高宮 脩

Factor VII (FVII) participates in the initial stages of blood coagulation. It is a vitamin K-dependent glycoprotein that is synthesized in the liver, secreted into the blood and circulates as a single-chain zymogen composed of 406 amino acid residues with an approximate molecular weight of 50 kDa. The light chain consists of an aminoterminal γ-carboxyglutamic acid rich domain, followed by two EGFlike domains. The heavy chain consists of the serine protease catalytic domain. The gene for FVII is located on chromosome 13 at q34-qter, spans 12.8 kilobase pairs, and contains exons 1a and 1b (which encode the 5′ untranslated region and most of the pre-pro leader sequence) and exons 2 to 8 (which encode the mature protein).

FVII and FVIIa form a one-to-one stoichiometric complex with tissue factor TF on endothelium cells recruited by vessel damage. Once complexed to TF, FVII zymogen is converted to its active form by various coagulation proteases such as FXa. The TF-FVIIa complex readily activates zymogen FX and FIX to active enzymes and promotes fibrin-formation.

Hereditary FVII deficiency is a rare autosomal recessive bleeding disorder that has an estimated prevalence of one per 500,000 in the general population.

FVII knockout mice die at birth, or shortly after, from major abdominal and intracranial hemorrhaging. In humans, the clinical phenotype exhibited by patients with FVII deficiency correlates with poor diagnostic laboratory tests.

Differences between the clinical and laboratory phenotypes may be due to the complexity of biochemical interactions that occur with the initiation of hemostasis or because of a lack of sensitivity and accuracy in the assays used to measure very low levels of FVII:C.

We have reported various problematic issues with currently available commercial reagents and/or reference standard plasma.

However, no data regarding the inter-laboratory variability of FVII:C determinations in samples with low to very low FVII:C have so far been reported. It is very important to compare the results of different determinations of FVII deficiency for accurate diagnosis and treatment. We distributed three deficient plasma samples prepared via immunoaffinity chromatography among 58 laboratories in Japan. These samples were measured using the routine protocol in place at each laboratory and a calibration reference plasma and recombinant thromboplastin were supplied as common reagents. We conclude that the results of the FVII:C assays, especially for cases with very low to low FVII:C concentrations, are greatly influenced by the number of plasma dilutions used in constructing a standard activity curve in additional to the type of thromboplastin and calibration plasma utilized to perform the tests. These results should prove useful in the development of more sensitive and accurate systems to measure FVII:C for the diagnosis and therapy of FVII deficiency.