What is hemophilia C (deficiency of factor XI)?

Updated: Dec 18, 2020
  • Author: Vineeta Gupta, MD, DNB, MAMS, FRCPCH, FUICC; Chief Editor: Hassan M Yaish, MD  more...
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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]

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. [3]

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. [4] 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:

  • Additional clotting factor disorders, especially von Willebrand disease, or a more subtle change in hemostatic balance

  • 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.

  • 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.

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