The investigation of a large family affected with Von Willebrand's disease.

Originally in 1926 and later in 1931 and 1933 von Willebrand and his colleagues published details of a family with a hereditary haemorrhagic diathesis which has since become established as the clinical syndrome known as von Willebrand's disease (von Willebrand, 1926, 1931; von Willebrand and Jirgens, 1933; Jurgens and Naumann, 1931). Of the 66 members in this family, 22 were affected. The dyscrasia was characterized by a tendency to bleed, especially in the form of recurrent epistaxis and intractable haemorrhage following dental extractions, accompanied by a normal coagulation time, no reduction in the number of platelets, a prolonged bleeding time, and, in the one case so investigated, efficient clot retraction. In this particular family both sexes were affected, the disease being inherited as a Mendelian dominant, but while the disease in females appeared to be either severe or mild in degree, the males were all affected to the same moderate degree. von Willebrand and his collagues sought to prove that in this condition the platelets were qualitatively deficient. This theory led von Willebrand and his colleagues, and later other authors reporting further similar families, to regard this dyscrasia as being an example of 'thromboasthenia' akin to the condition described by Glanzmann (1918), in which the bleeding tendency was characterized by deficient clot retraction and abnormal platelet morphology. In 1941 Macfarlane described five cases resembling those of von Willebrand. He demonstrated that there was no platelet abnormality and that clot retraction was normal, but that the capillaries of the nail folds were abnormal in shape and failed to contract after puncture. He suggested that the abnormality was caused by an inherited capillary defect and not by a platelet functional deficiency, pointing out that in the literature of similar cases the clot retraction had usually been reported as normal. Estren, Sanchez Medal and Dameshek (1946) reviewed 62 cases from the literature and added 11 of their own which they had investigated, adding weight and detail to the clinical picture of the condition but confusion to its aetiology by reverting to von WiUebrand's original name of 'pseudohaemophilia', for, as is pointed out by Biggs and Macfarlane (1953) in their review of the literature, this haemorrhagic diathesis 'bears no genetic, clinical or pathological resemblance to true haemophilia'. Gradually the clinical features of the syndrome and the haematological findings in it have become clarified until a definite disease entity is now established. Perkins (1946) reported a family of 37 members in which six males were affected in five generations, confirming the general pattern of the condition and adding that it appeared to be cyclic and tended to become less severe with increasing age. The same capillary abnormality noted by Macfarlane was observed, and in this family the disease appeared to be sex-linked. Levy (1947) investigated a family of 62 members extending over four generations and containing 20 affected persons, 12 females and eight males. The onset of the abnormality varied from 4 months to 4 years, and again it appeared to be cyclic and to diminish in severity with the years. One affected member suffered from haematuria for which only the dyscrasia could be found as the cause, and two-thirds of the affected females suffered from menorrhagia and postpartum haemorrhages. Five members had died of haemorrhage-three intrapulmonary, one following a gun-shot wound, and one of uterine origin. Once more the capillary abnormality was reported. These symptoms were again in addition to the accepted pattern of recurrent epistaxis, easy bruising, intractable bleeding following dental extractions, haemorrhage from the gastro-intestinal tract, occasional joint involvenmnt, and the hazard of surgical interference. Revol, Favre-Gilly and Ollagnier (1950) critically reviewed 91 published cases, agreeing that the platelets seemed to be normal in all respects. Lelong and Soulier (1950) again confirmed the