Abstract
Prothrombin (factor II [FII]) deficiency is a rare inherited coagulation disorder,
having a prevalence of approximately 1 in 2,000,000. Two phenotypes can be distinguished:
(1) true hypoprothrombinemia (type I deficiency), characterized by concomitantly low
levels of the zymogen antigen; and (2) dysprothrombinemia (type II deficiency), characterized
by the normal or near-normal synthesis of a dysfunctional protein. In the latter case,
recent studies showed that particular mutations in the catalytic domain of active
thrombin can even impair the enzyme interaction with antithrombin, favoring thromboembolic
diseases. In some cases, hypoprothrombinemia associated with dysprothrombinemia was
also described in compound heterozygous defects. Prothrombin is essential for the
development of mammalian organisms. No living patient with undetectable plasma prothrombin
has been reported to date. Prothrombin is encoded by a ≈21 kb gene located on chromosome
11 and containing 14 exons. Thirty-nine different mutations have been identified and
characterized in prothrombin deficiency. Many of these are present in the catalytic
site, whereas some involve regulatory domains, such as the anion-binding exosite I,
the Na+-binding loop, and the light A-chain. Most hypoprothrombinemia-associated mutations
are missense, but nonsense mutations leading to stop codons and one single nucleotide
deletion have also been identified. Finally, recent developments in the therapy of
congenital prothrombin deficiency are presented and discussed.
Keywords
prothrombin deficiency - congenital bleeding diseases - thrombin - coagulation - hemorrhagic
disorders
