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Von Willebrand Disease

von Willebrand Disease (vWD), the most common inherited bleeding disorder, is an autosomally transmitted dominant disease whose prevalence is estimated in screening studies to be 0.5-1.0% in the population; there is variable penetrance, and the majority of these patients have mild disease that is not diagnosed unless they sustain trauma or undergo surgery. This brief review will include a discussion of the clinical presentation and diagnosis, the specific assays with background information about the relationship of the tests to the structure of von Willebrand factor (vWF), the classification of the different types of vWD, and the treatment(s) for vWD.

Clinical presentation of von Willebrand disease

Patients with vWD may present at any age because of the wide spectrum in the severity of bleeding symptoms. Most patients are heterozygous, and they have mild or moderate disease. Because one of the primary functions of vWF is to support normal platelet function, the bleeding manifestations are similar to those expected for platelet disorders: bruising and mucous membrane bleeding such as epistaxis, menorrhagia, and gastrointestinal bleeding. Many patients are discovered as a result of post-surgical bleeding (tooth extractions or tonsillectomy) or with the onset of menses. The rare homozygous or doubly heterozygous patients.

The severity of bleeding can vary modestly among affected family members and, to a much lesser degree, in an individual patient. Levels of vWD are labile and vary for unknown reasons as well as for known physiological reasons such as levels of estrogen, pregnancy, exercise, adrenergic stimuli, and inflammation (these increase vWF levels). Blood groups influence the individual's level of vWF, and normal subjects with type O blood group have lower levels (approximately 25% lower) than other ABO groups. An additional problem is that none of the current tests, though valuable for the diagnosis of vWD, is predictive for bleeding.

Diagnosis of von Willebrand disease

The diagnosis of vWD is classically made in a patient with a positive family history of mucosal bleeding symptoms transmitted in an autosomal dominant manner and a prolonged aPTT and bleeding time. The aPTT and bleeding time may not be abnormal, however, in patients with milder forms of vWD. More specific and sensitive tests which are decreased in patients with vWD include the 1 -Ristocetin cofactor assay ("vWF activity") and collagen binding assay, 2 - vWF antigen, and 3 - Factor VIII level. Additionally, 4 - Electrophoresis for vWF multimers and 5 - Ristocetin-induced platelet aggregation (RIPA) should be performed once the diagnosis of vWD is made in order to determine what type of vWD the patient has.

Diagnostic tests and structure-function relationships of von Willebrand factor

The diagnostic tests for vWD reflect the different functions of vWF which include 1-support of primary hemostasis, including platelet adherence to subendothelium and platelet-platelet aggregation in vessels with high shear flow; and 2-support of fibrin clot formation (enhancing coagulation reactions by acting as a protective carrier for factor VIII [antihemophilic factor] to prevent premature clearance of factor VIII from the circulation). Functional tests for vWF platelet-related functions include the ristocetin cofactor assay, collagen binding assays, and the more global bleeding time test; vWF protein levels are assessed using antigen assays. To measure the role of vWF in secondary hemostasis, functional (clotting) assays.

von Willebrand factor is a large multimeric glycoprotein that is synthesized in endothelial cells and megakaryocytes and circulates as a series of different sized multimers; its size varies from 500,000 to over 20 million daltons. Because each subunit contains binding sites that are important for the functions noted above (binding to subendothelium and platelets and to factor VIII), the multimers of largest size contain the greatest number of binding sites and are thus the most hemostatically functional molecules. This is particularly true for the platelet support functions. The multimers of plasma vWF can be directly visualized after electrophoresis.

An important additional test which assesses the functional ability of vWF to bind to platelet GPIb is the ristocetin-induced platelet aggregation (RIPA), a test in which several different concentrations of ristocetin are added to the patient's freshly prepared platelet-rich plasma samples. This test indicates whether the patient's abnormal vWF binds less avidly to platelet GPIb or binds more avidly to GPIb. One subtype of vWD has this latter characteristic, and it is extremely important to know this information in formulating a treatment plan.

vWF can be extracted from platelets and assessed in ristocetin cofactor, vWF antigen, and multimer assays. When compared to plasma, platelets contains lower levels of vWF antigen and somewhat lower ristocetin cofactor activity; they contain multimers of higher molecular weight.

Classification of von Willebrand disease

Changes in the classification of vWD which accommodate recent genetic findings have altered some of the designations, but the classification retains the basic three types from the original classification (see Table 2 and below); clinical presentations of types 1 and 2 are indistinguishable from each other; type 3 is usually more severe and includes soft tissue bleeding and hemarthroses as well as mucosal bleeding.

Type 1 (75%) - Patients have a quantitative abnormality, with a concordant decrease in vWF antigen, ristocetin cofactor, and factor VIII; all vWF multimers are present in decreased quantity. Type 2 (15-25%) - Patients have qualitative abnormalities in their vWF which can be seen on multimer studies and/or in functional studies that assess binding activities for platelet GPIb or for factor VIII (RIPA). (See below for specific subtypes). These patients, except type 2N, usually have decreased vWF activity assays and may or may not have a decreased quantity of vWF antigen. Specific mutations have been identified in the vWF gene in many of these patients.

Type 3 (Rare) - Patients usually have unmeasurable levels of vWF antigen and ristocetin cofactor and low levels of factor VIII (2-10%). They may be homozygous or doubly heterozygous. In a few families, large deletions have been identified in the vWF gene; others have rnissense or other mutations.

Type 2 vWD has been further classified into subtypes that include 2A, 2B, 2M, and 2N. Types 2A and 2B comprise the majority of these cases:

Type 2A - The most common variant (10-20%), this type is characterized by decreased vWF antigen and decreased ristocetin eofactor activity, the latter usually more decreased than the antigen. Factor VIII levels may be normal or decreased. The high and intermediate-sized multimers are absent on gel electrophoresis studies of plasma.

Acquired von Willebrand disease

Acquired vWD is usually associated with diseases that lead to decreased levels of vWF by one of several mechanisms: increased proteolysis of vWF, antibodies to vWF, or abnormal binding of vWF, usually by tumor cells that remove it from the circulation. Examples include noncyanotic congenital and acquired valvular heart diseases.

Treatment of von Willebrand disease

Selection of the correct treatment for the prevention or termination of bleeding in a patient with vWD requires knowledge of the patient's subtype of vWD; it also is important to obtain information about the patient's past bleeding history, the factor VIII and vWF levels.

The general aim of therapy is to raise and maintain the levels of vWF above 50%, despite the fact that bleeding symptoms have not been shown to correlate well with specific levels. Correction of the bleeding time is probably not necessary, although this continues to be a controversial question; however, many surgical procedures have been performed without excessive bleeding in patients who have received treatment sufficient to raise their vWF.

DDAVP

DDAVP (or desmopressin) is a synthetic analogue of vasopressin which causes release of vWF and factor VIII from storage sites (endothelial cells) by an indirect mechanism. It is administered intravenously as an infusion (0.3 microgram/kg to a maximum dose of 20 micrograms) in 50 mL saline over 20-30 minutes, or it can be administered more conveniently by nasal spray. The vWF and factor VIII levels usually reach a maximum of 2-5 times baseline at approximately 45 minutes after IV infusion, and the levels persist for approximately 4 hours.

Plasma-derived products

Intermediate purity factor VIII concentrates that contain vWF, including the high molecular weight multimers, are currently the product of choice for patients requiring replacement therapy. At least one factor VIII/vWF concentrate has been labeled for use in vWD patients, and it is an available source of vWF that is relatively safe due to the viral inactivation procedures.

Fibrinolytic inhibitors

The fibrinolytic inhibitors, epsilon-aminocaproic acid and tranexamic acid, are useful adjunctive medications, particularly for patients with mucous membrane bleeding.

Estrogens are known to increase the synthesis of vWF and have been used successfully in women with mild to moderate vWD.