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.