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Chapter 138 Structure, Biology, and Genetics of von Willebrand Factor 2055

asialoglycoprotein receptor in both cell types and sialic-acid-binding-
immunoglobulin-like-lectin 5 in macrophages. C-type lactic domain
family 4 member M on endothelial cells has also been shown to
mediate VWF clearance in a glycan-dependent manner. Further
studies are needed to decipher the relative contribution of each of
these mechanisms as determinants of VWF levels.
The VWF propeptide remains associated with VWF multimers
stored in WPBs and is secreted in a 1 : 1 molar ratio with the mature
VWF subunit. After secretion, the propeptide (VWFpp) dissociates
from VWF and circulates at a concentration of approximately 1 µg/
mL and with a half-life of 2–3 hours. In contrast, VWF circulates at
a plasma concentration of approximately 10 µg/mL and has a half-life
of approximately 12–20 hours. The ratio between VWFpp and mature
VWF (vWFpp/VWF : Ag) can be used to estimate the relative half-life
of mature VWF; elevated ratios indicate enhanced clearance.
Changes in VWF glycosylation or point mutations can be associ-
ated with increased clearance. Blood group O subjects (see the fol-
lowing section on ABO Blood Groups) exhibit increased VWF
clearance compared with the other blood types and have consistently
elevated vWFpp/VWF : Ag ratios and shorter VWF survival after
DDAVP administration. Several point mutations may lead to acceler-
ated VWF clearance and are associated with either a type 1 or type
2A VWD phenotype. The vast majority of these are localized to the
D3 domain (e.g., R1205H and C1130F), but point mutations in the
A1 (I1416N), CK (C2617), and D4 domains (S2179F) have also
been implicated.
VWF mutations associated with accelerated clearance are not
necessarily associated with increased susceptibility to proteolysis by
NHP T1 2A 2B 2M 2N T3 ADAMTS13 and vice versa. For example, the VWD Vicenza muta-
tion, R1205, is the prototypical clearance mutation. Patients with
Fig. 138.4 EXAMPLE OF A MULTIMER ANALYSIS (2.25% AGAROSE this mutation have severely reduced plasma FVIII and VWF levels,
GEL). Lane 1 normal human plasma (NHP) represents normal plasma an increased vWFpp/VWF : Ag, and a VWF half-life of 1–2 hours.
multimer patterns with a characteristic “triplet” pattern of satellite bands However, there is no association between increased clearance of this
flanking each main multimer. Lanes 2–7 show the plasma VWF multimer mutant VWF and altered susceptibility to ADAMTS13 proteolysis.
analysis for patients with the different subtypes of VWD (T1, type 1; 2A,
type 2A; 2B, type 2B; 2M, type 2M; 2N, type 2N; T3, type 3). Type 2A and
type 2B VWD both show variable loss of high-molecular-weight multimers. ABO BLOOD GROUPS
Types 1, 2M, and 2N demonstrate the presence of high molecular weight
multimers. Finally, with type 3 VWD, there is an absence of any VWF. Blood group O subjects have VWF levels that are on average 25%
lower than those with non-O blood types: the mean VWF level in
blood group O subjects is 74.8 IU/dL as compared with 105.9 IU/
flanking each main multimer band that is observed on multimer dL, 116.9 IU/dL, and 123.3 IU/dL in blood group A, B, and AB
analysis gels. (Fig. 138.4). subjects, respectively. ABO antigens are added to N-linked oligosac-
VWF proteolysis is influenced by glycosylation and specific charide chains on the VWF subunit. Thus patients with the type O
polymorphisms. For example, nonglycosylated recombinant VWF is blood group genotype lack the functional glycosyltransferase that
cleaved more rapidly than its plasma-derived glycosylated counter- adds N-acetylgalactosamine and D-galactose to the H antigen on
parts. Likewise, addition of A or B blood group antigens to N-linked VWF in blood group A and B subjects, respectively. Altered glyco-
oligosaccharide chains of VWF attenuates ADAMTS13 proteolysis sylation of VWF in subjects with blood type O leads to lower plasma
compared with VWF bearing the O blood group antigen. Finally, the VWF levels as a result of increased proteolysis and/or more rapid
differential glycosylation of platelet VWF renders it resistant to clearance. Blood group O VWF is more susceptible to ADAMTS13
ADAMTS13 proteolysis. Single-nucleotide polymorphisms, such as proteolysis, and blood group O subjects have elevated VWFpp : vWFAg
the A/G polymorphism at position 24/1282 resulting in Tyr/Cys at ratios and shorter VWF survival after DDAVP. The mean half-life of
1584, have also been shown to affect the susceptibility of VWF to VWF in type O subjects is approximately 10 hours compared with
proteolysis. a half-life of approximately 25.5 hours in those with other ABO
Alterations in the balance between ADAMTS13 activity and blood types. Clinically, the difference in VWF levels results in an
VWF proteolysis can lead to a number of disease states. Congenital overrepresentation of blood group O patients with type 1 VWD,
or acquired deficiency of ADAMTS13 can result in thrombotic which is defined by a reduction in VWF levels.
thrombocytopenic purpura (see Chapter 134). On the other hand,
enhanced proteolysis can give rise to a bleeding phenotype. For
example, mutant VWF in a subtype of type 2A VWD exhibits AREAS OF ONGOING INVESTIGATION
enhanced susceptibility to ADAMTS13 cleavage, which results in loss
of large VWF multimers. There is emerging evidence that VWF may have a role in the regula-
tion of vascular endothelial growth factor-dependent angiogenesis
directly through its interaction with integrins on endothelial cells and
CLEARANCE indirectly via regulation of WPB formation and secretion of constitu-
ents such as angiopoietin-2. In addition, VWF may protect against
VWF clearance is complex and involves multiple receptors and tumor metastasis. Patients with increased VWF levels are at risk for
cell-types. Data suggest that macrophages and hepatocytes internal- cardiovascular events; it is unclear whether VWF contributes to
ize and clear VWF in a process that is independent of multimer atherosclerosis or whether it is a marker of endothelial dysfunction.
size and mediated by lipoprotein receptor-related protein and Nonetheless, VWF plays an important role in atherothrombosis, and