Presentation Highlights

Owen McCarty, Ph.D. presented his research on “Factor XI and XII in Blood Clotting and Beyond: Contact Pathway Under Flow” at Wednesday’s State-of-the-Art Session. The key points of this presentation included:

  • The role of the contact pathway in coagulation is becoming more defined, specifically with respect to factors XI (FXI) and factor XII (FXII).
  • FXI promotes local and distal platelet activation.
  • Platelet polyphosphate is a cofactor for FXI inactivation of TF pathway inhibitor.
  • The endothelium inactivates FXIa.
  • Inhibiting FXI is protective in a primate model of sepsis.
  • Inhibiting FXI may be useful and safe.

Owen McCarty, Ph.D. has a special interest in studying blood flow and blood cells in the context of the microenvironment, fluid dynamics, and thermodynamics. In his research, he has evaluated the role of contact activation. When blood comes in contact with a foreign surface (e.g., a catheter), it will activate and initiate the coagulation cascade. Therefore, in certain situations where a foreign surface is introduced into the body, anticoagulation is necessary to prevent thrombus formation.

In recent years, however, scientists have come to understand that there are substances (RNA, DNA, and neutrophils) that occur naturally and could be seen by the body as a foreign but do not activate the clotting process. This begs the question: what role, if any, does the contact activation pathway play in hemostasis?

FXII-deficient patients do not have a bleeding phenotype, while the bleeding phenotype of FXI is usually very mild. These proteins are potentially good targets for inhibition in circumstances where this would be beneficial, such as catheter insertion or in certain thromboembolic disease settings. However, if the contact pathway is targeted for anti-thrombotic therapy, it is important to understand the extent to which it is efficacious without causing bleeding.

McCarty and colleagues explored the relationship between factors XI and XII within the contact pathway. Factor XII is important in regulating inflammation, and the interaction between FXII and cells involved in inflammatory processes is important to characterize.

FXI has been shown to promote local and distal platelet activation. Triggers and cofactors for the contact pathway include long polyphosphates, often found on bacteria, and short polyphosphates found in platelets. In a recent study, it was demonstrated that FXII was activated by long polyphosphates and promotes thrombus formation in a FXI-independent pathway. In several analyses, these long polyphosphates can also promote local and distant platelet activation. Short polyphosphates, on the other hand are weak activators of FXII.

The researchers believe that crosstalk between FXII and FXI may drive inflammation and thrombin generation in the setting of infectious disease. They suspect factor XII could have a barrier or protective effect, and there may be a tipping point between both it and factor XI in inflammatory conditions such as sepsis. Inhibition of activation of factor XI by factor XII could be a key step.

All the functions of FXII and FXI may not be known, and the consequences of targeting them are therefore also not clear. Targeting the enzymatic function of factor XI may have the potential to cause bleeding in certain vascular beds. Investigators are currently studying an anti-FXI monoclonal antibody, xisomab, in a safety and tolerability trial (NCT03097341) in healthy adult subjects.

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