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Coagulation

Hereditary bleeding disorders

Factor XI deficiency

Reviewers: Kendall Crookston, M.D., Ph.D., University of New Mexico; Lizabeth Rosenbaum, M.D., University of New Mexico; Julie Gober-Wilcox, M.D., Resident, University of New Mexico (see Reviewers page)
Revised: 16 October 2010, last major update October 2010
Copyright: (c) 2002-2010, PathologyOutlines.com, Inc.

Definition
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● Factor XI deficiency is a rare bleeding disorder that is inherited most commonly as an autosomal recessive trait, and is characterized by variable bleeding episodes

Terminology
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● Also known as plasma thromboplastin antecedent deficiency or hemophilia C

Epidemiology
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● Incidence of 1 in 450 in Ashkenazi Jewish populations and 1 in 1,000,000 in non-Jewish populations

Sites
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● Bleeding into skin and mucosa, genitourinary tract, gastrointestinal tract (see clinical features below)

Pathophysiology
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● Factor XI is a serine protease that is produced in the liver, and is involved in the contact (intrinsic) pathway
● It is activated by factor XIIa, thrombin or autoactivated, and activates factor IX, which in turn activates factor X to convert prothrombin to thrombin
● Its biologic half-life is 60-80 hrs

Coagulation cascade

Etiology
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● Most commonly inherited as an autosomal recessive trait
● An autosomal dominant pattern of inheritance is possible, as the dimeric structure of factor XI may result in a dominant negative effect through intracellular heterodimer formation (Blood 2004;104:128)
● The gene for factor XI is located on the long arm of chromosome 4
● To date, over 180 mutations have been described with three main genotypes: type I are splice site mutations, type II are nonsense mutations and type III are missense mutations
● Type II and III mutations are predominantly seen in Ashkenazi Jews
● Type II mutations are also seen in Iraqi Jews and Israeli Arabs

Clinical features
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● Deficiency can occur in homozygous, heterozygous or a combined heterozygous form
● Bleeding manifestations do not correlate with factor XI levels
● Most bleeding episodes in patients with severe deficiency are injury-related
● Spontaneous bleeding is rare
● May be associated with bruising, epistaxis, menorrhagia, GI/GU bleeding, umbilical stump bleeding or bleeding after surgery, trauma, dental procedures, pregnancy or circumcision
● Up to 33% of patients with severe deficiency develop inhibitors after replacement therapy

Laboratory
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● Prolonged PTT that corrects with mixing study
● Normal PT, thrombin time
● Specific factor XI assay

Case reports
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● Cerebellar hemorrhage due to factor XI deficiency (Cerebrovasc Dis 2005;19:138)

Treatment
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● 10-20 ml fresh frozen plasma/kg, then 5-10 ml/kg every 24 hours as necessary
● Antifibrinolytic therapy has been used in women with factor XI deficiency and menorrhagia
● Patients with inhibitors have been treated successfully with plasma, prothrombin complex concentrates, and recombinant activated factor VII
● Note: factor XI concentrates may promote thromboembolic complications

Differential diagnosis
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● Acquired factor XI deficiency associated with systemic lupus erythematosus
● Other factor deficiency causing prolonged PTT (factor VIII, IX, XII, but factor XII deficiency is not associated with bleeding manifestations)
● von Willebrand Disease
● Heparin contamination
● Liver dysfunction
● Combined familial factor deficiency

Additional references
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● J Thromb Haemost 2009;7 Suppl 1:84, Semin Thromb Hemost 2009;35:416

End of Coagulation > Hereditary bleeding disorders > Factor XI deficiency

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