Factor XI Deficiency

Practice Essentials

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

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

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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Epidemiology

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%. 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]

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.

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Race-, Sex-, and Age-related Demographics

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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History

Bleeding in persons with factor XI (FXI) deficiency occurs with dental extractions, trauma, or surgery. The FXI level does not correlate with or act as a predictor of bleeding risk.^[16] Within individual patients and their family, highly variable and unpredictable bleeding patterns occur. Bleeding can be immediate or delayed.

Considerations in the history are as follows:

• 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.^[2]
• An inconsistent history of bleeding in the same patient may be observed with FXI deficiency.
• FXI deficiency in an asymptomatic patient may be identified only by a prolonged activated partial thromboplastin time (aPTT) on routine preoperative testing.
• Family history may reflect an autosomal dominant or recessive pattern of inheritance.

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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.

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Causes

See the list below:

• FXI deficiency is predominantly an inherited disorder.
• 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.
• 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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Laboratory Studies

Activated partial thromboplastin time (aPTT) should be measured. In patients with severe factor XI (FXI) deficiency, the aPTT value will be more than two standard deviations above the normal mean; in heterozygotes, the aPTT may be slightly prolonged APTT or within the normal range.^[11]

An FXI assay may help confirm the diagnosis, although levels can be in the normal range.^[11] Homozygotes and compound heterozygotes will have an FXI level of less than 15%. The expected FXI level in heterozygotes is 25-70%.

A mixing study using normal pooled plasma may help identify a factor deficiency. If the sample is incubated and, subsequently, the aPTT is prolonged, then the presence of an inhibitor needs to be considered. Based on the data regarding high risk of inhibitor development in patients who have severe (< 1%) FXI deficiency, checking an inhibitor titer before proceeding with surgery is recommended.

Factor assays for the intrinsic coagulation system should be performed with at least three dilutions.

In a patient who is newly diagnosed and without previous bleeding history or family history (neither is uncommon in a patient with FXI deficiency), care must be taken by the coagulation laboratory to separate out a nonspecific inhibitor or lupus anticoagulant versus a true FXI deficiency.

Researchers are exploring the use of novel laboratory tests, such as thrombin generation assays and clot stability assays, to predict bleeding risk in patients with FXI deficiency.^[1]  For example, Gidley et al reported that combining the apTT with the rate of clot formation and area under the curve in fibrinolysis assays identifies most FXI-deficient patients with a bleeding tendency.^[17]

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Approach Considerations

Patients with factor XI (FXI) deficiency do not need treatment or prophylaxis for routine functions or activities, but may need treatment for dental extractions, surgery, and childbirth.^{[11, 18]}  Treatment of FXI deficiency is determined by patient factors and clinical circumstances.

Fresh frozen plasma (FFP) has been the most available source of FXI. The recovery of FXI function from plasma is excellent, and the half-life is 40-80 hours. FXI concentrates are produced in the United Kingdom and France, but are not available in the United States.^[11]

Dental extractions have been performed safely in severely FXI-deficient patients with the use of antifibrinolytic therapy alone. Tranexamic acid, 1 g four times daily, was started 12 hours before the procedure and continued for 7 days afterward.^[19]  Antifibrinolytic therapy has also been used in the treatment of women with FXI deficiency and menorrhagia.^[2]

Invasive surgical procedures often require replacement therapy with FFP. This should be continued for 7-14 days after surgery. Remember that the half-life of FXI is approximately 52 hours (2 d). Because FFP carries risks of volume overload, transmission of infectious agents, thrombosis, allergic reactions, and development of inhibitors to FXI; even patients with severe FXI deficiency do not inevitably bleed with surgery; and bleeding most often occurs with procedures involving tissues that exhibit fibrinolytic activity, Salomon et al suggest that surgeons may consider forgoing replacement therapy in procedures involving sites that do not have local fibrinolytic activity.^[20]

Pregnant women will need FFP if cesarean delivery is planned. Peripartum treatment of women with FXI deficiency is controversial. One group treats patients to maintain FXI levels above 50% during labor and then continues treatment for 3-4 days after vaginal delivery and 7 days after cesarean delivery. This is recommended because of the high incidence of postpartum hemorrhage. The recommendation to treat expectantly must be understood in the context of the known variability of bleeding manifestations based on patient history and FXI level, as well as the unpredictable risk of exposure to blood-borne pathogens with the use of FFP.

The use of desmopressin, a vasopressin analog, used for patients with factor VIII deficiency, von Willebrand disease, and platelet function abnormalities, has been tried in a handful of patients with FXI deficiency.^{[21, 22, 23]}  In the patients reported, three of whom had baseline FXI levels ranging from 34-45%, factor level increased from 12% to 23%. In one patient with severe (< 1%) FXI deficiency, the level did not increase. The four patients presented in these published reports had no surgical bleeding. The true benefit of this treatment is unclear, and it is not recommended for major surgical procedures.

Salomon et al reported success with a single, very low dose of recombinant factor VIIa (rFVIIa) along with tranexamic acid as prophylactic treatment for FXI-deficient patients undergoing surgery. In their study of 12 procedures in 10 patients, rFVIIa was given in a single dose of 10 to 15 μg/kg at the end of surgery; tranexamic acid, 4 g/day, was started 2 hours before surgery and continued for 3 to 5 days.^[24]

Minami et al reported that emicizumab potentiates coagulation function in FXI-deficient plasma. These authors suggest that this agent might provide possibilities for clinical application in patients with FXI deficiency.^[25] Emicizumab, the bispecific antibody to factors IX/IXa and X/Xa, is currently approved for routine prophylaxis in patients with hemophilia A. 

Treatment of patients with acquired antibodies to FXI has not been standardized because of the infrequency of this occurrence. Successful treatment has been reported during invasive procedures with the use of FFP, prothrombin complex concentrates, and rFVIIa. Reports also exist of patients with inhibitors who have no spontaneous bleeds.

Unless needed for another medical indication, aspirin products should be avoided by patients with FXI deficiency.

Immunization with hepatitis A virus and hepatitis B virus vaccines is recommended prior to planned surgery and plasma product replacement. Consultation with a hematologist is recommended.

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Medication Summary

Medications for prophylaxis and treatment of bleeding in patients with factor XI deficiency include fresh frozen plasma and antifibrinolytic agents. Treatment choices are guided by patient factors and clinical circumstances.

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Fresh frozen plasma (FFP, Octaplas)

• Dosing, Interactions, etc.

Clinical Context:  Plasma is the fluid compartment of blood containing the soluble clotting factors. Octaplas is a solvent detergent treated, pooled FFP.

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Class Summary

To achieve a FXI level of 50%, a patient needs to have half of their plasma volume replaced.

Directed-donor fresh frozen plasma can be arranged for elective procedures, but a large volume of plasma will need to be stored to transfuse for the required 7-14 days after surgery. One study has demonstrated that solvent detergent fresh frozen plasma has a half-life of 45 hours, while a second study has shown that FXI is decreased in the product.

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Aminocaproic acid (Amicar)

• Dosing, Interactions, etc.

Clinical Context:  Inhibits fibrinolysis via inhibition of plasminogen activator substances and, to a lesser degree, through antiplasmin activity. Main problem is that the thrombi that form during treatment are not lysed, and effectiveness is uncertain.

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Tranexamic acid injection (Cyklokapron)

• Dosing, Interactions, etc.

Clinical Context:  Alternative to aminocaproic acid. Inhibits fibrinolysis by displacing plasminogen from fibrin.

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Class Summary

May consider prophylactic administration with antifibrinolytics prior to minor procedures (eg, dental).

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Prognosis

See the list below:

• 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, prognosis depends on the secondary viral infection and resultant liver disease.

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Patient Education

See the list below:

• 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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