eMedicine Specialties > Pediatrics: General Medicine > Hematology

Hemophilia C

Author: Prasad Mathew, MB, BS, DCH, Director, Hemostasis and Hematology Program, Professor of Pediatrics, University of New Mexico
Coauthor(s): Paula H B Bolton-Maggs, DM, FRCP, FRCPCH, FRCPath, Consultant Haematologist, Manchester Royal Infirmary, UK
Contributor Information and Disclosures

Updated: Mar 10, 2009

Introduction

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.

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 less than 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. People with severe factor XI deficiency have a lower incidence of ischemic stroke.

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 spontaneously bleed.

Frequency

United States

Hemophilia C (severe form) 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;^1,2 in Israel, the estimated rate for heterozygosity is 8%. In the United Kingdom national database, 1696 patients (many were non-Jewish) with factor XI deficiency were registered in a population of about 60 million (data for 2006);³  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 290,000.⁴

Mortality/Morbidity

Levels of factor XI activity are not closely correlated with the patient's bleeding tendency, especially in those with partial deficiency. Severe deficiency is defined as factor XIc activity of less than 15-20 U/dL or lower. Patients with partial deficiency have levels of about 20-60 U/dL (lower limit of the range that should be assessed). About 30-50% of individuals with partial deficiency may have excessive bleeding; however, identifying these persons in advance is difficult. Most individuals with severe deficiency do not spontaneously bleed but are at risk of bleeding after surgery. Furthermore, normal infants without hemophilia C are likely to have low factor XIc levels 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.⁵ 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 = 0.0001), and severe factor XI deficiency was a strong predictor of bleeding (P =0.011). 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 < 0.01).

Other possible explanations for variations in patient 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 no correlation between mutation type and bleeding tendency has been identified.
• 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 but not completely recessive because heterozygotes may have bleeding;⁶ it equally affects males and females.

Age

People of any age groups are affected. Note that normal 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. After this, factor XI levels do not change with age.

Clinical

History

• Bleeding after surgery or after injury is the usual presenting symptom in individuals with hemophilia C.
• Individuals with factor XI levels less than 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 whereas other patients with mild deficiency do bleed excessively.
• Some unusual presentations with spontaneous bleeding have been reported. In these cases, other pathologic features may contributed to the bleeding because spontaneous bleeding is generally not a feature of hemophilia C. The unusual presentations include the following:
  • 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 and abnormal bleeding after childbirth may also occur.

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 hemophilia C 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 is sometimes 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. These individuals may have other coagulation defects and should be carefully assessed prior to surgery.

Causes

Mutations in the factor XI gene cause the congenital deficiency of factor XI clotting activity. Factor XI is a zymogen that, upon 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 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, a database maintained by the University of North Carolina School of Medicine, and Factorxi.org, an interactive database maintained by University College London. The published mutations include missense mutations, nonsense mutations, deletions and/or insertions, and splice-site mutations. Those described so far are associated with mainly 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.⁷ Both mutations result in a factor XI level of less than 1 U/dL in affected homozygotes.
• 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 mental retardation.

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