IN 1948, BERNARD AND SOULIER described a young male patient with a severe bleeding disorder that was characterized by a prolonged bleeding time, thrombocytopenia, and extremely large platelets. 1 They termed the disorder ‘‘la dystrophie thrombocytaire-hémorragipare congénitale.’’Since then, an identical or similar disorder has been described in a large number of individuals, virtually always transmitted in an autosomal recessive manner and often occurring in persons whose parents are close relatives. The first clue to the molecular abnormality affecting the platelets of patients with this disorder (now known as the Bernard-Soulier syndrome [BSS]) came in 1969 from the work of Gröttum and Solum, 2 who noted reduced electrophoretic mobility of the platelets due to a marked decrease in the concentration of sialic acid on their membranes. Subsequently, Howard et al3 and Caen and Levy-Toledano4 found that the platelets of BSS patients failed to aggregate to ristocetin, a peptide antibiotic known to aggregate normal platelets but not the platelets of patients suffering from von Willebrand disease. Weiss et al5 in 1974 extended this observation by demonstrating a defect in the ability of BSS platelets to adhere to rabbit aortic subendothelium. They also suggested that the defect resulted from absence of a receptor for von Willebrand factor (vWF) on the platelet surface. Numerous other phenotypic abnormalities have been described in BSS, including defective platelet aggregation to bovine vWF, 3, 6 abnormalities of membrane phospholipid content7, 8 and coagulant activity, 6, 8 and morphological characteristics that include large size and disordered cytoskeletal structure. 9, 10

The nature of the missing vWF receptor was suggested in 1975 when Nurden and Caen11 demonstrated that 1 of the 3 major carbohydrate-containing proteins on the platelet surface, glycoprotein I, was virtually absent in the platelets of BSS patients. The biochemical defect was defined further in the laboratories of Clemetson et al12 and Berndt et al, 13 when they demonstrated, in unrelated patients with BSS, deficiencies of 4 polypeptides: glycoproteins (GP) Ib, Ib, IX, and V. These polypeptides all associate on the platelet surface to form a receptor called the GP Ib-IX-V complex. The importance of this receptor for normal hemostasis is perhaps best illustrated by the clinical history of the original patient described by Bernard and Soulier. 14 As both a child and a young man, this patient suffered numerous bleeding problems, including prolonged bleeding after tooth extraction, lifethreatening cerebrospinal hemorrhage, and orbital and perior-