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Coagulation

Hereditary bleeding disorders

Factor I (fibrinogen) deficiency


Reviewers: Kendall Crookston, M.D., Ph.D., University of New Mexico; Julie Gober-Wilcox, M.D., Resident, University of New Mexico (see Reviewers page)
Revised: 15 October 2010, last major update September 2010
Copyright: (c) 2002-2010, PathologyOutlines.com, Inc.

Definition / General
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● Factor I (fibrinogen) deficiency is an inherited bleeding disorder that is characterized by a variable bleeding diathesis or paradoxically by thrombosis
● Deficiencies are classified as quantitative (afibrinogenemia and hypofibrinogenemia) or qualitative (dysfibrinogenemia) defects of the fibrinogen molecule, or both (hypodysfibrinogenemia)
● Fibrinogen is a soluble glycoprotein that is converted to fibrin by thrombin; it is synthesized mainly in the liver as a hexamer comprised of two sets of three different chains
● Normal fibrinogen levels are 1.53.5 g/L, with a half-life of 2-4 days

Terminology
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● Afibrinogenemia is the most severe form of fibrinogen deficiency; patients have no detectable circulating fibrinogen in the plasma or platelets
● Hypofibrinogenemia is a milder form of fibrinogen deficiency; patients have fibrinogen levels < 1.5 g/L
● Dysfibrinogenemia is the synthesis of abnormal fibrinogen molecules
● Hypodysfibrinogenemia is characterized by both low levels of fibrinogen and abnormal fibrinogen molecules

Epidemiology
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● Estimated prevalence of afibrinogenemia is 1 in 1,000,000
● More than 400 cases of dysfibrinogenemia have been reported
● Hypofibrinogenemia and dysfibrinogenemia are more frequent than afibrinogenemia, but prevalence is difficult to establish due to the large number of asymptomatic patients

Sites
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● Bleeding of skin and mucosa, joint and muscle, genitourinary tract, gastrointestinal tract, CNS (see clinical features below)

Etiology
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● Encoded by FGA, FGB and FGG on chromosome 4 (Wikipedia)
● Afibrinogenemia is inherited in an autosomal recessive pattern
● Hypofibrinogenemia is inherited in an autosomal dominant or recessive pattern; mutations in all three genes have been described, and include deletions, frameshift, nonsense or splicing mutations; these mutations can lead to problems that affect fibrinogen synthesis, assembly, intracellular processing (with or without endoplasmic retention), domain stability and protein secretion
● Dysfibrinogenemia is inherited in an autosomal dominant or autosomal recessive pattern; most patients are heterozygous for missense mutations in one of the three fibrinogen genes, which can cause absent or delayed release of Aa and Bb, delayed or enhanced polymerization, defective cross-linking, decreased thrombin binding and defective assembly of the fibrinolytic system

Clinical features
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● Afibrinogenemia is typically diagnosed in the neonatal period due to umbilical cord stump bleeding or bleeding after circumcision; patients can have bleeding or thrombosis
● Hypofibrinogenemia is associated with milder bleeding episodes, usually due to trauma or surgical challenge; patients are usually asymptomatic
● Dysfibrinogenemia is usually diagnosed in adulthood; patients can be asymptomatic, have bleeding or thrombosis or both
● Bleeding symptoms can include umbilical cord stump bleeding, bleeding after circumcision, easy bruising, mucosal bleeding, GI/GU bleeding, hemarthrosis, intracranial hemorrhage, recurrent fetal loss, menorrhagia, menometrorrhagia, placental abruption or postpartum hemorrhage; rarely patients can have hemopericardium, hemoperitoneum or spontaneous splenic rupture
● Arterial and venous thrombosis may occur

Laboratory
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● Prolonged PT/PTT that corrects with mixing study (may not correct with mixing study in patients with dysfibrinogenemia)
● Prolonged thrombin time
● Low or absent fibrinogen; levels may be normal in dysfibrinogenemia
● Prolonged reptilase time
● Specific fibrinogen assays including clotting and immunologic assays
● Mild thrombocytopenia has been reported in 25% of patients with afibrinogenemia

Case reports
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● Patient with congenital afibrinogenemia with retrochorionic hematoma during pregnancy (Am J Hematol 2007;82:317)

Treatment
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● Use cryoprecipiate to keep level at 50-100 mg/dL in acute bleeding episodes, preoperative state or during pregnancy
● FFP or fibrinogen concentrates may also be used

Differential diagnosis
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● Acquired fibrinogen deficiency (DIC, liver disease, medication use, autoimmune disease)

Additional references
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Semin Thromb Hemost 2009; 35;356, Haemophilia 2008;14:1151, Consultative Hemostasis and Thrombosis: Elsevier, 2007

End of Coagulation > Hereditary bleeding disorders > Factor I (fibrinogen) deficiency


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