Factor XI Deficiency

Updated: Jun 15, 2022
  • Author: Jamie E Siegel, MD; Chief Editor: Srikanth Nagalla, MD, MS, FACP  more...
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Overview

Practice Essentials

Factor XI (FXI) deficiency is a rare autosomal disorder that may be associated with bleeding. [1] (See the image below.)

Factor XI deficiency. Diagram from the traditional Factor XI deficiency. Diagram from the traditional cascade-waterfall model of coagulation shows the place of factor XI in the intrinsic pathway, which leads to the common pathway.

FXI deficiency can manifest as an incidental laboratory abnormality—for example, when a preoperative workup for elective surgery reveals an unexpected prolongation of the activated partial thromboplastin time (aPTT). When abnormal bleeding does occur, it tends to be much milder than in hemophilia A and B, and to involve different tissues; unlike the soft tissue bleeds and hemarthroses that characterize hemophilia A and B, abnormal bleeding in FXI deficiency typically involves mucosal tissues, which are rich in fibrinolytic activity (eg, the oral and nasal cavities and urinary tract). Severe spontaneous bleeding is rare, but epistaxis and, in women, menorrhagia are relatively common. [2, 1]  

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 FXI deficiency often show little correlation with the FXI level.

Treatment of FXI deficiency is determined by the intervention planned. Options include factor replacement with fresh frozen plasma, antifibrinolytic therapy with tranexamic acid, and fibrin glue.  

 

 

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Background

Rosenthal and colleagues first described factor XI deficiency in 1953. [3]  They identified the abnormality as a deficiency in a clotting factor, which they termed plasma thromboplastin antecedent (PTA). The coagulation defect in plasma from these patients was corrected on mixing with plasma from patients with hemophilia, indicating that these patients lacked a factor different from those involved in hemophilia. [1]  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. Hence, older terms for this disorder included Rosenthal syndrome, PTA deficiency, and hemophilia C.

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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. [4, 5]

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. Platelet FXI is synthesized only in the megakaryocyte.

The sole site of synthesis of the FXI plasma protein is the liver. This finding is supported by 2 reports of patients undergoing liver transplantation. In one case, the donor had a known FXI deficiency, with a level of 26%. The recipient's level after transplantation was 22%. [6] In the second case, the donor had a known prolonged aPTT and bleeding history and was of Ashkenazi Jewish descent. The recipient's subsequent FXI level was 2%. [7]

FXI deficiency can result from mutations that impair either the synthesis of the FXI molecule or the secretion of the FXI molecule from the producing cell. A proposed classification system of FXI deficiency, based on the mechanism of the disorder, contains the following three categories of underlying mutations [8] :

  • Category 1 – Mutations that prevent or reduce synthesis of FXI polypeptide, including nonsense mutations such as Glu117Stop, frame shifts, deletions, splicing defects, and possibly amino acid substitutions that cause severe polypeptide instability. In persons heterozygous for such mutations, FXI production by the normal allele would result in 50% FXI antigen and activity levels; in the homozygous state, no measurable FXI is produced.
  • Category 2 – Mutations (eg, the A4 domain substitutions Phe283Leu and Gly350Glu) that result in the synthesis of polypeptides that dimerize poorly, resulting in intracellular retention of monomers. In heterozygotes, synthesis and excretion of FXI dimers by the normal allele is unimpeded; the mutant would dimerize poorly with wild-type polypeptide, but heterodimers that do form are secreted, so FXI levels average 60%. Levels in the homozygous state average 10%. 
  • Category 3 – Mutations (eg, Ser225Phe, Cys398T) that result in the synthesis of polypeptides that form dimers but are secreted poorly in homodimeric or heterodimeric forms. Antigen and activity levels are 25% for heterozygotes and 0% for homozygotes.

The Glu117Stop and Phe283Leu mutations (called type II and type III, respectively, in an older classification system) are the predominant causes of FXI deficiency in patients of Ashkenazi Jewish descent. [9] Phe283Leu mutation is a missense mutation; Glu117Stop causes premature chain termination. The Glu117Stop 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. [10]

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 populations with the Glu117Stop and Phe283Leu mutations, also all come from a common founder. [11]

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 postpartum bleeding, bleeding after dental work, and epistaxis. Her aPTT was normal and her FXI level was 67-72%. [12]

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 with decreased protein synthesis, is also consistent with an autosomal dominant form of inheritance. A second mutation (Gly555Glu) with a dysfunctional FXI protein has also 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+). [13] 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. [13]

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 complication of replacement therapy needs to be 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 whether low levels of FXI protect from venous thrombosis.

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Etiology

FXI deficiency is predominantly an inherited disorder. Acquired alloantibodies to FXI may occur in patients who are congenitally deficient and who have been exposed to FXI via blood products.

Reports exist of acquired FXI deficiency associated with systemic lupus erythematosus. However, some reagents used for FXI laboratory testing are particularly sensitive to the lupus anticoagulant and results may be falsely interpreted as an FXI 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.

The FXI level may decrease, along with levels of the other factors synthesized in the liver, when interference with liver synthetic function occurs.

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Epidemiology

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.

In Israel, the allele frequency for Ashkenazi Jewish people is reported to be from 8-13.4%. One 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. The prevalence of hemophilia in mainland China is estimated at 3.6 per 100,000, with 6.45% of patients having FXI deficiency. [14]

In a prospective cohort study of 112 patients in the Netherlands with heavy menstrual bleeding and 28 healthy controls, Knol and colleagues found that four patients had FXI deficiency, six had Von Willebrand's disease, and one had factor VII deficiency. Compared with controls, patients had a significantly longer activated partial thromboplastin time that was caused by significantly lower, but not deficient, median levels of FXI. [15]

FXI deficiency is observed predominantly in people of Ashkenazi Jewish heritage. FXI deficiency is an autosomal disorder and, therefore, should occur in equal numbers in men and women. The disorder can manifest at any age beginning from circumcision, menarche, or when dental extractions, trauma, or surgery occur.

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Prognosis

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.

The prognosis is not affected by FXI deficiency unless the patient experiences severe trauma or undergoes major surgery without adequate FXI replacement. If a patient develops hepatitis C after receiving a plasma-derived product, the prognosis depends on the secondary viral infection and resultant liver disease.

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Patient Education

Instruct patients to inform all of their physicians regarding the diagnosis of FXI deficiency. It is critical that patients provide this information to the physician before any invasive or surgical procedure is performed.

The National Hemophilia Foundation maintains a Web site with extensive information for patients and caregivers.

For excellent patient education resources, see eMedicineHealth's patient education article Hemophilia.

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