True Congenital Prothrombin Deficiency Due to a New Mutation in the Pre-Propeptide (ARG-39 GLN)

easy bruising, epistaxis. Her metrorrhagias responded to oral contraception. At the age of 26, during an interruption of oral contraception she became pregnant. She delivered a healthy boy at term but presented a postpartum bleeding in spite of transfusional protection. The son turned out to be, as expected, heterozygote for the defect showing about 50% of normal FII activity and antigen. Oral contraceptives were resumed again with a good control of menorrhagias. At the age of 29, during another suspension of oral contraceptives, the patient presented a hemoperitoneum which was cured conservatively with substitution therapy and bed rest. Oral contraceptives were resumed and continued for several years. At the age of 49 she went into menopause and oral contraceptives were discontinued. At present she still presents occasional epistaxis and easy bruising. Molecular studies were carried out in her (homozygote) and in a heterozygote. The heterozygote studied was the son of the homozygous proposita. For comparison, 91 subjects, coming from the same geographical area, were also investigated in a similar manner to rule out polymorphisms. Clotting, chromogenic and immunological assays have been carried out as previously reported by us [4–6] . Immunological assays were carried out on repeated occasions during all these years by means of three methods, namely electroimmunoassay, radial immunodiffuCongenital prothrombin deficiency is one of the rarest coagulation disorders. It is usually subdivided into type I, in which there is a concomitant and parallel decrease of activity and antigen levels, and type II in which there is a decrease in activity and a normal or near normal antigen. The ratio between type I and type II is 1 to 2 or 1 to 3 [1, 2] . The hereditary transmission is autosomal recessive for both forms of prothrombin deficiency [3] . Since complete prothrombin deficiency is incompatible with life, even type I patients, namely those with ‘true’ deficiency, usually show in their plasma levels of prothrombin between 1 and 10% of normal. This is so regardless of the method used, clotting, chromogenic or antigenic. Bleeding is severe and characterized by epistaxis, easy bruising, menometrorrhagias, bleeding after tooth extractions, and hemarthrosis [1] . The purpose of the present work is to report on a new molecular defect seen in a family with true prothrombin deficiency both at the homozygote and heterozygote level. The patients studied belong to a large kindred which has been previously reported by us [3] . All these patients have been regularly followed by us during the past 35 years. The proposita, a homozygote for true prothrombin deficiency was in her early 20s when first diagnosed. The main bleeding manifestations were menometrorrhagia, Received: July 14, 2008 Accepted after revision: August 14, 2008 Published online: October 14, 2008