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Coagulation

Hereditary bleeding disorders

Factor II (prothrombin) 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: 23 August 2010, last major update August 2010
Copyright: (c) 2002-2010, PathologyOutlines.com, Inc.

Definition
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● Congenital deficiency of prothrombin (factor II) that results in reduced prothrombin activity and normal or reduced prothrombin antigen levels
● Prothrombin (factor II) is a vitamin-K dependent cofactor which is activated by factor Xa to form thrombin, which then converts fibrinogen to fibrin


Coagulation cascade

Terminology
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● Hypoprothrombinemia (type I deficiency) is a decrease in the overall synthesis of prothrombin and is characterized by reduced prothrombin activity and antigen levels
● Dysprothrombinemia (type II deficiency) is the synthesis of dysfunctional prothrombin molecules and is characterized by reduced activity and normal antigen levels

Epidemiology
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● Rare; fewer than 100 cases have been reported
● Prevalence rate of approximately 1:2,000,000 in the general population

Sites
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● Mucocutaneous and soft tissue bleeding (see below)

Etiology
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● Forty different mutations in the prothrombin gene have been identified, the majority of which are missense mutations (~80%). However, insertion or deletion mutations (~10%) and nonsense mutations (~4%) have also been identified.
● The gene is transmitted in an autosomal recessive pattern with homozygous, heterozygous or compound heterozygous genotypes
● Homozygous individuals have functional prothrombin levels of 2-25%
● Heterozygous patients have prothrombin levels of 40-60%
● Biologic half life is 48-120 hours

Clinical features
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● Complete deficiency is incompatible with life
● Severe hemorrhage typically occurs when levels are < 5%
● Need levels of 10-40% for surgical hemostasis
● Patients have lifelong history or family history of bleeding; varies from asymptomatic to minor bleeding to severe bleeding (depending on the mutation)
● Also easy bruising, postoperative bleeding, epistaxis, menorrhagia, miscarriage, postpartum hemorrhage, hemarthroses and intracranial bleeding (if severe deficiency)

Laboratory
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● Prolonged PT and PTT that correct with mixing study (1:1 mixture of patient and normal pooled plasma)
● Type I (true deficiency) patients will have both activity and antigen levels <10%
● Type II patients will have normal antigen levels and low activity

Treatment
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● Recombinant factor VIIa, alternatively 10-20 ml fresh frozen plasma/kg, then 3 ml/kg every 12-24 hours as necessary
● Plasma infusion for recurrent bleeding episodes every 3-5 weeks
● Prothrombin complex concentrates may be used for serious bleeding

Differential diagnosis
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● Must rule out other coagulation factor deficiencies that cause prolonged PT and PTT (e.g. factor V deficiency or factor X deficiency)
● Acquired prothrombin deficiency due to severe liver disease, vitamin K deficiency or anti-prothrombin antibodies (antiphospholipid syndrome)

Additional references
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Semin Thromb Hemost 2009;35:367, Consultative Hemostasis and Thrombosis (2007)

End of Coagulation > Hereditary bleeding disorders > Factor II (prothrombin) deficiency


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