WSC 2025 | The mechanistic rationale for targeting Factor XI for secondary acute ischemic stroke prevention

We’ve been wrestling with how to explain this over the last several years. Every diagram we make of the coagulation cascade seems more confusing than illuminating. But really the rationale for looking at Factor XI and activated Factor XI comes from human genetic data. So our individual risk of being deficient in Factor XI is about one in a million. There are some populations, mostly in Israel, where it’s up to one in 450. This allows us to study the natural history of people who are deficient in Factor XI. What you find is they have a substantially reduced risk of stroke but do not experience severe life-threatening hemorrhages and do not have an increase in intracerebral hemorrhage. So Factor XI has the potential and inhibition of it has the potential to uncouple a therapeutic effect from hemorrhage and that really is the target that we’ve been striving for for these past few decades. The reason it can do that is because the mechanisms involved in hemostasis and in pathologic thrombosis are different in the involvement of tissue factor. With hemostasis, you have a hole in the blood vessel. Blood is exposed to large amounts of tissue factor on the exterior surface of the vessel, and that drives thrombosis. The feedback loop, thrombin through Factor XI to more thrombin, is relatively unimportant there with large amounts of tissue factor. With pathologic thrombi, there is a small amount of tissue factor inside the vessel and then that feedback loop is proportionately more important. Inhibiting it preferentially inhibits intravascular pathologic thrombi and leaves hemostasis relatively unimpaired.

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