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2172 Part XII: Hemostasis and Thrombosis Chapter 126: von Willebrand Disease 2173

Bleeding Assessment Test for research purposes. Although high hemophilia A (Chap. 123). After infusion of VWF-containing plasma
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bleeding scores are suggestive of a bleeding diathesis and can predict fractions, some of these patients develop anti-VWF antibodies that neu-
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future bleeding, no bleeding questionnaire as yet is clearly diagnos- tralize VWF (reviewed in Ref. 277).
tic for VWD. These observations, together with the limited sensitivity Other heritable coagulopathies can coexist with VWF deficiency.
and specificity of the currently available laboratory tests (see below), An evaluation for other factor deficiencies or platelet disorders should
makes the diagnosis of mild VWD quite difficult and probably contrib- be considered in patients that have a suggestive family history, a bleed-
utes to the wide range of prevalence figures for type 1 VWD currently ing phenotype out or proportion or inconsistent with an expected VWD
in the literature. A National Heart Lung and Blood Institute Expert pattern, or a poor response to therapy. In VWD patients with combina-
Panel has proposed clinical guidelines for evaluating patients to deter- tion coagulopathies, treatment of both disorders may be necessary to
mine whether laboratory testing for VWD or other bleeding disorders achieve a good clinical result. 278
is warranted. 150
Epistaxis occurs in approximately 60 percent of type 1 VWD
patients, 40 percent have easy bruising and hematomas, 35 percent have LABORATORY FEATURES
menorrhagia, and 35 percent have gingival bleeding. Gastrointestinal In the initial laboratory evaluation of patients suspected by history
bleeding occurs in approximately 10 percent of patients. An appar- of having VWD, the following tests are routinely performed: assay of
150
ent association between hereditary hemorrhagic telangiectasia (HHT) FVIII:C, VWF:Ag, and VWF:RCo. Other tests that are commonly used
and VWD has been reported in several families. The causative genes include RIPA, VWF:CB, and VWF multimer analysis. Routine coagula-
in HHT were identified and are located on chromosomes 9q33–34, tion studies, such as prothrombin time (PT) or activated partial-throm-
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and 12q13 (Chap. 122), distinct from the VWF gene on chromo- boplastin time (aPTT), are generally not useful in the evaluation of
some 12p13. However, because inheriting VWD is likely to increase the VWD. However, the aPTT can be prolonged in subjects with VWF defi-
severity of bleeding from HHT, the diagnosis is more likely to be made ciency, or in patients with homozygous type 2N VWD, because of the
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in patients inheriting both defects. Mucocutaneous bleeding is com- reduction in FVIII level. The wide range of normal and the considerable
mon after trauma, with approximately 50 percent of patients reporting overlap with the levels observed in type 1 VWD make borderline levels
bleeding after dental extraction, approximately 35 percent after trauma difficult to interpret. A variety of concurrent diseases and drugs may
or wounds, 25 percent postpartum, and 20 percent postoperatively. modify the results of individual tests. Many conditions, such as recent
Hemarthroses in patients with moderate disease are extremely rare exercise, age, pregnancy, time of the menstrual cycle, estrogen ther-
and are generally only encountered after major trauma. The bleeding apy, hypo- or hyperthyroidism, diabetes, uremia, liver disease, infec-
symptoms can be quite variable among patients within the same family tion, myeloproliferative neoplasms, or malignancy can affect the FVIII
and even in the same patient over time. An individual may experience activity, VWF:Ag, and ristocetin cofactor activity levels. These values
postpartum bleeding with one pregnancy but not with others, and clin- can be regarded as acute-phase reactants, and even minor illnesses can
ical symptoms in mildly to moderately affected type 1 individuals often increase the levels in a VWD patient to normal. Appropriate process-
ameliorate by the second or third decade of life. Aside from an infre- ing of laboratory specimens is also critical as VWF parameters can be
quent type 3 patient, death from bleeding rarely occurs in VWD. artifactually skewed (either high or low) by phlebotomy conditions or
Thrombocytopenia is a common feature of type 2B VWD and is specimen handling (reviewed in Ref. 150). Even controlling for many
not seen in any other form of VWD. Most patients only experience of these factors, the coefficients of variation of repeated VWF:Ag and
thrombocytopenia at times of increased VWF production or secretion, ristocetin cofactor assays in a single person are quite large, and can be
280
such as during physical effort, in pregnancy, in newborn infants, post- influenced by numerous factors including diurnal variation. For this
281
operatively, or if an infection develops. The platelet count rarely drops to reason, repeated measurements are usually necessary, and the diagnosis
levels thought to contribute to clinical bleeding. 273,274 Infants with type of VWD or its exclusion should generally not be based on a single set of
2B VWD may present with neonatal thrombocytopenia, which could be laboratory values.
confused with neonatal alloimmune thrombocytopenia, neonatal sep- The laboratory diagnosis of type 1 VWD can be confounded by
sis, or congenital thrombocytopenia. the wide range of VWF levels in “normals” and borderline laboratory
Patients who are homozygous or compound heterozygous for results. An alternative strategy is to classify some patients for whom the
type 2N VWD generally have normal levels of VWF:Ag and VWF:RCo diagnosis of VWD is ambiguous as “low VWF,” recognizing that these
and normal VWF platelet adhesive function. However, FVIII levels are patients may have an increased risk of bleeding without labeling them as
moderately decreased, resulting in a mild to moderate hemophilia-like type 1 VWD. 282,283 In response to this need to distinguish those patients
phenotype. In contrast to patients with classic hemophilia A (FVIII with VWD from nonbleeding individuals with moderately low levels
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deficiency), these patients do not respond to infusion of purified FVIII of VWF (30 to 50 IU/dL), a threshold of less than 30 IU/dL has been
275
and should be treated with VWF-containing concentrates. Heterozy- recommended. In clinical practice there remains wide variation in the
150
gotes for this disorder may have mildly decreased FVIII levels but are assignment of normal VWF ranges and in the interpretation of labora-
generally asymptomatic. Although type 2N VWD appears to be con- tory results to make a VWD diagnoses. 284–286
siderably less common than classic hemophilia A, it should be con-
sidered in the differential diagnosis of FVIII deficiency, particularly if
any features suggest an autosomal pattern of inheritance. Although the FACTOR VIII
FVIII level rarely drops below 5 percent, type 2N VWD mutation can FVIII levels in VWD patients are generally coordinately decreased
be associated with FVIII levels as low as 1 percent, when co-inherited along with plasma VWF, although skewing of FVIII-to-VWF ratios can
with a type 3 VWD allele. The latter observation further suggests that be observed. Levels in type 3 VWD generally range from 3 to 10 per-
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276
a diagnosis of type 2N VWD should also be considered in patients with cent. In contrast, the levels in type 1 and the type 2 VWD variants (other
marked reductions of FVIII. than 2N) are variable and usually only mildly or moderately decreased.
Patients with type 3 VWD can suffer from severe clinical bleed- The FVIII level in type 2N VWD is more severely decreased, but rarely
ing and experience hemarthroses and muscle hematomas, as in severe to less than 5 percent.

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