INSERM U698, UFR de médecine Paris 7 Denis-Diderot, France, Service d’hématologie biologique, hôpital Beaujon, 92110 Clichy, France, Service de biochimie, hôpital Beaujon, 92110 Clichy, France, Service d’hématologie et immunologie, hôpital Bichat, 75018 Paris, France
Inherited prothrombin deficiency (blood clotting factor II) is a very rare autosomal recessive bleeding disorder. Total deficiency, probably lethal, has not been reported in humans. About 40 families have been identified in the world, presenting with a moderate or severe deficiency due to a quantitative (hypoprothrombinemia) or qualitative defect (dysprothrombinemia). The clinical phenotype is highly variable. Quantitative defects are associated with bleeding manifestations that may be severe, in particular in homozygous or composite heterozygous patients, and are grossly correlated with plasma prothrombin level. The bleeding risk associated with dysprothrombinemia is much more variable and poorly related with prothrombin activity. Prothrombin deficiency is related to mutations spread all over the gene. Dysprothrombinemias result from defects in the thrombin catalytic site or in the prothrombin cleavage sites by factor Xa, that are generally associated with severe bleeding episodes. Substitutions that affect thrombin exosite I or sodium binding site are rarely associated with bleeding. Identification of these natural mutations has given us insights into the cause of inherited disorders and has improved our understanding of the structure function relationship of prothrombin.