eMedicine Specialties > Hematology > Coagulation, Hemostasis, and Disorders

Factor XI Deficiency

Jamie E Siegel, MD, Director, Cardeza Foundation Hemophilia Treatment Center, Thomas Jefferson University

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.

Differential Diagnoses

Other Problems to Be Considered

Differential with an isolated prolonged aPTT

Factor VIII deficiency
Factor IX deficiency
Factor XI deficiency
Factor XII deficiency
Lupus anticoagulant
Heparin contamination

Differential with a mild or intermittent bleeding disorder

Von Willebrand disease
Factor VIII deficiency/carrier state
Factor IX deficiency/carrier state
Factor VII deficiency (mild)
Platelet function disorder
Early liver dysfunction

Workup

Laboratory Studies

• An aPTT should be performed.
• 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 levels, it is recommended that an inhibitor titer be checked before proceeding with surgery.
• Factor assays for the intrinsic system should be performed with at least 3 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.
• Homozygotes and compound heterozygotes will have a factor level of less than 15%. The expected FXI level in heterozygotes is 25-70%.

Treatment

Medical Care

Patients with FXI deficiency do not need treatment or prophylaxis for routine functions or activities. They do need treatment for dental extractions and surgery. Expectant treatment of a pregnant woman is controversial if a cesarean delivery is not planned. Treatment of FXI deficiency is determined by the intervention planned.

• Fresh frozen plasma 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.
• Dental procedures have been performed safely with the use of factor replacement. Administration of antifibrinolytics alone was attempted when patients with FXI deficiency were recognized to be more likely to bleed in areas of high fibrinolysis. Patients since have been treated successfully with the use of tranexamic acid alone in preparation for dental extraction. The treatment is begun before the procedure and continued for an additional week.
• Invasive surgical procedures often require fresh frozen plasma replacement. This should be continued for 7-14 days after surgery. Remember that the half-life of FXI is approximately 52 hours (2 d).
• Pregnant women will need fresh frozen plasma 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 fresh frozen plasma.
• 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. In the patients reported, 3 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 4 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.
• Antifibrinolytic therapy has been used in the treatment of women with FXI deficiency and menorrhagia.
• 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 plasma, prothrombin complex concentrates, and recombinant activated factor VII. 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.

Surgical Care

Immunization by hepatitis A virus and hepatitis B virus vaccines is recommended prior to planned surgery and plasma product replacement.

Consultations

Consultation with a hematologist is recommended.

Diet

No dietary restrictions are indicated.

Activity

No restrictions on activity are necessary.

Medication

Blood products

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.

Fresh frozen plasma (FFP)

Plasma is the fluid compartment of blood containing the soluble clotting factors.

Dosing

Adult

20 mL/kg IV; continued dosing is required after surgery

Pediatric

Administer as in adults

Interactions

None reported

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

A - Safe in pregnancy

Precautions

Viral contamination and infection are possible but unlikely due to prescreening; ineffective in patients with FXI inhibitors; may induce anamnestic response

Aminocaproic acid (Amicar)

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.

Dosing

Adult

0.1 g/kg IV before surgery, followed by 0.1 g/kg PO q6h for 10 d; not to exceed 24 g/24 h
4-5 g IV, followed by 1 g q1h for up to 8 h
Menorrhagia: 2 g PO q6h may be used

Pediatric

5-30 g/d PO/IV in divided doses q3-6h; not to exceed 18 g/m²/24h

Interactions

Coadministration with estrogens may cause increase in clotting factors, leading to hypercoagulable state

Contraindications

Documented hypersensitivity; evidence of active intravascular clotting process; because aminocaproic acid can be fatal in patients with DIC, differentiating between hyperfibrinolysis and DIC is important

Precautions

Pregnancy

C - Safety for use during pregnancy has not been established.

Precautions

Do not administer unless diagnosis of hyperfibrinolysis has been established definitely; caution in cardiac, hepatic, or renal disease

Tranexamic acid (Cyklokapron)

Alternative to aminocaproic acid. Inhibits fibrinolysis by displacing plasminogen from fibrin. (Not available in United States)

Dosing

Adult

10 mg/kg IV, followed by 25 mg/kg PO tid/qid for 2-8 d
25 mg/kg PO tid/qid beginning 1 d before surgery
Menorrhagia: 0.5 g PO 6 times per day or 1 g
PO q6h or 4 g PO qd for 3 d
Dental extractions: 1 g PO qid 12 h before oral surgery; continue for 1 wk

Pediatric

Administer as in adults

Interactions

None reported

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Safety for use during pregnancy has not been established.

Precautions

Caution in renal impairment

Follow-up

Prognosis

• 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.

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, visit eMedicine's Blood and Lymphatic System Center. Also, see eMedicine's patient education article Hemophilia.

Miscellaneous

Medicolegal Pitfalls

• If preoperative testing has been performed and a prolonged aPTT result has been obtained, then this laboratory finding needs to be evaluated further for the possibility of an occult FXI (or FVIII or FIX) disorder. These three deficiencies are associated with increased bleeding risk. Factor XII deficiency, also a cause of a prolonged aPTT, is not associated with bleeding (and possibly associated with thrombosis) and therefore should not be treated with plasma or any other agent to prevent bleeding.
• In view of the high frequency of FXI deficiency in patients of Jewish background, a preoperative aPTT should be ordered in these patients before elective surgery.

Special Concerns

• Predicting bleeding risk based on history and factor level is difficult; therefore, treating all patients expectantly before major surgical procedures is prudent.
• When procedures are planned in which morbidity is not high if bleeding were to occur and if a patient can be observed closely, then expectant treatment with plasma is an option. This particularly is true for dental procedures in which antifibrinolytic therapy has been demonstrated to be effective. The benefit of this approach is to avoid the use of fresh frozen plasma and its inherent risk of transmission of a blood-borne pathogen.
• A FXI activity level of greater than 50% may still be associated with a bleeding disorder. This appears to be more of a qualitative than a quantitative abnormality and is inherited in an autosomal dominant mode of inheritance. In addition, women may be symptomatic with menorrhagia when they demonstrate a FXI level greater than 50%.
• Bleeding appears to be greatest at areas of high local fibrinolytic activity.

Multimedia

Media file 1: Factor XI deficiency. Graph depicts factor deficiencies.

References

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Keywords

factor XI deficiency, FXI deficiency, hemophilia C, plasma thromboplastin antecedent deficiency, Rosenthal's syndrome, Rosenthal syndrome, PTA deficiency, bleeding disorder

Contributor Information and Disclosures

Author

Jamie E Siegel, MD, Director, Cardeza Foundation Hemophilia Treatment Center, Thomas Jefferson University
Jamie E Siegel, MD is a member of the following medical societies: American College of Physicians, American Society for Clinical Pathology, American Society of Hematology, and International Society on Thrombosis and Haemostasis
Disclosure: Nothing to disclose.

Medical Editor

Paul Schick, MD, Emeritus Professor, Department of Internal Medicine, Thomas Jefferson University Medical College; Research Professor, Department of Internal Medicine, Drexel University College of Medicine; Adjunct Professor of Medicine, Lankenau Hospital, Wynnewood, PA
Paul Schick, MD is a member of the following medical societies: American College of Physicians, American Heart Association, American Society of Hematology, International Society on Thrombosis and Haemostasis, and New York Academy of Sciences
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Ronald A Sacher, MB, BCh, MD, FRCPC, Professor, Internal Medicine and Pathology, Director, Hoxworth Blood Center, University of Cincinnati Academic Health Center
Ronald A Sacher, MB, BCh, MD, FRCPC is a member of the following medical societies: American Society of Hematology
Disclosure: Glaxo Smith Kline Honoraria Speaking and teaching; Talecris Honoraria Board membership

CME Editor

Rebecca J Schmidt, DO, FACP, FASN, Professor of Medicine, Section Chief, Department of Medicine, Section of Nephrology, West Virginia University School of Medicine
Rebecca J Schmidt, DO, FACP, FASN is a member of the following medical societies: American College of Osteopathic Internists, American College of Physicians, American Medical Association, American Society of Nephrology, International Society of Nephrology, National Kidney Foundation, Renal Physicians Association, and West Virginia State Medical Association
Disclosure: Abbott Grant/research funds Speaking and teaching; Genzyme Honoraria Consulting; Amgen Honoraria Speaking and teaching; Ortho Biotech Honoraria Speaking and teaching

Chief Editor

Emmanuel C Besa, MD, Professor, Department of Medicine, Division of Hematologic Malignancies, Kimmel Cancer Center, Thomas Jefferson University
Emmanuel C Besa, MD is a member of the following medical societies: American Association for Cancer Education, American College of Clinical Pharmacology, American Federation for Medical Research, American Society of Hematology, and New York Academy of Sciences
Disclosure: Nothing to disclose.

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