Factor XI Deficiency

Disease Overview

Factor XI (FXI) deficiency results in a mild bleeding disorder. It was first reported in 19531 when an American physician reported a Jewish family with abnormal bleeding after tonsillectomy and dental extractions. As this was manifested in both sexes, two sisters and their maternal uncle, the clinical features were not consistent with hemophilia A or B and was called hemophilia C2. Overall, spontaneous bleeding is very rarely reported, even with absent measurable FXI but bleeding may occur after accidents or surgery, particularly in areas of high fibrinolytic activity, such as the oropharynx and genitourinary tract.

Factor XI is a serine protease that is produced in the liver. This coagulation factor is unique in circulating as a dimer complexed to high molecular weight kininogen (HK). It contains four homologous tandem repeats (apple domains) and a catalytic serine protease domain. The crystal structure of FXI shows a circle of apple domains as a disc in relation to the catalytic domain3. Activation of FXI is associated with a structural shift exposing the FIX binding site. Activation of FIX reinforces the intrinsic pathway of coagulation.

The role of FXI in the coagulation pathway has been debated. Although the traditional view is that it is activated by the ‘contact’ pathway by activated Factor XII (FXII), it was not clear how this related to normal physiologic hemostatic mechanisms. The discovery that FXI is activated by thrombin led to a revised view of the coagulation system in which FXI is not critical in initiation of coagulation, but reinforces the intrinsic pathway by activation of factor IX after its triggering by thrombin4,5.

Recent research shows that the FXII-contact pathway and thereby FXI activation by FXIIa is important in development of thrombosis. Absence of FXII is not associated with a bleeding disorder and in fact is protective against thrombosis. FXII links hemostasis with the kinin and complement systems. Animal experiments show that mouse gene knockouts for either FXI or FXII are protected against thrombosis and do not have a bleeding disorder.6

Thrombin activation of FXI is triggered by polyphosphate release from activated platelets. Polyphosphates are ubiquitous in nature. These cofactor molecules of polymer length 60-100 phosphate units provide a template for assembly of FXI and FIX5,7. This supports physiological FXI activation in hemostasis triggering by platelet polyphosphates and explains why the contact pathway is not required for hemostasis.

The FXI gene was elucidated in 19878 and is located on chromosome 4. Two mutations are responsible for most FXI deficiency in the Jewish population9; these are a stop codon in apple 2, Glu117Stop, and a missense mutation in apple 3, Phe283Leu, which results in reduced secretion of FXI. Many other mutations, mainly point missense changes, have also been reported, 192 are detailed on the factor XI website which was last updated in September 2009 (www.factorxi.org ). A third of mutations are reported in the serine protease domain, and others are spread across the 4 apples.

Individuals with two mutations, homozygous or compound heterozygous, usually have FXI levels less than 15 IU/dL. Homozygotes for the Glu117Stop mutation produce no FXI and have a higher bleeding risk than homozygotes for Phe283Leu whose baseline level is approximates 10 IU/dLl. Compound heterozygotes have levels intermediate between these two. Some heterozygous individuals have a lower than expected FXI level due to inhibition of release of normal FXI dimers. This occurs where the mutant FXI interferes with and binds to wild-type FXI in the cell, a so called dominant-negative effect. A number of different mutations with this complication have been described10 11.

FXI deficiency has been divided into ‘severe’ with FXI levels of 15-20 IU/dLl and below, and ‘mild’ or partial deficiency where the levels are higher than this. The classification divides heterozygotes from homozygotes or compound heterozygotes, but does not reflect bleeding risk. This terminology needs updating. The classification of hemophilia A and B into severe, moderate and mild as defined by factor levels and clinical features is not applicable or appropriate in FXI deficiency.

A recent review of the classification of the rare bleeding disorders based on published evidence and review of four national and international databases noted that there is either a poor or no relationship between the FXI level and observed bleeding severity12. Individuals with no detectable FXI activity may never experience bleeding.

Recent work suggests that measurement of thrombin generation in a low tissue factor environment may relate more closely to bleeding tendency13 and may help elucidate the relationship between FXI levels and bleeding tendency. A further example of a lack of correlation between the laboratory tests and the bleeding tendency  is provided by a mutation in the platelet binding domain (Ser248Asn), which is associated with bleeding but a normal APTT14.