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2170 Part XII: Hemostasis and Thrombosis Chapter 126: von Willebrand Disease 2171

explain the observed modifying effect of the ABO blood group glyco- can also disrupt intracellular processing and secretion via defective mul-
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syltransferases on plasma VWF survival. Additional genetic factors timerization and/or loss of regulated storage. In the second subset, or
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have been implicated to influence VWF via altered survival, including group 2, mutant VWF is normally processed and secreted in vitro, and
the clearance receptors CLEC4M and LRP1 (CD91) (reviewed in Ref. thus loss of multimers in vivo is presumed to occur based on increased
185). The biologic consequences of VWF modifiers identified in normal susceptibility to proteolysis in plasma 98,206–209 at the Tyr1605-Met1606
populations are unclear, and studies are needed to determine their sig- site cleaved by ADAMTS13. 101,210 The susceptibility of type 2A VWD
nificance in VWD. mutations to proteolysis by ADAMTS13 in vitro supports accelerated
proteolysis as a mechanism for the loss of high-molecular-weight VWF
Type 3 von Willebrand Disease multimers in these patients. 204
Patients with type 3 VWD account for 1 to 5 percent of clinically signifi- The multimer structure of platelet VWF correlates well with the
cant VWD, have very low or undetectable levels of plasma and platelet underlying type 2A mechanisms. Group 1 patients show loss of large
VWF:Ag and VWF:RCo, and generally present early in life with severe VWF multimers within platelets as a result of defective synthesis, while
bleeding. FVIII coagulant activity is markedly reduced but usually group 2 patients have normal VWF multimers within the protected
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detectable at levels of 3 to 10 percent of normal. Type 3 VWD has gen- environment of the α granule. These observations confirm the earlier
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erally been considered an autosomal recessive disorder, but in a recent subclassification of type 2A VWD based on platelet multimers. Sub-
Canadian study of 100 individuals in 34 families, 48 percent of “carri- classification into group 1 or 2 might be expected to predict response to
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ers” had a diagnosis of type 1 VWD, suggesting the dominant type 1 DDAVP therapy, although this remains to be demonstrated.
VWD pattern of inheritance is common in type 3 VWD families. In addition to the major classes of type 2A VWD described above,
Mutations associated with type 3 VWD have been reported a number of rare variants historically classified as types IIC to IIH, type
throughout the VWF gene (http://www.vwf.group.shef.ac.uk/). Gross IB, and “platelet discordant” are included in the more general type 2A
VWF gene deletion detectable by Southern blot 26,187–190 or multiple liga- category. Most of these rare variants were distinguished on the basis
tion-probe amplification 161,191 is the molecular mechanism for type 3 of subtle differences in the multimer pattern (see Fig. 126–4; multimer
VWD in only a small subset of families. However, large deletions may changes relative to the location of type 2 mutations is reviewed in Ref.
confer an increased risk for the development of alloantibodies against 211). The IIC variant is usually inherited as an autosomal recessive trait
VWF. 26,189 A similar correlation between gene deletion and risk for and is associated with loss of large multimers and a prominent dimer
alloantibody formation has been observed in hemophilia (Chap. 123). band. Several mutations have been identified in the VWFpp of these
Comparative analysis of VWF genomic DNA and platelet VWF mRNA patients, 212–214 presumably interfering with multimer assembly and/or
has identified nondeletion defects resulting in complete loss of VWF trafficking to storage granules. A mutation at the C terminus of VWF,
mRNA expression as a molecular mechanism in some patients with interfering with dimer formation, was described in a patient with the
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type 3 VWD. 192,193 A number of nonsense and frameshift mutations that IID variant. Most of the other reported variants of type 2A VWD are
would be predicted to result in loss of VWF protein expression or in quite rare, often limited to single case reports.
expression of a markedly truncated or disrupted protein have been iden-
tified in some type 3 VWD families. 168,194–196 A frameshift mutation in Type 2B von Willebrand Disease
exon 18 appears to be a particularly common cause of type 3 VWD in Type 2B VWD is usually inherited as an autosomal dominant disorder
the Swedish population and has been shown to be the defect responsi- and is characterized by thrombocytopenia and loss of large VWF mul-
ble for VWD in the original Åland Island pedigree. 197,198 This mutation timers. The plasma VWF in type 2B VWD binds to normal platelets
results in a stable mRNA encoding a truncated protein that is rapidly in the presence of lower concentrations of ristocetin than does normal
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degraded in the cell. This mutation also appears to be common among VWF and can aggregate platelets spontaneously. Accelerated clearance
type 3 VWD patients in Germany, but not in the United States. 201 of the resulting complexes between platelets and the large, most adhe-
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sive forms of VWF accounts for the thrombocytopenia and the charac-
Type 2A von Willebrand Disease teristic multimer pattern (see Fig. 126–4).
Type 2A is the most common qualitative variant of VWD and is gener- The peculiar functional abnormality characteristic of type 2B
ally associated with autosomal dominant inheritance and selective loss VWD suggested a molecular defect within the GPIb binding domain
of the large and intermediate VWF multimers from plasma (see Fig. of VWF. For this reason, initial DNA sequence analysis focused on
126–4). A 176-kDa proteolytic fragment present in normal individuals the corresponding portion of VWF exon 28. 216,217 Type 2B mutations
is markedly increased in quantity in many type 2A VWD patients. This are located within the VWF A1 domain at one surface of the described
fragment is consistent with proteolytic cleavage of the peptide bond crystallographic structure. 124,129 The four most common mutations are
between Tyr1605 and Met1606. 98,202 Based on this observation, initial clustered within a 36-amino-acid stretch between Arg1306 and Arg1341
DNA sequence analysis in patients centered on VWF exon 28, in the (see Fig. 126–3); together, these account for more than 80 percent of
region encoding this segment of the VWF protein, leading to the iden- type 2B VWD patients. Functional analysis of mutant recombinant
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tification of the first point mutations responsible for VWD. Since that VWF 218–222 confirms that these single-amino-acid substitutions are suf-
time, a large number of mutations have been identified, accounting for ficient to account for increased GPIb binding and the resulting charac-
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the majority of type 2A VWD patients. Many of these mutations are teristic type 2B VWD phenotype. Structural studies of type 2B VWD
clustered within a 134-amino-acid segment of the VWF A2 domain mutations show that these residues interact with the leucine rich repeats
(between Gly1505 and Glu1638; see Fig. 126–3), and the most common, of GPIb thought to be critical to the VWF A1–GPIb interactions under
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Arg1597Trp, appears to account for about one-third of type 2A VWD shear. Type 2B mutations have now been modeled extensively in mice,
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patients. 194,195,204 all of which exhibited accelerated VWF clearance, as expected. Type
Type 2A VWD mutations have been grouped by two distinct molec- 2B VWD mice also had short-lived platelets, with evidence of macro-
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ular mechanisms. In the first subset, classified as group 1, the type 2A phage-mediated platelet clearance. In these models, platelets were
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VWD mutation has been commonly considered a defect in intracellu- observed to be coated by type 2B VWF, a phenomenon that may con-
lar transport, with retention of mutant VWF in the ER. In addition to tribute to a previously unsuspected acquired platelet function defect.
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retention or degradation of mutant VWF in the ER, type 2A mutations Interestingly, mice with the same type 2B mutations exhibit variable loss

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