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CHAPTER 126 DEFINITION AND HISTORY

VON WILLEBRAND DISEASE In 1926, Eric von Willebrand described a bleeding disorder in 24 of 66
members of a family from the Åland Islands. Both sexes were afflicted,
1
and the bleeding time was prolonged despite normal platelet counts and
normal clot retraction. von Willebrand distinguished this condition
Jill Johnsen and David Ginsburg from the other hemostatic diseases known at the time and recognized
its genetic basis, calling the disorder “hereditary pseudohemophilia,”
but incorrectly characterizing the inheritance as X-linked dominant.
von Willebrand’s confusion about the inheritance pattern was probably
SUMMARY the result of, at least in part, the greater recognition of bleeding symp-
toms in women because of the hemostatic stresses of menstruation and
von Willebrand factor (VWF) is a central component of hemostasis, serving parturition. The proband in the original family, Hjördis, was 5 years old
both as an adhesive link between platelets and the injured blood vessel wall at the time of von Willebrand’s initial evaluation and ultimately died at
and as a carrier for clotting factor VIII (FVIII). Abnormalities in VWF function age 13 years during her fourth menstrual cycle. Four of Hjördis’ sisters
result in von Willebrand disease (VWD), the most common inherited bleeding died between the ages of 2 and 4 years, and deaths in the family were
disorder in humans. The overall prevalence of VWD has been estimated to be as also noted during childbirth.
high as 1 percent of the general population, although the prevalence of clin- An apparently similar disorder was independently reported in the
ically significant disease is probably closer to 1:1000. VWD is associated with United States by Minot and others in 1928. The original family in the
either quantitative deficiency (type 1 and type 3) or qualitative abnormalities Åland Islands was reexamined by von Willebrand and Jürgens in 1933,
leading to the conclusion that the defect in this disorder was caused by
of VWF (type 2). The uncommon type 3 variant is the most severe form of an impairment of platelet function. It was not until 1953 that Alexan-
VWD and is characterized by very low or undetectable levels of VWF, a severe der and Goldstein demonstrated reduced levels of coagulation factor
bleeding diathesis, and a generally autosomal recessive pattern of inheritance. VIII (FVIII) in von Willebrand disease (VWD) patients, along with
Type 1 VWD, the most common variant, is characterized by VWF that is normal prolonged bleeding time. This observation was confirmed by others,
in structure and function but decreased in quantity (in the range of 20 to 50 including studies of the original von Willebrand pedigree by Nilsson
percent of normal). In type 2 VWD, the VWF is abnormal in structure and/or and coworkers. In the late 1950s, Nilsson and coworkers demonstrated
function. Type 2A VWD is associated with selective loss of the largest and most that a fraction of plasma referred to as “I-O” could correct the FVIII
functionally active VWF multimers. Type 2A is further subdivided into group deficiency and normalize the bleeding time, indicating that the defect
1, as a result of mutations that interfere with biosynthesis and secretion, and in VWD was a result of the deficiency of a plasma factor rather than
group 2, in which the mutant VWF exhibits an increased sensitivity to proteoly- an intrinsic platelet abnormality. Infusion of fraction I-O promptly
sis in plasma. Type 2B VWD is caused by mutations clustered within the VWF A1 increased the FVIII level in a hemophilic patient, while in VWD the
FVIII level rose gradually, peaking at 5 to 8 hours. Fraction I-O pre-
domain, in a segment critical for binding to the platelet glycoprotein Ib recep- pared from a hemophilia A patient was also shown to correct the defect
tor. These mutations produce a “gain of function” resulting in spontaneous VWF in VWD, demonstrating that these disorders were caused by deficien-
binding to platelets and clearance of the resulting platelet complexes, leading cies of distinct plasma factors (reviewed in Refs. 2 and 3).
to thrombocytopenia and loss of the most active (large) VWF multimers. Type It was not until 1971 that Zimmerman, Ratnoff, and Powell pre-
2N VWD is characterized by mutations within the FVIII binding domain of VWF, pared the first antibodies against what was thought to be a highly puri-
leading to disproportionately decreased factor VIII and a disorder resembling fied form of FVIII. This FVIII-related antigen was found to be normal
4
mild to moderate hemophilia A, but with autosomal rather than X-linked in hemophilia A patients but decreased in VWD. This puzzle was finally
inheritance. Type 1 VWD can often be effectively managed by treatment with resolved with the demonstration that von Willebrand factor (VWF) and
DDAVP (1-deamino-8-D-arginine vasopressin, desmopressin), which produces FVIII are closely associated, with more than 98 percent of the mass of
a two- to threefold increase in plasma VWF level due to release from endo- the complex made up of VWF (see section The Function of von Wille-
thelial storage sites in the vessel wall. Response to DDAVP is generally poor in brand Factor below). Thus, antibodies raised against this complex pre-
dominantly recognize VWF. The first direct assay of VWF function was
type 3 and some type 2 VWD variants. These disorders often require treatment based on the observation that the antibiotic ristocetin induced throm-
with factor replacement in the form of VWF/FVIII concentrates containing large bocytopenia and the demonstration by Howard and Firkin that risto-
5
quantities of intact VWF multimers. cetin-induced platelet aggregation (RIPA) was absent in some VWD
patients. Weiss and coworkers used this observation to develop a quan-
6
titative assay for VWF function that remains a mainstay of laboratory
evaluation for VWD to this day. In 1973, several groups succeeded in
dissociating VWF from FVIII procoagulant activity. 7,8
Final proof that VWF and FVIII are independent proteins encoded
by distinct genes came with the complementary DNA (cDNA) clon-
Acronyms and Abbreviations: ADAMTS13, a disintegrin and metalloprotease with ing of the two molecules in 1984 and 1985. 9–14 These discoveries also
thrombospondin type 1 motifs; aPTT, activated partial thromboplastin time; DDAVP, marked the beginning of the molecular genetic era for the study of
1-desamino-8-D-arginine vasopressin or desmopressin; ER, endoplasmic reticulum; VWF and FVIII, leading to the identification of gene mutations in many
GP, glycoprotein; HHT, hereditary hemorrhagic telangiectasia; PCR, polymerase chain patients with hemophilia and VWD, as well as considerable insight into
reaction; RIPA, ristocetin-induced platelet aggregation; VWD, von Willebrand dis- the structure and function of these related proteins.
ease; VWF, von Willebrand factor. Table 126–1 summarizes the current nomenclature and terminol-
ogy for FVIII and VWF. VWD is a heterogeneous disorder with more

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