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2174 Part XII: Hemostasis and Thrombosis Chapter 126: von Willebrand Disease 2175

ratio may correlate with heterozygosity for a type 2N VWF mutation. being considered, genetic counseling should be provided before the
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Although this assay is widely used in European hemostasis laboratories, decision to test is made as well as following the procedure.
its availability in the United States is currently limited to a few special-
ized reference laboratories. DIFFERENTIAL DIAGNOSIS
An assay measuring the VWFpp can be used to calculate the
VWFpp:antigen ratio (VWFpp:Ag ratio) to detect a subset of VWD PLATELET-TYPE (PSEUDO-) VON
patients with decreased VWF survival. Good correlation has been
reported between subjects with significantly shortened VWF half-life WILLEBRAND DISEASE
after DDAVP challenge and an increased VWFpp:Ag ratio. 287,303,304 This Platelet-type (pseudo-) VWD is a platelet defect that phenotypically
assay is currently available in a few reference laboratories. A normal mimics VWD (Chap. 120). Patients have mucocutaneous bleeding,
platelet VWF:Ag in the setting of decreased plasma VWF laboratory plasma VWF often lacks the largest multimers, RIPA is enhanced at low
parameters also suggests an accelerated clearance phenotype such as concentrations of ristocetin, and thrombocytopenia of variable degree
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that seen in VWD type Vicenza, but platelet VWF:Ag testing also is is often present. Molecular analysis has identified missense mutations
not widely available in clinical laboratories. within the GPIbα gene as the molecular basis for pseudo-VWD. These
A number of other assays for VWF activity have been developed. mutations are located within the segment of GPIb that encodes the
The PFA-100 system, which measures platelet binding under high VWF binding domain and appear to induce the conformational change
shear, 306,307 is controversial in the diagnosis or monitoring of VWD. complementary to that produced in VWF by type 2B VWD mutations
Although the PFA-100 is usually abnormal in type 2 VWD and in more (reviewed in Ref. 316).
severe type 1 and type 3 VWD cases, milder type 1 VWD and some The specialized RIPA test should be performed at low ristocetin
type 2 VWD patients can have normal results. Other VWF assays can concentrations to distinguish type 2B and platelet type VWD from type
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measure binding of an antibody to the GPIb binding site on VWF as a 2A VWD. In this test, purified normal plasma VWF or cryoprecipitate
proposed screening test for VWD. 308–311 Additional assays can measure added to platelet preparations from patients with platelet-type VWD
platelet agglutination induced by botrocetin (which is no longer com- causes platelet aggregation, distinguishing this disorder from type 2B
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mercially available) and other snake venom proteins. In the National VWD where patient platelets aggregate only at higher ristocetin con-
Heart Lung and Blood Institute Expert Panel guidelines (http://www. centrations. In addition, type 2B VWD plasma transfers the enhanced
nhlbi.nih.gov/files/docs/guidelines/vwd.pdf), none of these tests are RIPA to normal platelets, whereas plasma from patients with platelet-
recommended for screening for VWD. 150 type VWD interacts normally with control platelets.
With advances in understanding the molecular genetics of VWD,
it is now possible to precisely diagnose and subclassify many variants of ACQUIRED VON WILLEBRAND SYNDROME
VWD on the basis of DNA mutations (reviewed in Ref. 313). DNA test-
ing, particularly for type 2 VWD mutations which cluster within spe- Acquired VWD, or acquired von Willebrand syndrome (AVWS), is
cific regions of the VWF gene (see Fig. 126–3), can be used to confirm a relatively rare acquired bleeding disorder that usually presents as a
the diagnosis and is available in specialized reference laboratories. The late-onset bleeding diathesis in a patient with no prior bleeding his-
analysis of type 3 and type 1 VWD is more complex, as the currently tory and a negative family history of bleeding (reviewed in Ref. 317).
known mutations are scattered throughout the gene and account only Decreased levels of FVIII, VWF:Ag, and VWF:RCo are common, and
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for a subset of patients. VWF multimers can be abnormal. AVWS is usually associated with
The bleeding time is mentioned here for historical purposes only, another underlying disorder and has been reported to occur in patients
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as it was used as a screening test for VWD and other abnormalities of with myeloproliferative neoplasms, amyloidosis, benign or malig-
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platelet function. Bleeding time varied considerably with the experience nant B-cell disorders, hypothyroidism, autoimmune disorders,
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of the operator and a variety of other factors, did not prolong with FVIII several solid tumors (particularly Wilms tumor), cardiac or vascu-
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deficiency, and correlated poorty with bleeding risk. Thus, the bleeding lar defects (such as aortic stenosis), ventricular assist devices, or
time is no longer recommended in the evaluation of VWD. 150 in association with several drugs, including ciprofloxacin and valproic
acid. 326,327
The mechanisms that cause AVWS can generally be attributed to
PRENATAL TESTING an associated medical condition. A variety of B-cell disorders have been
associated with the development of anti-VWF autoantibodies. In most
Given the mild clinical phenotype of most patients with the common cases the AVWS appears to be due to rapid clearance of VWF induced
variants of VWD, prenatal diagnosis for the purpose of deciding on by the circulating inhibitor, although these antibodies may also interfere
terminating a pregnancy is rarely performed. However, type 3 VWD with VWF function. Hypothyroidism results in decreased VWF syn-
patients often have a profound bleeding disorder, similar to or more thesis. In some cases of malignancy, AVWS is thought to be due to
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severe than classic hemophilia, and some families may request prena- selective adsorption of VWF to the tumor cells or in myeloproliferative
tal diagnosis. In those cases of VWD in which the precise mutation is neoplasms, clearance/alterations of VWF by the high circulating plate-
known, DNA diagnosis can be performed rapidly and accurately by let mass. AVWS associated with valvular heart disease, ventricular assist
polymerase chain reaction (PCR) from amniotic fluid or chorionic villus devices, or certain drugs, VWF may be lost by accelerated destruction
biopsies (reviewed in Ref. 313) and would be expected to be compatible or proteolysis under shear. 325–327
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with new noninvasive prenatal testing methods. In those cases where Although the VWF multimers in AVWS usually exhibit a type
the mutation is unknown, diagnosis can still be attempted by genetic 2A pattern with relative depletion of the large multimer forms, AVWS
linkage analysis using the large panel of known polymorphisms within can manifest as a wide range of VWD phenotypes. 322,328 Distinguishing
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the VWF gene. Although all cases of VWD analyzed to date appear to AVWS from genetic VWD can be difficult, as testing for the associated
be linked to the VWF gene, the possibility of locus heterogeneity (i.e., autoantibodies is generally not available in the clinical setting. The diag-
a similar phenotype caused by a mutation in a gene other than VWF) nosis often rests on the late onset of the disease, the absence of a family
should be considered. As with all DNA testing, if prenatal testing is history, and the identification of an associated underlying disorder.
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