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Factor XII and the contact system:
cross-talk between thrombosis and inflammation

Final Report Summary - F12 (Factor XII and the contact system: cross-talk between thrombosis and inflammation)

An increasing amount of clinical and experimental evidence indicates that combinations of proinflammatory and procoagulant reactions are the unifying principle for a variety of thromboembolic and vascular diseases, collectively the most common causes of death in the developed world. The plasma contact system is a proinflammatory and procoagulant protease cascade that is initiated by factor XII (FXII, Hageman factor), in a reaction involving high molecular weight kininogen (HK) and plasma kallikrein (PK). FXII is the zymogen form of the serine protease factor XIIa (FXIIa). FXII is activated to FXIIa by PK or by its unique property to auto-activate following binding (“contact”) to negatively-charged artificial or biologic surfaces (contact activation). FXII was first recognized as essential for surface-activated diagnostic blood coagulation assays [e.g. the activated partial thromboplastin time (aPTT)] that are commonly used as a clinical measure of global plasma coagulation. FXIIa initiates the intrinsic pathway of coagulation and leads to liberation of the proinflammatory mediator bradykinin (BK) from high molecular weight kininogen (HK). Serpin C1 esterase inhibitor (C1INH) is the major plasma inhibitor of FXIIa. Deficiency or a dysfunctional C1INH is associated with a BK-mediated life-threatening inherited swelling disorder, hereditary angioedema (HAE) type I or II, respectively (Maas & Renne, Blood 2018).

The selective importance of FXII in pathologic thrombosis raises the exciting possibility that targeting FXII is an effective strategy for the prevention and treatment of pathologic thrombosis without the bleeding risk that is characteristic of current anticoagulants. We generated a fully-human, FXIIa neutralizing antibody, 3F7. Targeting FXIIa with 3F7 provided protection from thrombosis in an experimental model of extracorporeal membrane oxygenation (ECMO) system in rabbits, as effectively as heparin. Most importantly however, unlike heparin, 3F7 did not increase bleeding (Larsson, Sci Transl Med 2014). This study led to a paradigm shift in the design of anticoagulant therapies and motivated pharmaceutical companies to pursue the strategy of FXII inhibition as a safe therapeutic approach for the treatment of thromboembolic diseases.

To interfere with polyP activities, we developed the first specific polyP inhibitors, based on recombinant E. coli exopolyposphatase (PPX) mutants (Labberton, Nat Commun 2016). Supporting a specific function of the polyP/FXII axis in thrombosis, targeting polyP also provided safe thromboprotection in vivo. We visualized polyP nanoparticles on the surface of procoagulant platelets in vivo, and identified a function of polyP/FXII in cancer-associated thrombosis (Verhoef, Blood 2017; Nickel, Blood 2015). We also established a fluorescence-activated cell sorting (FACS) assay to measure polyP in patients based on a recombinant polyP-specific probe (PPX_Δ12) (Labberton, Flow Cytometry 2017). Furthermore, we identified polyP and heparin that are released from mast cells as FXII contact activators involved in anaphylaxis and vascular leak (Sala, JACI 2015). We also have uncovered the mechanism underlying HAE type III that consists of normal C1INH but is associated with FXII-activating mutations. FXII in HAE type III patients is defective at a single glycosylation site that leads to aberrant FXII contact activation, excessive BK production, and edema that 3F7 interferes with (Björqvist, JCI 2015; Maat, JACI 2016).

Collectively, our findings obtained in the ERC grant provided novel, innovative, mechanism-based strategies for combating thrombotic and inflammatory diseases.