During Wednesday’s State-of-the-Art Session, Thomas Renné, M.D., Ph.D. presented his fascinating work on “Factor XII and the Contact System”. Highlights included:
- The factor XII-driven (FXII) contact system is essential for thrombosis but has no function in hemostasis, which makes this system an ideal target for anticoagulant drug development.
- Polyphosphate is an in vivo activator of the FXII-driven contact system with implications for thrombotic and inflammatory diseases.
- Platelets have two pools of polyphosphate (polyP): short-chain/soluble that are secreted and long-chain polymers that are retained as Ca+2-rich nanoparticles on the membrane.
- Targeting platelet polyP provides safe thromboprotection, indicating that polyP operates via FXII activation in vivo.
The contact system consists of a series of proteases and cofactors that assemble on platelets and inflammatory cells. The role of the contact system was not understood until recently because deficiency in contact system proteins are not associated with increased bleeding. However, when FXII-deficient mice were generated, a striking phenotype was discovered: these mice were protected from thrombotic disease, but had normal hemostasis. These results in FXII-deficient mice demonstrated that it is possible to block thrombosis without increased bleeding, suggesting that thrombosis and hemostasis occur via different mechanisms.
Inhibitors of FXII or its activated form, such as the antibody 3F7, block thrombosis as efficiently as heparin but do not cause increased bleeding. These findings have far-reaching implications for therapeutic strategies in settings where anticoagulation-related hemorrhage is a major concern, such as ECMO, cancer-associated thrombosis, and stroke.
FXII is activated by the inorganic polymer polyphosphate (polyP). Platelets have two pools of polyP, short chain molecules that are soluble and released to the supernatant; these molecules may support other procoagulant mechanisms. In contrast, long chain polyphosphate particles (nano-particles) are released from activated platelets and retained on the platelet membrane surface. These particles potently activate FXII and drive thrombosis in a FXII-dependent manner. Targeting platelet polyphosphates with exopolyphosphates (PPX) interferes with thrombosis, but does not increase bleeding, supporting their effects via FXII activation in vivo.