Page 2196 - Williams Hematology ( PDFDrive )

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

224
227
168
of large multimers and varying degrees of thrombocytopenia, sim- incomplete. Laboratory values and clinical symptoms can vary con-
ilar to the variation observed in human pedigrees. Individual type 2B siderably, even within the same individual, and establishing a definite
patients can also exhibit varying multimer structure and platelet counts diagnosis of VWD is often difficult. In two large families with type 1
over time. For example, two siblings with the Arg1306Trp mutation and VWD, only 65 percent of individuals with both an affected parent and
abnormal multimers intermittently regained normal VWF multimer an affected descendent had significant clinical symptoms. For com-
249
distribution during periods of thrombocytopenia. 228 parison, 23 percent of the unrelated spouses of the patients, who pre-
Families have been described that exhibit enhanced VWF binding sumably did not have a bleeding disorder, were judged to have a positive
to GPIb but a normal distribution of VWF multimers. These variants, bleeding history.
previously referred to as type I New York, type I Malmö, and type I A number of factors have long been known to modify VWF levels,
Sydney, are now all designated as type 2B VWD. Type I New York and including ABO blood group, secretor blood group, estrogens, thyroid
type I Malmö are caused by the same VWF mutation, Pro1266Leu. This hormones, age, and stress. 250–252 ABO blood group is the best character-
mutation is located within the cluster of type 2B mutations in the VWF ized of these factors. Genome-wide linkage has repeatedly confirmed
A1 domain and results in a similar increase in platelet GPIb binding. 229 strong linkage between the ABO locus and VWF levels (reviewed in
Ref. 253). Mean VWF:Ag levels are approximately 75 percent for type
Type 2N von Willebrand Disease O individuals and 123 percent for type AB individuals when compared
As described in Chap. 123, hemophilia A results from defects in the to a pool of normal donor plasmas. Thus, it may be difficult to differen-
FVIII gene and is inherited in an X-linked recessive manner. Distinct tiate between a low-normal VWF value and mild type 1 VWD in blood
from hemophilia A, families have been reported in which the inheri- group O individuals. In recent years, additional modifiers of VWF
tance of low FVIII appeared to be autosomal, based on the occurrence have been identified in large genetic association studies, 254,255 including
of affected females or direct transmission from an affected father. 230,231 genes associated with VWF intracellular trafficking (STXBP5 256,257 ) and
Several cases of an apparent autosomal recessive decrease in FVIII were VWF clearance (CLEC4M ). Additionally, a genome-wide association
258
shown to be caused by decreased VWF binding of FVIII, 232–234 now study identified a novel genetic locus on chromosome 2 contributing to
referred to as VWD type 2N, after the Normandy province of origin variation in plasma VWF. The variable expressivity and incomplete
259
of the first patient. DNA sequence analysis has identified more than 37 penetrance of type 1 VWD and overlap in VWF levels between mild
distinct mutations associated with this disorder, most located at the type 1 VWD and normal populations has complicated the determina-
235
VWF N terminus (see Fig. 126–3) (curated in the Scientific and Stan- tion of accurate incidence figures for VWD, with estimates ranging from
dardisation Committee of the International Society on Thrombosis and as high as 1 percent 260,261 to as low as 2 to 10 per 100,000 population. 262
Haemostasis VWF Database, http://www.vwf.group.shef.ac.uk/). One of In general, the type 2 VWD variants, which comprise 20 to 30 per-
these mutations, Arg854Gln, appears to be particularly common, may cent of all VWD diagnoses, are more uniformly penetrant. Type 2A
263
236
contribute to variability in the severity of type 1 VWD in some cases, and type 2B VWD account for the vast majority of patients with quali-
and may also cause a VWF secretion defect. Rare cases of misdiagnosis tative VWF abnormalities. Types 2A, 2B, and 2M are generally autoso-
237
of type 2N have led to treatment with recombinant FVIII for presumed mal dominant in inheritance, although Type 2N and other rare cases of
hemophilia A, with poor responses and adverse clinical outcomes. 238 apparent recessive inheritance have been reported.
Estimates of prevalence for severe (type 3) VWD range from 0.5 to
Type 2M von Willebrand Disease 5.3 per 1,000,000 population. 264–266 Although this variant is frequently
This category was classically reserved for rare VWD variants in which defined as autosomal recessive in inheritance, this is not a consistent
a defect in VWF platelet-dependent function leads to significant bleed- finding. As described above, one or both parents of a severe VWD
ing but VWF multimer structure is not affected (although some have patient can be clinically asymptomatic and have entirely normal lab-
subtle multimer abnormalities). Most contemporary type 2M variants oratory test results, although in many families one or both parents
are indeed associated with absent ristocetin cofactor activity but normal appear to be affected with classic type 1 VWD. Thus, in some families,
platelet binding with other agonists. A total of 28 type 2M VWD muta- severe VWD may represent the homozygous form of type 1 VWD. In
235
tions have been described, including a number of other families with this model, the apparent recessive inheritance in a subset of families
normal VWF multimers and disproportionately decreased ristocetin could simply be the result of the incomplete penetrance of type 1 VWD.
cofactor activity, 239,240 families with a combination of defects in VWF:CB Alternatively, there may be a fundamental difference in the molecular
and VWF–GPIb interactions of varying severities, 241,242 and mutations mechanisms responsible for type 1 and type 3 VWD. 168
235
with isolated defects in VWF:CB with normal VWF:RCo activity. Compound heterozygosity (the presence of more than one VWF
Several families have also been described with a VWD variant (VWD gene mutation) can occur, and the clinical presentation in such cases can
Vicenza) characterized by larger-than-normal VWF multimers and depend on the interaction between the different mutant VWF proteins.
243
classified as either type 1 or type 2M VWD. Genetic linkage analy- Compound heterozygosity can impact response to therapy because of a
244
sis indicates that the Vicenza defect lies within the VWF gene, and complex VWD phenotype and has implications for genetic counseling.
mutations within the VWF gene have been reported to be associated If compound heterozygosity is deduced from the family history and/or
with VWD Vicenza. The underlying molecular mechanism responsi- laboratory studies or discovered during genetic testing, the most recent
245
ble for the VWD Vicenza phenotype remains controversial, although update to the VWD nomenclature represents both types separated by a
246
recent kinetic modeling suggests that altered VWF survival alone could slash (/), such as VWD type 2B/2N. 151
account for the VWF perturbations observed in this disorder. 247
CLINICAL FEATURES CLINICAL SYMPTOMS
Mucocutaneous bleeding is the most common symptom in patients
INHERITANCE with type 1 VWD. It is important to note that more than 20 percent
249
Type 1 VWD is generally transmitted as an autosomal dominant dis- of normal individuals may give a positive bleeding history. Bleeding
267
order, and accounts for approximately 70 percent of clinically signifi- assessment scores have evolved over many years, leading the Inter-
268
cant VWD. However, disease expressivity is variable, and penetrance is national Society on Thrombosis and Haemostasis to propose a unified

Kaushansky_chapter 126_p2163-2182.indd 2171 9/21/15 3:15 PM