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Factor XI Deficiency
Factor XI (FXI) deficiency, was first described in 1953. It is characterized by a highly variable bleeding phenotype. Some patients have no apparent excessive bleeding while others have more substantial bleeding. In contrast to other coagulation factor deficiencies, excessive bleeding in FXI deficiency is also highly variable in an individual patient, who might hemorrhage after one hemostatic challenge but not after another. Homozygotes or compound heterozygotes with <15% FXI levels usually have more severe bleeding tendencies than heterozygotes who have 25%–70% FXI levels (and who have little or no excessive bleeding). Although FXI deficiency is classified among rare inherited coagulation disorders (estimated prevalence of severe deficiency in most populations is 1:1,000,000), its frequency is remarkably higher among Ashkenazi Jews (1:450 individuals).
Biochemistry
FXI is synthesized in both the liver and perhaps to a minor extent in megakaryocytes. FXI is a 160-kDa glycoprotein, which separates into two 80-kDa subunits linked by disulfide bonds. It comprises heavy chains with four repeats that have binding sites for high-molecular-weight kininogen (HK), thrombin, platelets, FIX, and FXII. It also comprises a light chain where the serine protease is located. It is converted to the active serine protease form, FXIa. This conversion is accelerated by calcium, platelets (a source of phospholipids), and thrombin. Originally, FXI was thought to predominantly be activated by FXII or HK, due to contact activation and the so-called intrinsic pathway. Contact activation is not thought to be as important in the physiologic activation of FXI, and instead the activation of FXI is predominately mediated by thrombin. Thrombin’s role in the activation of FXI is the result of a “feed-forward loop” to promote stable clot formation and protection against fibrinolysis by thrombin activatable fibrinolytic inhibitor (TAFI). This latter relationship between FXI and fibrinolysis might explain why, in contrast to other coagulation factor deficiencies, FXI deficiency leads to excessive mucosal bleeding.
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