Abstract Number: PB0751
Meeting: ISTH 2020 Congress
Background: Proteolytic degradation of PAI-1 by APC has been suggested to contribute to a hyperfibrinolytic state in acquired coagulopathies in sepsis or trauma. However, in vivo evidence remains inconclusive. Recently, we have shown increased APC generation in FVL and PTM carriers in response to in vivo thrombin formation triggered by low-dose administration of recombinant activated factor VIIa (rFVIIa).
Aims: To investigate the effects of this approach of stimulated hemostasis activity pattern evaluation (SHAPE) on fibrinolysis.
Methods: Blood samples were collected from FVL/PTM carriers (30 each) and 29 healthy controls immediately before and over 8 hours following injection of 15 µg/kg rFVIIa. APC plasma levels were measured using an oligonucleotide-based enzyme capture assay (OECA). Other monitored parameters included prothrombin activation fragment 1+2 (F1+2), thrombin-antithrombin complexes (TAT), tissue-type plasminogen (t-PA), PAI-1, α2-antiplasmin, plasmin-α2-antiplasmin complexes (PAP), soluble fibrin monomers, d-dimer, and thrombin-activatable fibrinolysis inhibitor (TAFI) antigen and activity levels.
Results: PAI-1 levels were higher in FVL (29.8 ng/mL, P< 10-4) and PTM carriers (27.7 ng/mL, P=0.002) than in controls (9.1 ng/mL). Other baseline parameters did not differ significantly. In all cohorts a comparable increase of F1+2 and TAT was observed after administration of rFVIIa, whereas the APC increase was greater in FVL (by 7.79 pmol/L, P< 10-4) and PTM carriers (by 4.71 pmol/L, P< 10-4) than in controls (by 2.38 pmol/L) (Fig. 1). Concurrently, PAI-1 levels decreased more in FVL (by 19.9 ng/mL, P=2·10-4) and PTM carriers (by 21.0 ng/mL, P=0.009) than in controls (by 5.5 pmol/L) (Fig. 2). TAFI antigen, PAP, and d-dimer increased at comparable extents within reference ranges in all cohorts. Other parameters remained unchanged.
Conclusions: Increased APC formation rates in thrombophilic mutation carriers were associated with a greater decline of PAI-1 levels in the absence of interfering changes in t-PA levels. These data provide further in vivo evidence that APC down-regulates PAI-1.
To cite this abstract in AMA style:Reda S, Winterhagen FI, Berens C, Müller J, Oldenburg J, Pötzsch B, Rühl H. Down-regulation of Plasminogen Activator Inhibitor-1 (PAI-1) by in vivo Thrombin Generation and Subsequent Formation of Activated Protein C (APC) in Carriers of the Factor V Leiden (FVL) and Prothrombin 20210G>A Mutation (PTM) [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/down-regulation-of-plasminogen-activator-inhibitor-1-pai-1-by-in-vivo-thrombin-generation-and-subsequent-formation-of-activated-protein-c-apc-in-carriers-of-the-factor-v-leiden-fvl-and-prothromb/. Accessed January 28, 2022.
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