abstract in AMA style:Potzeha F, Yetim M, Vivien D, Gaberel T, Gauberti M, Martinez de Lizarrondo S. Exogenous Microparticles Bearing Tissue Factor Improve Outcome After Collagenase-Induced Intracranial Hemorrhage [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/exogenous-microparticles-bearing-tissue-factor-improve-outcome-after-collagenase-induced-intracranial-hemorrhage/. Accessed January 21, 2022.
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