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Coagulation

Hereditary bleeding disorders

Factor XII 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: 30 October 2010, last major update October 2010
Copyright: (c) 2002-2010, PathologyOutlines.com, Inc.

Definition
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● Factor XII deficiency is a congenital disorder that is most commonly inherited as an autosomal recessive trait and is not associated with a bleeding diathesis
● It is typically discovered in individuals with an isolated prolonged PTT
● Homozygous individuals have undetectable factor XII levels
● Heterozygous individuals have factor XII levels between 20-60%

Terminology
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● Factor XII is also known as the Hageman factor
● Factor XII deficiency is also known as Hageman factor deficiency or Hageman trait

Pathophysiology
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● Factor XII is a coagulation protein which is either autoactivated by contact with a number of artificial or biologic negatively charged surfaces (contact activation) or by proteolytic activation on the surface of endothelial cells by prekallikrein/kallikrein and high molecular weight kininogen
● Activated factor XII converts prekallikrein to kallikrein (which activates more factor XII, liberates bradykinin from high molecular weight kininogen, and activates complement components C3 and C5), activates factor XI which eventually leads to thrombin generation via the intrinsic pathway, and also activates C1 esterase, thereby activating the complement system

     

Coagulation cascade


     

Mechanisms of Factor XII activation

Epidemiology
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● Actual prevalence difficult to determine since individuals are asymptomatic
● One study of 300 healthy blood donors reported a prevalence of 2.3% (Thromb Haemost 1994;71:68)

Sites
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● Rarely skin and mucosa (see clinical features below)

Etiology
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● Most commonly inherited in an autosomal recessive pattern
● Autosomal dominant inheritance has been described in one family (Blood 1972;40:412)

Clinical features
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● Not associated with bleeding episodes, even after major surgical procedures or trauma
● Most patients are detected by routine preoperative coagulation studies (isolated prolonged PTT)
● Very rarely may manifest with epistaxis or easy bruising
● There is some debate about the association of factor XII deficiency and an increased risk of arterial and venous thrombosis, myocardial infarction and pulmonary embolism

Laboratory
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● Prolonged PTT that corrects with mixing study
● Normal PT, thrombin time and bleeding time
● Specific factor XII assay is diagnostic

Case reports
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● Combined factor VIII and factor XII deficiency (Am J Hematol. 1992;39:137)
● Acquired factor XII deficiency by orthotopic liver transplant (Am J Transplant 2006;6:1743)

Differential diagnosis
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● Acquired factor XII deficiency: associated with nephrotic syndrome, liver transplantation, autoimmune disease)
● Heparin contamination
● Liver disease
Lupus anticoagulants
Prekallikrein deficiency
High molecular weight kininogen deficiency
● Factor XII deficiency in association with von Willebrand disease, factor VIII or factor IX deficiency

Additional references
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J Clin Invest 2008;118:3006, Consultative Hemostasis and Thrombosis (2007)

End of Coagulation > Hereditary bleeding disorders > Factor XII deficiency


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