eMedicine Specialties > Hematology > Coagulation, Hemostasis, and Disorders
Factor XI Deficiency
Updated: Aug 6, 2009
Introduction
Background
Factor XI (FXI) deficiency is an autosomal disorder that may be associated with bleeding. Other terms for this disorder include plasma thromboplastin antecedent (PTA) deficiency, Rosenthal syndrome, and hemophilia C. Rosenthal first described this bleeding disorder in 1953. He identified the abnormality as a factor deficiency, which he termed PTA, that was distinct from the already identified antihemophilic globulin. This disorder was found in both sexes and was understood to be inherited but was identified as being a less severe abnormality than that observed with hemophilia A and B. Also noted was that FXI deficiency occurred in patients without a family history. Since then, it has been identified in patients predominantly, but not exclusively, of Jewish heritage.
FXI deficiency can manifest first as a bleeding disorder or as an incidental laboratory abnormality. The bleeding manifestations can present at circumcision (rarely) or much later in life during elective surgery. An unexpected and incidental preoperative finding of a prolonged activated partial thromboplastin time (aPTT) can be quite disruptive and may prevent the scheduled surgery. Bleeding associated with FXI deficiency is predictable neither within a patient nor within a family. In contrast to hemophilias A and B, bleeding manifestations in hemophilia C do not correlate with the FXI level.
Pathophysiology
FXI circulates at a concentration of approximately 5 mcg/mL. It is a 160,000-d protein composed of a disulfide-linked dimer with identical polypeptide chains. FXI is a zymogen, and when activated by factor XIIa or thrombin or when it is autoactivated, FXI becomes a trypsinlike serine protease. Plasma FXI complexes with high–molecular-weight kininogen, which then aids in the binding of FXI to negatively charged surfaces. FXI remains on the surface and activates factor IX in plasma. Activated factor XI can be inactivated by antithrombin III, alpha1-protease inhibitor, C1 inhibitor, and alpha2-antiplasmin. The half-life of FXI is approximately 52 hours.
The gene controlling the production of plasma FXI is on the distal end of the long arm of chromosome 4. The gene is 23 kilobases in size. A platelet FXI that is similar, but not identical, to plasma FXI also exists.
The sole site of synthesis of the FXI plasma protein is the liver. This finding is supported by 2 reports of patients undergoing liver transplant. One transplant was from a patient with known FXI deficiency, with a level of 26%. The recipient's level after transplantation was 22%. The second donor had a known prolonged aPTT, bleeding history, and was of Ashkenazi Jewish descent. The recipient's subsequent FXI level was 2%. Platelet FXI is synthesized only in the megakaryocyte.
Normal dimerization is required for secretion of factor XI from the producing cell. A proposed classification system for factor XI deficiency is based on the patterns of protein production or dimerization of the FXI molecule. This system separates mutations that (1) result in decreased synthesis of the protein (Glu117Stop or Type II) producing no measurable FXI in the homozygous state, (2) abnormal dimerization of the protein (Phe283Leu or Type III) producing approximately 10% of FXI in the homozygous state, or (3) dimerization that results in the FXI protein to be poorly secreted (Ser225Phe and Cys398Tyr). This results in no measurable FXI in the homozygous state and a measurable factor XI level that is lower than the expected 50% in the heterozygous state. This third group is thought to explain the dominant mutation patterns that are seen in some families with FXI deficiency.
Two predominant mutations, type II and III (using an older classification system) cause the FXI deficiency in patients of Ashkenazi Jewish descent. The type III mutation is an amino acid substitution (Phe283Leu) resulting in a missense mutation. This results in impaired dimerization and secretion of the FXI molecule. The second is the type II mutation; this causes premature chain termination and results in very low levels of circulating FXI. The type II mutation also has been found in people of Iraqi Jewish and Israeli Arabic descent. Both mutations are thought to originate from a common founder, one occurring before and one after the divergence of the Jewish people.
Patients who are type II/II homozygotes have a mean factor level of 1.2%; type III/III homozygotes have a mean factor level of 9.7%, and type II/III heterozygotes have a mean factor level of 3.3%. Spontaneous bleeding was rare in all groups, but patients with the type III/III mutation had fewer trauma-induced bleeding events. All groups had more bleeding with surgeries involving surfaces with fibrinolytic activity, ie, the mouth, tonsils, and urinary tract, compared with other surgeries.
Those patients with FXI deficiency who are of non-Jewish heritage are more likely to have other genetic defects.
A mutation (Cys128Stop) has been found in families from the northwest area of England and has an allele frequency of 0.009, with a resultant frequency of 1 per 10,000 for homozygous or severe FXI deficiency. This explains why FXI deficiency is almost as common as FIX deficiency in the United Kingdom. It is considered that these patients, like the Jewish patients with the type II and type III mutations, also all come from a common founder.
Most patients known to have FXI deficiency with the associated genetic alterations were found to have a decreased level of protein synthesis. An African American family was found to have the first genetic defect associated with functional abnormality that was out of proportion to the reduced protein level. In this family, a child and his mother had significant bleeding manifestations. The 9-year-old boy had bleeding with dental procedures and after circumcision, as well as epistaxis. He had received plasma for some of his bleeding episodes. His aPTT was minimally prolonged, and his FXI level ranged from 42-55%. His mother had bleeding in the postpartum period, after dental work, and epistaxis. Her aPTT produced normal results and her FXI level was 67-72%.
The child was found to be a compound heterozygote for an abnormality in the third apple domain of the heavy chain of the FXI protein. This site includes binding sites between factor IX and platelets. In particular, the site mutation found in both the mother and the child is associated with a defect in platelet binding that interferes with FXI activation. The change in protein function found in this family, compared to decreased protein synthesis, is also consistent with an autosomal dominant form of inheritance. A second mutation (Gly555Glu) with a dysfunctional FXI protein has recently been described.
New mutations are being reported in the literature, and a repository of this data is available via the FXI deficiency associated mutation database (see Human Gene Mutation Database).
Saunders et al analyzed 8 novel and 112 previously reported missense mutations in the University College London F XI Deficiency Mutation Database (http://www.FactorXI.org). The investigators found the most numerous defects in FXI were from low-protein plasma levels (Type I: CRM-) due to protein misfolding rather than from defects (Type II: CRM+).34 Analysis of 70 apple (Ap) domain missense mutations demonstrated the entire Ap domain was affected, as well as 47 serine protease (SP) missense mutations throughout the SP domain structure. Residue changes affected at different locations in the Ap domain led to different involvement in structural perturbations. Saunders et al concluded that the abundance of type I defects in FXI results from the sensitivity of the Ap domain folding to residue changes within it, which may improve understanding of FXI deficiencies.34
Development of FXI inhibitors (IgG) occurs at a rate of up to 33% in patients with severe ( <1%) FXI deficiency after exposure to exogenous FXI, usually via plasma products. This needs to be a recognized complication of replacement therapy and evaluated for in patients before a planned invasive procedure.
Epidemiologic data has shown that high levels of FXI are associated with an increased risk of venous thrombosis. Deficiency of FXI does not protect from myocardial infarction. It is not known if low levels of FXI protect from venous thrombosis.
Frequency
United States
In Jewish people of Ashkenazi (European) heritage, the allele frequency is reported to be somewhere from 8-13.4%. In the non-Jewish population, FXI deficiency is observed in approximately 1 per million population.
International
In Israel, the allele frequency for Ashkenazi Jewish people is reported to be from 8-13.4%. A second report describes 1 of 190 (0.5%) people as being affected by homozygous severe FXI deficiency. Another estimate is that severe deficiency occurs in 1 of 450 (0.2%) Ashkenazi Jews. In addition, Iraqi Jewish people carry the type II mutation at a reported frequency of 3.7%. People of Arabic background living in Israel and Jewish people of Sephardic (Spanish) background carry the type II mutation, but at a much lower frequency. Of patients with bleeding disorders in the United Kingdom, 5% have FXI deficiency, and most of these patients are not of Jewish heritage.
Mortality/Morbidity
In the literature, no report exists of any effect of FXI deficiency on mortality. Certainly, morbidity occurs in individuals with FXI deficiency in whom the condition remains unrecognized and who then have bleeding manifestations from surgery, dental procedures, or menorrhagia.
Race
FXI deficiency is observed predominantly in people of Jewish heritage.
Sex
FXI deficiency is an autosomal disorder and, therefore, should occur in equal numbers in men and women.
Age
FXI deficiency is an inherited disorder. It can manifest at any age beginning from circumcision, menarche, or when dental extractions, trauma, or surgery occur.
Clinical
History
Bleeding occurs with dental extractions, trauma, or surgery. The factor level does not correlate with or act as a predictor of bleeding risk. Within the patient and within the family, highly variable and unpredictable bleeding patterns occur. Bleeding can be immediate or delayed.
- Circumcision may be the first manifestation of this bleeding disorder, but a negative history does not exclude FXI deficiency.
- Bleeding with dental extractions is a common manifestation.
- Menorrhagia has been reported in as many as 59% of women with FXI deficiency. In one study of women with menorrhagia, 4% were found to have FXI deficiency.
- An inconsistent history of bleeding in the same patient may be observed with FXI deficiency.
- A patient may be found only by abnormal findings on the aPTT on routine preoperative testing.
- Family history may reflect an autosomal dominant or recessive pattern of inheritance.
Physical
Physical manifestations of FXI deficiency are rare. Bruising and petechiae usually are not observed with this coagulation disorder. No chronic joint abnormalities occur. After a surgical procedure, if a patient has remained undiagnosed and untreated, a significant hematoma may occur in the area of surgery.
Causes
- FXI deficiency is predominantly an inherited disorder.
- Reports exist of acquired FXI deficiency associated with systemic lupus erythematosus. In addition, when measuring the FXI level in the laboratory, some reagents are particularly sensitive to the lupus anticoagulant and results may be falsely interpreted as a factor XI deficiency. Therefore, a diagnosis of FXI deficiency must be made with caution in a patient without a family history and who is not of Jewish heritage.
- Acquired alloantibodies to FXI may occur in patients who are congenitally deficient and who have been exposed to FXI via blood products.
- The FXI level may decrease, as do the other factors synthesized in the liver, when interference with liver synthetic function occurs.
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Further Reading
Keywords
factor XI deficiency, FXI deficiency, hemophilia C, plasma thromboplastin antecedent deficiency, Rosenthal's syndrome, Rosenthal syndrome, PTA deficiency, bleeding disorder
