Congenital factor XI deficiency: an update.

Area of Science:

• Hematology
• Genetics

Background:

• Severe factor XI (FXI) deficiency is an inherited bleeding disorder, prevalent in Ashkenazi Jews due to specific mutations, but globally rare with diverse genetic causes.
• Over 220 FXI gene mutations identified, with 7 showing founder effects. Inhibitors to FXI can develop post-exposure to plasma or FXI concentrates.

Purpose of the Study:

• To explore the dual role of FXI in hemostasis and thrombosis.
• To evaluate FXI as a therapeutic target for thrombosis prevention.

Main Methods:

• Review of reported FXI gene mutations and inhibitor development.
• Analysis of animal models targeting FXI (gene knockout, neutralizing antibodies, antisense oligonucleotides, peptidomimetic inhibitors).
• Assessment of recombinant activated factor VII in vitro via thrombin generation tests.

Main Results:

• FXI deficiency is linked to bleeding disorders, but FXI also plays a role in thrombosis.
• Animal models demonstrate that targeting FXI effectively prevents arterial and venous thrombosis.
• Lower doses of recombinant activated factor VII show promise in vitro for managing FXI deficiency-related bleeding.

Conclusions:

• Targeting FXI presents a novel strategy for thrombosis prevention with minimal impact on hemostasis.
• FXI's role in thrombosis is a recent concept, potentially benefiting patients with FXI deficiency throughout their lives.