AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Hemophilia C (deficiency of factor XI) was described first in 2 sisters and a maternal uncle of an American Jewish family. All 3 bled after dental extractions, and the sisters also bled after tonsillectomy. Hemophilia C can be distinguished from hemophilia A (deficiency of factor VIII) and hemophilia B (deficiency of factor IX) by the absence of bleeding into joints and muscles and by its occurrence in individuals of either sex. Unlike the bleeding tendency in hemophilia A or B, which is clearly related to the factor level, the bleeding risk in hemophilia C is not always influenced by the severity of the deficiency, especially in individuals with partial deficiency. This unpredictability makes hemophilia C more difficult to manage than hemophilia A or B.

Pathophysiology

The severity of the deficiency is based on plasma factor XIc (clotting) activity. Severe factor XI deficiency is present when the activity of factor XI in plasma is <1-15 U/dL. Factor XI is a dimeric serine protease, which is composed of chains that each weigh 80,000 Da. Factor XIIa activates factor XI and factor IX in the original intrinsic pathway of blood coagulation. Also, thrombin directly activates factor XI, and this direct activation may be more important than the activation due to factor XII. Patients with factor XII deficiency, even severe deficiency, do not necessarily have a tendency to bleed. Hence, the absence of factor XII appears to be irrelevant to factor XI.

Factor XI is a zymogen that, on activation, undergoes conversion to a serine protease that leads to activation of factor IX, followed by thrombin generation. The sustained generation of thrombin also leads to the activation of thrombin-activatable fibrinolysis inhibitor (TAFI), which impairs the conversion of plasminogen to plasmin. Thus, factor XI serves both as a procoagulant and antifibrinolytic agent, and the lack of factor XI in plasma results in a tendency to bleed.

Factor XI has no role in the complement or kinin pathways but has been shown to activate fibrinolysis. Alpha-1 antitrypsin is the main inhibitor of factor Xia and is responsible for two thirds of its inhibition. C1 esterase inhibitor, antithrombin III, and alpha-2 antiplasmin cause the remaining inhibition.

In severe deficiency, bleeding is related to injury, especially when trauma involves tissues rich in fibrinolytic activators, such as the oral mucosa, the nose, and the urinary tract. Unlike patients with severe hemophilia A or B, patients with severe deficiency do not bleed spontaneously.

Frequency

United States

Hemophilia C occurs with an estimated prevalence of 1 case per 100,000 population, a rate that makes hemophilia A 10 times more common than hemophilia C.

International

Hemophilia C has a high prevalence among Ashkenazi and Iraqi Jews; in Israel, the estimate rate is 8%. In the United Kingdom, 383 patients with hemophilia C were registered in a population of 58 million; therefore, hemophilia C represents 3% of inherited coagulation disorders. In the French Basque country (home to the most ancient ethnic group of Western Europe, ie, the Basques), 39 patients were identified among the general population of 290,000.

Mortality/Morbidity

Levels of factor XI activity are not correlated with the patient's bleeding tendency, especially in those with partial deficiency. Severe deficiency is defined as factor XIc activity <20 U/dL. Patients with partial deficiency have levels of 20-60 U/dL. About 20-50% of individuals with partial deficiency have excessive bleeding, but identifying these persons in advance is difficult. Most individuals with severe deficiency do not spontaneously bleed, but they are at risk of bleeding after surgery. Furthermore, in infants without hemophilia C, factor XIc levels may be low until they are older than 6 months.

The unpredictable bleeding tendency in patients with factor XI deficiency is not fully understood.

Brenner et al (1997) used a logistic regression model to analyze parameters influencing bleeding tendency in subjects with factor XI deficiency from 45 families. Odds ratios for bleeding were 13 in homozygotes or double heterozygotes (95% confidence interval, 3.8-45) and 2.6 in heterozygotes (95% confidence interval, 0.8-9). Bleeding was negatively correlated with the level of factor XI (r = -0.36, P = .0001), with severe factor XI deficiency being a strong predictor of bleeding (P =.011). Minor factor XI deficiency and blood group O contributed minimally to bleeding. Levels of factor VIII and von Willebrand factor were not predictors of bleeding. Bleeding was most common after surgical procedures involving mucosal membranes (P < .01).

Other possible explanations for variations in patients' bleeding tendencies include the following:

• Additional clotting factor disorders, especially von Willebrand disease
• Variant factor XI molecules, ie, those with a discrepancy between factor XI clotting activity compared with antigen: These variants are rare and have been described in only 4 individuals to date.
• Associated platelet defects and deficiency of platelet factor XI
• Increased fibrinolysis at certain surgical sites: Factor XI has been associated with bleeding problems after surgery or trauma to areas of the body in which the fibrinolytic activity is particularly high (eg, urogenital tract, oral cavity after dental extraction or tonsillectomy). Hence, women can present with menorrhagia or with bleeding related to childbirth or gynecologic surgery.

Race

Deficiency of factor XI is reported in most racial groups, with the highest frequency in persons of Ashkenazi or Iraqi Jewish descent.

Sex

The inheritance pattern of factor XI is autosomal recessive, and it affects male and female individuals equally.

Age

All age groups are affected. Infants younger than 6 months have low levels of factor XI because of the time is required for factor XI to reach normal levels observed in adults.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

• Bleeding after surgery or after injury is the usual presenting symptom in individuals prone to bleeding.
• Individuals with factor XI levels <15-20 U/dL are usually at risk of excessive bleeding after surgery or trauma.
• A paradoxical finding is that some patients with severe deficiency do not have a bleeding tendency.
• The following presentations have been reported:
• • Massive hemothorax
  • Cerebral hemorrhage
  • Subarachnoid hemorrhage
  • Spinal epidural hematoma with the Brown-Sequard syndrome
• Hematuria and spontaneous hemarthrosis are rare.
• In women, menorrhagia is an important finding.

Physical

Physical findings are usually normal except when bleeding occurs. Bruising may occur at unusual sites. The patient may have signs of pallor, fatigue, and tachycardia with excessive bleeding.

Suspect factor XI deficiency in any patient with a prolonged activated partial thromboplastin time (aPTT), especially if the family history suggests a mild-to-moderate lifelong bleeding disorder that affects both male and female individuals.

Acquired factor XI deficiency occurs in patients who develop inhibitors to the protein, as sometimes is observed in patients with systemic lupus erythematosus and other immunologic diseases.

Factor XI deficiency is described as a common finding in patients with Noonan syndrome, which is characterized by congenital cardiac abnormalities, short stature, and mental retardation.

Causes

Mutations in the factor XI gene cause the congenital deficiency of factor XI clotting activity. Factor XI is a zymogen that, on activation, undergoes conversion to a serine protease that leads to activation of factor IX, followed by thrombin generation. The sustained generation of thrombin also leads to activation of TAFI, which impairs the conversion of plasminogen to plasmin. Thus, factor XI serves both as a procoagulant and antifibrinolytic agent, and the lack of factor XI in plasma results in a bleeding tendency.

• The gene for factor XI is near the gene for prekallikrein on the distal arm of chromosome 4 (4q35). It is 23 kb, with 15 exons and 14 introns. Factor XI is synthesized in the liver and circulates in the plasma as a complex with high-molecular-weight kininogen. Factor XI has a half-life of about 52 hours.
• The first 3 mutations in the factor XI gene were described in 6 persons of Ashkenazi Jewish descent who were affected severely.
• About 53 other mutations that cause factor XI deficiency are described, and most are listed in Mutations of patients with factor XI deficiency, a database maintained by the University of North Carolina School of Medicine. Of the 53 published mutations, 27 are missense mutations, 11 are nonsense mutations, 8 are deletions and/or insertions, and 7 are splice-site mutations. Those described so far are associated with mainly failed or reduced production of the active protein, and only 1 is related to the production of a dysfunctional molecule.
• In biologic terms, 4 mutations (types I-IV) have been identified in people of Ashkenazi Jewish descent. Two of these mutations occur with increased frequency in this population. Type II, which is a nonsense mutation (Glu117stop) is prevalent in Ashkenazi and Iraqi Jews. Type III, a missense mutation (Phe283Leu) is present only in Ashkenazi Jews. Homozygotes for type II or type III mutations have a factor XI activity of 1 and 10 U/dL, respectively, whereas compound heterozygotes for type II or type III have factor XI activity of 3-5 U/dL.
• A variety of mutations have been identified in persons who are not Jewish. Two ancestral mutations are described: a mutation with a Cys38Arg substitution in exon 3 observed in the French Basque Country, and the mutation C128X in exon 5 occurring in the northwest of England. Both mutations result in a level of <1 U/dL in affected homozygotes.
• Acquired factor XI deficiency occurs in patients who develop inhibitors to this protein, as is sometimes observed in patients with systemic lupus erythematosus or other immunologic diseases.
• Factor XI deficiency is a common finding in patients with Noonan syndrome, which is characterized by congenital cardiac abnormalities, short stature, and mental retardation.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Abnormalities in platelet function
Other clotting factor deficiencies
Combined deficiencies of clotting factor
Uncommon coagulopathies

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Laboratory studies should include the following:
• • CBC determination
  • Measurement of factor XI levels
  • Measurement of factor VIII and von Willebrand factor, including multimers
• Prothrombin time (PT), aPTT, and thrombin time (TT)
• • The aPTT is prolonged in factor XI deficiency, whereas the PT and TT are normal.
  • A specific assay for factor XI activity is necessary to confirm the diagnosis.
  • Assays of other clotting factors and platelet function may be needed to exclude a combined hereditary deficiency of factor XI and other factors.

Imaging Studies

• No imaging studies are necessary in diagnosing factor XI deficiency. However, imaging studies may be obtained to evaluate the extent of bleeding in the management of bleeding at any site.

Other Tests

• Genetic analysis for the mutation in factor XI is helpful in determining which mutation caused the deficiency.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

Treatment of patients with factor XI deficiency is a challenge. Patients with severe deficiency are clearly and commonly at risk of bleeding from surgical procedures. Bleeding in these patients can start at the time of injury, or it can be delayed for several hours and persists until specific treatment is administered. Therefore, patients with severe factor XI deficiency require replacement therapy before they undergo a surgical procedure, even if they have never bled after surgery before. Patients with partial deficiency can also have bleeding episodes similar to these.

The basic principle of management consists of altering the balance between bleeding and clotting. Therapy consists of replacing the deficient factor and using other measures, such as fibrin glue and antifibrinolytics.

Consultations

Consult a pediatric or adult hematologist when the patient presents with excessive bleeding or when a preoperative laboratory evaluation reveals a prolonged aPTT.

Diet

No diet restrictions are necessary.

Activity

Advise patients to participate in only age-appropriate activities. Physical activity precautions also apply to patients with factor XI deficiency who have a bleeding tendency. Advise them against participating in contact sports if patient has severe disease.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Bleeding of the soft tissue may not require treatment. When therapy is required, available options for patients with factor XI deficiency include fresh-frozen plasmaga (FFP), solvent-detergent–treated FFP, and factor XI concentrates. Factor XI concentrates are available in Europe but not in the United States.

Adjunctive measures include the use of fibrin glue, antifibrinolytic agents, and desmopressin (DDAVP). Desmopressin is a synthetic antidiuretic hormone with actions mimicking those of vasopressin. It also increases levels of factor VIII and von Willebrand factor. DDAVP has widely been used as an adjunct to control bleeding during surgery since its discovery in a variety of congenital bleeding disorders. To date, little documentation addresses the use of desmopressin in factor XI deficiency.

Although some patients may not bleed during surgery, the physician has no way to ascertain which patients will not bleed. A history of clinically significant surgery without therapy and without excessive bleeding strongly suggests, but does not guarantee, satisfactory hemostasis with subsequent surgery. In the United States, patients with factor XI deficiency should be given plasma products before surgery when their risk is in doubt.

Replacement therapy during and/or after vaginal delivery is not mandatory in women with severe deficiency, and it can be restricted to patients in whom severe hemorrhage occurs. For women undergoing cesarean delivery, the same policy can be advocated, but additional observations are required. Tooth extractions can be managed by using only antifibrinolytic agents without replacement therapy. Epidural anesthesia without replacement therapy is not recommended in these patients.

Development of inhibitors is a known complication of therapy in patients with hemophilia A or B. Few reports in the literature address the development and management of factor XI inhibitors in patients with congenital deficiency. One reason for the infrequent presence of inhibitors may be that many patients with factor XI deficiency never receive treatment with plasma products. However, when inhibitors do develop, they may cause clinically significant inhibition and clinical problems similar to those occurring in hemophilia A or B. Development of factor X inhibitors may be treated successfully with plasma products, prothrombin complex concentrates, or recombinant factor VIIa. Before patients with hemophilia C undergo elective surgery in which plasma products will be used, they should be screened for inhibitors, as is done in patients with hemophilia A or B.

Drug Category: Plasma products

FFP is the first product used to treat patients with hemophilia C. The main advantage of FFP is its availability. Disadvantages of its use include the large volumes required, the potential for transmission of infective agents, and the possibility of allergic reactions.

Solvent-detergent–treated FFP has a factor XI half-life similar to FFP (mean, 45 h). It is safer than regular FFP because it reduces the transmission of known enveloped viral agents. However, it is not protective against nonenveloped viruses, such as hepatitis A virus (HAV).

Drug Category: Factor XI concentrates

Factor XI concentrates provide the best source for factor XI replacement. Since 1984, 3 products were developed and used in Europe, 2 of which currently are available there. The 2 products are Hemoleven (Laboratoire français du Fractionnement et des Biotechnologies [LFB], Les Ulis, France) and factor XI concentrate (Bio Products Laboratory [BPL], Elstree, Hertfordshire, United Kingdom). Both are heat treated and not expected to transmit HIV or hepatitis viruses. Both products also contain antithrombin III and heparin in different concentrations. These products appear to provide good treatment for selected patients.

The typical dose is £30 U/kg.

Advantages of factor XI concentrates include selective delivery of the deficient factor, a reduced volume of infusion, and viral safety. However, they are plasma-derived products; therefore, they can have all the attendant disadvantages of any plasma-derived product.

Several issues are encountered with the use of factor XI concentrates. In reports from Israel, 2 of 3 patients who received transfusions of a locally available concentrate and had activation of the coagulation system with D-dimer production and died (Gitel, 1991). This product has been withdrawn from the market. The 2 previously mentioned concentrates, Hemoleven (LFB) and factor XI concentrate (BPL) are hemostatically effective and virally safe, but they are associated with evidence of activation of the coagulation system and some thrombotic events, especially in patients with preexisting vascular disease.

Briggs et al reported their experience with factor XI concentrate (BPL). They studied 229 treatment episodes in 161 patients aged 3-88 years and observed 21 adverse events in 19 patients, 12 of whom were probably or definitely thrombotic. Good hemostatic efficacy was reported in all. No transmission of HIV or hepatitis was reported. Mean factor XI recovery was 91% of the injected dose, and the mean half-life was 52 hours.

Factor XI concentrate (BPL) was also used in the United States in a study of elective surgery in 12 patients aged 24-81 years (Aledort, 1997). Only 1 patient developed anaphylaxis, and laboratory (not clinical) evidence of disseminated intravascular coagulation (DIC) was present. In all other patients, BPL was used successfully. Hemoleven, (LFB) produced results similar to those of factor XI concentrate from BPL. Thirty-one patients aged 5-76 years undergoing 33 procedures received Hemoleven (LFB). Recovery was 80% ± 16%, with a half-life of 46 hours (range, 32-52 h). Thromboembolic events occurred as complication in 3 infusions exceeding 30 U/kg.

Drug Category: Fibrin glue

Fibrin glue is sometimes used as an adjunct to or substitute for plasma products. Centeon glue (Beriplast) has been used successfully in Israel in patients with congenital bleeding disorders who are undergoing dental extractions without blood product replacement. The glue is applied with a pair of syringes, 1 containing calcium and thrombin and 1 containing fibrinogen, factor XIII, and aprotinin.

The US Food and Drug Administration (FDA) recently approved a fibrin sealant (Tisseel VH; Baxter Healthcare Corporation, Westlake Village, CA) for adjunctive topical hemostasis.

Drug Category: Antifibrinolytic agents

Antifibrinolytic agents are important adjuncts in patients undergoing surgery in areas of the body prone to increased fibrinolysis (oral cavity, bladder, uterus). These agents may be effective when used alone in patients who have severe factor XI deficiency and who are undergoing dental extractions.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• Depending on the surgical procedure, the patient's history with other surgical procedures, and the patient's bleeding tendency if any, replacement with plasma products may be needed in the preoperative, intraoperative, and postoperative periods.
• Replacement with plasma products must be coordinated with the hemophilia treatment center.
• After a surgical procedure, patients may be discharged when complete hemostasis is achieved.

Further Outpatient Care

• Annual visits to a hemophilia treatment center are recommended to provide the following care:
• • Monitoring of bleeding episodes
  • Planning for any elective surgical procedures
  • Monitoring for the development of hepatitis
  • Administering preventive immunizations as needed. (In patients with severe deficiency, administer all vaccinations subcutaneously because of the risk of inducing a muscle hematoma. These patients should be vaccinated against HAV and hepatitis B virus [HBV] because they have or may have been exposed to plasma products as part of their treatment.
  • Continuing patient education about the bleeding condition and applying any therapeutic advances that may become available

In/Out Patient Meds

• Advise patients to avoid taking aspirin or other nonsteroidal agents that inhibit platelet function.

Complications

• Complications of factor XI deficiency commonly involve the unpredictable nature of bleeding.
• Patients who receive plasma products may be at risk for contracting unknown virally transmissible infections.
• Patients may also develop inhibitors to factor XI.
• In addition, patients who receive factor XI concentrates may be at risk for thrombotic events.

Prognosis

• The prognosis is excellent in patients with partial deficiency without bleeding manifestations.
• In patients with bleeding tendencies, hemorrhage and bleeding into organs may be life threatening.

Patient Education

• Patients must be counseled about the unpredictable nature of their bleeding tendency, and they should be informed of the preparations needed before elective surgery.
• The usual precautions regarding physical activity for individuals with a bleeding disorder apply to patients with factor XI deficiency who have a bleeding tendency. Patients should be encouraged to wear seat belts, to use protective gear (eg, bike helmets), and to avoid contact sports.
• Patients should be advised to keep up to date with their vaccinations, especially HAV and HBV vaccinations.
• Stress the importance of annual visits to hemophilia treatment centers.
• Patients should receive genetic counseling with regard to their marriage partners and the potential risks to their offspring.
• For excellent patient education resources, visit eMedicine's Blood and Lymphatic System Center. Also, see eMedicine's patient education article Hemophilia.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Because factor XI concentrates are not yet available in the United States, the only potential problems are a failure to diagnose factor XI deficiency, volume overloading with the infusion of plasma products, and poor management of any hypersensitivity reactions to the infusions.
• If factor XI concentrates are available, take care in selecting candidates for infusion, and avoid excessive dosing. See Medication.

Special Concerns

• The unpredictable nature of bleeding is a concern, especially in patients with partial deficiency. Bleeding episodes cannot be predicted on the basis of factor XI levels alone.
• Transmission of infections is a risk when plasma products are used for treatment.
• Thrombotic events are a risk in patients who receive factor XI concentrates.
• All prophylaxis vaccinations should be administered subcutaneously.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

• Aledort LM, Forster A, Maksoud J, et al. BPL factor XI concentrate: clinical experience in the USA. Haemophilia. 1997;3:59-62.
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• Asakai R, Chung DW, Ratnoff OD, Davie EW. Factor XI (plasma thromboplastin antecedent) deficiency in Ashkenazi Jews is a bleeding disorder that can result from three types of point mutations. Proc Natl Acad Sci U S A. Oct 1989;86(20):7667-71. [Medline].
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• Imanaka Y, McVey JH, Nichimura T, et al. Identification and characterization of mutations in factor XI gene of non-Jewish factor XI deficient patients. Thromb Haemost. 1993;69:752-60.
• Kadir RA, Economides DL, Sabin CA, et al. Frequency of inherited bleeding disorders in women with menorrhagia. Lancet. Feb 14 1998;351(9101):485-9. [Medline].
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• Mannhalter C, Hellstern P, Deutsch E. Identification of a defective factor XI cross-reacting material in a factor XI-deficient patient. Blood. Jul 1987;70(1):31-7. [Medline].
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• Ragni MV, Sinha D, Seaman F, et al. Comparison of bleeding tendency, factor XI coagulant activity, and factor XI antigen in 25 factor XI-deficient kindreds. Blood. Mar 1985;65(3):719-24. [Medline].
• Rosenthal RL, Dreskin OH, Rosenthal N. Plasma thromboplastin antecedent (PTA) deficiency; clinical, coagulation, therapeutic and hereditary aspects of a new hemophilia-like disease. Blood. Feb 1955;10(2):120-31. [Medline].
• Salomon O, Zivelin A, Livnat T, et al. Prevalence, causes, and characterization of factor XI inhibitors in patients with inherited factor XI deficiency. Blood. Jun 15 2003;101(12):4783-8. [Medline].
• Salomon O, Seligsohn U. New observations on factor XI deficiency. Haemophilia. Oct 2004;10 Suppl 4:184-7.
• Seligsohn U. Factor XI deficiency. Thromb Haemost. Jul 1 1993;70(1):68-71. [Medline].
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Article Last Updated: Dec 18, 2006