Abstract Number: LPB0102
Meeting: ISTH 2021 Congress
Background: Antiphospholipid antibodies (aPL) cause the antiphospholipid syndrome (APS) and promote rapid complement- and protein disulfide isomerase (PDI)-dependent tissue factor (TF) decryption on monocytes. In this context, aPL induce procoagulant phosphatidylserine exposure by a rapid thrombin-dependent translocation of acidic sphingomyelinase (ASM) to the cell surface, where ASM is specifically activated by the endosomal lysobisphosphatidic acid (LBPA) presented by the endothelial protein C receptor (EPCR). aPL are also found in COVID-19 patients and effective therapeutic approaches to prevent TF-dependent thrombosis in APS associated with viral infections are needed.
Aims: Analyze the effect of rNAPc2, a hookworm-derived inhibitor of the TF initiation complex, in COVID-19 aPL immunoglobulin (Ig)-induced thrombosis in mice.
Methods: Isolated Ig from hospitalized COVID-19 patients or healthy controls were injected into C57Bl/6J wild type mice to induce aPL-amplified thrombosis in a flow restricted inferior vena cava (IVC) model. Labeled platelets and leukocytes were tracked over 3 hours and thrombus size was quantified by intravital microscopy.
Results: COVID-19 Ig accelerated thrombus formation significantly in comparison to isolated Ig from healthy controls (31528 vs 302 µm2; p<0.0001). This increase was not impaired by non-inhibitory aEPCR injected prior to COVID-19 Ig but blocked by aEPCR which specifically inhibits EPCR-LBPA induction of ASM activity. These data showed that COVID-19 Ig triggered the same prothrombotic pathway elucidated for aPL from APS patients. Administration of the TF complex inhibitor rNAPc2 30 min prior to COVID-19 Ig-induced thrombosis markedly reduced thrombus size to levels comparable to control Ig injected mice (31527 vs 1399 µm2; p<0.0001), demonstrating that thrombosis is induced by TF activation.
Conclusions: Blockade of TF with rNAPc2 is effective to prevent COVID-19 Ig-induced thrombosis in a preclinical model of APS.
To cite this abstract in AMA style:Pedrosa D, Müller-Calleja N, Hollerbach A, Lackner K, Ruf W. Blockade Of COVID-19 Antiphospholipid Antibody-Induced Thrombosis by a Specific Inhibitor of the TF Initiation Complex [abstract]. Res Pract Thromb Haemost. 2021; 5 (Suppl 2). https://abstracts.isth.org/abstract/blockade-of-covid-19-antiphospholipid-antibody-induced-thrombosis-by-a-specific-inhibitor-of-the-tf-initiation-complex/. Accessed September 24, 2023.
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