Abstract 181: Sub-picomolar Amounts of Coagulation Factor XIa Promote Spatial Clot Growth and Thrombin Generation Inside Propagating Clot

Abstract

Background: Activated coagulation factor XI (FXIa) was found in the immunoglobulin products that were associated with higher than usual incidence of thrombotic events (TEs). However, TEs after thrombogenic immunoglobulin administration are very rare and are often recorded as late as 48 hours after administration. Objective: This study was aimed to elucidate the mechanisms behind FXIa thrombogenicity. We hypothesized that low amounts of FXIa are not able to activate clotting directly, but can promote on-going coagulation events at a site of vascular lesion. Materials and methods: FXIa activity was characterized by kinetic clotting and thrombin generation (TG) assays. Spatial clot growth and thrombin wave propagation in stagnant plasma were studied using thrombodynamics, a time-lapse videomicroscopy-based approach. To model coagulation events at the site of vascular wall lesion, spatial clot growth was initiated by plastic surfaces covered with immobilized tissue factor (TF). Human plasma deficient in various coagulation factors was used to study pathways of FXI activation. Results: Low plasma FXIa levels of less than 0.3 pM did not induce thrombin generation or clotting, but increased TG in plasma mixed with TF. Higher FXIa levels (>0.3 pM) activated coagulation directly. In stagnant plasma activated by surface with immobilized TF, sub-picomolar amounts of FXIa were also not able to initiate clotting, but was able to enhance TG inside clots. FXIa-induced TG was localized to the propagating edge of the clot and associated with increased clot growth rate. Conclusion: Sub-picomolar amounts of FXIa may promote growth of clot in the vicinity of vascular lesion and have no procoagulant effect in the absence of exposed TF. These in vitro findings suggest that the patient’s condition might contribute to the thrombogenicity of FXIa.