Three problems of hemophilia B : a study of abnormal factor IX molecules with an inhibitor neutralization assay

Abstract

Hemophilia is a sex linked, recessive, hereditary disorder characterized

by excessive bleeding. This bleeding tendency manifests

itself in spontaneous hemorrhages in the joint cavities and muscles,

and in excessive bleeding after trauma or surgical procedures. The first written references to the disease can be found in the Babylonian Talmud, in which it can be read that Rabbi Judah the Patriarch exempted the third son from circumcision if his mother had already lost two sons because they had bled to death after this operation ( 1 ) . Rabbi Simon hen Gamaliel even forbade a boy to be circumcised whien sons of his mother's three elder sisters had died from bleeding after circumcision ( 2). In the 19th century Wardrop discovered the prolonged clotting time of hemophilic blood. For a long time lack of prothrombin was held responsible for the clotting defect until in 1935 Quick found that the prothrombin time of hemophilic plasma was normal ( 2) . Patek and Taylor reported in 1937 that the prolonged clotting time of hemophilic plasma could be normalized by the addition of a globulin fraction of normal blood. For this reason the lacking clotting component was called antihemophilic globulin; later, by international agreement, it was named clotting factor VIII (2). In 1944 Pavlovsky observed that a mixture of the blood of two hemophiliacs known to him had a normal clotting time ( 3, 4). The right interpretation of this finding was given only in 1952 and not by Pavlovsky himself. In that year reports from New York, San Francisco, and Oxford described a disease which was clinically and genetically undistinguishable from hemophilia, but the lacking clotting component was not factor VIII ( 5-7). The missing factor in this new disorder, PTC-deficiency, Christmas disease or hemophilia B, was later called factor IX.