Abstract Number: PB0076
Meeting: ISTH 2021 Congress
Background: Despite a few studies showing the potential for FXIIa and kallikrein to contribute to clot formation in a FXI-independent manner, thrombin generation via the intrinsic pathway is often considered FXI-dependent.
Aims: Investigate FXI bypass pathways of coagulation via selective inhibition of the contact activation system and mathematical modelling.
Methods: Various aPTT data sets were generated using different concentrations of functional antibodies against FXII/XIIa (termed 3F7), FXI/XIa, and kallikrein. The aPTT data sets were simulated in three stages to mimic the in vitro assay:
1) binding of antibodies to their targets,
2) incubation of plasma with phospholipids and negatively charged FXII activator,
3) addition of calcium ions to trigger coagulation.
Four distinct reaction pathways need to be included in the mathematical model to accurately reproduce the full range of aPTT data sets: rapid activation of FXI by FXIIa, direct activation of FIX by kallikrein, and slow activation of prothrombin by both kallikrein and FXIIa (Figure 1). High concentrations of 3F7 block all four downstream pathways of thrombin generation. Blocking the activation of FIX with a FXI/XIa antibody has little effect on the clotting time due to upstream reactions circumventing this reaction. Inhibition of kallikrein prolongs the clotting time only slightly, as the activation of FXII is the dominant trigger in an aPTT assay. Blocking both kallikrein and FXIa prolonged the clotting time more than threefold, highlighting the role of kallikrein in the absence of FXI and the presence of a thrombin generation pathway independent of FXI and kallikrein (Figure 2).
Conclusions: Our results suggest that in the absence of FXI, both kallikrein and FXIIa are able to generate thrombin via the contact activation pathway of coagulation.
To cite this abstract in AMA style:Rezvani-Sharif A, Rauth S, Arthur J, Niebl P, Dower S, Panousis C, Muir I. FXI-independent Pathways of Contact Activation: Analysis of Activated Partial Thromboplastin Time (aPTT) Data Using Mathematical Modelling [abstract]. Res Pract Thromb Haemost. 2021; 5 (Suppl 2). https://abstracts.isth.org/abstract/fxi-independent-pathways-of-contact-activation-analysis-of-activated-partial-thromboplastin-time-aptt-data-using-mathematical-modelling/. Accessed February 27, 2024.
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