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C H A P T E R 138

STRUCTURE, BIOLOGY, AND GENETICS OF VON

WILLEBRAND FACTOR

Paula James and Natalia Rydz

Von Willebrand factor (VWF) is an adhesive multimeric plasma gly- absence of VWF, FVIII has a half-life of approximately 2 hours in
coprotein that mediates platelet adhesion to injured subendothelium contrast to a normal half-life of 12–20 hours when bound to VWF.
via glycoprotein (GP) 1bα, and binds and stabilizes factor VIII (FVIII)
in the circulation, protecting it from proteolytic degradation. This
important multifunctional protein was named after the Finnish physi- BASAL VON WILLEBRAND FACTOR LEVELS
cian, Dr. Erik von Willebrand, who first described von Willebrand
disease (VWD) in 1926. In the original publication he described a The normal level for VWF is highly variable and ranges from 50 to
severe mucocutaneous bleeding problem in a family living on the Åland 150 IU/dL. Factors that contribute to the variable VWF levels
archipelago in the Baltic Sea. The index case, a young woman named include ABO genotype (see section on ABO blood groups later),
Hjördis, bled to death during her fourth menstrual period at the age Secretor genotype, race, and age. Plasma VWF concentrations have
of 13. Dr. von Willebrand referred to the condition as pseudohemophilia, been reported to be approximately 20% higher in subjects homozy-
but noted that in contrast to hemophilia, this condition affected both gous for the Secretor (Se) allele as compared with those who are
genders, with females typically being more severely affected. heterozygous. VWF levels in blacks are 15% higher than those in
In the mid-1950s it was recognized that VWD was usually whites. Increased age has also been associated with higher VWF
accompanied by a reduced level of FVIII activity and that the bleed- levels, with studies suggesting that the levels may increase by as much
ing phenotype could be corrected by the infusion of normal plasma. as 15–17 U/mL per decade.
In the early 1970s the critical immunologic distinction between Within subjects, VWF levels often vary over time as a result of
FVIII and VWF was made, and since that time significant progress β-adrenergic stimuli, drugs, or more sustained physiologic factors,
has been made in our understanding of the molecular pathophysiol- such as pregnancy, hypothyroidism, chronic illness, or long-term use
ogy of this disorder. Cloning and characterization of the VWF gene of certain medications. The vasopressin analogue, 1-deamino-(8-D-
in the 1980s has facilitated further investigation into the function of arginine)-vasopressin (DDAVP, desmopressin) transiently and reliably
VWF and the genetic basis of VWD. increases VWF and FVIII levels—a fact that, in addition to an
acceptable side effect profile, has led to the use of DDAVP as a
first-line treatment in certain types of VWD and mild hemophilia A.
FUNCTIONS OF VON WILLEBRAND FACTOR Several physiologic stressors involving β-adrenergic stimulation, such
as exercise, surgery, and psychological distress, can produce an acute
VWF is a multifunctional adhesive protein that plays an important increase in VWF levels. VWF levels remain elevated for up to 6 days
role in both primary hemostasis and blood coagulation. In primary after surgery, suggesting that after the acute secretory response, there
hemostasis, VWF initiates platelet adhesion at the site of endothelial is upregulation of VWF production. A sustained elevation of VWF
injury, whereas in coagulation, VWF stabilizes FVIII in the circula- levels can occur with chronic diseases, such as hyperthyroidism, renal
tion (Fig. 138.1). failure, diabetes, liver disease, atherosclerosis, chronic inflammatory
states, and cancer. Conversely, acquired VWD, characterized by
qualitative or quantitative VWF defects, can occur with certain
Platelet Adhesion medications, such as valproic acid, and with some chronic medical
conditions (see section later on acquired VWD).
At the site of endothelial injury, VWF adheres to exposed collagen. VWF levels are increased by estrogen. In premenopausal women,
The hemostatically important forms of collagen include types I, VWF levels vary in a cyclical fashion, with the lowest levels occur-
III, and VI, but VWF preferentially binds to type III collagen. The ring in the early follicular phase of the menstrual cycle (days 1–7)
interactions of VWF with collagen are predominately mediated by and peak values occurring during the luteal phase. Oral contracep-
the VWF A3 domain (Fig. 138.2). Once immobilized, VWF tives increase VWF levels and dampen the cyclical variation. This
is subjected to the high shear rates of the arterial circulation and dose-dependent effect is mediated by the estrogen component
undergoes a conformational change that exposes the platelet GPIbα and is evident with ethynylestradiol doses of 0.5 µg or higher.
binding site within the VWF A1 domain. High affinity, rapid and Lower estrogen doses have little or no effect on VWF levels. VWF
reversible interaction between VWF and GPIbα tethers platelets to levels increase in pregnancy starting in the second trimester and
the endothelium where they roll until they are immobilized and achieve levels threefold higher than baseline values by the end of
activated by direct platelet-collagen binding which is mediated by the third trimester. VWF levels return to baseline 1–3 weeks after
two collagen receptors on platelets, GPVI and the integrin α2β1 delivery.
(or GPIa/IIa). The Arg-Gly-Asp (RGD) sequence within the VWF
C1 domain also contributes to platelet adhesion by interacting with
GPIIb-IIIa of activated platelets. VON WILLEBRAND FACTOR GENE

Located on the short arm of chromosome 12 at p13.3, the VWF gene
Factor VIII Stabilization spans 178 kb and is composed of 52 exons that range in size from
1.3 kb (exon 28) to 40 bp (exon 50) (Fig. 138.2A). There is a partial,
VWF binds FVIII through the VWF D′D3 domains and protects it unprocessed pseudogene, vWFP, located on the long arm chromo-
from proteolytic degradation, thereby prolonging its half-life. In the some 22 at q 11.2, measuring 21–29 kb, which duplicates the VWF

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