Factor XI is part of the intrinsic pathway of blood coagulation. Factor XI deficiency leads to hemophilia C, which is a rare and relatively mild disorder with unpredictable bleeding tendencies. The function of the factor, and the pathology of the disease are incompletely understood.
Factor XI functions as a serine protease and activates factor IX, which, together with factor VIII activates factor X. Factor XI also acts to decrease fibrinolysis , and may have a role in inflammatory processes. The protein circulates as a homodimer, and dimerization is required for secretion into the bloodstream.
Deficiency of factor XI has a high incidence of occurrence in people of Ashkenazi Jewish heritage. In this population, there are two prevalent mutations, one substituting for an amino acid, and another resulting in premature chain termination. As may be expected, people homozygous for the nonsense mutation tend to bleed more extensively than those with the missense mutation. However, in most other cases the severity of the disease is not well correlated with genotype or with residual amount or activity of the protein   , possibly owing to aberrant interactions between factor XI and other coagulation factors when those are at suboptimal levels . For example, members of the same family with similar factor XI deficiency were found with incongruous symptoms . The disease is normally inherited in a recessive manner. However, some mutant proteins can bind normal monomers in heterodimer structures that cannot be secreted. In a situation like this, the secretion of the normal protein is prevented in a heterozygote, and the inheritance becomes dominant .
Spontaneous bleeding in factor XI deficiency is very rare, as is bruising or hemarthrosis. Unusual bleeding usually follows trauma, such as circumcision, dental work, tonsillectomy or other surgeries, but there is a tendency for it to occur mainly in the mouth and genitourinary systems, where fibrinolytic activity is high. This may be explained by the role of factor XI in inhibiting fibrinolysis. Menorrhagia and postpartum bleeding are frequent signs of factor XI deficiency. In some cases, a family history of a mild bleeding disorder may be a sign of the deficiency. In other cases, factor XI deficiency may be discovered during follow-up of an incidental finding of prolonged activated partial thromboplastin time (aPTT), which is measured routinely before surgeries. Factor XI deficiency may be acquired as a consequence of systemic lupus erythematosus. The levels of factor XI will decrease, together with many other proteins, when liver function is compromised.
A suspicion of coagulopathy calls for the usual coagulation tests, which comprise the prothrombin time (PT), (APTT), and fibrinogen level. If a prolonged APTT result is obtained, mixing studies with normal plasma are usually performed to determine whether the anomaly is due to deficiency of a factor, or to the presence of an inhibitor. This determination has obvious implications for therapy. More than a quarter of the patients with a severe factor XI deficiency harbor an inhibitor to the factor , and very small amounts of factor XI in blood-derived preparations have been shown to trigger formation of the inhibitor . In interpreting the APTT test results, the variability of different testing agents should be kept in mind. On the one hand, some reagents are oversensitive to lupus anticoagulant antibodies, and therefore may show false positive results. On the other hand, the sensitivity of some test reagents may be too low so that false negative results will be observed . People with bleeding abnormalities should undergo tests with individual clotting factors.
Homozygotes, or people with two differently affected alleles (compound heterozygotes), usually have less than 10% of normal factor XI levels, whereas heterozygotes have about 50%.