History

The earliest record of the existence of hereditary hemorrhagic disease is in the Babylonian Talmud. Recurrent descriptions of what was probably hemo­philia were recorded thereafter, but it was only in 1803 that John Otto, a Philadelphia physician, recog­nized that this disorder was limited to males and transmitted by certain of their asymptomatic female relatives.

The mechanism underlying the defect in classic hemophilia was elucidated by A. J. Patek, Jr., and R. H. Stetson in 1936, who determined that the pa­tients were functionally deficient in what is now called antihemophilic factor (factor VIII). Only later was it realized independently by P. N. Aggeler, I. Schulman, and R. Biggs that an essentially identical disorder, inherited in the same way, resulted from a deficiency of Christmas factor (factor IX). In 1926, E. A. von Willebrand recognized the disease that now bears his name among inhabitants of the Aland Is­lands in the Gulf of Rothnia. This hereditary hemor­rhagic disorder affects both sexes and was detected in succeeding generations; these characteristics, along with the presence of a prolonged bleeding time, distinguishes von Willebrand’s disease from hemophilia. In 1953, several independent groups of investigators found that the titer of antihemophilic factor (factor VIII) was abnormally low in patients with von Willebrand’s disease, and some years later T. S. Zimmerman reported a deficiency also in the concentration of what is now called von Willebrand factor.

With few exceptions, the existence of the various clotting factors required for normal coagulation of blood was detected by the study of patients with unusual hemorrhagic disorders. In each instance, a protein extracted from normal plasma corrected the specific defect in the patient’s plasma. Thus, current knowledge about the physiology of blood clotting has been derived from the interplay between the clinic and the laboratory.

Oscar D. Ratnoff