Excerpt from Hemophilia C

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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.

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