Practice Essentials
Hemophilia C (deficiency of factor XI) was described first in two sisters and a maternal uncle of an American Jewish family. All three bled after dental extractions, and the sisters also bled after tonsillectomy. (See Etiology and Epidemiology.)
The entity missing from the patients’ plasma was initially referred to as plasma thromboplastin antecedent (PTA), as named by Robert Rosenthal. In 1961, however, to distinguish it from the missing factors in hemophilia A (factor VIII) and B (factor IX) and in Hageman trait (factor XII), the International Committee for the Nomenclature of Blood Clotting Factors proposed that this entity be designated factor XI. [1, 2, 3]
Clinicians and basic scientists have faced practical and conceptual challenges with regard to the bleeding disorder in factor XI–deficient patients (sometimes called Rosenthal syndrome). Of the known congenital coagulation factor deficiencies, it has been found that factor XI deficiency has the poorest correlation between factor levels and symptoms. [2] Unlike the bleeding tendency in hemophilia A or hemophilia B, which is clearly related to the factor level, some patients with severe deficiency of factor XI do not have a bleeding tendency. On the other hand, some patients with mild deficiency of factor XI bleed excessively, and this unpredictability, which is not fully understood, makes hemophilia C more difficult to manage than hemophilia A or B. [4]
Severe deficiency is defined as factor XIc activity of 15-20 U/dL or lower. However, this is no longer suitable terminology, since the bleeding disorder is not clinically severe, even at very low levels of factor XI; a better term would be "major deficiency." Spontaneous bleeding rarely occurs, but bleeding may occur after surgery, more commonly in those with the lowest levels. The levels in this range, less than about 15 U/dL, generally identify individuals who have 2 FXI gene mutations. Patients with partial deficiency, generally heterozygous with a single FXI gene mutation, have levels of about 20-60 U/dL (ie, the lower limit of the normal range). About 30-50% of individuals with partial deficiency may still have excessive bleeding; however, identifying these persons in advance is difficult. Furthermore, normal infants without hemophilia C are likely to have low factor XIc levels until they are older than 6 months. (See Etiology and History and Physical Examination.)
Brenner et al used a logistic regression model to analyze parameters influencing bleeding tendency in subjects with factor XI deficiency from 45 families. [5] Odds ratios for bleeding were 13 in homozygotes or double heterozygotes and 2.6 in heterozygotes. Bleeding was negatively correlated with the level of factor XI, and severe factor XI deficiency was a strong predictor of bleeding. 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.
Other possible explanations for variations in patient bleeding tendencies include the following:
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Additional clotting factor disorders, especially von Willebrand disease, or a more subtle change in hemostatic balance
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Variant factor XI molecules (ie, those with a discrepancy between factor XI clotting activity compared with antigen): These variants are rare, and no correlation between mutation type and bleeding tendency has been identified.
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Increased fibrinolysis at certain surgical sites
With regard to the last item, factor XI deficiency 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. (See History and Physical Examination and Treatment.)
Go to Acquired Hemophilia, Hemophilia A, and Hemophilia B for complete information on these topics.
Signs and symptoms of hemophilia C
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.
Diagnosis of hemophilia C
Laboratory studies for suspected hemophilia C should include the following:
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Complete blood count (CBC)
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Measurement of factor XI levels
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Measurement of factor VIII and von Willebrand factor
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Prothrombin time (PT), activated partial thromboplastin time (aPTT), and thrombin time (TT) (usually performed before the measurement of factors)
Management of hemophilia C
In patients with hemophilia C undergoing a surgical procedure, replacement with plasma products may be needed in the preoperative, intraoperative, and postoperative periods, depending on the procedure, the patient's history with other surgical procedures, and the person's bleeding tendency, if any.
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 with absent factor XI may also develop inhibitors to factor XI.
In addition, some patients (with preexisting risk factors) who receive factor XI concentrates may be at risk for thrombotic events.
Prognosis
The prognosis is excellent in patients with partial factor XI deficiency without bleeding manifestations.
Etiology
The severity of the deficiency is based on plasma factor XIc (clotting) activity. Major factor XI deficiency is present when the activity of factor XI in plasma is less than 15 IU/dL, but the level does not reflect the severity of the bleeding risk. However, a pediatric study by Barg et al suggested that in children, the severity of factor XI deficiency may be associated with such risk. [6]
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. Recently, it has been shown that thrombin activation of factor XI is triggered by polyphosphate release from activated platelets. These molecules provide a template for assembly of factor XI and factor IX. 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 as a procoagulant and an antifibrinolytic agent, and the lack of factor XI in plasma results in a tendency to bleed. People with severe factor XI deficiency have a lower incidence of ischemic stroke. [7]
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 major deficiency factor XI, 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 major factor XI deficiency do not spontaneously bleed.
Gene mutations
Mutations in the factor XI gene cause the congenital deficiency of factor XI clotting activity. [8] The inheritance pattern of factor XI is autosomal but not completely recessive, because heterozygotes may have bleeding. [9]
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 severely affected.
More than 200 other mutations that cause factor XI deficiency have been described and are listed in online databases.
Databases include Mutations of Patients with Factor XI Deficiency, which is maintained by the University of North Carolina School of Medicine, and an interactive database maintained by University College London. [10] The published mutations include missense mutations, nonsense mutations, deletions and/or insertions, and splice-site mutations. Those described so far are associated mainly with failed or reduced production of the active protein, and only a few are related to the production of a dysfunctional molecule.
Four 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.
Various 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 England). [9] Both mutations result in a factor XI level of less than 1 U/dL in affected homozygotes.
A study by Asselta et al found significant differences between various populations with regard to heterozygote frequencies for factor XI deficiency. Allele frequencies for these populations were reported to be as follows [11] :
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African = 0.0016
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East Asian = 0.0045
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European = 0.0036
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Finnish = 0.00030
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Latino = 0.0021
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South Asian = 0.0015
People with mutations leading to absent protein (eg, Glu117Stop, C128X) are at risk of development of inhibitors (antibodies) to factor XI; this should be considered when selecting treatment for these patients.
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 intellectual disability.
Epidemiology
Hemophilia C (major form) occurs with an estimated prevalence of 1 case per 100,000 population in the United States, a rate that makes hemophilia A 10 times more common than hemophilia C.
Internationally, deficiency of factor XI is reported in most racial groups, with the highest frequency in persons of Ashkenazi or Iraqi Jewish descent [12, 13] ; in Israel, the estimated rate for heterozygosity is 8%. In the United Kingdom national database, 1696 patients (many of whom were non-Jewish) with factor XI deficiency were registered in a population of about 60 million (data for 2006), but most of these have partial deficiency [14] ; factor XI deficiency is more common than factor IX deficiency (hemophilia B). In the French Basque country (home to the most ancient ethnic group of Western Europe, the Basques), 39 patients were identified among the general population of 290,000. [15]
A study from Austria, by Gebhart et al, found that out of 418 patients with mild to moderate bleeding disorders, at least 3 (0.7%) had factor XI deficiency, compared with 11 (2.6%), 3 (0.7%), and 1 (0.2%) with factor VIII, IX, and XIII deficiency. [16]
Hemophilia C equally affects males and females. Moreover, people of any age group can be affected. Note that normal infants younger than age 6 months have low levels of factor XI because of the time required for factor XI to reach normal levels observed in adults. After this is reached, factor XI levels do not change with age.
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 hepatitis A virus and hepatitis B virus 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 patient education information, see Hemophilia.
